Modelling negative feedback networks for activating transcription factor 3 predicts a dominant role for miRNAs in immediate early gene regulation

Activating transcription factor 3 (Atf3) is rapidly and transiently upregulated in numerous systems, and is associated with various disease states. Atf3 is required for negative feedback regulation of other genes, but is itself subject to negative feedback regulation possibly by autorepression. In cardiomyocytes, Atf3 and Egr1 mRNAs are upregulated via ERK1/2 signalling and Atf3 suppresses Egr1 expression. We previously developed a mathematical model for the Atf3-Egr1 system. Here, we adjusted and extended the model to explore mechanisms of Atf3 feedback regulation. Introduction of an autorepressive loop for Atf3 tuned down its expression and inhibition of Egr1 was lost, demonstrating that negative feedback regulation of Atf3 by Atf3 itself is implausible in this context. Experimentally, signals downstream from ERK1/2 suppress Atf3 expression. Mathematical modelling indicated that this cannot occur by phosphorylation of pre-existing inhibitory transcriptional regulators because the time delay is too short. De novo synthesis of an inhibitory transcription factor (ITF) with a high affinity for the Atf3 promoter could suppress Atf3 expression, but (as with the Atf3 autorepression loop) inhibition of Egr1 was lost. Developing the model to include newly-synthesised miRNAs very efficiently terminated Atf3 protein expression and, with a 4-fold increase in the rate of degradation of mRNA from the mRNA/miRNA complex, profiles for Atf3 mRNA, Atf3 protein and Egr1 mRNA approximated to the experimental data. Combining the ITF model with that of the miRNA did not improve the profiles suggesting that miRNAs are likely to play a dominant role in switching off Atf3 expression post-induction.

Mark Casson: the Entrepreneur at 30 -continued relevance?

Mark Casson's The Entrepreneur: An Economic Theory (1982) has become one of the most influential books in the field of entrepreneurship. For the first time, this article outlines its origins and summarizes its main themes. The article goes on to show how Casson's subsequent research has closely followed the research agenda he set for himself in The Entrepreneur and illustrates the continuing challenge his work presents to entrepreneurship scholars. The article is based on an interview the authors conducted with Mark Casson on the thirtieth anniversary of the book's publication. Copyright © 2014 Strategic Management Society.

Providing persuasive feedback through interactive posters to motivate energy-saving behaviours

The behaviour of building occupants can have a significant impact on in-use energy performance. In these pilot studies, based on the Elaboration Likelihood Model, interactivity was incorporated in the design of behavioural interventions to assess its effectiveness in promoting energy-saving behaviours. An interactive poster and an interactive prompt were designed to ‘nudge’ occupants’ behaviours towards energy-saving. The poster was installed in an office building and was intended to encourage occupants to save energy by taking the stairs, rather than the lifts, by providing them with cumulative metaphorical feedback. The prompt was installed in student halls of residence and intended to act as a reminder to the occupants to turn the lights off by providing them with an immediate playful reward. The results showed that interactivity can ‘nudge’ occupants’ behaviours when it is combined with a clear message/feedback. The results also suggest that simple immediate feedback can be effective in encouraging energy-efficient behaviours.

The dependence of radiative forcing and feedback on evolving patterns of surface temperature change in climate models

Experiments with CO2 instantaneously quadrupled and then held constant are used to show that the relationship between the global-mean net heat input to the climate system and the global-mean surface-air-temperature change is nonlinear in Coupled Model Intercomparison Project phase 5 (CMIP5) Atmosphere-Ocean General Circulation Models (AOGCMs). The nonlinearity is shown to arise from a change in strength of climate feedbacks driven by an evolving pattern of surface warming. In 23 out of the 27 AOGCMs examined the climate feedback parameter becomes significantly (95% confidence) less negative – i.e. the effective climate sensitivity increases – as time passes. Cloud feedback parameters show the largest changes. In the AOGCM-mean approximately 60% of the change in feedback parameter comes from the topics (30N-30S). An important region involved is the tropical Pacific where the surface warming intensifies in the east after a few decades. The dependence of climate feedbacks on an evolving pattern of surface warming is confirmed using the HadGEM2 and HadCM3 atmosphere GCMs (AGCMs). With monthly evolving sea-surface-temperatures and sea-ice prescribed from its AOGCM counterpart each AGCM reproduces the time-varying feedbacks, but when a fixed pattern of warming is prescribed the radiative response is linear with global temperature change or nearly so. We also demonstrate that the regression and fixed-SST methods for evaluating effective radiative forcing are in principle different, because rapid SST adjustment when CO2 is changed can produce a pattern of surface temperature change with zero global mean but non-zero change in net radiation at the top of the atmosphere (~ -0.5 Wm-2 in HadCM3).

Probabilistic parameterisation of the surface mass balance--elevation feedback in regional climate model simulations of the Greenland ice sheet

We present a new parameterisation that relates surface mass balance (SMB: the sum of surface accumulation and surface ablation) to changes in surface elevation of the Greenland ice sheet (GrIS) for the MAR (Modèle Atmosphérique Régional: Fettweis, 2007) regional climate model. The motivation is to dynamically adjust SMB as the GrIS evolves, allowing us to force ice sheet models with SMB simulated by MAR while incorporating the SMB–elevation feedback, without the substantial technical challenges of coupling ice sheet and climate models. This also allows us to assess the effect of elevation feedback uncertainty on the GrIS contribution to sea level, using multiple global climate and ice sheet models, without the need for additional, expensive MAR simulations. We estimate this relationship separately below and above the equilibrium line altitude (ELA, separating negative and positive SMB) and for regions north and south of 77� N, from a set of MAR simulations in which we alter the ice sheet surface elevation. These give four “SMB lapse rates”, gradients that relate SMB changes to elevation changes. We assess uncertainties within a Bayesian framework, estimating probability distributions for each gradient from which we present best estimates and credibility intervals (CI) that bound 95% of the probability. Below the ELA our gradient estimates are mostly positive, because SMB usually increases with elevation: 0.56 (95% CI: −0.22 to 1.33) kgm−3 a−1 for the north, and 1.91 (1.03 to 2.61) kgm−3 a−1 for the south. Above the ELA, the gradients are much smaller in magnitude: 0.09 (−0.03 to 0.23) kgm−3 a−1 in the north, and 0.07 (−0.07 to 0.59) kgm−3 a−1 in the south, because SMB can either increase or decrease in response to increased elevation. Our statistically founded approach allows us to make probabilistic assessments for the effect of elevation feedback uncertainty on sea level projections (Edwards et al., 2014).

Effect of uncertainty in surface mass balance--elevation feedback on projections of the future sea level contribution of the Greenland ice sheet

We apply a new parameterisation of the Greenland ice sheet (GrIS) feedback between surface mass balance (SMB: the sum of surface accumulation and surface ablation) and surface elevation in the MAR regional climate model (Edwards et al., 2014) to projections of future climate change using five ice sheet models (ISMs). The MAR (Modèle Atmosphérique Régional: Fettweis, 2007) climate projections are for 2000–2199, forced by the ECHAM5 and HadCM3 global climate models (GCMs) under the SRES A1B emissions scenario. The additional sea level contribution due to the SMB– elevation feedback averaged over five ISM projections for ECHAM5 and three for HadCM3 is 4.3% (best estimate; 95% credibility interval 1.8–6.9 %) at 2100, and 9.6% (best estimate; 95% credibility interval 3.6–16.0 %) at 2200. In all results the elevation feedback is significantly positive, amplifying the GrIS sea level contribution relative to the MAR projections in which the ice sheet topography is fixed: the lower bounds of our 95% credibility intervals (CIs) for sea level contributions are larger than the “no feedback” case for all ISMs and GCMs. Our method is novel in sea level projections because we propagate three types of modelling uncertainty – GCM and ISM structural uncertainties, and elevation feedback parameterisation uncertainty – along the causal chain, from SRES scenario to sea level, within a coherent experimental design and statistical framework. The relative contributions to uncertainty depend on the timescale of interest. At 2100, the GCM uncertainty is largest, but by 2200 both the ISM and parameterisation uncertainties are larger. We also perform a perturbed parameter ensemble with one ISM to estimate the shape of the projected sea level probability distribution; our results indicate that the probability density is slightly skewed towards higher sea level contributions.