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.

Influence of sugar type on the bioavailability of cocoa flavanols.

The beneficial effects of cocoa on vascular function are mediated by the absorption of monomeric flavanols into the circulation from the small intestine. As such, an understanding of the impact of the food matrix on the delivery of flavanols to the circulation is critical in assessing the potential vascular impact of a food. In the present study, we investigated the impact of carbohydrate type on flavanol absorption and metabolism from chocolate. A randomised, double-blind, three-arm cross-over study was conducted, where fifteen volunteers were randomly assigned to either a high-flavanol (266 mg) chocolate containing maltitol, a high-flavanol (251 mg) chocolate with sucrose or a low-flavanol (48 mg) chocolate with sucrose. Test chocolates were matched for micro- and macronutrients, including the alkaloids theobromine and caffeine, and were similar in taste and appearance. Total flavanol absorption was lower after consumption of the maltitol-containing test chocolate compared with following consumption of its sucrose-containing equivalent (P = 0·002). Although the O-methylation pattern observed for absorbed flavanols was unaffected by sugar type, individual levels of unmethylated ( - )-epicatechin metabolites, 3'-O-methyl-epicatechin and 4'-O-methyl-epicatechin metabolites were lower for the maltitol-containing test chocolate compared with the sucrose-containing equivalent. Despite a reduction in the total plasma pool of flavanols, the maximum time (T max) was unaffected. The present data indicate that full assessment of intervention treatments is vital in future intervention trials with flavanols and that carbohydrate content is an important determinant for the optimal delivery of flavanols to the circulation.

Credit risk in covered bonds

Covered bonds are a promising alternative for prime mortgage securitization. In this paper, we explore risk premia in the covered bond market and particularly investigate whether and how credit risk is priced. In extant literature, yield spreads between high-quality covered bonds and government bonds are often interpreted as pure liquidity premia. In contrast, we show that although liquidity is important, it is not the exclusive risk factor. Using a hand-collected data set of cover pool information, we find that the credit quality of the cover assets is an important determinant of covered bond yield spreads. This effect is particularly strong in times of financial turmoil and has a significant influence on the issuer's refinancing cost.

Some numerical experiments on the effect of the variation of static stability in two-layer quasi-geostrophic models

A method to solve a quasi-geostrophic two-layer model including the variation of static stability is presented. The divergent part of the wind is incorporated by means of an iterative procedure. The procedure is rather fast and the time of computation is only 60–70% longer than for the usual two-layer model. The method of solution is justified by the conservation of the difference between the gross static stability and the kinetic energy. To eliminate the side-boundary conditions the experiments have been performed on a zonal channel model. The investigation falls mainly into three parts: The first part (section 5) contains a discussion of the significance of some physically inconsistent approximations. It is shown that physical inconsistencies are rather serious and for these inconsistent models which were studied the total kinetic energy increased faster than the gross static stability. In the next part (section 6) we are studying the effect of a Jacobian difference operator which conserves the total kinetic energy. The use of this operator in two-layer models will give a slight improvement but probably does not have any practical use in short periodic forecasts. It is also shown that the energy-conservative operator will change the wave-speed in an erroneous way if the wave-number or the grid-length is large in the meridional direction. In the final part (section 7) we investigate the behaviour of baroclinic waves for some different initial states and for two energy-consistent models, one with constant and one with variable static stability. According to the linear theory the waves adjust rather rapidly in such a way that the temperature wave will lag behind the pressure wave independent of the initial configuration. Thus, both models give rise to a baroclinic development even if the initial state is quasi-barotropic. The effect of the variation of static stability is very small, qualitative differences in the development are only observed during the first 12 hours. For an amplifying wave we will get a stabilization over the troughs and an instabilization over the ridges.

Can adherence to dietary guidelines address excess caloric intake? An empirical assessment for the UK

The facilitation of healthier dietary choices by consumers is a key element of government strategies to combat the rising incidence of obesity in developed and developing countries. Public health campaigns to promote healthier eating often target compliance with recommended dietary guidelines for consumption of individual nutrients such as fats and added sugars. This paper examines the association between improved compliance with dietary guidelines for individual nutrients and excess calorie intake, the most proximate determinant of obesity risk. We apply quantile regressions and counterfactual decompositions to cross-sectional data from the National Diet and Nutrition Survey (2000-01) to assess how excess calorie consumption patterns in the UK are likely to change with improved compliance with dietary guidelines. We find that the effects of compliance vary significantly across different quantiles of calorie consumption. Our results show that compliance with dietary guidelines for individual nutrients, even if successfully achieved, is likely to be associated with only modest shifts in excess calorie consumption patterns. Consequently, public health campaigns that target compliance with dietary guidelines for specific nutrients in isolation are unlikely to have a significant effect on the obesity risk faced by the population.

Past and recent changes in the North Atlantic oscillation

The North Atlantic oscillation (NAO) is under current climate conditions the leading mode of atmospheric circulation variability over the North Atlantic region. While the pattern is present during the entire year, it is most important during winter, explaining a large part of the variability of the large-scale pressure field, being thus largely determinant for the weather conditions over the North Atlantic basin and over Western Europe. In this study, a review of recent literature on the basic understanding of the NAO, its variability on different time scales and driving physical mechanisms is presented. In particular, the observed NAO variations and long-term trends are put into a long term perspective by considering paleo-proxy evidence. A representative number of recently released NAO reconstructions are discussed. While the reconstructions agree reasonably well with observations during the instrumental overlapping period, there is a rather high uncertainty between the different reconstructions for the pre-instrumental period, which leads to partially incoherent results, that is, periods where the NAO reconstructions do not agree even in sign. Finally, we highlight the future need of a broader definition of the NAO, the assessment of the stability of the teleconnection centers over time, the analysis of the relations to other relevant variables like temperature and precipitation, as well as on the relevant processes involved

The European storm Kyrill in January 2007: synoptic evolution, meteorological impacts and some considerations with respect to climate change

The synoptic evolution and some meteorological impacts of the European winter storm Kyrill that swept across Western, Central, and Eastern Europe between 17 and 19 January 2007 are investigated. The intensity and large storm damage associated with Kyrill is explained based on synoptic and mesoscale environmental storm features, as well as on comparisons to previous storms. Kyrill appeared on weather maps over the US state of Arkansas about four days before it hit Europe. It underwent an explosive intensification over the Western North Atlantic Ocean while crossing a very intense zonal polar jet stream. A superposition of several favourable meteorological conditions west of the British Isles caused a further deepening of the storm when it started to affect Western Europe. Evidence is provided that a favourable alignment of three polar jet streaks and a dry air intrusion over the occlusion and cold fronts were causal factors in maintaining Kyrill's low pressure very far into Eastern Europe. Kyrill, like many other strong European winter storms, was embedded in a pre-existing, anomalously wide, north-south mean sea-level pressure (MSLP) gradient field. In addition to the range of gusts that might be expected from the synoptic-scale pressure field, mesoscale features associated with convective overturning at the cold front are suggested as the likely causes for the extremely damaging peak gusts observed at many lowland stations during the passage of Kyrill's cold front. Compared to other storms, Kyrill was by far not the most intense system in terms of core pressure and circulation anomaly. However, the system moved into a pre-existing strong MSLP gradient located over Central Europe which extended into Eastern Europe. This fact is considered determinant for the anomalously large area affected by Kyrill. Additionally, considerations of windiness in climate change simulations using two state-of-the-art regional climate models driven by ECHAM5 indicate that not only Central, but also Eastern Central Europe may be affected by higher surface wind speeds at the end of the 21st century. These changes are partially associated with the increased pressure gradient over Europe which is identified in the ECHAM5 simulations. Thus, with respect to the area affected, as well as to the synoptic and mesoscale storm features, it is proposed that Kyrill may serve as an interesting study case to assess future storm impacts.

Employees' external representation of their workplace: key antecedents

Drawing on attitude theory, this study investigates the drivers of employees' expression of favorable opinions about their workplace. Despite its theoretical and managerial importance, the marketing literature largely ignores the topic. This study advances prior research by developing, and empirically testing, a conceptual framework of the relationship between workgroup support and favorable external representation of the workplace, mediated by emotional responses to this support. The present research investigates four new relationships: between workgroup support and emotional exhaustion, workgroup support and organizational commitment, workgroup support and job satisfaction, and emotional exhaustion and external representation of the workplace. Based on a sample of over 700 frontline service employees, this study finds that workgroup support affects favorable external representation of the workplace through various emotional responses (i.e., emotional exhaustion, organizational commitment and job satisfaction). In addition, the results identify employees' organizational commitment as the most important determinant of favorable external representation of the workplace, followed by job satisfaction and reduced emotional exhaustion. These results suggest that companies should develop practices that encourage workgroup support and organizational commitment to achieve favorable external representation of the workplace.

Key drivers of frontline employee generation of ideas for customer service improvement

Anchored in the service-dominant logic and service innovation literature, this study investigates the drivers of employee generation of ideas for service improvement (GISI). Employee GISI focuses on customer needs and providing the exact service wanted by customers. GISI should enhance competitive advantage and organizational success (cf. Berry et al. 2006; Wang and Netemeyer 2004). Despite its importance, there is little research on the idea generation stage of the service development process (Chai, Zhang, and Tan 2005). This study contributes to the service field by providing the first empirical evaluation of the drivers of GISI. It also investigates a new explanatory determinant of reading of customer needs, namely, perceived organizational support (POS), and an outcome of POS, in the form of emotional exhaustion. Results show that the major driver of GISI is reading of customer needs by employees followed by affective organizational commitment and job satisfaction. This research provides several new and important insights for service management practice by suggesting that special care should be put into selecting and recruiting employees who have the ability to read customer needs. Additionally, organizations should invest in creating work environments that encourage and reward the flow of ideas for service improvement

Risk perception and commitment to reduce global climate change in Spain

An online national survey among the Spanish population (n = 602) was conducted to examine the factors underlying a person’s support for commitments to global climate change reductions. Multiple hierarchical regression analysis was conducted in four steps and a structural equations model was tested. A survey tool designed by the Yale Project on Climate Change Communication was applied in order to build scales for the variables introduced in the study. The results show that perceived consumer effectiveness and risk perception are determinant factors of commitment to mitigating global climate change. However, there are differences in the influence that other factors, such as socio-demographics, view of nature and cultural cognition, have on the last predicted variable.

Information sources, ICTs and price information in rural agricultural markets

The spread and rapid uptake of mobile telephony in Sub-Saharan Africa has highlighted the potential role of Information Communication Technologies in improving market participation and welfare outcomes for farm producers in agricultural produce markets. This article explores the influence of different sources of information and transmission technologies on the quantum and reliability of market information flowing to farm producers, based on a survey of farm households in northern Ghana. Our results suggest that the principal role of radio broadcasts and mobile telephony is in providing a broader knowledge of markets by enhancing the quantum of market information flowing to farm producers. They do not, however, appear to have a significant impact on the quality/reliability of price information obtained by farmers for making marketing decisions. Information sources appear to be the chief determinant of the reliability of price information, with price information obtained from extension agents being the most credible. Our results provide some useful insights for the design and implementation of Market Information Systems aimed at encouraging market participation by rural farm producers in agricultural markets.

Prediction of Staphylococcus aureus antimicrobial resistance by whole-genome sequencing

Whole-genome sequencing (WGS) could potentially provide a single platform for extracting all the information required to predict an organism’s phenotype. However, its ability to provide accurate predictions has not yet been demonstrated in large independent studies of specific organisms. In this study, we aimed to develop a genotypic prediction method for antimicrobial susceptibilities. The whole genomes of 501 unrelated Staphylococcus aureus isolates were sequenced, and the assembled genomes were interrogated using BLASTn for a panel of known resistance determinants (chromosomal mutations and genes carried on plasmids). Results were compared with phenotypic susceptibility testing for 12 commonly used antimicrobial agents (penicillin, methicillin, erythromycin, clindamycin, tetracycline, ciprofloxacin, vancomycin, trimethoprim, gentamicin, fusidic acid, rifampin, and mupirocin) performed by the routine clinical laboratory. We investigated discrepancies by repeat susceptibility testing and manual inspection of the sequences and used this information to optimize the resistance determinant panel and BLASTn algorithm. We then tested performance of the optimized tool in an independent validation set of 491 unrelated isolates, with phenotypic results obtained in duplicate by automated broth dilution (BD Phoenix) and disc diffusion. In the validation set, the overall sensitivity and specificity of the genomic prediction method were 0.97 (95% confidence interval [95% CI], 0.95 to 0.98) and 0.99 (95% CI, 0.99 to 1), respectively, compared to standard susceptibility testing methods. The very major error rate was 0.5%, and the major error rate was 0.7%. WGS was as sensitive and specific as routine antimicrobial susceptibility testing methods. WGS is a promising alternative to culture methods for resistance prediction in S. aureus and ultimately other major bacterial pathogens.

Progress report on longitudinal and cross-sectional study of carbon disclosure strategies: evidence from UK listed companies

Global warming has attracted attention from all over the world and led to the concern about carbon emission. Kyoto Protocol, as the first major international regulatory emission trading scheme, was introduced in 1997 and outlined the strategies for reducing carbon emission (Ratnatunga et al., 2011). As the increased interest in carbon reduction the Protocol came into force in 2005, currently there are already 191 nations ratifying the Protocol(UNFCCC, 2012). Under the cap-and-trade schemes, each company has its carbon emission target. When company’s carbon emission exceeds the target the company will either face fines or buy emission allowance from other companies. Thus unlike most of the other social and environmental issues carbon emission could trigger cost for companies in introducing low-emission equipment and systems and also emission allowance cost when they emit more than their targets. Despite the importance of carbon emission to companies, carbon emission reporting is still operating under unregulated environment and companies are only required to disclose when it is material either in value or in substances (Miller, 2005, Deegan and Rankin, 1997). Even though there is still an increase in the volume of carbon emission disclosures in company’s financial reports and stand-alone social and environmental reports to show their concern of the environment and also their social responsibility (Peters and Romi, 2009), the motivations behind corporate carbon emission disclosures and whether carbon disclosures have impact on corporate environmental reputation and financial performance have not yet to explore. The problems with carbon emission lie on both the financial side and non-financial side of corporate governance. On one hand corporate needs to spend money in reducing carbon emission or paying penalties when they emit more than allowed. On the other hand as the public are more interested in environmental issues than before carbon emission could also impact on the image of corporate regarding to its environmental performance. The importance of carbon emission issue are beginning to be recognized by companies from different industries as one of the critical issues in supply chain management (Lee, 2011) and 80% of companies analysed are facing carbon risks resulting from emissions in the companies’ supply chain as shown in a study conducted by the Investor Responsibility Research Centre Institute for Corporate Responsibility (IRRCI) and over 80% of the companies analysed found that the majority of greenhouse gas (GHG) emission are from electricity and other direct suppliers (Trucost, 2009). The review of extant literature shows the increased importance of carbon emission issues and the gap in the study of carbon reporting and disclosures and also the study which links corporate environmental reputation and corporate financial performance with carbon reporting (Lohmann, 2009a, Ratnatunga and Balachandran, 2009, Bebbington and Larrinaga-Gonzalez, 2008). This study would focus on investigating the current status of UK carbon emission disclosures, the determinant factors of corporate carbon disclosure, and the relationship between carbon emission disclosures and corporate environmental reputation and financial performance of UK listed companies from 2004-2012 and explore the explanatory power of classical disclosure theories.

Information strategies and the theory of the Firm

Information costs play a key role in determining the relative efficiency of alternative organisational structures. The choice of locations at which information is stored in a firm is an important determinant of its information costs. A specific example of information use is modelled in order to explore what factors determine whether information should be stored centrally or locally and if it should be replicated at different sites. This provides insights into why firms are structured hierarchically, with some decisions and tasks being performed centrally and others at different levels of decentralisation. The effects of new information technologies are also discussed. These can radically alter the patterns and levels of information costs within a firm and so can cause substantial changes in organisational structure.

The APOB insertion/deletion polymorphism (rs17240441) influences postprandial lipaemia in healthy adults

BACKGROUND: Apolipoprotein (apo)B is the structural apoprotein of intestinally- and liver- derived lipoproteins and plays an important role in the transport of triacylglycerol (TAG) and cholesterol. Previous studies have examined the association between the APOB insertion/deletion (ins/del) polymorphism (rs17240441) and postprandial lipaemia in response to a single meal; however the findings have been inconsistent with studies often underpowered to detect genotype-lipaemia associations, focused mainly on men, or with limited postprandial characterisation of participants. In the present study, using a novel sequential test meal protocol which more closely mimics habitual eating patterns, we investigated the impact of APOB ins/del polymorphism on postprandial TAG, non-esterified fatty acids, glucose and insulin levels in healthy adults. FINDINGS: Healthy participants (n = 147) consumed a standard test breakfast (0 min; 49 g fat) and lunch (330 min; 29 g fat), with blood samples collected before (fasting) and on 11 subsequent occasions until 480 min after the test breakfast. The ins/ins homozygotes had higher fasting total cholesterol, LDL-cholesterol, TAG, insulin and HOMA-IR and lower HDL-cholesterol than del/del homozygotes (P < 0.017). A higher area under the time response curve (AUC) was evident for the postprandial TAG (P < 0.001) and insulin (P = 0.032) responses in the ins/ins homozygotes relative to the del/del homozygotes, where the genotype explained 35% and 7% of the variation in the TAG and insulin AUCs, respectively. CONCLUSIONS: In summary, our findings indicate that the APOB ins/del polymorphism is likely to be an important genetic determinant of the large inter-individual variability in the postprandial TAG and insulin responses to dietary fat intake.