Absence of association between the INSIG2 gene polymorphism (rs7566605) and obesity in the European Youth Heart Study (EYHS)

The first genome-wide association study for BMI identified a polymorphism, rs7566605, 10 kb upstream of the insulin-induced gene 2 (INSIG2) transcription start site, as the most significantly associated variant in children and adults. Subsequent studies, however, showed inconsistent association of this polymorphism with obesity traits. This polymorphism has been hypothesized to alter INSIG2 expression leading to inhibition of fatty acid and cholesterol synthesis. Hence, we investigated the association of the INSIG2 rs7566605 polymorphism with obesity- and lipid-related traits in Danish and Estonian children (930 boys and 1,073 girls) from the European Youth Heart Study (EYHS), a school-based, cross-sectional study of pre- and early pubertal children. The association between the polymorphism and obesity traits was tested using additive and recessive models adjusted for age, age-group, gender, maturity and country. Interactions were tested by including the interaction terms in the model. Despite having sufficient power (98%) to detect the previously reported effect size for association with BMI, we did not find significant effects of rs7566605 on BMI (additive, P = 0.68; recessive, P = 0.24). Accordingly, the polymorphism was not associated with overweight (P = 0.87) or obesity (P = 0.34). We also did not find association with waist circumference (WC), sum of four skinfolds, or with total cholesterol, triglycerides, low-density lipoprotein, or high-density lipoprotein. There were no gender-specific (P = 0.55), age-group-specific (P = 0.63) or country-specific (P = 0.56) effects. There was also no evidence of interaction between genotype and physical activity (P = 0.95). Despite an adequately powered study, our findings suggest that rs7566605 is not associated with obesity-related traits and lipids in the EYHS.

Structurally-related (−)-epicatechin metabolites in humans: assessment using de novo chemically synthesized authentic standards

Accumulating data suggest that diets rich in flavanols and procyanidins are beneficial for human health. In this context, there has been a great interest in elucidating the systemic levels and metabolic profiles at which these compounds occur in humans. While recent progress has been made, there still exist considerable differences and various disagreements with regard to the mammalian metabolites of these compounds, which in turn is largely a consequence of the lack of availability of authentic standards that would allow for the directed development and validation of expedient analytical methodologies. In the present study, we developed a method for the analysis of structurally-related flavanol metabolites using a wide range of authentic standards. Applying this method in the context of a human dietary intervention study using comprehensively characterized and standardized flavanol- and procyanidin-containing cocoa, we were able to identify the structurally-related (−)-epicatechin metabolites (SREM) postprandially extant in the systemic circulation of humans. Our results demonstrate that (−)-epicatechin-3′-β-D-glucuronide, (−)-epicatechin-3′-sulfate, and a 3′-O-methyl(−)-epicatechin-5/7-sulfate are the predominant SREM in humans, and further confirm the relevance of the stereochemical configuration in the context of flavanol metabolism. In addition, we also identified plausible causes for the previously reported discrepancies regarding flavanol metabolism, consisting to a significant extent of inter-laboratory differences in sample preparation (enzymatic treatment and sample conditioning for HPLC analysis) and detection systems. Thus, these findings may also aid in the establishment of consensus on this topic.

Sensitivity of radar backscatter to desert surface roughness

Synthetic aperture radar (SAR) data have proved useful in remote sensing studies of deserts, enabling different surfaces to be discriminated by differences in roughness properties. Roughness is characterized in SAR backscatter models using the standard deviation of surface heights (sigma), correlation length (L) and autocorrelation function (rho(xi)). Previous research has suggested that these parameters are of limited use for characterizing surface roughness, and are often unreliable due to the collection of too few roughness profiles, or under-sampling in terms of resolution or profile length (L-p). This paper reports on work aimed at establishing the effects of L-p and sampling resolution on SAR backscatter estimations and site discrimination. Results indicate significant relationships between the average roughness parameters and L-p, but large variability in roughness parameters prevents any clear understanding of these relationships. Integral equation model simulations demonstrate limited change with L-p and under-estimate backscatter relative to SAR observations. However, modelled and observed backscatter conform in pattern and magnitude for C-band systems but not for L-band data. Variation in surface roughness alone does not explain variability in site discrimination. Other factors (possibly sub-surface scattering) appear to play a significant role in controlling backscatter characteristics at lower frequencies.

Intrinsic disorder prediction from the analysis of multiple protein fold recognition models

Motivation: Intrinsic protein disorder is functionally implicated in numerous biological roles and is, therefore, ubiquitous in proteins from all three kingdoms of life. Determining the disordered regions in proteins presents a challenge for experimental methods and so recently there has been much focus on the development of improved predictive methods. In this article, a novel technique for disorder prediction, called DISOclust, is described, which is based on the analysis of multiple protein fold recognition models. The DISOclust method is rigorously benchmarked against the top.ve methods from the CASP7 experiment. In addition, the optimal consensus of the tested methods is determined and the added value from each method is quantified. Results: The DISOclust method is shown to add the most value to a simple consensus of methods, even in the absence of target sequence homology to known structures. A simple consensus of methods that includes DISOclust can significantly outperform all of the previous individual methods tested.

The impact of multiskilling on UK construction manpower

The overall significance of the construction and building services sector internationally cannot be overemphasised. In the UK, the industry currently accounts for 10% gross domestic product (GDP) and employs 2 million people, which is more than 1 in 14 of the total workforce. However, regardless of its output (approximately £65 billion annually) there has been a steady decline in the number of trade entrants into the construction and building services sector. Consequently, the available ‘pool of labour’ is inadequately resourced; productivity is low; the existing labour force is overstressed; there is an increase in site deaths; and a long-term labour shortage is envisaged. Today, the evidence seems to suggest that multiskilling is a tentative redress for ameliorating the skills crisis in the construction and building sectors. A 43-year time-series of data on 23 manpower attributes was evaluated as part of this investigation. The developed linear regression models show that the concept of multiskilling obeys the ‘law of diminishing returns'. That is, a weak relation was found between construction output and a three or more combination of manpower attributes. An optimisation model is prescribed for traditional trades.

Conformational studies of mixed-ligand copper(II) chelates. Crystal and molecular structure of (N,N-dimethyl-N′-ethyl-1,2-diaminoethane-(1-phenyl-1,3,-butanedionato)copper(II) perchlorate

The IR and ligand field spectra and the structure of the mixed-ligand compound [N,N-dimethyl-N′-ethyl-1,2-diaminoethane(1-phenyl-1,3-butanedionato)(perchlorato)copper(II)]), [Cu(dmeen)bzac(OClO3)], are reported. The structure was determined by single crystal X-ray diffraction analysis (triclinic, space group ). The structure is square pyramidal with the apical position occupied by one oxygen of the tetrahedral perchlorato group (distance from copper 2.452(5) Å). The plane of the phenyl ring is tilted forming an angle of 16.72(14)° with the plane of the β-dionato moiety. The nitrogenous base adopts the gauche conformation with torsional angle of 108.72(14)°. The ethyl group is cis oriented relative to the phenyl group, occupying the equatorial position with the vector of the carbon-nitrogen bond forming an angle of 143.9(3)° with the CuNN plane. The interactions of the adjacent axial hydrogen with an oxygen of the perchlorato group result in hydrogen bond formation. The IR spectra reveal that in the solid state the Br− or Cl− displace easily the ClO4− group. The shifts in the ligand field spectra indicate that polar solvents participate in donor-acceptor interactions with the metal centre along an axis perpendicular to the CuN2O2 plane.

Inside the black box: unravelling the development viability appraisal process

Over the last decade issues related to the financial viability of development have become increasingly important to the English planning system. As part of a wider shift towards the compartmentalisation of planning tasks, expert consultants are required to quantify, in an attempt to rationalise, planning decisions in terms of economic ‘viability’. Often with a particular focus on planning obligations, the results of development viability modelling have emerged as a key part of the evidence base used in site-specific negotiations and in planning policy formation. Focussing on the role of clients and other stakeholders, this paper investigates how development viability is tested in practice. It draws together literature on the role of calculative practices in policy formation, client feedback and influence in real estate appraisals and stakeholder engagement and consultation in the planning literature to critically evaluate the role of clients and other interest groups in influencing the production and use of development viability appraisal models. The paper draws upon semi-structured interviews with the main producers of development viability appraisals to conclude that, whilst appraisals have the potential to be biased by client and stakeholder interests, there are important controlling influences on potential opportunistic behaviour. One such control is local authorities’ weak understanding of development viability appraisal techniques which limits their capacity to question the outputs of appraisal models. However, this also is of concern given that viability is now a central feature of the town planning system.

Estrogens and thyroid hormone: Non-genomic effects are coupled to transcription.

Estrogens and thyroid hormones are regulators of important diverse physiological processes such as reproduction, thermogenesis, neural development, neural differentiation and cardiovascular functions. Both are ligands for receptors in the nuclear receptor superfamily, which act as ligand-dependent transcription factors, regulating transcription. However, estrogens and thyroid hormones also rapidly (within minutes or seconds) activate kinase cascades and calcium increases, presumably initiated at the cell membrane. We discuss the relevance of both modes of hormone action, including the membrane estrogen receptor, to physiology, with particular reference to lordosis behavior. We first showed that estrogen restricted to the membrane can, in fact, lead to subsequent increases in transcription from a consensus estrogen response element-based reporter in the neuroblastoma cell line, SK-N-BE(2)C. Using a novel hormonal paradigm, we also showed that the activation of protein kinase A, protein kinase C, mitogen activated protein kinase and increases in calcium were important in the ability of the membrane-limited estrogen to potentiate transcription. We discuss the source of calcium important in transcriptional potentiation. Since estrogens and thyroid hormones have common effects on neuroprotection, cognition and mood, we also hypothesized that crosstalk could occur between the rapid actions of thyroid hormones and the genomic actions of estrogens. In neural cells, we showed that triiodothyronine acting rapidly via MAPK can increase transcription by the nuclear estrogen receptor ERa from a consensus estrogen response element, possibly by the phosphorylation of the ERa. Novel mechanisms that link signals initiated by hormones from the membrane to the nucleus are physiologically relevant and can achieve neuroendocrine integration

Kazakhstan: long-term economic growth and the role of the oil sector

This study combines a narrative and modelling framework to analyse the development of Kazakhstan’s oil sector since its takeoff following separation from the USSR. As in the case of other emerging or transitional countries with large natural resource endowments, a key question is whether the exploitation of the natural resource is a benefit to longer term economic development: is it a curse, a blessing – or neither? Narrative evidence suggests that the establishment of good governance, in terms of institutions and policies, provides a background to sound long-term development, especially if combined with the development of sectors outside the natural resource sector, for example diversification into manufacturing and services, often through attracting FDI. The narrative is supported by econometric modelling of the relationship between domestic output, overseas output and exports of oil, which finds in favour of a sustained positive effect of oil exports on GDP. The model then provides a basis for projection of the growth in GDP given a consensus view of likely developments in the oil price.

Plant remains as evidence for seasonality of site use in the Mesolithic period

Attempts to identify the seasons during which Mesolithic sites may have been occupied have usually concentrated on evidence from faunal assemblages, while the potential of plant remains has been largely neglected. In this paper the use of plant remains as indicators of seasonality is discussed, especially where they represent the accidental charring of species unlikely to have been deliberately collected and stored. This is illustrated with reference to the early Mesolithic site of Star Carr, North Yorkshire, and discussed in the context of other Mesolithic sites from which assemblages of charred plant remains have been recovered.

Quantifying uncertainty in critical loads: (B) acidity mass balance critical loads on a sensitive site

This paper reports an uncertainty analysis of critical loads for acid deposition for a site in southern England, using the Steady State Mass Balance Model. The uncertainty bounds, distribution type and correlation structure for each of the 18 input parameters was considered explicitly, and overall uncertainty estimated by Monte Carlo methods. Estimates of deposition uncertainty were made from measured data and an atmospheric dispersion model, and hence the uncertainty in exceedance could also be calculated. The uncertainties of the calculated critical loads were generally much lower than those of the input parameters due to a "compensation of errors" mechanism - coefficients of variation ranged from 13% for CLmaxN to 37% for CL(A). With 1990 deposition, the probability that the critical load was exceeded was > 0.99; to reduce this probability to 0.50, a 63% reduction in deposition is required; to 0.05, an 82% reduction. With 1997 deposition, which was lower than that in 1990, exceedance probabilities declined and uncertainties in exceedance narrowed as deposition uncertainty had less effect. The parameters contributing most to the uncertainty in critical loads were weathering rates, base cation uptake rates, and choice of critical chemical value, indicating possible research priorities. However, the different critical load parameters were to some extent sensitive to different input parameters. The application of such probabilistic results to environmental regulation is discussed.