Disruption of ephrin B1 in collagen I producing cells in mice results in severe skull defects and reduced bone formation. Because ephrin B1 is also expressed during osteoclast differentiation and because little is known on the role of ephrin B1 reverse signaling in bone resorption, we examined the bone phenotypes in ephrin B1 conditional knockout mice, and studied the function of ephrin B1 reverse signaling on osteoclast differentiation and resorptive activity. Targeted deletion of ephrin B1 gene in myeloid lineage cells resulted in reduced trabecular bone volume, trabecular number and trabecular thickness caused by increased TRAP positive osteoclasts and bone resorption. Histomorphometric analyses found bone formation parameters were not changed in ephrin B1 knockout mice. Treatment of wild-type precursors with clustered soluble EphB2-Fc inhibited RANKL induced formation of multinucleated osteoclasts, and bone resorption pits. The same treatment of ephrin B1 deficient precursors had little effect on osteoclast differentiation and pit formation. Similarly, activation of ephrin B1 reverse signaling by EphB2-Fc treatment led to inhibition of TRAP, cathepsin K and NFATc1 mRNA expression in osteoclasts derived from wild-type mice but not conditional knockout mice. Immunoprecipitation with NHERF1 antibody revealed ephrin B1 interacted with NHERF1 in differentiated osteoclasts. Treatment of osteoclasts with exogenous EphB2-Fc resulted in reduced phosphorylation of ezrin/radixin/moesin. We conclude that myeloid lineage produced ephrin B1 is a negative regulator of bone resorption in vivo, and that activation of ephrin B1 reverse signaling inhibits osteoclast differentiation in vitro in part via a mechanism that involves inhibition of NFATc1 expression and modulation of phosphorylation status of ezrin/radixin/moesin.
We report a scanning tunneling microscopy study of the amino acid l-methionine on highly ordered pyrolytic graphite deposited under ambient conditions. Our experiments demonstrate the ability of l-methionine to form highly regular structures on the surface of the graphite template. By means of self-assembly, the amino acid arranges itself into an array of molecular wires, i.e., well-ordered stripes of uniform width and separation. The spacing of these wires can be controlled with the deposition amount of the amino acid, whereas the width stays constant. The width of the wires is determined by two methionine molecules arranged with their carboxyl group facing each other. The regular separation of individual wires suggest a long-range interaction among them. Molecular mechanics calculations are used to compare the experimental results with a basic model for the methionine configuration on the surface. A model for the adsorption geometry of methionine on graphite is presented.
People living with HIV (PLWH) may be at higher risk for adverse outcomes indirectly associated with the severe acute respiratory syndrome coronavirus (SARS-CoV-2). When comparing responses to questionnaires administered when social distancing and quarantine guidelines were first implemented, we found that PLWH were more likely to have restricted access to medical care, increased financial stress, increased symptoms of anxiety and depression, and increased substance use compared to demographically-similar people without HIV.
Objectives Studies of HIV-associated brain atrophy often focus on a priori brain regions of interest, which can introduce bias. A data-driven, minimally-biased approach was used to analyze changes in brain volumetrics associated with HIV and their relationship to aging, viral factors, and combination antiretroviral therapy (cART), as well as gender and smoking. Design A cross-sectional study of 51 HIV-uninfected (HIV−) and 146 HIV-infected (HIV+) participants. Methods Structural MRI of participants was analyzed using principal component analysis (PCA) to reduce dimensionality and determine topographies of volumetric changes. Neuropsychological (NP) assessment was examined using global and domain-specific scores. The effects of HIV disease factors (e.g. viral load, CD4, etc.) on brain volumes and NP were investigated using penalized regression (LASSO). Results Two components of interest were visualized using PCA. An aging effect predominated for both components. The first component, a cortically-weighted topography, accounted for a majority of variance across participants (43.5% of variance) and showed independent effects of HIV as well as smoking. A secondary, subcortically-weighted topography (4.6%) showed HIV-status accentuated age-related volume loss. In HIV+ patients, the cortical topography correlated with global NP scores and nadir CD4, while subcortical volume loss was associated with recent viral load. Conclusions Cortical regions showed the most prominent volumetric changes due to aging and HIV. Within HIV+ participants, cortical volumes were associated with immune history while subcortical changes correlated with current immune function. Cognitive function was primarily associated with cortical volume changes. Observed volumetric changes in chronic HIV+ patients may reflect both past infection history and current viral status.
Inflammation occurs after HIV infection and persists despite highly active antiretroviral therapy (HAART). Diffusion tensor imaging (DTI), measures HIV associated white matter changes, but can be confounded by inflammation. Currently, the influence of inflammation on white matter integrity in well-controlled HIV+ patients remains unknown. We used diffusion basis Spectrum imaging (DBSI) derived cellularity to isolate restricted water diffusion associated with inflammation separated from the anisotropic diffusion associated with axonal integrity. Ninety-two virologically suppressed HIV+ patients on HAART and 66 HIV uninfected (HIV-) controls underwent neuropsychological performance (NP) testing and neuroimaging. NP tests assessed multiple domains (memory, psychomotor speed, and executive functioning). DTI and DBSI derived fractional anisotropy (FA) maps were processed with tract based spatial statistics for comparison between both groups. Cellularity was assessed with regards to age, HIV status, and NP. Within the HIV+ cohort, cellularity was compared to clinical (HAART duration) and laboratory measures of disease (e.g. CD4 cell current and nadir). NP was similar for both groups. DTI derived FA was lower in HIV+ compared to HIV- individuals. In contrast, DBSI derived FA was similar for both groups. Instead, diffuse increases in cellularity were present in HIV+ individuals. Observed changes in cellularity were significantly associated with age, but not NP, in HIV+ individuals. A trend level association was seen between cellularity and HAART duration. Elevated inflammation, measured by cellularity, persists in virologically well-controlled HIV+ individuals. Widespread cellularity changes occur in younger HIV+ individuals and diminish with aging and duration of HAART.
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