Unraveling the mechanism of the cadherin-catenin-actin catch bond.

The adherens junctions between epithelial cells involve a protein complex formed by E-cadherin, ß-catenin, α-catenin and F-actin. The stability of this complex was a puzzle for many years, since in vitro studies could reconstitute various stable subsets of the individual proteins, but never the entirety. The missing ingredient turned out to be mechanical tension: a recent experiment that applied physiological forces to the complex with an optical tweezer dramatically increased its lifetime, a phenomenon known as catch bonding. However, in the absence of a crystal structure for the full complex, the microscopic details of the catch bond mechanism remain mysterious. Building on structural clues that point to α-catenin as the force transducer, we present a quantitative theoretical model for how the catch bond arises, fully accounting for the experimental lifetime distributions. The underlying hypothesis is that force induces a rotational transition between two conformations of α-catenin, overcoming a significant energy barrier due to a network of salt bridges. This transition allosterically regulates the energies at the interface between α-catenin and F-actin. The model allows us to predict these energetic changes, as well as highlighting the importance of the salt bridge rotational barrier. By stabilizing one of the α-catenin states, this barrier could play a role in how the complex responds to additional in vivo binding partners like vinculin. Since significant conformational energy barriers are a common feature of other adhesion systems that exhibit catch bonds, our model can be adapted into a general theoretical framework for integrating structure and function in a variety of force-regulated protein complexes.

National estimates of 30-day readmissions among children hospitalized for asthma in the United States.

OBJECTIVE: Previous single-center studies have reported that up to 40% of children hospitalized for asthma will be readmitted. The study objectives are to investigate the prevalence and timing of 30-day readmissions in children hospitalized with asthma, and to identify factors associated with 30-day readmissions. METHODS: Data (n = 12,842) for children aged 6-18 years hospitalized for asthma were obtained from the 2013 Nationwide Readmission Database (NRD). The primary study outcome was time to readmission within 30 days after discharge attributable to any cause. Several predictors associated with the risk of admission were included: patient (age, sex, median household income, insurance type, county location, and pediatric chronic complex condition), admission (type, day, emergency services utilization, length of stay (LOS), and discharge disposition), and hospital (ownership, bed size, and teaching status). Cox's proportional hazards model was used to identify predictors. RESULTS: Of 12,842 asthma-related index hospitalizations, 2.5% were readmitted within 30-days post-discharge. Time to event models identified significantly higher risk of readmission among asthmatic children aged 12-18 years, those who resided in micropolitan counties, those with >4-days LOS during index hospitalization, those who were hospitalized in an urban hospital, who had unfavorable discharge (hazard ratio 2.53, 95% confidence interval 1.33-4.79), and those who were diagnosed with a pediatric complex chronic condition, respectively, than children in respective referent categories. CONCLUSION: A multi-dimensional approach including effective asthma discharge action plans and follow-up processes, home-based asthma education, and neighborhood/community-level efforts to address disparities should be integrated into the routine clinical care of asthma children.

Improve it or lose it: Evolvability cost of competition for expression.

Expression level is known to be a strong determinant of a protein's rate of evolution. But the converse can also be true: evolutionary dynamics can affect expression levels of proteins. Having implications in both directions fosters the possibility of an "improve it or lose it" feedback loop, where higher expressed systems are more likely to improve and be expressed even higher, while those that are expressed less are eventually lost to drift. Using a minimal model to study this in the context of a changing environment, we demonstrate that one unexpected consequence of such a feedback loop is that a slow switch to a new environment can allow genotypes to reach higher fitness sooner than a direct exposure to it.