CSF1R inhibition depletes brain macrophages and reduces brain virus burden in SIV-infected macaques.

Perivascular macrophages (PVMs) and, to a lesser degree, microglia are targets and reservoirs of HIV and simian immunodeficiency virus (SIV) in the brain. Previously, we demonstrated that colony-stimulating factor 1 receptor (CSF1R) in PVMs was upregulated and activated in chronically SIV-infected rhesus macaques with encephalitis, correlating with SIV infection of PVMs. Herein, we investigated the role of CSF1R in the brain during acute SIV infection using BLZ945, a brain-penetrant CSF1R kinase inhibitor. Apart from three uninfected historic controls, nine Indian rhesus macaques were infected acutely with SIVmac251 and divided into three groups (n = 3 each): an untreated control and two groups treated for 20-30 days with low- (10 mg/kg/day) or high- (30 mg/kg/day) dose BLZ945. With the high-dose BLZ945 treatment, there was a significant reduction in cells expressing CD163 and CD206 across all four brain areas examined, compared with the low-dose treatment and control groups. In 9 of 11 tested regions, tissue viral DNA (vDNA) loads were reduced by 95%-99% following at least one of the two doses, and even to undetectable levels in some instances. Decreased numbers of CD163+ and CD206+ cells correlated significantly with lower levels of vDNA in all four corresponding brain areas. In contrast, BLZ945 treatment did not significantly affect the number of microglia. Our results indicate that doses as low as 10 mg/kg/day of BLZ945 are sufficient to reduce the tissue vDNA loads in the brain with no apparent adverse effect. This study provides evidence that infected PVMs are highly sensitive to CSF1R inhibition, opening new possibilities to achieve viral clearance.

Leukocyte mitochondrial DNA copy number and built environment in Mexican Americans: a cross-sectional study.

Mitochondrial DNA (mtDNA) copy number in leukocytes has been regarded as a biomarker for various environmental exposures and chronic diseases. Our previous study showed that certain demographic factors (e.g. age, gender, BMI, etc.) significantly affect levels of leukocyte mtDNA copy number in Mexican Americans. However, the effect of the built environment on leukocyte mtDNA copy number has not been studied previously. In this cross-sectional study, we examined the association between multiple components of the built environment with leukocyte mtDNA copy number among 5,502 Mexican American adults enrolled in Mano-A-Mano, the Mexican American Cohort Study (MACS). Based on the median levels of mtDNA copy number, the study population was stratified into low mtDNA copy number group (< median) and high mtDNA copy number group (≥ median). Among all built environment exposure variables, household density and road/intersection ratio were found to be statistically significant between groups with low and high mtDNA copy number (P < 0.001 and 0.002, respectively). In the multivariate logistic regression analysis, individuals living in areas with elevated levels of household density had 1.24-fold increased odds of having high levels of mtDNA copy number [Odds ratio (OR) = 1.24, 95% confidence interval (CIs) 1.08, 1.36]. Similarly, those living in areas with elevated levels of road/intersection ratio had 1.12-fold increased odds of having high levels of mtDNA copy number (OR = 1.12, 95% CI 1.01, 1.27). In further analysis, when both variables were analyzed together in a multivariate logistic regression model, the significant associations remained. In summary, our results suggest that selected built environment variables (e.g. population density and road/intersection ratio) may influence levels of mtDNA copy number in leukocytes in Mexican Americans.

Do ring-necked snakes choose retreat sites based upon thermal preferences?

Biochemical reaction rates are highly sensitive to temperature, and the body temperatures of ectotherms covary with their immediate environment. Therefore, ectotherms should choose microhabitats that permit the maintenance of physiological function. While some previous studies have found that squamate reptiles choose retreat sites that allow them to maintain physiologically optimal body temperatures, this research has been limited in context and taxonomic scope. We sought to test these empirical patterns by studying the properties of retreat sites in the context of physiological preferences and tolerances in a population of semifossorial ring-necked snakes (Diadophis punctatus). We measured environmental temperature distributions of retreat sites, field body temperatures, thermal preferences, and both upper voluntary temperature and critical thermal minima of snakes. We found that ring-necked snakes are under larger and warmer rocks, but that body temperatures in the field do not match thermal preferences measured in the laboratory. Specifically, we found aggregated ring-necked snakes (those occurring with multiple conspecifics) select rocks providing environmental temperatures averaging 3°C higher than their preferred temperature. By contrast, solitary snakes select rocks that allowed them to maintain their body temperatures very close to their preferred temperatures. These results imply that there is substantial within and among-species variation in the role of thermal considerations in retreat-site selection. Our work also highlights the complex tradeoffs between physiological and ecological requirements that organisms must navigate in heterogeneous habitats.

Impact of wheelchair seat height on neck and shoulder range of motion during functional task performance.

Wheelchair users are at high risk for developing repetitive stress injuries (RSI) of the cervical spine and glenohumeral joints due to increased demands on active range of motion (AROM) when performing functional tasks from a seated position. The addition of a seat elevation device may alleviate the risk factors that lead to the development of RSI. However, there are no studies which establish that wheelchair seat height impacts upon arthrokinematic requirements at vulnerable joints. Additionally, Medicare and most insurance carriers do not cover the cost of power seat elevators because this feature has not been shown to be a "medical necessity." This study examined differences in AROM at the cervical spine and glenohumeral joint during performance of two functional tasks while seated in a wheelchair with the seat elevation feature at minimum and maximum height. Results revealed statistically significant differences in AROM requirements for cervical extension and shoulder abduction between the two wheelchair seat heights. These findings provide preliminary support for the value of the power seat elevation function in minimizing the risk of RSI at the shoulder complex and cervical spine in wheelchair users.

Facile synthesis of 1-alkoxy-1H-benzo- and 7-azabenzotriazoles from peptide coupling agents, mechanistic studies, and synthetic applications.

(1H-Benzo[d][1,2,3]triazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1H-benzo[d][1,2,3]triazol-1-yl 4-methylbenzenesulfonate (Bt-OTs), and 3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl 4-methylbenzenesulfonate (At-OTs) are classically utilized in peptide synthesis for amide-bond formation. However, a previously undescribed reaction of these compounds with alcohols in the presence of a base, leads to 1-alkoxy-1H-benzo- (Bt-OR) and 7-azabenzotriazoles (At-OR). Although BOP undergoes reactions with alcohols to furnish 1-alkoxy-1H-benzotriazoles, Bt-OTs proved to be superior. Both, primary and secondary alcohols undergo reaction under generally mild reaction conditions. Correspondingly, 1-alkoxy-1H-7-azabenzotriazoles were synthesized from At-OTs. Mechanistically, there are three pathways by which these peptide-coupling agents can react with alcohols. From (31)P{(1)H}, [(18)O]-labeling, and other chemical experiments, phosphonium and tosylate derivatives of alcohols seem to be intermediates. These then react with BtO(-) and AtO(-) produced in situ. In order to demonstrate broader utility, this novel reaction has been used to prepare a series of acyclic nucleoside-like compounds. Because BtO(-) is a nucleofuge, several Bt-OCH2Ar substrates have been evaluated in nucleophilic substitution reactions. Finally, the possible formation of Pd π-allyl complexes by departure of BtO(-) has been queried. Thus, alpha-allylation of three cyclic ketones was evaluated with 1-(cinnamyloxy)-1H-benzo[d][1,2,3]triazole, via in situ formation of pyrrolidine enamines and Pd catalysis.