Structure of full-length TSH receptor in complex with antibody K1-70™.

Determination of the full-length thyroid-stimulating hormone receptor (TSHR) structure by cryo-electron microscopy (cryo-EM) is described. The TSHR complexed with human monoclonal TSHR autoantibody K1-70™ (a powerful inhibitor of TSH action) was detergent solubilised, purified to homogeneity and analysed by cryo-EM. The structure (global resolution 3.3 Å) is a monomer with all three domains visible: leucine-rich domain (LRD), hinge region (HR) and transmembrane domain (TMD). The TSHR extracellular domain (ECD, composed of the LRD and HR) is positioned on top of the TMD extracellular surface. Extensive interactions between the TMD and ECD are observed in the structure, and their analysis provides an explanation of the effects of various TSHR mutations on TSHR constitutive activity and on ligand-induced activation. K1-70™ is seen to be well clear of the lipid bilayer. However, superimposition of M22™ (a human monoclonal TSHR autoantibody which is a powerful stimulator of the TSHR) on the cryo-EM structure shows that it would clash with the bilayer unless the TSHR HR rotates upwards as part of the M22™ binding process. This rotation could have an important role in TSHR stimulation by M22™ and as such provides an explanation as to why K1-70™ blocks the binding of TSH and M22™ without activating the receptor itself.

Walk Score®: associations with purposive walking in recent Cuban immigrants.

BACKGROUND: Walk Score® is a nationally and publicly available metric of neighborhood walkability based on proximity to amenities (e.g., retail, food, schools). However, few studies have examined the relationship of Walk Score to walking behavior. PURPOSE: To examine the relationship of Walk Score to walking behavior in a sample of recent Cuban immigrants, who overwhelmingly report little choice in their selection of neighborhood built environments when they arrive in the U.S. METHODS: Participants were 391 recent healthy Cuban immigrants (mean age=37.1 years) recruited within 90 days of arrival in the U.S., and assessed within 4 months of arrival (mean=41.0 days in the U.S.), who resided throughout Miami-Dade County FL. Data on participants' addresses, walking, and sociodemographics were collected prospectively from 2008 to 2010. Analyses conducted in 2011 examined the relationship of Walk Score for each participant's residential address in the U.S. to purposive walking, controlling for age, gender, education, BMI, days in the U.S., and habitual physical activity level in Cuba. RESULTS: For each 10-point increase in Walk Score, adjusting for covariates, there was a significant 19% increase in the likelihood of purposive walking, a 26% increase in the likelihood of meeting physical activity recommendations by walking, and 27% more minutes walked in the previous week. CONCLUSIONS: Results suggest that Walk Score is associated with walking in a sample of recent immigrants who initially had little choice in where they lived in the U.S. These results support existing guidelines indicating that mixed land use (such as parks and restaurants near homes) should be included when designing walkable communities.