The goal of the this study was to re-evaluate tigecycline bone concentrations in subjects undergoing elective orthopedic surgery, using multiple doses and a more robust bone assay than was used in a previous study. Each subject received three intravenous doses of tigecycline (one 100-mg infusion followed by two 50-mg infusions, each administered over 30?minutes). A single bone sample was collected from each subject at one of the following times: 1, 2, 4, 6, 8, or 12?hours after the third dose. Four blood samples were collected from each subject: before the first dose, before and after the third dose, and within 15?minutes of the collection time of the bone sample. Noncompartmental pharmacokinetic analysis serum and bone area under the curve for the given dose interval (AUC? ) values were 2,402?ng?h/mL and 11,465?ng?h/g, and maximum concentration (Cmax ) values were 974?ng/mL and 2,262?ng/g, respectively. The bone to serum ratio calculated using the AUC? values was 4.77, confirming tigecycline penetration into bone.
Mesoderm development (MESD) is a 224 amino acid mouse protein that acts as a molecular chaperone for the low-density lipoprotein receptor (LDLR) family. Here, we provide evidence that the region 45-184 of MESD is essential and sufficient for this function and suggest a model for its mode of action. NMR studies reveal a ?-?-?-?-?-? core domain with an ?-helical N-terminal extension that interacts with the ? sheet in a dynamic manner. As a result, the structural ensemble contains open (active) and closed (inactive) forms, allowing for regulation of chaperone activity through substrate binding. The mutant W61R, which is lethal in Drosophila, adopts only the open state. The receptor motif recognized by MESD was identified by in vitro-binding studies. Furthermore, in vivo functional evidence for the relevance of the identified contact sites in MESD is provided.
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