Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation (preprint)

The MAP kinase p38α is a central component of signalling in inflammation and the immune response, and is therefore an important drug target. Little is known about the molecular mechanism of its activation by double-phosphorylation from MAP2Ks, due to the challenge of trapping a transient and dynamic hetero-kinase complex. Here, we applied a multidisciplinary approach to generate the first structure of p38α in complex with its MAP2K MKK6 and understand the activation mechanism. Integrating cryo-EM with MD simulations and in cellulo experiments, we demonstrate a dynamic, multi-step, phosphorylation mechanism, reveal new catalytically relevant interactions, and show that MAP2K disordered N-termini determine pathway specificity. Our work captures, for the first time, a fundamental step of cell signalling: a kinase phosphorylating its downstream target kinase. One-Sentence Summary Integrative Cryo-EM and MD analysis of an active hetero-kinase complex reveals details of cellular signal transmission

Moderate to vigorous physical activity and sedentary behavior change in self-isolating adults during the COVID-19 pandemic in Brazil: A cross-sectional survey exploring correlates (preprint)

BackgroundSelf-distancing measures imposed major changes in daily life. This study aimed to (i) evaluate the changes (pre-versus during pandemic) in time spent in moderate to vigorous physical activity (MVPA) and sedentary behavior (SB) in self-isolating Brazilians during the COVID-19 pandemic, and (ii) to explore correlates of MVPA and SB. MethodsA cross-sectional self-report online survey, evaluating the time spent in MVPA and SB pre and during the COVID-19 pandemic. Sociodemographic, behavioral, clinical, variables, and time in self-isolation were also obtained. Changes in MVPA and SB and their correlates were explored using generalized estimating equations (GEE). ResultsA total of 877 participants (72.7% women, 53.7% young adults [18-34 years]) were included. Overall, participants reported a 59.7% reduction (95%CI:35.6 to 82.2) in time spent on MVPA during the pandemic. Time spent in SB increased 42.0% (95%CI:31.7 to 52.5). Greater reductions in MVPA and/or increases in SB were seen in younger adults, those not married, those employed and those with a self-reported previous diagnosis of a mental disorder. ConclusionsPeople in self-isolation significantly reduced MVPA levels and increased SB. Public health strategies should be implemented during epidemic times to mitigate the impact of self-isolation on MVPA and SB, particularly in vulnerable groups.