Subtype-specific modulation of estrogen receptor-coactivator interaction by phosphorylation.

The estrogen receptor (ER) is the number one target for the treatment of endocrine responsive breast cancer and remains a highly attractive target for new drug development. Despite considerable efforts to understand the role of ER post-translational modifications (PTMs), the complexity of these modifications and their impact, at the molecular level, are poorly understood. Using a chemical biology approach, fundamentally rooted in an efficient protein semisynthesis of tyrosine phosphorylated ER constructs, the complex role of the ER tyrosine phosphorylation is addressed here for the first time on a molecular level. The semisynthetic approach allows for the site-specific introduction of PTMs as well as biophysical probes. A combination of biophysical techniques, including NMR, with molecular dynamics studies reveals the role of the phosphorylation of the clinically relevant tyrosine 537 (Y537) in ERα and the analogous tyrosine (Y488) in ERβ. Phosphorylation has important effects on the dynamics of the ER Helix 12, which is centrally involved in receptor activity regulation, and on its interplay with ligand and cofactor binding, but with differential regulatory effects of the analogous PTMs on the two ER subtypes. Combined, the results bring forward a novel molecular model of a phosphorylation-induced subtype specific ER modulatory mechanism, alternative to the widely accepted ligand-induced activation mechanism

Effects of Age and Illumination on Night Driving: A Road Test

OBJECTIVE: This study investigated the effects of drivers' age and low light on speed, lane keeping, and visual recognition of typical roadway stimuli. BACKGROUND: Poor visibility, which is exacerbated by age-related changes in vision, is a leading contributor to fatal nighttime crashes. There is little evidence, however, concerning the extent to which drivers recognize and compensate for their visual limitations at night. METHOD: Young, middle-aged, and elder participants drove on a closed road course in day and night conditions at a "comfortable" speed without speedometer information. During night tests, headlight intensity was varied over a range of 1.5 log units using neutral density filters. RESULTS: Average speed and recognition of road signs decreased significantly as functions of increased age and reduced illumination. Recognition of pedestrians at night was significantly enhanced by retroreflective markings of limb joints as compared with markings of the torso, and this benefit was greater for middle-aged and elder drivers. Lane keeping showed nonlinear effects of lighting, which interacted with task conditions and drivers' lateral bias, indicating that older drivers drove more cautiously in low light. CONCLUSION: Consistent with the hypothesis that drivers misjudge their visual abilities at night, participants of all age groups failed to compensate fully for diminished visual recognition abilities in low light, although older drivers behaved more cautiously than the younger groups. APPLICATION: These findings highlight the importance of educating all road users about the limitations of night vision and provide new evidence that retroreflective markings of the limbs can be of great benefit to pedestrians' safety at night