Top single nucleotide polymorphisms affecting carbohydrate metabolism in Metabolic Syndrome: from the LIPGENE study

Rationale:Metabolic Syndrome (MetS) is a high prevalence condition characterized by altered energy metabolism, insulin resistance and elevated cardiovascular risk.Objectives:Although many individual single nucleotide polymorphisms (SNPs) have been linked to certain MetS features, there are few studies analyzing the influence of SNPs on carbohydrate metabolism in MetS.Methods:904 SNPs (tag SNPs and functional SNPs) were tested for influence in eight fasting and dynamic markers of carbohydrate metabolism, performing an intravenous glucose tolerance test in 450 participants of the LIPGENE study.Findings:From 382 initial gene-phenotype associations between SNPs and any phenotypic variables, 61 (a 16 % of the pre-selected) remained significant after Bootstrapping. Top SNPs affecting glucose metabolism variables were as follows: fasting glucose: rs26125 (PPARGC1B); fasting insulin: rs4759277 (LRP1); C peptide: rs4759277 (LRP1); HOMA-IR: rs4759277 (LRP1); QUICKI: rs184003 (AGER); SI: rs7301876 (ABCC9), AIRg: rs290481 (TCF7L2) and DI: rs12691 (CEBPA).Conclusions:We describe here the top SNPs linked to phenotypic features in carbohydrate metabolism among aproximately 1000 candidate gene variations in fasting and postprandial samples of 450 patients with MetS from the LIPGENE study.

The water quality of the River Enborne, UK: observations from high-frequency Monitoring in a rural, lowland river system

This paper reports the results of a 2-year study of water quality in the River Enborne, a rural river in lowland England. Concentrations of nitrogen and phosphorus species and other chemical determinands were monitored both at high-frequency (hourly), using automated in situ instrumentation, and by manual weekly sampling and laboratory analysis. The catchment land use is largely agricultural, with a population density of 123 persons km−2. The river water is largely derived from calcareous groundwater, and there are high nitrogen and phosphorus concentrations. Agricultural fertiliser is the dominant source of annual loads of both nitrogen and phosphorus. However, the data show that sewage effluent discharges have a disproportionate effect on the river nitrogen and phosphorus dynamics. At least 38% of the catchment population use septic tank systems, but the effects are hard to quantify as only 6% are officially registered, and the characteristics of the others are unknown. Only 4% of the phosphorus input and 9% of the nitrogen input is exported from the catchment by the river, highlighting the importance of catchment process understanding in predicting nutrient concentrations. High-frequency monitoring will be a key to developing this vital process understanding.

Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features

The recent identification of multiple dominant mutations in the gene encoding β-catenin in both humans and mice has enabled exploration of the molecular and cellular basis of β-catenin function in cognitive impairment. In humans, β-catenin mutations that cause a spectrum of neurodevelopmental disorders have been identified. We identified de novo β-catenin mutations in patients with intellectual disability, carefully characterized their phenotypes, and were able to define a recognizable intellectual disability syndrome. In parallel, characterization of a chemically mutagenized mouse line that displays features similar to those of human patients with β-catenin mutations enabled us to investigate the consequences of β-catenin dysfunction through development and into adulthood. The mouse mutant, designated batface (Bfc), carries a Thr653Lys substitution in the C-terminal armadillo repeat of β-catenin and displayed a reduced affinity for membrane-associated cadherins. In association with this decreased cadherin interaction, we found that the mutation results in decreased intrahemispheric connections, with deficits in dendritic branching, long-term potentiation, and cognitive function. Our study provides in vivo evidence that dominant mutations in β-catenin underlie losses in its adhesion-related functions, which leads to severe consequences, including intellectual disability, childhood hypotonia, progressive spasticity of lower limbs, and abnormal craniofacial features in adults

Distraction control processes in free recall: benefits and costs to performance

How is semantic memory influenced by individual differences under conditions of distraction? This question was addressed by observing how visual target words—drawn from a single category—were recalled whilst ignoring spoken distracter words that were either members of the same, or members of a different (single) category. Working memory capacity (WMC) was related to disruption only with synchronous, not asynchronous, presentation and distraction was greater when the words were presented synchronously. Subsequent experiments found greater negative priming of distracters amongst individuals with higher WMC but this may be dependent on targets and distracters being comparable category exemplars. With less dominant category members as distracters, target recall was impaired – relative to control – only amongst individuals with low WMC. The results highlight the role of cognitive control resources in target-distracter selection and the individual-specific cost implications of such cognitive control.

Alterations in predicted regulatory and coding regions of the sterol 14α-demethylase gene (CYP51) confer decreased azole sensitivity in the oilseed rape pathogen Pyrenopeziza brassicae

The incidence and severity of light leaf spot epidemics caused by the ascomycete fungus Pyrenopeziza brassicae on UK oilseed rape crops is increasing. The disease is currently controlled by a combination of host resistance, cultural practices and fungicide applications. We report decreases in sensitivities of modern UK P. brassicae isolates to the azole (imidazole and triazole) class of fungicides. By cloning and sequencing the P. brassicae CYP51 (PbCYP51) gene, encoding the azole target sterol 14α-demethylase, we identified two non-synonymous mutations encoding substitutions G460S and S508T associated with reduced azole sensitivity. We confirmed the impact of the encoded PbCYP51 changes on azole sensitivity and protein activity by heterologous expression in a Saccharomyces cerevisiae mutant YUG37::erg11 carrying a controllable promoter of native CYP51 expression. In addition, we identified insertions in the predicted regulatory regions of PbCYP51 in isolates with reduced azole sensitivity. The presence of these insertions was associated with enhanced transcription of PbCYP51 in response to sub-inhibitory concentrations of the azole fungicide tebuconazole. Genetic analysis of in vitro crosses of sensitive and resistant isolates confirmed the impact of PbCYP51 alterations in coding and regulatory sequences on a reduced sensitivity phenotype, as well as identifying a second major gene at another locus contributing to resistance in some isolates. The least sensitive field isolates carry combinations of upstream insertions and non-synonymous mutations, suggesting PbCYP51 evolution is on-going and the progressive decline in azole sensitivity of UK P. brassicae populations will continue. The implications for the future control of light leaf spot are discussed.

Development and validation of a parent report measure for detection of cognitive delay in infancy

Aim To develop a brief, parent-completed instrument (‘ERIC’) for detection of cognitive delay in 10-24 month-olds born preterm, or with low birth weight, or with perinatal complications, and to establish its diagnostic properties. Method Scores were collected from parents of 317 children meeting ≥1 inclusion criteria (birth weight <1500g; gestational age <34 completed weeks; 5-minute Apgar <7; presence of hypoxic-ischemic encephalopathy) and meeting no exclusion criteria. Children were assessed for cognitive delay using a criterion score on the Bayley Scales of Infant and Toddler Development Cognitive Scale III1 <80. Items were retained according to their individual associations with delay. Sensitivity, specificity, Positive and Negative Predictive Values were estimated and a truncated ERIC was developed for use <14 months. Results ERIC detected 17 out of 18 delayed children in the sample, with 94.4% sensitivity (95% CI [confidence interval] 83.9-100%), 76.9% specificity (72.1-81.7%), 19.8% positive predictive value (11.4-28.2%); 99.6% negative predictive value (98.7-100%); 4.09 likelihood ratio positive; and 0.07 likelihood ratio negative; the associated Area under the Curve was .909 (.829-.960). Interpretation ERIC has potential value as a quickly-administered diagnostic instrument for the absence of early cognitive delay in preterm or premature infants of 10-24 months, and as a screen for cognitive delay. Further research may be needed before ERIC can be recommended for wide-scale use.

Intensive approaches for childhood fears

This chapter reports on the implementation of a brief psychological intervention for the treatment of fears in childhood.

Adding value to the urban lawnscape: insect abundance and diversity in grass-free lawns

Insect diversity may be declining even more rapidly than in plants and vertebrates, particularly in areas where indigenous habitats are replaced by an anthropogenic one. The most common component of anthropogenic greenspace is the ornamental lawn. Intensively managed and offering limited habitat opportunities for both plants and insects, lawns are biodiversity poor and ecologically insensitive. An alternative lawn format that positively influences biodiversity and reduces management requirements would be a useful tool in eco-friendly urban greenspace management. In investigating the potential for a forb-only alternative to the grass lawn we sampled both trial grass-free lawn formats and turf lawns to identify any influence that lawn composition and grass-free lawn specific mowing regimes might have on the abundance and diversity of insect families. In addition to the mowing regimes, both the composition and origin of lawn flora were found to significantly influence insect abundance and diversity and these factors rarely interacted. Native-only and mixed origin grass-free lawns hosted greater numbers of adult insects than found in turf and an equivalent diversity of insect families, however the mowing regime applied was distinct from traditional turf lawn management by being substantially less intensive and our results suggest that there is the potential for even greater abundance and diversity via the grass-free format that may offer additional resources to insectivorous garden species such as birds. When the composition of grass-free lawns included native forbs the diversity of insect families was found be sufficiently different from turf lawns to form distinct assemblages and in so doing contribute to beta diversity within urban greenspace. In sum, grass-free lawns may be a useful and aesthetically appropriate tool for adding value to the generally biodiversity poor urban lawnscape.

Impact of the enhanced permeability and retention (EPR) effect and cathepsins levels on the activity of polymer-drug conjugates

Polymer-drug conjugates have demonstrated clinical potential in the context of anticancer therapy. However, such promising results have, to date, failed to translate into a marketed product. Polymer-drug conjugates rely on two factors for activity: (i) the presence of a defective vasculature, for passive accumulation of this technology into the tumour tissue (enhanced permeability and retention (EPR) effect) and (ii) the presence of a specific trigger at the tumour site, for selective drug release (e.g., the enzyme cathepsin B). Here, we retrospectively analyse literature data to investigate which tumour types have proved more responsive to polymer-drug conjugates and to determine correlations between the magnitude of the EPR effect and/or expression of cathepsin B. Lung, breast and ovarian cancers showed the highest response rate (30%, 47% and 41%, respectively for cathepsin-activated conjugates and 31%, 43%, 40%, across all conjugates). An analysis of literature data on cathepsin content in various tumour types showed that these tumour types had high cathepsin content (up to 3835 ng/mg for lung cancer), although marked heterogeneity was observed across different studies. In addition, these tumour types were also reported as having a high EPR effect. Our results suggest that a pre-screening of patient population could bring a more marked clinical benefit.

Potential influences on the United Kingdom's floods of winter 2013/14

During the winter of 2013/14, much of the UK experienced repeated intense rainfall events and flooding. This had a considerable impact on property and transport infrastructure. A key question is whether the burning of fossil fuels is changing the frequency of extremes, and if so to what extent. We assess the scale of the winter flooding before reviewing a broad range of Earth system drivers affecting UK rainfall. Some drivers can be potentially disregarded for these specific storms whereas others are likely to have increased their risk of occurrence. We discuss the requirements of hydrological models to transform rainfall into river flows and flooding. To determine any general changing flood risk, we argue that accurate modelling needs to capture evolving understanding of UK rainfall interactions with a broad set of factors. This includes changes to multiscale atmospheric, oceanic, solar and sea-ice features, and land-use and demographics. Ensembles of such model simulations may be needed to build probability distributions of extremes for both pre-industrial and contemporary concentration levels of atmospheric greenhouse gases.

Secondary school teachers' perspectives on teaching about topics that bridge science and religion

The question of where to locate teaching about the relationships between science and religion has produced a long-running debate. Currently, Science and Religious Education (RE) are statutory subjects in England and are taught in secondary schools by different teachers. This paper reports on an interview study in which 16 teachers gave their perceptions of their roles and responsibilities when teaching topics that bridge science and religion and the extent to which they collaborated with teachers in the other subject area. We found that in this sample, teachers reported very little collaboration between the curriculum areas. Although the science curriculum makes no mention of religion, all the science teachers said that their approaches to such topics were affected by their recognition that some pupils hold religious beliefs. All the RE teachers reported struggling to ensure students know of a range of views about how science and religion relate. The paper concludes with a discussion about implications for curriculum design and teacher training.

Mixed layer lateral eddy fluxes mediated by air-sea interaction

The modulation of air–sea heat fluxes by geostrophic eddies due to the stirring of temperature at the sea surface is discussed and quantified. It is argued that the damping of eddy temperature variance by such air–sea fluxes enhances the dissipation of surface temperature fields. Depending on the time scale of damping relative to that of the eddying motions, surface eddy diffusivities can be significantly enhanced over interior values. The issues are explored and quantified in a controlled setting by driving a tracer field, a proxy for sea surface temperature, with surface altimetric observations in the Antarctic Circumpolar Current (ACC) of the Southern Ocean. A new, tracer-based diagnostic of eddy diffusivity is introduced, which is related to the Nakamura effective diffusivity. Using this, the mixed layer lateral eddy diffusivities associated with (i) eddy stirring and small-scale mixing and (ii) surface damping by air–sea interaction is quantified. In the ACC, a diffusivity associated with surface damping of a comparable magnitude to that associated with eddy stirring (;500 m2 s21) is found. In frontal regions prevalent in the ACC, an augmentation of surface lateral eddy diffusivities of this magnitude is equivalent to an air–sea flux of 100 W m22 acting over a mixed layer depth of 100 m, a very significant effect. Finally, the implications for other tracer fields such as salinity, dissolved gases, and chlorophyll are discussed. Different tracers are found to have surface eddy diffusivities that differ significantly in magnitude.

Genetical and comparative genomics of Brassica under altered Ca supply identifies Arabidopsis Ca-transporter orthologs

Although Ca transport in plants is highly complex, the overexpression of vacuolar Ca2+ transporters in crops is a promising new technology to improve dietary Ca supplies through biofortification. Here, we sought to identify novel targets for increasing plant Ca accumulation using genetical and comparative genomics. Expression quantitative trait locus (eQTL) mapping to 1895 cis- and 8015 trans-loci were identified in shoots of an inbred mapping population of Brassica rapa (IMB211 × R500); 23 cis- and 948 trans-eQTLs responded specifically to altered Ca supply. eQTLs were screened for functional significance using a large database of shoot Ca concentration phenotypes of Arabidopsis thaliana. From 31 Arabidopsis gene identifiers tagged to robust shoot Ca concentration phenotypes, 21 mapped to 27 B. rapa eQTLs, including orthologs of the Ca2+ transporters At-CAX1 and At-ACA8. Two of three independent missense mutants of BraA.cax1a, isolated previously by targeting induced local lesions in genomes, have allele-specific shoot Ca concentration phenotypes compared with their segregating wild types. BraA.CAX1a is a promising target for altering the Ca composition of Brassica, consistent with prior knowledge from Arabidopsis. We conclude that multiple-environment eQTL analysis of complex crop genomes combined with comparative genomics is a powerful technique for novel gene identification/prioritization.