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The contributions of skeletal cells to the processes of B cell development in the bone marrow (BM) have not been completely described. The von-Hippel Lindau protein (VHL) plays a key role in cellular responses to hypoxia. Previous work showed that Dmp1 -Cre; Vhl conditional knockout mice ( Vhl cKO), which deletes Vhl in subsets of mesenchymal stem cells, late osteoblasts and osteocytes, display dysregulated bone growth and reduction in B cells. Here, we investigated the mechanisms underlying the B cell defects using flow cytometry and high-resolution imaging. In the Vhl cKO BM, B cell progenitors were increased in frequency and number, whereas Hardy Fractions B-F were decreased. Vhl cKO Fractions B-C cells showed increased apoptosis and quiescence. Reciprocal BM chimeras confirmed a B cell-extrinsic source of the Vhl cKO B cell defects. In support of this, Vhl cKO BM supernatant contained reduced CXCL12 and elevated EPO levels. Intravital and ex vivo imaging revealed Vhl cKO BM blood vessels with increased diameter, volume, and a diminished blood-BM barrier. Staining of Vhl cKO B cells with an intracellular hypoxic marker indicated the natural existence of distinct B cell microenvironments that differ in local oxygen tensions and that the B cell developmental defects in Vhl cKO BM are not initiated by hypoxia. Our studies identify novel mechanisms linking altered bone homeostasis with drastic BM microenvironmental changes that dysregulate B cell development. 

Insight into the composition and function of the tick microbiome has expanded considerably in recent years. Thus far, tick microbiome studies have focused on species and life stages that are responsible for transmitting disease. In this study we conducted extensive field sampling of six tick species in the far-western United States to comparatively examine the microbial composition of sympatric tick species: Ixodes pacificus, Ixodes angustus, Dermacentor variabilis, Dermacentor occidentalis, Dermacentor albipictus, and Haemaphysalis leporispalustris. These species represent both common vectors of disease and species that rarely encounter humans, exhibiting a range of host preferences and natural history. We found significant differences in microbial species diversity and composition by tick species and life stage. The microbiome of most species examined were dominated by a few primary endosymbionts. Across all species, the relative abundance of these endosymbionts increased with life stage while species richness and diversity decreased with development. Only one species, I. angustus, did not show the presence of a single dominant microbial species indicating the unique physiology of this species or its interaction with the surrounding environment. Tick species that specialize in a small number of host species or habitat ranges exhibited lower microbiome diversity, suggesting that exposure to environmental conditions or host blood meal diversity can affect the tick microbiome which in turn may affect pathogen transmission. These findings reveal important associations between ticks and their microbial community and improve our understanding of the function of non-pathogenic microbiomes in tick physiology and pathogen transmission.