Glycogen synthase kinase 3 (GSK3) in the heart: a point of integration in hypertrophic signalling and a therapeutic target? A critical analysis

Glycogen synthase kinase 3 (GSK3, of which there are two isoforms, GSK3alpha and GSK3beta) was originally characterized in the context of regulation of glycogen metabolism, though it is now known to regulate many other cellular processes. Phosphorylation of GSK3alpha(Ser21) and GSK3beta(Ser9) inhibits their activity. In the heart, emphasis has been placed particularly on GSK3beta, rather than GSK3alpha. Importantly, catalytically-active GSK3 generally restrains gene expression and, in the heart, catalytically-active GSK3 has been implicated in anti-hypertrophic signalling. Inhibition of GSK3 results in changes in the activities of transcription and translation factors in the heart and promotes hypertrophic responses, and it is generally assumed that signal transduction from hypertrophic stimuli to GSK3 passes primarily through protein kinase B/Akt (PKB/Akt). However, recent data suggest that the situation is far more complex. We review evidence pertaining to the role of GSK3 in the myocardium and discuss effects of genetic manipulation of GSK3 activity in vivo. We also discuss the signalling pathways potentially regulating GSK3 activity and propose that, depending on the stimulus, phosphorylation of GSK3 is independent of PKB/Akt. Potential GSK3 substrates studied in relation to myocardial hypertrophy include nuclear factors of activated T cells, beta-catenin, GATA4, myocardin, CREB, and eukaryotic initiation factor 2Bvarepsilon. These and other transcription factor substrates putatively important in the heart are considered. We discuss whether cardiac pathologies could be treated by therapeutic intervention at the GSK3 level but conclude that any intervention would be premature without greater understanding of the precise role of GSK3 in cardiac processes.

Component processes of early reading, spelling, and narrative writing skills in Turkish: a longitudinal study

The study examined: (a) the role of phonological, grammatical, and rapid automatized naming (RAN) skills in reading and spelling development; and (b) the component processes of early narrative writing skills. Fifty-seven Turkish-speaking children were followed from Grade 1 to Grade 2. RAN was the most powerful longitudinal predictor of reading speed and its effect was evident even when previous reading skills were taken into account. Broadly, the phonological and grammatical skills made reliable contributions to spelling performance but their effects were completely mediated by previous spelling skills. Different aspects of the narrative writing skills were related to different processing skills. While handwriting speed predicted writing fluency, spelling accuracy predicted spelling error rate. Vocabulary and working memory were the only reliable longitudinal predictors of the quality of composition content. The overall model, however, failed to explain any reliable variance in the structural quality of the compositions

Use of the statistical properties of the wavelet-transform coefficients for optimization of integration time in Fourier transform spectrometry

We show that an analysis of the mean and variance of discrete wavelet coefficients of coaveraged time-domain interferograms can be used as a specification for determining when to stop coaveraging. We also show that, if a prediction model built in the wavelet domain is used to determine the composition of unknown samples, a stopping criterion for the coaveraging process can be developed with respect to the uncertainty tolerated in the prediction.

Expert judgement in the processes of commercial property market forecasting

In this paper, we investigate the role of judgement in the formation of forecasts in commercial property markets. The investigation is based on interview surveys with the majority of UK forecast producers, who are using a range of inputs and data sets to form models to predict an array of variables for a range of locations. The findings suggest that forecasts need to be acceptable to their users (and purchasers) and consequently forecasters generally have incentives to avoid presenting contentious or conspicuous forecasts. Where extreme forecasts are generated by a model, forecasters often engage in ‘self‐censorship’ or are ‘censored’ following in‐house consultation. It is concluded that the forecasting process is significantly more complex than merely carrying out econometric modelling, forecasts are mediated and contested within organisations and that impacts can vary considerably across different organizational contexts.

Expert judgement in the processes of commercial property market forecasting

In this paper we investigate the role of judgement in the formation of forecasts in commercial real estate markets. Based on interview surveys with the majority of forecast producers, we find that real estate forecasters are using a range of inputs and data sets to form models to predict an array of variables for a range of locations. The findings suggest that forecasts need to be acceptable to their users (and purchasers) and consequently forecasters generally have incentives to avoid presenting contentious or conspicuous forecasts. Where extreme forecasts are generated by a model, forecasters often engage in ‘self-censorship’ or are ‘censored’ following in-house consultation. It is concluded that the forecasting process is more complex than merely carrying out econometric modelling and that the impact of the influences within this process vary considerably across different organizational contexts.

Study of picosecond processes of an intercalated dipyridophenazine Cr(iii) complex bound to defined sequence DNAs using transient absorption and time-resolved infrared methods

Picosecond transient absorption (TA) and time-resolved infrared (TRIR) measurements of rac-[Cr(phen)2(dppz)]3+ (1) intercalated into double-stranded guanine-containing DNA reveal that the excited state is very rapidly quenched. As no evidence was found for the transient electron transfer products, it is proposed that the back electron transfer reaction must be even faster (<3 ps).

Vertical structure and physical processes of the Madden-Julian oscillation: Linking hindcast fidelity to simulated diabatic heating and moistening

Many theories for the Madden-Julian oscillation (MJO) focus on diabatic processes, particularly the evolution of vertical heating and moistening. Poor MJO performance in weather and climate models is often blamed on biases in these processes and their interactions with the large-scale circulation. We introduce one of three components of a model-evaluation project, which aims to connect MJO fidelity in models to their representations of several physical processes, focusing on diabatic heating and moistening. This component consists of 20-day hindcasts, initialised daily during two MJO events in winter 2009-10. The 13 models exhibit a range of skill: several have accurate forecasts to 20 days' lead, while others perform similarly to statistical models (8-11 days). Models that maintain the observed MJO amplitude accurately predict propagation, but not vice versa. We find no link between hindcast fidelity and the precipitation-moisture relationship, in contrast to other recent studies. There is also no relationship between models' performance and the evolution of their diabatic-heating profiles with rain rate. A more robust association emerges between models' fidelity and net moistening: the highest-skill models show a clear transition from low-level moistening for light rainfall to mid-level moistening at moderate rainfall and upper-level moistening for heavy rainfall. The mid-level moistening, arising from both dynamics and physics, may be most important. Accurately representing many processes may be necessary, but not sufficient for capturing the MJO, which suggests that models fail to predict the MJO for a broad range of reasons and limits the possibility of finding a panacea.

Vertical structure and physical processes of the Madden-Julian oscillation: synthesis and summary

The "Vertical structure and physical processes of the Madden-Julian oscillation (MJO)" project comprises three experiments, designed to evaluate comprehensively the heating, moistening and momentum associated with tropical convection in general circulation models (GCMs). We consider here only those GCMs that performed all experiments. Some models display relatively higher or lower MJO fidelity in both initialized hindcasts and climate simulations, while others show considerable variations in fidelity between experiments. Fidelity in hindcasts and climate simulations are not meaningfully correlated. The analysis of each experiment led to the development of process-oriented diagnostics, some of which distinguished between GCMs with higher or lower fidelity in that experiment. We select the most discriminating diagnostics and apply them to data from all experiments, where possible, to determine if correlations with MJO fidelity hold across scales and GCM states. While normalized gross moist stability had a small but statistically significant correlation with MJO fidelity in climate simulations, we find no link with fidelity in medium-range hindcasts. Similarly, there is no association between timestep-to-timestep rainfall variability, identified from short hindcasts, and fidelity in medium-range hindcasts or climate simulations. Two metrics that relate precipitation to free-tropospheric moisture--the relative humidity for extreme daily precipitation, and variations in the height and amplitude of moistening with rain rate--successfully distinguish between higher- and lower-fidelity GCMs in hindcasts and climate simulations. To improve the MJO, developers should focus on relationships between convection and both total moisture and its rate of change. We conclude by offering recommendations for further experiments.

Vertical structure and physical processes of the Madden-Julian oscillation: exploring key model physics in climate simulations

Aimed at reducing deficiencies in representing the Madden-Julian oscillation (MJO) in general circulation models (GCMs), a global model evaluation project on vertical structure and physical processes of the MJO was coordinated. In this paper, results from the climate simulation component of this project are reported. It is shown that the MJO remains a great challenge in these latest generation GCMs. The systematic eastward propagation of the MJO is only well simulated in about one-fourth of the total participating models. The observed vertical westward tilt with altitude of the MJO is well simulated in good MJO models, but not in the poor ones. Damped Kelvin wave responses to the east of convection in the lower troposphere could be responsible for the missing MJO preconditioning process in these poor MJO models. Several process-oriented diagnostics were conducted to discriminate key processes for realistic MJO simulations. While large-scale rainfall partition and low-level mean zonal winds over the Indo-Pacific in a model are not found to be closely associated with its MJO skill, two metrics, including the low-level relative humidity difference between high and low rain events and seasonal mean gross moist stability, exhibit statistically significant correlations with the MJO performance. It is further indicated that increased cloud-radiative feedback tends to be associated with reduced amplitude of intraseasonal variability, which is incompatible with the radiative instability theory previously proposed for the MJO. Results in this study confirm that inclusion of air-sea interaction can lead to significant improvement in simulating the MJO.

Vertical structure and physical processes of the Madden-Julian oscillation: Biases and uncertainties at short range

An analysis of diabatic heating and moistening processes from 12-36 hour lead time forecasts from 12 Global Circulation Models are presented as part of the "Vertical structure and physical processes of the Madden-Julian Oscillation (MJO)" project. A lead time of 12-36 hours is chosen to constrain the large scale dynamics and thermodynamics to be close to observations while avoiding being too close to the initial spin-up for the models as they adjust to being driven from the YOTC analysis. A comparison of the vertical velocity and rainfall with the observations and YOTC analysis suggests that the phases of convection associated with the MJO are constrained in most models at this lead time although the rainfall in the suppressed phase is typically overestimated. Although the large scale dynamics is reasonably constrained, moistening and heating profiles have large inter-model spread. In particular, there are large spreads in convective heating and moistening at mid-levels during the transition to active convection. Radiative heating and cloud parameters have the largest relative spread across models at upper levels during the active phase. A detailed analysis of time step behaviour shows that some models show strong intermittency in rainfall and differences in the precipitation and dynamics relationship between models. The wealth of model outputs archived during this project is a very valuable resource for model developers beyond the study of the MJO. In addition, the findings of this study can inform the design of process model experiments, and inform the priorities for field experiments and future observing systems.

'Nature concocts & expels': the agents and processes of recovery from disease in Early Modern England

The ‘golden saying’ in early modern medicine was ‘Nature is the healer of disease’. This article uncovers the meaning and significance of this forgotten axiom by investigating perceptions of the agents and physiological processes of recovery from illness in England, c.1580-1720. Drawing on sources such as medical texts and diaries, it shows that doctors and laypeople attributed recovery to three agents – God, Nature, and the practitioner. While scholars are familiar with the roles of providence and medicine, the vital agency of Nature has been overlooked. In theory, the agents operated in a hierarchy: Nature was ‘God’s instrument’, and the physician, ‘Nature’s servant’; but in practice the power balance was more ambivalent. Nature was depicted both as a housewife who cooked and cleaned the humours, and as a warrior, who defeated the disease. Through exploring these complex dynamics, the article sheds fresh light on concepts of gender, disease, and bodies.