Lactate signalling regulates fungal β-glucan masking and immune evasion

AJPB: This work was supported by the European Research Council (STRIFE, ERC- 2009-AdG-249793), The UK Medical Research Council (MR/M026663/1), the UK Biotechnology and Biological Research Council (BB/K017365/1), the Wellcome Trust (080088; 097377). ERB: This work was supported by the UK Biotechnology and Biological Research Council (BB/M014525/1). GMA: Supported by the CNPq-Brazil (Science without Borders fellowship 202976/2014-9). GDB: Wellcome Trust (102705). CAM: This work was supported by the UK Medical Research Council (G0400284). DMM: This work was supported by UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/K000306/1). NARG/JW: Wellcome Trust (086827, 075470,101873) and Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology (097377). ALL: This work was supported by the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1).Peer reviewedPostprin

Genetic Analysis of Central Carbon Metabolism Unveils an Amino Acid Substitution That Alters Maize NAD-Dependent Isocitrate Dehydrogenase Activity

Background: Central carbon metabolism (CCM) is a fundamental component of life. The participating genes and enzymes are thought to be structurally and functionally conserved across and within species. Association mapping utilizes a rich history of mutation and recombination to achieve high resolution mapping. Therefore, applying association mapping in maize (Zea mays ssp. mays), the most diverse model crop species, to study the genetics of CCM is a particularly attractive system. Methodology/Principal Findings: We used a maize diversity panel to test the CCM functional conservation. We found heritable variation in enzyme activity for every enzyme tested. One of these enzymes was the NAD-dependent isocitrate dehydrogenase (IDH, E.C. 1.1.1.41), in which we identified a novel amino-acid substitution in a phylogenetically conserved site. Using candidate gene association mapping, we identified that this non-synonymous polymorphism was associated with IDH activity variation. The proposed mechanism for the IDH activity variation includes additional components regulating protein level. With the comparison of sequences from maize and teosinte (Zea mays ssp. Parviglumis), the maize wild ancestor, we found that some CCM genes had also been targeted for selection during maize domestication. Conclusions/Significance: Our results demonstrate the efficacy of association mapping for dissecting natural variation in primary metabolic pathways. The considerable genetic diversity observed in maize CCM genes underlies heritable phenotypic variation in enzyme activities and can be useful to identify putative functional sites

Complex aetiology of an apparently Mendelian form of Mental Retardation

<p>Abstract</p> <p>Background</p> <p>Mental Retardation is a common heterogeneous neurodevelopment condition, which causes are still largely elusive. It has been suggested that half of the phenotypic variation of intelligence is explained by genetic variation. And genetic or inherited factors indeed account for most of the cases of mental retardation with an identifiable cause. However, only a few autosomal genes have been mapped and identified to date. In this report, the genetic causes for an apparently recessive form of mental retardation, in a large nordern swedish pedigree, are investigated.</p> <p>Methods</p> <p>After extensive evaluation of the patients, which ruled out recognizable patterns of malformation and excluded known causes of MR, a comprehensive genome-wide linkage analysis, with 500 microsatellite markers, was performed in 24 members of this family. Additionally, a genome-wide copy number analysis, using an affimetrix 250 K SNP chip, was performed in this pedigree.</p> <p>Results</p> <p>No significant LOD score was found with either parametric and non-parametric linkage analysis. The highest scores are located at chromosomes 13, 15 and 17. Genome-wide copy number analysis identified no clear cause for the disorder; but rather, several variants were present in the family members, irrespective of their affected status.</p> <p>Conclusion</p> <p>These results suggest that mental retardation in this family, unlikely what was expected, has a heterogeneous aetiology; and that several lower effect genes variants might be involved. To demonstrate such effects, our family may be too small. This study also indicates that the ascertainment of the cause of MR may be challenging, and that a complex aetiology may be present even within a pedigree, constituting an additional obstacle for genetic counselling. Variants in genes involved in molecular mechanisms of cellular plasticity, in genes involved in the development of underlying neural architectures, and in genes involved in neurodevelopment and in the ongoing function of terminally differentiated neurons may underlie the phenotypic variation of intelligence and explain instances of intellectual impairment.</p

Epithelial p38α Controls Immune Cell Recruitment in the Colonic Mucosa

Intestinal epithelial cells (IECs) compose the first barrier against microorganisms in the gastrointestinal tract. Although the NF-κB pathway in IECs was recently shown to be essential for epithelial integrity and intestinal immune homeostasis, the roles of other inflammatory signaling pathways in immune responses in IECs are still largely unknown. Here we show that p38α in IECs is critical for chemokine expression, subsequent immune cell recruitment into the intestinal mucosa, and clearance of the infected pathogen. Mice with p38α deletion in IECs suffer from a sustained bacterial burden after inoculation with Citrobacter rodentium. These animals are normal in epithelial integrity and immune cell function, but fail to recruit CD4+ T cells into colonic mucosal lesions. The expression of chemokines in IECs is impaired, which appears to be responsible for the impaired T cell recruitment. Thus, p38α in IECs contributes to the host immune responses against enteric bacteria by the recruitment of immune cells

Children’s rights online: challenges, dilemmas and emerging directions

In debates over internet governance, the interests of children figure unevenly, and only partial progress has been made in supporting children’s rights online globally. This chapter examines how the UN Convention on the Rights of the Child is helpful in mapping children’s rights to provision, protection and participation as they apply online as well as offline. However, challenges remain. First, opportunities and risks are positively linked, policy approaches are needed to resolve the potential conflict between protection on the one hand, and provision and participation on the other. Second, while parents may be relied on to some degree to balance their child’s rights and needs, the evidence suggests that a minority of parents are ill-equipped to manage this. Third, resolution is needed regarding the responsibility for implementing digital rights, since many governments prefer self-regulation in relation to internet governance. The chapter concludes by calling for a global governance body charged with ensuring the delivery of children’s rights

Elusive Copy Number Variation in the Mouse Genome

Array comparative genomic hybridization (aCGH) to detect copy number variants (CNVs) in mammalian genomes has led to a growing awareness of the potential importance of this category of sequence variation as a cause of phenotypic variation. Yet there are large discrepancies between studies, so that the extent of the genome affected by CNVs is unknown. We combined molecular and aCGH analyses of CNVs in inbred mouse strains to investigate this question.Using a 2.1 million probe array we identified 1,477 deletions and 499 gains in 7 inbred mouse strains. Molecular characterization indicated that approximately one third of the CNVs detected by the array were false positives and we estimate the false negative rate to be more than 50%. We show that low concordance between studies is largely due to the molecular nature of CNVs, many of which consist of a series of smaller deletions and gains interspersed by regions where the DNA copy number is normal.Our results indicate that CNVs detected by arrays may be the coincidental co-localization of smaller CNVs, whose presence is more likely to perturb an aCGH hybridization profile than the effect of an isolated, small, copy number alteration. Our findings help explain the hitherto unexplored discrepancies between array-based studies of copy number variation in the mouse genome

Effect of Training on the Reliability of Satiety Evaluation and Use of Trained Panellists to Determine the Satiety Effect of Dietary Fibre: A Randomised Controlled Trial

Background: The assessment of satiety effects on foods is commonly performed by untrained volunteers marking their perceived hunger or fullness on line scales, marked with pre-set descriptors. The lack of reproducibility of satiety measurement using this approach however results in the tool being unable to distinguish between foods that have small, but possibly important, differences in their satiety effects. An alternate approach is used in sensory evaluation; panellists can be trained in the correct use of the assessment line-scale and brought to consensus on the meanings of descriptors used for food quality attributes to improve the panel reliability. The effect of training on the reliability of a satiety panel has not previously been reported. Method: In a randomised controlled parallel intervention, the effect of training in the correct use of a satiety labelled magnitude scale (LMS) was assessed versus no-training. The test-retest precision and reliability of two hour postprandial satiety evaluation after consumption of a standard breakfast was compared. The trained panel then compared the satiety effect of two breakfast meals containing either a viscous or a non-viscous dietary fibre in a crossover trial.Results: A subgroup of the 23 panellists (n = 5) improved their test re-test precision after training. Panel satiety area under the curve, “after the training” intervention was significantly different to “before training” (p < 0.001). Reliability of the panel determined by intraclass correlation (ICC) of test and retest showed improved strength of the correlation from 0.70 pre-intervention to 0.95 post intervention. The trained “satiety expert panel” determined that a standard breakfast with 5g of viscous fibre gave significantly higher satiety than with 5g non-viscous fibre (area under curve (AUC) of 478.2, 334.4 respectively) (p ≤ 0.002). Conclusion: Training reduced between panellist variability. The improved strength of test-retest ICC as a result of the training intervention suggests that training satiety panellists can improve the discriminating power of satiety evaluation

Whole Genome Sequencing Highlights Genetic Changes Associated with Laboratory Domestication of C. elegans

Defining the mutational landscape when individuals of a species grow separately and diverge over many generations can provide insights into trait evolution. A specific example of this involves studying changes associated with domestication where different lines of the same wild stock have been cultivated independently in different standard environments. Whole genome sequence comparison of such lines permits estimation of mutation rates, inference of genes' ancestral states and ancestry of existing strains, and correction of sequencing errors in genome databases. Here we study domestication of the C. elegans Bristol strain as a model, and report the genome sequence of LSJ1 (Bristol), a sibling of the standard C. elegans reference wild type N2 (Bristol). The LSJ1 and N2 lines were cultivated separately from shortly after the Bristol strain was isolated until methods to freeze C. elegans were developed. We find that during this time the two strains have accumulated 1208 genetic differences. We describe phenotypic variation between N2 and LSJ1 in the rate at which embryos develop, the rate of production of eggs, the maturity of eggs at laying, and feeding behavior, all the result of post-isolation changes. We infer the ancestral alleles in the original Bristol isolate and highlight 2038 likely sequencing errors in the original N2 reference genome sequence. Many of these changes modify genome annotation. Our study provides a starting point to further investigate genotype-phenotype association and offers insights into the process of selection as a result of laboratory domestication

Neural Correlates of Appetite and Hunger-Related Evaluative Judgments

How much we desire a meal depends on both the constituent foods and how hungry we are, though not every meal becomes more desirable with increasing hunger. The brain therefore needs to be able to integrate hunger and meal properties to compute the correct incentive value of a meal. The present study investigated the functional role of the amygdala and the orbitofrontal cortex in mediating hunger and dish attractiveness. Furthermore, it explored neural responses to dish descriptions particularly susceptible to value-increase following fasting. We instructed participants to rate how much they wanted food menu items while they were either hungry or sated, and compared the rating differences in these states. Our results point to the representation of food value in the amygdala, and to an integration of attractiveness with hunger level in the orbitofrontal cortex. Dishes particularly desirable during hunger activated the thalamus and the insula. Our results specify the functions of evaluative structures in the context of food attractiveness, and point to a complex neural representation of dish qualities which contribute to state-dependent value

A whole genome association study of neuroticism using DNA pooling.

We describe a multistage approach to identify single nucleotide polymorphisms (SNPs) associated with neuroticism, a personality trait that shares genetic determinants with major depression and anxiety disorders. Whole genome association with 452 574 SNPs was performed on DNA pools from approximately 2000 individuals selected on extremes of neuroticism scores from a cohort of 88 142 people from southwest England. The most significant SNPs were then genotyped on independent samples to replicate findings. We were able to replicate association of one SNP within the PDE4D gene in a second sample collected by our laboratory and in a family-based test in an independent sample; however, the SNP was not significantly associated with neuroticism in two other independent samples. We also observed an enrichment of low P-values in known regions of copy number variations. Simulation indicates that our study had approximately 80% power to identify neuroticism loci in the genome with odds ratio (OR)&gt;2, and approximately 50% power to identify small effects (OR=1.5). Since we failed to find any loci accounting for more than 1% of the variance, the heritability of neuroticism probably arises from many loci each explaining much less than 1%. Our findings argue the need for much larger samples than anticipated in genetic association studies and that the biological basis of emotional disorders is extremely complex