Transplantation studies in mice and rats have shown that human embryonic stem cell-derived cardiomyocytes (hESC-CMs) can improve the function of infarcted hearts1–3, but two critical issues related to their electrophysiological behavior in vivo remain unresolved. First, the risk of arrhythmias following hESC-CM transplantation in injured hearts has not been determined. Second, the electromechanical integration of hESC-CMs in injured hearts has not been demonstrated, so it is unclear if these cells improve contractile function directly through addition of new force-generating units. Here we use a guinea pig model to show hESC-CM grafts in injured hearts protect against arrhythmias and can contract synchronously with host muscle. Injured hearts with hESC-CM grafts show improved mechanical function and a significantly reduced incidence of both spontaneous and induced ventricular tachycardia (VT). To assess the activity of hESC-CM grafts in vivo, we transplanted hESC-CMs expressing the genetically-encoded calcium sensor, GCaMP34, 5. By correlating the GCaMP3 fluorescent signal with the host ECG, we found that grafts in uninjured hearts have consistent 1:1 host-graft coupling. Grafts in injured hearts are more heterogeneous and typically include both coupled and uncoupled regions. Thus, human myocardial grafts meet physiological criteria for true heart regeneration, providing support for the continued development of hESC-based cardiac therapies for both mechanical and electrical repair.

Summary Type I CRISPR systems feature a sequential dsDNA target searching and degradation process, by crRNA-displaying Cascade and nuclease-helicase fusion enzyme Cas3, respectively. Here we present two cryo-EM snapshots of the Thermobifida fusca Type I-E Cascade: 1) unwinding 11-bp of dsDNA at the seed-sequence region to scout for sequence complementarity, and 2) further unwinding of the entire protospacer to form a full R-loop. These structures provide the much-needed temporal and spatial resolution to resolve key mechanistic steps leading to Cas3 recruitment. In the early steps, PAM recognition causes severe DNA bending, leading to spontaneous DNA unwinding to form a seed-bubble. The full R-loop formation triggers conformational changes in Cascade, licensing Cas3 to bind. The same process also generates a bulge in the non-target DNA strand, enabling its handover to Cas3 for cleavage. The combination of both negative and positive checkpoints ensures stringent yet efficient target degradation in Type I CRISPR-Cas systems.

Vitamin A homeostasis is critical to normal cellular function. Retinol-binding protein (RBP) is the sole specific carrier in the bloodstream for hydrophobic retinol, the main form in which vitamin A is transported. The integral membrane receptor STRA6 mediates cellular uptake of vitamin A by recognizing RBP-retinol to trigger release and internalization of retinol. We present the structure of zebrafish STRA6 determined to 3.9-angstrom resolution by single-particle cryo-electron microscopy. STRA6 has one intramembrane and nine transmembrane helices in an intricate dimeric assembly. Unexpectedly, calmodulin is bound tightly to STRA6 in a noncanonical arrangement. Residues involved with RBP binding map to an archlike structure that covers a deep lipophilic cleft. This cleft is open to the membrane, suggesting a possible mode for internalization of retinol through direct diffusion into the lipid bilayer.

The COVID-19 pandemic brought the global world of sports to a staggering halt. In unprecedented fashion and with few exceptions, professional leagues, mass participation endurance events, and youth sport around the globe went silent. In the face of a rapidly evolving health crisis, the decision to cancel or postpone sporting events was a logical and necessary step. COVID-19 is a highly contagious, potentially fatal virus that is transmitted primarily through contact with aerosolised or surfacedwelling respiratory secretions, a process that requires close human contact. 1 Competitive sport as we know it, from athletes 'elbowing' one another for position on the pitch to arenas packed with fans, may be the quintessential antithesis of social distancing. There is concern that the Champions League match between Atalanta and Valencia in Milan may have influenced the trajectory of COVID-19 cases in Europe. 2 In the absence of a vaccination or curative intervention, physical distancing emerged as the key step to slow or stop the spread of COVID-19. Thus, the decision to turn off the lights and to silence competitive athletics represented a logical, essential and highly visible component in the global fight against COVID-19. This has been an unusually quiet time for the sports medicine community. Athletic training rooms have gone dark, and many clinicians have been repurposed to meet the needs of patients with COVID-19. Fortunately, this will not last forever. The great American poet Robert Frost once said, 'In three words I can sum up everything I've learnt about life. It goes on', and indeed, there are early signs of progress in the fight against COVID-19. As rates of new infection begin to plateau and even decline in some countries, there

Participation in EET was associated with significant changes in LV twist mechanics characterized by increased apical rotation, LVT, and UTR. These findings suggest that LVT and UTR augmentation may be an important and previously unrecognized component of exercise-induced cardiac remodeling.