Trafficking and signaling of G protein-coupled receptors in the nervous system: implications for disease and therapy

G protein-coupled receptors (GPCRs) are expressed throughout the nervous system where they regulate multiple physiological processes, participate in neurological diseases, and are major targets for therapy. Given that many GPCRs respond to neurotransmitters and hormones that are present in the extracellular fluid and which do not readily cross the plasma membrane, receptor trafficking to and from the plasma membrane is a critically important determinant of cellular responsiveness. Moreover, trafficking of GPCRs throughout the endosomal system can initiate signaling events that are mechanistically and functionally distinct from those operating at the plasma membrane. This review discusses recent advances in the relationship between signaling and trafficking of GPCRs in the nervous system. It summarizes how receptor modifications influence trafficking, discusses mechanisms that regulate GPCR trafficking to and from the plasma membrane, reviews the relationship between trafficking and signaling, and considers the implications of GPCR trafficking to drug development.

Market power and its effects on equilibrium in the food system

When food processors have conjectures about rival firms' responses, their profit functions can be used to estimate the degree of market power in the food system. The effects of this power are investigated analytically and through applying the results to the U.S. pork sector

The European Flood Alert System and the communication, perception, and use of ensemble predictions for operational flood risk management

Although ensemble prediction systems (EPS) are increasingly promoted as the scientific state-of-the-art for operational flood forecasting, the communication, perception, and use of the resulting alerts have received much less attention. Using a variety of qualitative research methods, including direct user feedback at training workshops, participant observation during site visits to 25 forecasting centres across Europe, and in-depth interviews with 69 forecasters, civil protection officials, and policy makers involved in operational flood risk management in 17 European countries, this article discusses the perception, communication, and use of European Flood Alert System (EFAS) alerts in operational flood management. In particular, this article describes how the design of EFAS alerts has evolved in response to user feedback and desires for a hydrographic-like way of visualizing EFAS outputs. It also documents a variety of forecaster perceptions about the value and skill of EFAS forecasts and the best way of using them to inform operational decision making. EFAS flood alerts were generally welcomed by flood forecasters as a sort of ‘pre-alert’ to spur greater internal vigilance. In most cases, however, they did not lead, by themselves, to further preparatory action or to earlier warnings to the public or emergency services. Their hesitancy to act in response to medium-term, probabilistic alerts highlights some wider institutional obstacles to the hopes in the research community that EPS will be readily embraced by operational forecasters and lead to immediate improvements in flood incident management. The EFAS experience offers lessons for other hydrological services seeking to implement EPS operationally for flood forecasting and warning. Copyright © 2012 John Wiley & Sons, Ltd.

Mathematics applied to the climate system: outstanding challenges and recent progress

The societal need for reliable climate predictions and a proper assessment of their uncertainties is pressing. Uncertainties arise not only from initial conditions and forcing scenarios, but also from model formulation. Here, we identify and document three broad classes of problems, each representing what we regard to be an outstanding challenge in the area of mathematics applied to the climate system. First, there is the problem of the development and evaluation of simple physically based models of the global climate. Second, there is the problem of the development and evaluation of the components of complex models such as general circulation models. Third, there is the problem of the development and evaluation of appropriate statistical frameworks. We discuss these problems in turn, emphasizing the recent progress made by the papers presented in this Theme Issue. Many pressing challenges in climate science require closer collaboration between climate scientists, mathematicians and statisticians. We hope the papers contained in this Theme Issue will act as inspiration for such collaborations and for setting future research directions.

A model of the dynamic relationship between blood flow and volume changes during brain activation

The temporal relationship between changes in cerebral blood flow (CBF) and cerebral blood volume (CBV) is important in the biophysical modeling and interpretation of the hemodynamic response to activation, particularly in the context of magnetic resonance imaging and the blood oxygen level-dependent signal. Grubb et al. (1974) measured the steady state relationship between changes in CBV and CBF after hypercapnic challenge. The relationship CBV proportional to CBFPhi has been used extensively in the literature. Two similar models, the Balloon (Buxton et al., 1998) and the Windkessel (Mandeville et al., 1999), have been proposed to describe the temporal dynamics of changes in CBV with respect to changes in CBF. In this study, a dynamic model extending the Windkessel model by incorporating delayed compliance is presented. The extended model is better able to capture the dynamics of CBV changes after changes in CBF, particularly in the return-to-baseline stages of the response.

A model of the hemodynamic response and oxygen delivery to brain

A recent nonlinear system by Friston et al. (2000. NeuroImage 12: 466–477) links the changes in BOLD response to changes in neural activity. The system consists of five subsystems, linking: (1) neural activity to flow changes; (2) flow changes to oxygen delivery to tissue; (3) flow changes to changes in blood volume and venous outflow; (4) changes in flow, volume, and oxygen extraction fraction to deoxyhemoglobin changes; and finally (5) volume and deoxyhemoglobin changes to the BOLD response. Friston et al. exploit, in subsystem 2, a model by Buxton and Frank coupling flow changes to changes in oxygen metabolism which assumes tissue oxygen concentration to be close to zero. We describe below a model of the coupling between flow and oxygen delivery which takes into account the modulatory effect of changes in tissue oxygen concentration. The major development has been to extend the original Buxton and Frank model for oxygen transport to a full dynamic capillary model making the model applicable to both transient and steady state conditions. Furthermore our modification enables us to determine the time series of CMRO2 changes under different conditions, including CO2 challenges. We compare the differences in the performance of the “Friston system” using the original model of Buxton and Frank and that of our model. We also compare the data predicted by our model (with appropriate parameters) to data from a series of OIS studies. The qualitative differences in the behaviour of the models are exposed by different experimental simulations and by comparison with the results of OIS data from brief and extended stimulation protocols and from experiments using hypercapnia.

The ancient Greek address system and some proposed sociolinguistic universals

This article summarizes the results of a longer study of address forms in Ancient Greek, based on 11,891 address tokens from a variety of sources. It argues that the Greek evidence appears to contradict two tendencies, found in address forms in other languages, which have been claimed as possible sociolinguistic universals: the tendency toward T/V distinctions, and the principle that “What is new is polite.” It is suggested that these alleged universals should perhaps be re-examined in light of the Greek evidence, and that ancient languages in general have more to contribute to sociolinguistics than is sometimes realized. (Address, Ancient Greek, T/V distinctions)

International terrorism, domestic political instability, and the escalation effect

What are the main causes of international terrorism? Despite the meticulous examination of various candidate explanations, existing estimates still diverge in sign, size, and significance. This article puts forward a novel explanation and supporting evidence. We argue that domestic political instability provides the learning environment needed to successfully execute international terror attacks. Using a yearly panel of 123 countries over 1973–2003, we find that the occurrence of civil wars increases fatalities and the number of international terrorist acts by 45%. These results hold for alternative indicators of political instability, estimators, subsamples, subperiods, and accounting for competing explanations.

Greece in crisis: austerity, populism and the politics of blame

Within the broader debate on the Greek crisis, the theory of ‘populist democracy’ postulates that populism is fundamental to the sustenance of the Greek political system and is at the heart of Greece's endemic domestic weaknesses. This article tests this assumption empirically through the use of a sophisticated framing analysis of speeches delivered by the leaders of the five parties in the Greek parliament in the period 2009–11. The findings confirm that populism: (a) is expressed through the narratives of political actors; (b) is observed across the party system; (c) is expressed in the forms of blame-shifting and exclusivity; and (d) differs depending on position in the party system. The article contributes to the debate by testing and building on the theory of democratic populism, providing a novel way of measuring and operationalizing populism and identifying a new typology that distinguishes between mainstream and fringe populism.

The influence of system designer intention over collaborative tagging. an analysis of tagging behaviour in CiteULike and Delicious

Tagging provides support for retrieval and categorization of online content depending on users' tag choice. A number of models of tagging behaviour have been proposed to identify factors that are considered to affect taggers, such as users' tagging history. In this paper, we use Semiotics Analysis and Activity theory, to study the effect the system designer has over tagging behaviour. The framework we use shows the components that comprise the tagging system and how they interact together to direct tagging behaviour. We analysed two collaborative tagging systems: CiteULike and Delicious by studying their components by applying our framework. Using datasets from both systems, we found that 35% of CiteULike users did not provide tags compared to only 0.1% of Delicious users. This was directly linked to the type of tools used by the system designer to support tagging.