TYK2 Kinase Activity Is Required for Functional Type I Interferon Responses In Vivo

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family and is involved in cytokine signalling. In vitro analyses suggest that TYK2 also has kinase-independent, i.e., non-canonical, functions. We have generated gene-targeted mice harbouring a mutation in the ATP-binding pocket of the kinase domain. The Tyk2 kinase-inactive (Tyk2K923E) mice are viable and show no gross abnormalities. We show that kinase-active TYK2 is required for full-fledged type I interferon- (IFN) induced activation of the transcription factors STAT1-4 and for the in vivo antiviral defence against viruses primarily controlled through type I IFN actions. In addition, TYK2 kinase activity was found to be required for the protein’s stability. An inhibitory function was only observed upon over-expression of TYK2K923E in vitro. Tyk2K923E mice represent the first model for studying the kinase-independent function of a JAK in vivo and for assessing the consequences of side effects of JAK inhibitors

Evidence-based Kernels: Fundamental Units of Behavioral Influence

This paper describes evidence-based kernels, fundamental units of behavioral influence that appear to underlie effective prevention and treatment for children, adults, and families. A kernel is a behavior–influence procedure shown through experimental analysis to affect a specific behavior and that is indivisible in the sense that removing any of its components would render it inert. Existing evidence shows that a variety of kernels can influence behavior in context, and some evidence suggests that frequent use or sufficient use of some kernels may produce longer lasting behavioral shifts. The analysis of kernels could contribute to an empirically based theory of behavioral influence, augment existing prevention or treatment efforts, facilitate the dissemination of effective prevention and treatment practices, clarify the active ingredients in existing interventions, and contribute to efficiently developing interventions that are more effective. Kernels involve one or more of the following mechanisms of behavior influence: reinforcement, altering antecedents, changing verbal relational responding, or changing physiological states directly. The paper describes 52 of these kernels, and details practical, theoretical, and research implications, including calling for a national database of kernels that influence human behavior

Direct measurement of normal and shear forces between surface-grown polyelectrolyte layers.

This paper presents measurements, using the surface force balance (SFB), of the normal and shear forces in aqueous solutions between polyelectrolyte layers grown directly on mica substrates (grafted-from). The grafting-from was via surface-initiated atom transfer radical polymerization (surface-initiated ATRP) using a positively charged methacrylate monomer. X-ray reflectometry measurements confirm the successful formation of polyelectrolyte layers by this method. Surface-inititated ATRP has the advantages that the polymer chains can be strongly grafted to the substrate, and that high grafting densities should be achievable. Measured normal forces in water showed a long-range repulsion arising from an electrical double layer that extended beyond the polyelectrolyte layers, and a stronger, shorter-range repulsion when the polyelectrolyte brushes were in contact. Swollen layer thicknesses were in the range 15-40 nm. Upon addition of approximately 10(-2)-10(-1) M sodium nitrate, screening effects reduced the electrical double layer force to an undetectable level. Shear force measurements in pure water were performed, and the measured friction may arise from polymer chains bridging between the surfaces