👤 Aine Cronin

Physical inactivity post-stroke increases risk of recurrent stroke. Adaptive physical activity (PA) interventions are recommended, and alternative designs, such as sequential multiple assignment randomized trials (SMARTs) can be used. This SMART investigates the feasibility of a mobile health (mHealth) PA intervention post-stroke. People post-stroke are randomized to 12-week online exercise (EX) or lifestyle PA (LPA). Six-week daily step count data are used to classify participants as responders or nonresponses. Nonresponders are re-randomized to switch or augment their mHealth intervention, responders continue unchanged. Primary outcomes include recruitment, retention and adherence rates. Secondary outcomes include PA, sedentary behavior, fatigue, quality of life, psychological distress, and activities of daily living. General linear models estimate trends regarding first-stage interventions, nonresponse strategies, and adaptive interventions are examined using weighted and replicated regressions. Fifty participants are included. Recruitment, retention, and adherence rates are 85%, 84%, and 82%. Positive trends are seen for nonresponse strategies, switching interventions, on step count, fatigue, and quality of life. Starting with EX and switching to LPA show potential benefits for fatigue, quality of life and return to normal living. Potential benefits of these interventions are preliminary and require validation in a full-scale trial. This SMART offers novel evidence supporting the design of adaptive mHealth PA interventions post-stroke, confirming the feasibility of a definitive SMART. Show less

The poly(ADP-ribose) polymerase (PARP) Tankyrase (TNKS and TNKS2) is paramount to Wnt-β-catenin signaling and a promising therapeutic target in Wnt-dependent cancers. The pool of active β-catenin is normally limited by destruction complexes, whose assembly depends on the polymeric master scaffolding protein AXIN. Tankyrase, which poly(ADP-ribosyl)ates and thereby destabilizes AXIN, also can polymerize, but the relevance of these polymers has remained unclear. We report crystal structures of the polymerizing TNKS and TNKS2 sterile alpha motif (SAM) domains, revealing versatile head-to-tail interactions. Biochemical studies informed by these structures demonstrate that polymerization is required for Tankyrase to drive β-catenin-dependent transcription. We show that the polymeric state supports PARP activity and allows Tankyrase to effectively access destruction complexes through enabling avidity-dependent AXIN binding. This study provides an example for regulated signal transduction in non-membrane-enclosed compartments (signalosomes), and it points to novel potential strategies to inhibit Tankyrase function in oncogenic Wnt signaling. Show less

Many essential biological processes are mediated by complex molecular machines comprising multiple subunits. Knowledge on the architecture of individual subunits and their positions within the overall multimeric complex is key to understanding the molecular mechanisms of macromolecular assemblies. The anaphase-promoting complex/cyclosome (APC/C) is a large multisubunit complex that regulates cell cycle progression by ubiquitinating cell cycle proteins for proteolysis by the proteasome. The holo-complex is composed of 15 different proteins that assemble to generate a complex of 20 subunits. Here, we describe the crystal structures of Apc4 and the N-terminal domain of Apc5 (Apc5(N)). Apc4 comprises a WD40 domain split by a long α-helical domain, whereas Apc5(N) has an α-helical fold. In a separate study, we had fitted these atomic models to a 3.6-Å-resolution cryo-electron microscopy map of the APC/C. We describe how, in the context of the APC/C, regions of Apc4 disordered in the crystal assume order through contacts to Apc5, whereas Apc5(N) shows small conformational changes relative to its crystal structure. We discuss the complementary approaches of high-resolution electron microscopy and protein crystallography to the structure determination of subunits of multimeric complexes. Show less