Conformational transitions upon ligand binding: Holo-structure prediction from apo conformations.

Biological function of proteins is frequently associated with the formation of complexes with small-molecule ligands. Experimental structure determination of such complexes at atomic resolution, however, can be time-consuming and costly. Computational methods for structure prediction of protein/ligand complexes, particularly docking, are as yet restricted by their limited consideration of receptor flexibility, rendering them not applicable for predicting protein/ligand complexes if large conformational changes of the receptor upon ligand binding are involved. Accurate receptor models in the ligandbound state (holo structures), however, are a prerequisite for successful structure-based drug design. Hence, if only an unbound (apo) structure is available distinct from the ligand-bound conformation, structure-based drug design is severely limited. We present a method to predict the structure of protein/ligand complexes based solely on the apo structure, the ligand and the radius of gyration of the holo structure. The method is applied to ten cases in which proteins undergo structural rearrangements of up to 7.1 A ˚ backbone RMSD upon ligand binding. In all cases, receptor models within 1.6 A˚ backbone RMSD to the target were predicted and close-to-native ligand binding poses were obtained for 8 of 10 cases in the top-ranked complex models. A protocol is presented that is expected to enable structure modeling of protein/ligand complexes and structure-based drug design for cases where crystal structures of ligand-bound conformations are no

Probing renal blood volume with magnetic resonance imaging

Damage to the kidney substantially reduces life expectancy. Renal tissue hypoperfusion and hypoxia are key elements in the pathophysiology of acute kidney injury and its progression to chronic kidney disease. In vivo assessment of renal haemodynamics and tissue oxygenation remains a challenge. Blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI) is sensitive to changes in the effective transversal relaxation time (T(2)*) in vivo, is non-invasive and indicative of renal tissue oxygenation. However, the renal T(2)* to tissue pO(2) relationship is not governed exclusively by renal blood oxygenation, but is affected by physiological confounders with alterations in renal blood volume fraction (BVf) being of particular relevance. To decipher this interference probing renal BVf is essential for the pursuit of renal MR oximetry. Superparamagnetic iron oxide nanoparticle (USPIO) preparations can be used as MRI visible blood pool markers for detailing alterations in BVf. This review promotes the opportunities of MRI based assessment of renal BVf. Following an outline on the specifics of renal oxygenation and perfusion, changes in renal BVf upon interventions and their potential impact on renal T(2)* are discussed. We also describe the basic principles of renal BVf assessment using ferumoxytol enhanced MRI in the equilibrium concentration regime. We demonstrate that ferumoxytol does not alter control of renal haemodynamics and oxygenation. Preclinical applications of ferumoxytol enhanced renal MRI as well as considerations for its clinical implementation for examining renal BVf changes are provided alongside practical considerations. Finally, we explore the future directions of MRI based assessment of renal BVf

WIC Participation as a Risk Factor for Loss to Follow-Up in the Wisconsin EHDI System

In 2011, Wisconsin’s Early Hearing Detection and Intervention (EHDI) program, Wisconsin Sound Beginnings (WSB), developed multiple strategies to reduce loss to follow-up (LTFU) for babies who did not pass their newborn hearing screening: Medical Outreach, Family Outreach, Regional Outreach and WIC Alert. WSB evaluated the outcomes of babies identified as at-risk for LTFU to determine whether WIC participation was an indicator of their risk for LTFU. Additionally, WSB evaluated whether babies who were identified as at-risk for LTFU and receiving WIC services in two WIC projects serving areas and populations with known health disparities, were at even greater risk for LTFU. WSB found no statistically significant differences in outcomes between babies who were WIC participants and those who were not. This paper discusses implications of this research for other EHDI programs