The hemodynamic impulse response to a single neural event

This article investigates the relation between stimulus-evoked neural activity and cerebral hemodynamics. Specifically, the hypothesis is tested that hemodynamic responses can be modeled as a linear convolution of experimentally obtained measures of neural activity with a suitable hemodynamic impulse response function. To obtain a range of neural and hemodynamic responses, rat whisker pad was stimulated using brief (less than or equal to2 seconds) electrical stimuli consisting of single pulses (0.3 millisecond, 1.2 mA) combined both at different frequencies and in a paired-pulse design. Hemodynamic responses were measured using concurrent optical imaging spectroscopy and laser Doppler flowmetry, whereas neural responses were assessed through current source density analysis of multielectrode recordings from a single barrel. General linear modeling was used to deconvolve the hemodynamic impulse response to a single "neural event" from the hemodynamic and neural responses to stimulation. The model provided an excellent fit to the empirical data. The implications of these results for modeling schemes and for physiologic systems coupling neural and hemodynamic activity are discussed.

Genetic polymorphisms in the hypothalamic pathway in relation to subsequent weight change--the DiOGenes study

BACKGROUND: Single nucleotide polymorphisms (SNPs) in genes encoding the components involved in the hypothalamic pathway may influence weight gain and dietary factors may modify their effects. AIM: We conducted a case-cohort study to investigate the associations of SNPs in candidate genes with weight change during an average of 6.8 years of follow-up and to examine the potential effect modification by glycemic index (GI) and protein intake. METHODS AND FINDINGS: Participants, aged 20-60 years at baseline, came from five European countries. Cases ('weight gainers') were selected from the total eligible cohort (n = 50,293) as those with the greatest unexplained annual weight gain (n = 5,584). A random subcohort (n = 6,566) was drawn with the intention to obtain an equal number of cases and noncases (n = 5,507). We genotyped 134 SNPs that captured all common genetic variation across the 15 candidate genes; 123 met the quality control criteria. Each SNP was tested for association with the risk of being a 'weight gainer' (logistic regression models) in the case-noncase data and with weight gain (linear regression models) in the random subcohort data. After accounting for multiple testing, none of the SNPs was significantly associated with weight change. Furthermore, we observed no significant effect modification by dietary factors, except for SNP rs7180849 in the neuromedin β gene (NMB). Carriers of the minor allele had a more pronounced weight gain at a higher GI (P = 2 x 10⁻⁷). CONCLUSIONS: We found no evidence of association between SNPs in the studied hypothalamic genes with weight change. The interaction between GI and NMB SNP rs7180849 needs further confirmation.

Contribution of the geriatrician to the management of cancer in older patients

With an increasingly aged population, many patients will present with cancer in their 80s and 90s. Although some may be very fit, frail individuals will require the input of geriatricians to aid in the assessment of co-existing morbidity, in an attempt to assess those most likely to benefit from active treatment of their cancer, and those in whom the ‘giants of geriatric medicine’ require special consideration before undergoing definitive cancer therapy. The role of the geriatrician in assessment and management of such patients, together with communication and end of life care, may be more important in ensuring a good quality of life, than the cancer therapy itself. Whilst numbers of geriatricians will not be adequate to care for all elderly patients with cancer, a variety of assessment scales will help target financial and manpower resources to those most at risk.

A method to assess individual research outputs

We present here a straightforward method which can be used to obtain a quantitative indication of an individual research output for an academic. Different versions, selections and options are presented to enable a user to easily calculate values both for stand-alone papers and overall for the collection of outputs for a person. The procedure is particularly useful as a metric to give a quantitative indication of the research output of a person over a time window. Examples are included to show how the method works in practice and how it compares to alternative techniques.

An interdisciplinary modelling approach asessing the cost-effectiveness of agri-environmental measures on reducing nutrient concentration to WFD thresholds under climate change: the case of the Louros catchment

The application of the Water Framework Directive (WFD) in the European Union (EU) targets certain threshold levels for the concentration of various nutrients, nitrogen and phosphorous being the most important. In the EU, agri-environmental measures constitute a significant component of Pillar 2—Rural Development Policies in both financial and regulatory terms. Environmental measures also are linked to Pillar 1 payments through cross-compliance and the greening proposals. This paper drawing from work carried out in the REFRESH FP7 project aims to show how an INtegrated CAtchment model of plant/soil system dynamics and instream biogeochemical and hydrological dynamics can be used to assess the cost-effectiveness of agri-environmental measures in relation to nutrient concentration targets set by the WFD, especially in the presence of important habitats. We present the procedures (methodological steps, challenges and problems) for assessing the cost-effectiveness of agri-environmental measures at the baseline situation, and climate and land use change scenarios. Furthermore, we present results of an application of this methodology to the Louros watershed in Greece and discuss the likely uses and future extensions of the modelling approach. Finally, we attempt to reveal the importance of this methodology for designing and incorporating alternative environmental practices in Pillar 1 and 2 measures.

A new South American network to study the atmospheric electric field and its variations related to geophysical phenomena

In this paper we present the capability of a new network of field mill sensors to monitor the atmospheric electric field at various locations in South America; we also show some early results. The main objective of the new network is to obtain the characteristic Universal Time diurnal curve of the atmospheric electric field in fair weather, known as the Carnegie curve. The Carnegie curve is closely related to the current sources flowing in the Global Atmospheric Electric Circuit so that another goal is the study of this relationship on various time scales (transient/monthly/seasonal/annual). Also, by operating this new network, we may also study departures of the Carnegie curve from its long term average value related to various solar, geophysical and atmospheric phenomena such as the solar cycle, solar flares and energetic charged particles, galactic cosmic rays, seismic activity and specific meteorological events. We then expect to have a better understanding of the influence of these phenomena on the Global Atmospheric Electric Circuit and its time-varying behavior.

Calibration of structure in a distributed forecasting model for a semiarid flash flood: dynamic surface storage and channel roughness

Flash floods pose a significant danger for life and property. Unfortunately, in arid and semiarid environment the runoff generation shows a complex non-linear behavior with a strong spatial and temporal non-uniformity. As a result, the predictions made by physically-based simulations in semiarid areas are subject to great uncertainty, and a failure in the predictive behavior of existing models is common. Thus better descriptions of physical processes at the watershed scale need to be incorporated into the hydrological model structures. For example, terrain relief has been systematically considered static in flood modelling at the watershed scale. Here, we show that the integrated effect of small distributed relief variations originated through concurrent hydrological processes within a storm event was significant on the watershed scale hydrograph. We model these observations by introducing dynamic formulations of two relief-related parameters at diverse scales: maximum depression storage, and roughness coefficient in channels. In the final (a posteriori) model structure these parameters are allowed to be both time-constant or time-varying. The case under study is a convective storm in a semiarid Mediterranean watershed with ephemeral channels and high agricultural pressures (the Rambla del Albujón watershed; 556 km 2 ), which showed a complex multi-peak response. First, to obtain quasi-sensible simulations in the (a priori) model with time-constant relief-related parameters, a spatially distributed parameterization was strictly required. Second, a generalized likelihood uncertainty estimation (GLUE) inference applied to the improved model structure, and conditioned to observed nested hydrographs, showed that accounting for dynamic relief-related parameters led to improved simulations. The discussion is finally broadened by considering the use of the calibrated model both to analyze the sensitivity of the watershed to storm motion and to attempt the flood forecasting of a stratiform event with highly different behavior.

New animals, new landscapes and new worldviews: the Iron Age to Roman transition at Fishbourne

Anthropologists and cultural geographers have long accepted that animals play an important role in the creation of human cultures. However, such beliefs are yet to be embraced by archaeologists, who seldom give zooarchaeological data much consideration beyond the occasional economic or environmental reconstruction. In an attempt to highlight animal remains as a source of cultural information, this paper examines the evidence for the changing relationship between people and wild animals in Iron Age and Roman southern England. Special attention is given to ‘exotic’ species — in particular fallow deer, domestic fowl and the hare — whose management increased around AD 43. In Iron Age Britain the concept of wild game reserves was seemingly absent, but the post-Conquest appearance of new landscape features such as vivaria, leporaria and piscinae indicates a change in worldview from a situation where people seemingly negotiated with the ‘wilderness’ and ‘wild things’ to one where people felt they had the right or the responsibility to bring them to order. Using Fishbourne Roman Palace as a case study, we argue that wild and exotic animals represented far more than gastronomic treats or symbols of Roman identity, instead influencing the way in which people engaged with, traversed and experienced their surroundings.

From harmonisation to better, smart and fit food law

As the European Union (EU) approaches its 60th anniversary, it is worth assessing progress towards a key objective – the abolition of barriers to the marketing of food in the EU. Food has always created particular problems for the EU as national differences in diets, culture and geography make standardisation impossible. Early attempts focussed on direct measures to harmonise requirements or, later, to create an ‘internal market’. Subsequently a changed emphasis brought about the need to focus more clearly on the harmonisation of food safety. More widely, the recent recognition that too much legislation can itself create barriers has led legislators to attempt to consider more carefully the impact of their efforts. This paper reflects on the various stages in the creation of harmonised food controls and considers how case law has impacted the process. Today there are still differences and complete barrier-free trade seems some way off.

The structural effect of Methyl substitution on the binding of Polypyridyl Ru-dppz Complexes to DNA

ABSTRACT: Polypyridyl ruthenium complexes have been intensively studied and possess photophysical properties which are both interesting and useful. They can act as probes for DNA, with a substantial enhancement in emission when bound, and can induce DNA damage upon photoirradiation and therefore, the synthesis and characterization of DNA binding of new complexes is an area of intense research activity. Whilst knowledge of how the binding of derivatives compares to the parent compound is highly desirable, this information can be difficult to obtain. Here we report the synthesis of three new methylated complexes, [Ru(TAP)2(dppz-10-Me).2Cl, [Ru(TAP)2(dppz-10,12-Me2)].2Cl and [Ru(TAP)2(dppz-11-Me)].2Cl, and examine the consequences for DNA binding through the use of atomic resolution X-ray crystallography. We find that the methyl groups are located in discrete positions with a complete directional preference. This may help to explain the quenching behavior which is found in solution for analogous [Ru(phen)2(dppz)]2+ derivatives.

Uptake of agri-environmental schemes in the Less-Favoured Areas of Greece: The role of corruption and farmers' responses to the financial crisis

Vine-growing in the Less-Favoured Areas of Greece is facing multiple challenges that might lead to its abandonment. In an attempt to maintain rural populations, Rural Development Schemes have been created that offer the opportunity to rural households to maintain or expand their farming businesses including vine-growing. This paper stems from a study that used data from a cross-sectional survey of 204 farmers to investigate how farming systems and farmers’ perception of corruption, amongst other socio-economic factors, affected their decisions to continue vine-growing through participation in Rural Development Schemes, in three remote Less-Favoured Areas of Greece. The Theory of Planned Behaviour was used to frame the research problem with the assumption being that an individual’s intention to participate in a Scheme is based on their prior beliefs about it. Data from the survey were reduced and simplified by the use of non-linear principal component analysis. The ensuing variables were used in selectivity corrected ordered probit models to reveal farmers’ attitudes towards viticulture and rural development. It was found that economic factors, perceived corruption and farmers’ attitudes were significant determinants on whether to participate in the Schemes. The research findings highlight the important role of perceived corruption and the need for policies that facilitate farmers’ access to decision making centres.

On the threshold of adulthood: a new approach for the use of maturation indicators to assess puberty in adolescents from medieval England

Objectives: This study provides the first large scale analysis of the age at which adolescents in medieval England entered and completed the pubertal growth spurt. This new method has implications for expanding our knowledge of adolescent maturation across different time periods and regions. Methods: In total, 994 adolescent skeletons (10-25 years) from four urban sites in medieval England (AD 900-1550) were analysed for evidence of pubertal stage using new osteological techniques developed from the clinical literature (i.e. hamate hook development, CVM, canine mineralisation, iliac crest ossification, radial fusion). Results: Adolescents began puberty at a similar age to modern children at around 10-12 years, but the onset of menarche in girls was delayed by up to 3 years, occurring around 15 for most in the study sample and 17 years for females living in London. Modern European males usually complete their maturation by 16-18 years; medieval males took longer with the deceleration stage of the growth spurt extending as late as 21 years. Conclusions: This research provides the first attempt to directly assess the age of pubertal development in adolescents during the tenth to seventeenth centuries. Poor diet, infections, and physical exertion may have contributed to delayed development in the medieval adolescents, particularly for those living in the city of London. This study sheds new light on the nature of adolescence in the medieval period, highlighting an extended period of physical and social transition.

Targeted activation of toll-like receptors: conjugation of a toll-like receptor 7 agonist to a monoclonal antibody maintains antigen binding and specificity

Therapeutic activation of Toll-like receptors (TLR) has potential for cancer immunotherapy, for augmenting the activity of anti-tumor monoclonal antibodies (mAbs), and for improved vaccine adjuvants. A previous attempt to specifically target TLR agonists to dendritic cells (DC) using mAbs failed because conjugation led to non-specific binding and mAbs lost specificity. We demonstrate here for the first time the successful conjugation of a small molecule TLR7 agonist to an anti-tumour mAb (the anti-hCD 20 rituximab) without compromising antigen specificity. The TLR7 agonist UC-1V150 was conjugated to rituximab using two conjugation methods and yield, molecular substitution ratio, retention of TLR7 activity and specificity of antigen binding were compared. Both conjugation methods produced rituximab-UC-1V150 conjugates with UC-1V150 : rituximab ratio ranging from 1:1 to 3:1 with drug loading quantified by UV spectroscopy and drug substitution ratio verified by MALDI TOF mass spectroscopy. The yield of purified conjugates varied with conjugation method, and dropped as low as 31% using a method previously described for conjugating UC-1V150 to proteins, where a bifunctional crosslinker was firstly reacted with rituximab, and secondly to the TLR7 agonist. We therefore developed a direct conjugation method by producing an amine-reactive UV active version of UC-1V150, termed NHS:UC-1V150. Direct conjugation with NHS:UC-1V150 was quick and simple and gave improved conjugate yields of 65-78%. Rituximab-UC-1V150 conjugates had the expected pro-inflammatory activity in vitro (EC50 28-53 nM) with a significantly increased activity over unconjugated UC-1V150 (EC50 547 nM). Antigen binding and specificity of the rituxuimab-UC-1V150 conjugates was retained, and after incubation with human peripheral blood leukocytes, all conjugates bound strongly only to CD20-expressing B cells whilst no non-specific binding to CD20-negative cells was observed. Selective targeting of Toll-like receptor activation directly within tumors or to DC is now feasible.

Predicting how many animals will be where: how to build, calibrate and evaluate individual-based models

Individual-based models (IBMs) can simulate the actions of individual animals as they interact with one another and the landscape in which they live. When used in spatially-explicit landscapes IBMs can show how populations change over time in response to management actions. For instance, IBMs are being used to design strategies of conservation and of the exploitation of fisheries, and for assessing the effects on populations of major construction projects and of novel agricultural chemicals. In such real world contexts, it becomes especially important to build IBMs in a principled fashion, and to approach calibration and evaluation systematically. We argue that insights from physiological and behavioural ecology offer a recipe for building realistic models, and that Approximate Bayesian Computation (ABC) is a promising technique for the calibration and evaluation of IBMs. IBMs are constructed primarily from knowledge about individuals. In ecological applications the relevant knowledge is found in physiological and behavioural ecology, and we approach these from an evolutionary perspective by taking into account how physiological and behavioural processes contribute to life histories, and how those life histories evolve. Evolutionary life history theory shows that, other things being equal, organisms should grow to sexual maturity as fast as possible, and then reproduce as fast as possible, while minimising per capita death rate. Physiological and behavioural ecology are largely built on these principles together with the laws of conservation of matter and energy. To complete construction of an IBM information is also needed on the effects of competitors, conspecifics and food scarcity; the maximum rates of ingestion, growth and reproduction, and life-history parameters. Using this knowledge about physiological and behavioural processes provides a principled way to build IBMs, but model parameters vary between species and are often difficult to measure. A common solution is to manually compare model outputs with observations from real landscapes and so to obtain parameters which produce acceptable fits of model to data. However, this procedure can be convoluted and lead to over-calibrated and thus inflexible models. Many formal statistical techniques are unsuitable for use with IBMs, but we argue that ABC offers a potential way forward. It can be used to calibrate and compare complex stochastic models and to assess the uncertainty in their predictions. We describe methods used to implement ABC in an accessible way and illustrate them with examples and discussion of recent studies. Although much progress has been made, theoretical issues remain, and some of these are outlined and discussed.

Exploring methods to evaluate the carbon impact of network investment deferral

Replacement, expansion and upgrading of assets in the electricity network represents financial investment for the distribution utilities. Network Investment Deferral (NID) is a well discussed benefit of wider adoption of Distributed Generation (DG). There have been many attempts to quantify and evaluate the financial benefit for the distribution utilities. While the carbon benefits of NID are commonly mentioned, there is little attempt to quantify these impacts. This paper explores the quantitative methods previously used to evaluate financial benefits in order to discuss the carbon impacts. These carbon impacts are important for companies owning DG equipment for internal reporting and emissions reductions ambitions. Currently, a GB wide approach is taken as a means for discussing more regional and local methods to be used in future work. By investigating these principles, the paper offers a novel approach to quantifying carbon emissions from various DG technologies.