Human red blood cells at work: identification and visualization of erythrocytic eNOS activity in health and disease

A nitric oxide synthase (NOS)-like activity has been demonstrated in human red blood cells (RBCs), but doubts about its functional significance, isoform identity and disease relevance remain. Using flow cytometry in combination with the NO-imaging probe DAF-FM we find that all blood cells form NO intracellularly, with a rank order of monocytes > neutrophils > lymphocytes > RBCs > platelets. The observation of a NO-related fluorescence within RBCs was unexpected given the abundance of the NO-scavenger oxyhemoglobin. Constitutive normoxic NO formation was abolished by NOS inhibition and intracellular NO scavenging, confirmed by laser-scanning microscopy and unequivocally validated by detection of the DAF-FM reaction product with NO using HPLC and LC-MS/MS. Employing immunoprecipitation, ESI-MS/MS-based peptide sequencing and enzymatic assay we further demonstrate that human RBCs contain an endothelial NOS (eNOS) that converts L-3H-Arginine to L-3H-Citrulline in a Ca2+/Calmodulin-dependent fashion. Moreover, in patients with coronary artery disease, red cell eNOS expression and activity are both lower than in age-matched healthy individuals and correlate with the degree of endothelial dysfunction. Thus, human RBCs constitutively produce NO under normoxic conditions via an active eNOS isoform the activity of which is compromised in patients with coronary artery disease.

The contribution of primary and secondary somatosensory cortices to the representation of body parts and body sides: an fMRI adaptation study

Although the somatosensory homunculus is a classically used description of the way somatosensory inputs are processed in the brain, the actual contributions of primary (SI) and secondary (SII) somatosensory cortices to the spatial coding of touch remain poorly understood. We studied adaptation of the fMRI BOLD response in the somatosensory cortex by delivering pairs of vibrotactile stimuli to the finger tips of the index and middle fingers. The first stimulus (adaptor) was delivered either to the index or to the middle finger of the right or left hand, whereas the second stimulus (test) was always administered to the left index finger. The overall BOLD response evoked by the stimulation was primarily contralateral in SI and was more bilateral in SII. However, our fMRI adaptation approach also revealed that both somatosensory cortices were sensitive to ipsilateral as well as to contralateral inputs. SI and SII adapted more after subsequent stimulation of homologous as compared with nonhomologous fingers, showing a distinction between different fingers. Most importantly, for both somatosensory cortices, this finger-specific adaptation occurred irrespective of whether the tactile stimulus was delivered to the same or to different hands. This result implies integration of contralateral and ipsilateral somatosensory inputs in SI as well as in SII. Our findings suggest that SI is more than a simple relay for sensory information and that both SI and SII contribute to the spatial coding of touch by discriminating between body parts (fingers) and by integrating the somatosensory input from the two sides of the body (hands).

A study into the accuracy of using meteorological wind data to estimate turbine generation output

Meteorological (met) station data is used as the basis for a number of influential studies into the impacts of the variability of renewable resources. Real turbine output data is not often easy to acquire, whereas meteorological wind data, supplied at a standardised height of 10 m, is widely available. This data can be extrapolated to a standard turbine height using the wind profile power law and used to simulate the hypothetical power output of a turbine. Utilising a number of met sites in such a manner can develop a model of future wind generation output. However, the accuracy of this extrapolation is strongly dependent on the choice of the wind shear exponent alpha. This paper investigates the accuracy of the simulated generation output compared to reality using a wind farm in North Rhins, Scotland and a nearby met station in West Freugh. The results show that while a single annual average value for alpha may be selected to accurately represent the long term energy generation from a simulated wind farm, there are significant differences between simulation and reality on an hourly power generation basis, with implications for understanding the impact of variability of renewables on short timescales, particularly system balancing and the way that conventional generation may be asked to respond to a high level of variable renewable generation on the grid in the future.

Endothelin-converting enzyme-1 degrades internalized somatostatin-14

Agonist-induced internalization of somatostatin receptors (ssts) determines subsequent cellular responsiveness to peptide agonists and influences sst receptor scintigraphy. To investigate sst2A trafficking, rat sst2A tagged with epitope was expressed in human embryonic kidney cells and tracked by antibody labeling. Confocal microscopical analysis revealed that stimulation with sst and octreotide induced internalization of sst2A. Internalized sst2A remained sequestrated within early endosomes, and 60 min after stimulation, internalized sst2A still colocalized with beta-arrestin1-enhanced green fluorescence protein (EGFP), endothelin-converting enzyme-1 (ECE-1), and rab5a. Internalized (125)I-Tyr(11)-SST-14 was rapidly hydrolyzed by endosomal endopeptidases, with radioactive metabolites being released from the cell. Internalized (125)I-Tyr(1)-octreotide accumulated as an intact peptide and was released from the cell as an intact peptide ligand. We have identified ECE-1 as one of the endopeptidases responsible for inactivation of internalized SST-14. ECE-1-mediated cleavage of SST-14 was inhibited by the specific ECE-1 inhibitor, SM-19712, and by preventing acidification of endosomes using bafilomycin A(1). ECE-1 cleaved SST-14 but not octreotide in an acidic environment. The metallopeptidases angiotensin-1 converting enzyme and ECE-2 did not hydrolyze SST-14 or octreotide. Our results show for the first time that stimulation with SST-14 and octreotide induced sequestration of sst2A into early endosomes and that endocytosed SST-14 is degraded by endopeptidases located in early endosomes. Furthermore, octreotide was not degraded by endosomal peptidases and was released as an intact peptide. This mechanism may explain functional differences between octreotide and SST-14 after sst2A stimulation. Moreover, further investigation of endopeptidase-regulated trafficking of neuropeptides may result in novel concepts of neuropeptide receptor inactivation in cancer diagnosis.

Measuring significant variability characteristics: An assessment of three UK renewables

The variability of renewable energy is widely recognised as a challenge for integrating high levels of renewable generation into electricity systems. However, to explore its implications effectively, variability itself should first be clearly understood. This is particularly true for national electricity systems with high planned penetration of renewables and limited interconnection such as the UK. Variability cannot be considered as a distinct resource property with a single measurable parameter, but is a multi-faceted concept best described by a range of distinct characteristics. This paper identifies relevant characteristics of variability, and considers their implications for energy research. This is done through analysis of wind, solar and tidal current resources, with a primary focus on the Bristol Channel region in the UK. The relationship with electricity demand is considered, alongside the potential benefits of resource diversity. Analysis is presented in terms of persistence, distribution, frequency and correlation between supply and demand. Marked differences are seen between the behaviours of the individual resources, and these give rise to a range of different implications for system integration. Wind shows strong persistence and a useful seasonal pattern, but also a high spread in energy levels at timescales beyond one or two days. The solar resource is most closely correlated with electricity demand, but is undermined by night-time zero values and an even greater spread of monthly energy delivered than wind. In contrast, the tidal resource exhibits very low persistence, but also much greater consistency in energy values assessed across monthly time scales. Whilst this paper focuses primarily on the behaviour of resources, it is noted that discrete variability characteristics can be related to different system impacts. Persistence and predictability are relevant for system balancing, whereas statistical distribution is more relevant when exploring issues of asset utilisation and energy curtailment. Areas of further research are also identified, including the need to assess the value of predictability in relation to other characteristics.

Addressee orientation in political speeches: tracing the dialogical 'other' in argumentative monologue

This article suggests that the addressees as the dialogical ‘other’ loom large in monological political speeches. However, political speeches are produced under conditions of addressee heterogeneity, i.e. the speakers do not actually know who they will be talking to. It will be argued that the addressees are nevertheless a crucial element in speakers’ context models, that speakers orientate towards imagined addressees and that certain aspects – what possible addressees may do, think or believe and that they are a part of an imagined community – are particularly relevant from the speakers’ point of view. An analysis of addressee orientation in political speeches aims at reconstructing speakers’ conceptualisations of possible addressees. The analysis reveals patterns of addressee orientation which suggest that the addressees are framed in terms of presumed nearness (i.e. agreement) or distance (i.e. disagreement) to the speakers. Both presumed agreement and disagreement will be discussed in terms of how the speakers aim to impose their default perspectives on the addressees. The analysis is based on examples from a substantial corpus of German chancellors’ political speeches from 1951-2001.

Exploring the role of reanalysis data in simulating regional wind generation variability over Northern Ireland

As wind generation increases, system impact studies rely on predictions of future generation and effective representation of wind variability. A well-established approach to investigate the impact of wind variability is to simulate generation using observations from 10 m meteorological mast-data. However, there are problems with relying purely on historical wind-speed records or generation histories: mast-data is often incomplete, not sited at a relevant wind generation sites, and recorded at the wrong altitude above ground (usually 10 m), each of which may distort the generation profile. A possible complimentary approach is to use reanalysis data, where data assimilation techniques are combined with state-of-the-art weather forecast models to produce complete gridded wind time-series over an area. Previous investigations of reanalysis datasets have placed an emphasis on comparing reanalysis to meteorological site records whereas this paper compares wind generation simulated using reanalysis data directly against historic wind generation records. Importantly, this comparison is conducted using raw reanalysis data (typical resolution ∼50 km), without relying on a computationally expensive “dynamical downscaling” for a particular target region. Although the raw reanalysis data cannot, by nature of its construction, represent the site-specific effects of sub-gridscale topography, it is nevertheless shown to be comparable to or better than the mast-based simulation in the region considered and it is therefore argued that raw reanalysis data may offer a number of significant advantages as a data source.

Promotion carryover as a missing data problem

An important feature of agribusiness promotion programs is their lagged impact on consumption. Efficient investment in advertising requires reliable estimates of these lagged responses and it is desirable from both applied and theoretical standpoints to have a flexible method for estimating them. This note derives an alternative Bayesian methodology for estimating lagged responses when investments occur intermittently within a time series. The method exploits a latent-variable extension of the natural-conjugate, normal-linear model, Gibbs sampling and data augmentation. It is applied to a monthly time series on Turkish pasta consumption (1993:5-1998:3) and three, nonconsecutive promotion campaigns (1996:3, 1997:3, 1997:10). The results suggest that responses were greatest to the second campaign, which allocated its entire budget to television media; that its impact peaked in the sixth month following expenditure; and that the rate of return (measured in metric tons additional consumption per thousand dollars expended) was around a factor of 20.

The application of Regional Climate Model output for the simulation of high-mountain permafrost scenarios

This study investigates the possibilities and limitations of using Regional Climate Model (RCM) output for the simulation of alpine permafrost scenarios. It focuses on the general problem of scale mismatch between RCMs and impact models and, in particular, the special challenges that arise when driving an impact model in topographically complex high-mountain environments with the output of an RCM. Two approaches are introduced that take into account the special difficulties in such areas, and thus enable the use of RCM for alpine permafrost scenario modelling. Intended as an initial example, they are applied at the area of Corvatsch (Upper Engadine, Switzerland) in order to demonstrate and discuss the application of the two approaches, rather than to provide an assessment of future changes in permafrost occurrence. There are still many uncertainties and inaccuracies inherent in climate and impact models, which increase when driving one model with the output of the other. Nevertheless, our study shows that the use of RCMs offers new and promising perspectives for the simulation of high-mountain permafrost scenarios

Cartels and rent sharing at the farmer–trader interface: evidence from Ghana’s tomato sector

Itinerant traders provide an important route for West Africa’s farmers’ to get their perishable produce rapidly to the distant urban markets. But these farmers often accuse the traders of offering “unfairly” low prices while preventing direct access to these markets. Using Ghana’s tomato sector as a case study, we provide the first detailed exploration of the interface between Ghana’s farmers and traders, combining a theoretical model with novel empirical data on daily sales prices and tomato quality. We find that although the prices traders pay farmers are lower than prices in the urban markets, taking into account transport costs, these prices are higher than farmers receive from the local rural market. Our article suggests that policymakers would do better to focus on opening up access to the urban markets rather than on strengthening farmers’ bargaining power with the traders, which restricts market volumes further and harms farmers unable to sell to traders.

Dynamical and cloud-radiation feedbacks in El Niño and greenhouse warming

An El Niño-like steady response is found in a greenhouse warming simulation resulting from coupled ocean-atmosphere dynamical feedbacks similar to those producing the present-day El Niños. There is a strong negative cloud-radiation feedback on the sea surface temperature (SST) anomaly associated with this enhanced eastern equatorial Pacific warm pattern. However, this negative feedback is overwhelmed by the positive dynamical feedbacks and cannot diminish the sensitivity of the tropical SST to enhanced greenhouse gas concentrations. The enhanced eastern-Pacific warming in the coupled ocean-atmosphere system suggests that coupled dynamics can strengthen this sensitivity.

Impact of global warming on the interannual and interdecadal climate modes in a coupled GCM

In this study, we investigated the impact of global warming on the variabilities of large-scale interannual and interdecadal climate modes and teleconnection patterns with two long-term integrations of the coupled general circulation model of ECHAM4/OPYC3 at the Max-Planck-Institute for Meteorology, Hamburg. One is the control (CTRL) run with fixed present-day concentrations of greenhouse gases. The other experiment is a simulation of transient greenhouse warming, named GHG run. In the GHG run the averaged geopotential height at 500 hPa is increased significantly, and a negative phase of the Pacific/North American (PNA) teleconnection-like distribution pattern is intensified. The standard deviation over the tropics (high latitudes) is enhanced (reduced) on the interdecadal time scales and reduced (enhanced) on the interannual time scales in the GHG run. Except for an interdecadal mode related to the Southern Oscillation (SO) in the GHG run, the spatial variation patterns are similar for different (interannual + interdecadal, interannual, and interdecadal) time scales in the GHG and CTRL runs. Spatial distributions of the teleconnection patterns on the interannual and interdecadal time scales in the GHG run are also similar to those in the CTRL run. But some teleconnection patterns show linear trends and changes of variances and frequencies in the GHG run. Apart from the positive linear trend of the SO, the interdecadal modulation to the El Niño/SO cycle is enhanced during the GHG 2040 ∼ 2099. This is the result of an enhancement of the Walker circulation during that period. La Niña events intensify and El Niño events relatively weaken during the GHG 2070 ∼ 2090. It is interesting to note that with increasing greenhouse gas concentrations the relation between the SO and the PNA pattern is reversed significantly from a negative to a positive correlation on the interdecadal time scales and weakened on the interannual time scales. This suggests that the increase of the greenhouse gas concentrations will trigger the nonstationary correlation between the SO and the PNA pattern both on the interdecadal and interannual time scales.

Unwritten law in Hobbesian political thought

In Hobbesian terminology, ‘unwritten laws’ are natural laws enforced within a polity, by a non-sovereign judge, without some previous public promulgation. This article discusses the idea in the light of successive Hobbesian accounts of ‘law’ and ‘obligation’. Between De Cive and Leviathan, Hobbes dropped the idea that natural law is strictly speaking law, but he continued to believe unwritten laws must form a part of any legal system. He was unable to explain how such a law could claim a legal status. His loyalty to the notion, in spite of all the trouble that it caused, is a sign of his belief that moral knowledge is readily accessible to all.

The impact and reach of MOOCs:a developing countries’ perspective

Massively Open Online Courses (MOOCs) are a recent but hugely popular phenomenon in the online learning world. They are hailed by many as a solution for the developing world’s lack of access to education because MOOCs can provide learning opportunities to a massive number of learners from anywhere in the world as long as they can access the course through Internet. However, a close consideration of the ability of learn- ers from most developing countries to make use of MOOCs seems to contradict this rhetoric. This paper discusses features of MOOCs and looks at them from a developing countries’ perspective to conclude that due to a complicated set of conditions (‘access’, language, computer literacy among others) prevailing in developing countries, MOOCs may not be a viable solution for education for a large proportion of people in these ar- eas of the world. The paper further shows the need for more data on the demograph- ics of MOOC participants from developing countries to form a better understanding of MOOCs role in educating people from developing countries.