Minimum Distance Estimation of Milky Way Model Parameters and Related Inference

We propose a method to estimate the location of the Sun in the disk of the Milky Way using a method based on the Hellinger distance and construct confidence sets on our estimate of the unknown location using a bootstrap based method. Assuming the Galactic disk to be two-dimensional, the sought solar location then reduces to the radial distance separating the Sun from the Galactic center and the angular separation of the Galactic center to Sun line, from a pre-fixed line on the disk. On astronomical scales, the unknown solar location is equivalent to the location of us earthlings who observe the velocities of a sample of stars in the neighborhood of the Sun. This unknown location is estimated by undertaking pairwise comparisons of the estimated density of the observed set of velocities of the sampled stars, with densities estimated using synthetic stellar velocity data sets generated at chosen locations in the Milky Way disk according to four base astrophysical models. The "match" between the pair of estimated densities is parameterized by the affinity measure based on the familiar Hellinger distance. We perform a novel cross-validation procedure to establish a desirable "consistency" property of the proposed method.Comment: 25 pages, 10 Figures. This version incorporates the suggestions made by the referees. To appear in SIAM/ASA Journal on Uncertainty Quantificatio

Molecular basis for the recognition of 24-(S)-hydroxycholesterol by integrin αvβ3

Abstract A growing body of evidence suggests that oxysterols such as 25-hydroxycholesterol (25HC) are biologically active and involved in many physiological and pathological processes. Our previous study demonstrated that 25HC induces an innate immune response during viral infections by activating the integrin-focal adhesion kinase (FAK) pathway. 25HC produced the proinflammatory response by binding directly to integrins at a novel binding site (site II) and triggering the production of proinflammatory mediators such as tumor necrosis factor-α (TNF) and interleukin-6 (IL-6). 24-(S)-hydroxycholesterol (24HC), a structural isomer of 25HC, plays a critical role in cholesterol homeostasis in the human brain and is implicated in multiple inflammatory conditions, including Alzheimer’s disease. However, whether 24HC can induce a proinflammatory response like 25HC in non-neuronal cells has not been studied and remains unknown. The aim of this study was to examine whether 24HC produces such an immune response using in silico and in vitro experiments. Our results indicate that despite being a structural isomer of 25HC, 24HC binds at site II in a distinct binding mode, engages in varied residue interactions, and produces significant conformational changes in the specificity-determining loop (SDL). In addition, our surface plasmon resonance (SPR) study reveals that 24HC could directly bind to integrin αvβ3, with a binding affinity three-fold lower than 25HC. Furthermore, our in vitro studies with macrophages support the involvement of FAK and NFκB signaling pathways in triggering 24HC-mediated production of TNF. Thus, we have identified 24HC as another oxysterol that binds to integrin αvβ3 and promotes a proinflammatory response via the integrin-FAK-NFκB pathway