Folding Circular Permutants of IL-1β: Route Selection Driven by Functional Frustration

Interleukin-1β (IL-1β) is the cytokine crucial to inflammatory and immune response. Two dominant routes are populated in the folding to native structure. These distinct routes are a result of the competition between early packing of the functional loops versus closure of the β-barrel to achieve efficient folding and have been observed both experimentally and computationally. Kinetic experiments on the WT protein established that the dominant route is characterized by early packing of geometrically frustrated functional loops. However, deletion of one of the functional loops, the β-bulge, switches the dominant route to an alternative, yet, as accessible, route, where the termini necessary for barrel closure form first. Here, we explore the effect of circular permutation of the WT sequence on the observed folding landscape with a combination of kinetic and thermodynamic experiments. Our experiments show that while the rate of formation of permutant protein is always slower than that observed for the WT sequence, the region of initial nucleation for all permutants is similar to that observed for the WT protein and occurs within a similar timescale. That is, even permutants with significant sequence rearrangement in which the functional-nucleus is placed at opposing ends of the polypeptide chain, fold by the dominant WT “functional loop-packing route”, despite the entropic cost of having to fold the N- and C- termini early. Taken together, our results indicate that the early packing of the functional loops dominates the folding landscape in active proteins, and, despite the entropic penalty of coalescing the termini early, these proteins will populate an entropically unfavorable route in order to conserve function. More generally, circular permutation can elucidate the influence of local energetic stabilization of functional regions within a protein, where topological complexity creates a mismatch between energetics and topology in active proteins

From 'trading zones' to 'buffer zones': Art and metaphor in the communication of psychiatric genetics to publics

Psychiatric genetics has a difficult relationship with the public given its unshakeable connection to eugenics. Drawing from a five-year public engagement programme that emerged from an internationally renowned psychiatric genetics centre, we propose the concept of the Buffer Zone to consider how an exchange of viewpoints between groups of people – including psychiatric geneticists and lay publics - who are often uneasy in one another’s company can be facilitated through the use of art and metaphor. The artwork at the exhibitions provided the necessary socio-cultural context for scientific endeavours, whilst also enabled public groups to be part of, and remain in, the conversation. Crucial to stress is that this mitigation was not to protect the science; it was to protect the discussion

Organizing risk: organization and management theory for the risk society

Risk has become a crucial part of organizing, affecting a wide range of organizations in all sectors. We identify, review and integrate diverse literatures relevant to organizing risk, building on an existing framework that describes how risk is organized in three ‘modes’ – prospectively, in real-time, and retrospectively. We then identify three critical issues in the existing literature: its fragmented nature; its neglect of the tensions associated with each of the modes; and its tendency to assume that the meaning of an object in relation to risk is singular and stable. We provide a series of new insights with regard to each of these issues. First, we develop the concept of a risk cycle that shows how organizations engage with all three modes and transition between them over time. Second, we explain why the tensions have been largely ignored and show how studies using a risk work perspective can provide further insights into them. Third, we develop the concept of risk translation to highlight the ways in the meanings of risks can be transformed and to identify the political consequences of such translations. We conclude the paper with a research agenda to elaborate these insights and ideas further

Perspectives on ‘the lens of risk’ interview series: interviews with Tom Horlick-Jones, Paul Slovic and Andy Alaszewski

This article is the fourth and final of an interview series with a selection of significant contributors to the social science of risk. It provides quasi-verbatim interviews with Tom Horlick-Jones, Paul Slovic and Andy Alaszewski. Tom Horlick-Jones contributed to Chapter 6 of the Royal Society Risk monograph, on risk management. He offers further insights into the debates which underlay its production to those given by Nick Pidgeon in the first article of this series. Paul Slovic provides a North American perspective on risk social science. Andy Alaszewski, in the last of the eight interviews, discusses his views about risk in relation to the evolution of his journal, Health, Risk & Society

Separated at birth? Consensus and contention in the UK agriculture and human biotechnology commissions

In 1999, the UK Government responded to escalating tensions surrounding biotechnology governance by creating two strategic, non-statutory advisory bodies: the Agriculture and Environment Biotechnology Commission (AEBC) and the Human Genetics Commission (HGC). They were designed to represent diverse stakeholder perspectives, operate transparently and engage with a variety of interested individuals and groups. This was a shift in meta-governance involving the creation of boundary organisations, discipline-bridging instruments of governance that serve to stabilise, clarify and legitimise policy advice. This paper has two main objectives: to conduct a comparative exploration of the relative success of HGC and AEBC as boundary organisations; and to test the utility of an analysis of public meeting transcripts, supplemented by interview data, in identifying factors contributing to consensus and contention in these twin Commissions