Transdiagnostic Processes as Mediators of Change in an Internet-Delivered Intervention Based on the Unified Protocol

Background Transdiagnostic treatments target shared mechanisms between disorders to facilitate change across diagnoses. The Unified Protocol (UP) aims at changing dysfunctional reactions towards emotions by increasing mindful emotion awareness and cognitive flexibility, as well as decreasing anxiety sensitivity and emotion avoidance. Method We investigated whether these transdiagnostic processes were malleable by treatment and mediated the relationship between treatment and outcome in an internet-delivered adaptation of the UP. N = 129 participants with mixed anxiety, depressive, and somatic symptom disorders were randomized to treatment or waitlist. Results The treatment yielded significant changes in all transdiagnostic processes over time in comparison to a waitlist condition. In separate mediator models, significant mediating effects were found for mindfulness, cognitive flexibility, behavioral activation, and experiential avoidance. When all mediators were combined in a multiple mediator model, the indirect effects through mindfulness and cognitive flexibility emerged as significant. Conclusion These findings add to the growing body of research on transdiagnostic processes as mediators of change and emphasize mindfulness and cognitive flexibility as a transdiagnostic treatment target. However, these results should be interpreted cautiously, as temporal precedence could not be established

Phosphorylation of Argonaute proteins affects mRNA binding and is essential for microRNA‐guided gene silencing in vivo

Argonaute proteins associate with microRNAs and are key components of gene silencing pathways. With such a pivotal role, these proteins represent ideal targets for regulatory post-translational modifications. Using quantitative mass spectrometry, we find that a C-terminal serine/threonine cluster is phosphorylated at five different residues in human and Caenorhabditis elegans. In human, hyper-phosphorylation does not affect microRNA binding, localization, or cleavage activity of Ago2. However, mRNA binding is strongly affected. Strikingly, on Ago2 mutants that cannot bind microRNAs or mRNAs, the cluster remains unphosphorylated indicating a role at late stages of gene silencing. In C. elegans, the phosphorylation of the conserved cluster of ALG-1 is essential for microRNA function in vivo. Furthermore, a single point mutation within the cluster is sufficient to phenocopy the loss of its complete phosphorylation. Interestingly, this mutant retains its capacity to produce and bind microRNAs and represses expression when artificially tethered to an mRNA. Altogether, our data suggest that the phosphorylation state of the serine/threonine cluster is important for Argonaute-mRNA interactions

Analysis of Outcomes in Ischemic vs Nonischemic Cardiomyopathy in Patients With Atrial Fibrillation A Report From the GARFIELD-AF Registry

IMPORTANCE Congestive heart failure (CHF) is commonly associated with nonvalvular atrial fibrillation (AF), and their combination may affect treatment strategies and outcomes