A zebrafish functional genomics model to investigate the role of human A20 variants in vivo

Germline loss-of-function variation in TNFAIP3, encoding A20, has been implicated in a wide variety of autoinflammatory and autoimmune conditions, with acquired somatic missense mutations linked to cancer progression. Furthermore, human sequence data reveals that the A20 locus contains ~ 400 non-synonymous coding variants, which are largely uncharacterised. The growing number of A20 coding variants with unknown function, but potential clinical impact, poses a challenge to traditional mouse-based approaches. Here we report the development of a novel functional genomics approach that utilizes a new A20-deficient zebrafish (Danio rerio) model to investigate the impact of TNFAIP3 genetic variants in vivo. A20-deficient zebrafish are hyper-responsive to microbial immune activation and exhibit spontaneous early lethality. Ectopic addition of human A20 rescued A20-null zebrafish from lethality, while missense mutations at two conserved A20 residues, S381A and C243Y, reversed this protective effect. Ser381 represents a phosphorylation site important for enhancing A20 activity that is abrogated by its mutation to alanine, or by a causal C243Y mutation that triggers human autoimmune disease. These data reveal an evolutionarily conserved role for TNFAIP3 in limiting inflammation in the vertebrate linage and show how this function is controlled by phosphorylation. They also demonstrate how a zebrafish functional genomics pipeline can be utilized to investigate the in vivo significance of medically relevant human TNFAIP3 gene variants.Daniele Cultrone, Nathan W. Zammit, Eleanor Self, Benno Postert, Jeremy Z. R. Han, Jacqueline Bailey ... et al

Unresolved questions in nudging research: Putting the psychology back in nudging

Nudging interventions are broadly defined as a rearrangement of a choice context that gently suggests a specific choice. Their increasing popularity has attracted attention and discussion from researchers, policy makers, and practitioners alike. After some applications to domains such as health, environmental issues, and retirement savings, the next step in nudging is to understand the psychological boundary conditions when applied to varied domains of daily life. It is yet unclear for example to what extent nudging interventions can be transparent without losing effectiveness, or how permanent the effects are. These unresolved questions may have contributed to heated political and scientific discussions, on for example the ethics of using nudges in the public health domain, due to the missing scientific evidence. Indeed, this popularity may have led to forget how nudging harnesses insights from decades of research in psychology to change people’s behavior. The aim of this paper is to shift the focus back to the psychological premises nudges were built upon. It summarizes several outstanding questions that future research in the psychology of nudging should address. Advancing research in nudging will help to improve our understanding of applied nudging interventions and provide clarity to debates such as ethical appropriateness, effectiveness, and public approval

Cueing healthier alternatives for take-away: a field experiment on the effects of (disclosing) three nudges on food choices

Background The current field experiment demonstrates the effectiveness of nudging to promote healthy food choices. Methods Three types of nudges were implemented at a take-away food vendor: 1) an accessibility nudge that placed fruits at the front counter; 2) a salience nudge that presented healthy bread rolls to be more visually attractive; and 3) a social proof nudge that conveyed yoghurt as a popular choice. We additionally assessed whether nudging effects would remain robust when a disclosure message was included. The field experiment was conducted over a seven-week period. The measured outcome was the sales of the targeted healthy food products. Results The accessibility nudge significantly increased the sales of the fresh fruits. The impact of the salience nudge was limited presumably due to existing preferences or habits that typically facilitate bread purchases. As the sales of the yoghurt shakes remained consistently low over the seven-week period the impact of the social proof nudge remained unexamined. Critically, disclosing the purpose of the nudges did not interfere with effects. Conclusions Current findings suggest nudging as an effective strategy for healthy food promotion, and offer implications for topical debate regarding the ethics of nudges

Buckley–James-type of estimators under the classical case cohort design

Case-cohort study, Buckley–James estimator, Right-censorship, Linear regression model, Self-consistent algorithm, Survival data,