Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference

Detailed phenotyping is required to deepen our understanding of the biological mechanisms behind genetic associations. In addition, the impact of potentially modifiable risk factors on disease requires analytical frameworks that allow causal inference. Here, we discuss the characteristics of Recall-by-Genotype (RbG) as a study design aimed at addressing both these needs. We describe two broad scenarios for the application of RbG: studies using single variants and those using multiple variants. We consider the efficacy and practicality of the RbG approach, provide a catalogue of UK-based resources for such studies and present an online RbG study planner.</p

The release of calcium from the endoplasmic reticulum induced by amyloid-beta and prion peptides activates the mitochondrial apoptotic pathway

In this study, we analyzed whether ER Ca2+ release, induced by amyloid-[beta] (A[beta]) and prion (PrP) peptides activates the mitochondrial-mediated apoptotic pathway. In cortical neurons, addition of the synthetic A[beta]1-40 or PrP106-126 peptides depletes ER Ca2+ content, leading to cytosolic Ca2+ overload. The Ca2+ released through ryanodine (RyR) and inositol 1,4,5-trisphosphate (IP3R) receptors was shown to be involved in the loss of mitochondrial membrane potential, Bax translocation to mitochondria and apoptotic death. Our data further demonstrate that Ca2+ released from the ER leads to the depletion of endogenous GSH levels and accumulation of reactive oxygen species, which were also involved in the depolarization of the mitochondrial membrane. These results illustrate that the early A[beta]- and PrP -induced perturbation of ER Ca2+ homeostasis affects mitochondrial function, activating the mitochondrial-mediated apoptotic pathway and help to clarify the mechanism implicated in neuronal death that occurs in AD and PrD.http://www.sciencedirect.com/science/article/B6WNK-4RWBSWS-2/1/e5d04335492f8e5aeee9fa1799fd301

An endoplasmic-reticulum-specific apoptotic pathway is involved in prion and amyloid-beta peptides neurotoxicity

Prion (PrP) and amyloid-[beta] (A[beta]) peptides are involved in the neuronal loss that occurs in Prion disorders (PrD) and Alzheimer's disease (AD), respectively, partially due to Ca2+ dysregulation. Besides, the endoplasmic reticulum (ER) stress has an active role in the neurotoxic mechanisms that lead to these pathologies. Here, we analyzed whether the ER-mediated apoptotic pathway is involved in the toxic effect of synthetic PrP and A[beta] peptides. In PrP106-126- and A[beta]1-40-treated cortical neurons, the release of Ca2+ through ER ryanodine (RyR) and inositol 1,4,5-trisphosphate (IP3R) receptors induces ER stress and leads to increased cytosolic Ca2+ and reactive oxygen species (ROS) levels and subsequently to apoptotic death involving mitochondrial cytochrome c release and caspases activation. These results demonstrate that the early PrP- and A[beta]-induced perturbation of ER Ca2+ homeostasis is a death message that leads to neuronal loss, suggesting that the regulation of ER Ca2+ levels may be a potential therapeutical target for PrD and AD.http://www.sciencedirect.com/science/article/B6WNK-4KF1HJF-2/1/1c70b53c2d3ffe42c231154f0fe9258

In silico discrimination of single nucleotide polymorphisms and pathological mutations in human gene promoter regions by means of local DNA sequence context and regularity

DNA sequence features were sought that could be used for the in silico ascertainment of the likely functional consequences of single nucleotide changes in human gene promoter regions. To identify relevant features of the local DNA sequence context, we transformed into consensus tables the nucleotide composition of sequences flanking 101 promoter SNPs of type CT or AG, defined empirically as being either 'functional' or 'non-functional' on the basis of a standardised reporter gene assay. The similarity of a given sequence to these consensus tables was then measured by means of the Shapiro-Senapathy score. A decision rule with the potential to discriminate between empirically ascertained functional and non-functional SNPs was proposed that potentiated discrimination between functional and non-functional SNPs with a sensitivity of 80% and a specificity of 20%. Two further datasets (viz. disease-associated SNPs of types AG and CT (N = 75) and pathological promoter mutations (transitions, N = 114)) were retrieved from the Human Gene Mutation Database (HGMD; http://www.hgmd.org/) and analyzed using consensus tables derived from the functional and non-functional promoter SNPs; approximately 70% were correctly recognized as being of probable functional significance. Complexity analysis was also used to quantify the regularity of the local DNA sequence environment. Functional SNPs/mutations of type CT were found to occur in DNA regions characterized by lower average sequence complexity as measured with respect to symmetric elements; complexity values increased gradually from functional SNPs and pathological mutations to functional disease-associated SNPs and non-functional SNPs. This may reflect the internal axial symmetry that frequently characterizes transcription factor binding sites

The use of Nutrition and Health Claims on Yoghurts on the Irish Market

AbstractThe use of nutrition and health claims on food is legislated for in Commission Regulation 1924/2006 and SI No. 11 of 2014. This legislation ensures that any claim made on a food label is clear, accurate and substantiated, enabling consumers to make informed choices. A study undertaken by the Food Safety Authority of Ireland (FSAI) in 2009 found that yoghurts were the food category with the highest use of nutrition and health claims on the Irish market.In 2018, the FSAI undertook a nutrition label verification study to verify the accuracy of declared nutrition information on yoghurts. The aims of this study were to measure the use of nutrition and health claims on a sample of yoghurts available on the Irish market in 2018 and assess their compliance with Regulation 1924/2006 Nutrition and Health Claims made on Food.Yoghurts identified in a 2016 market scan (n578) were weighted based on categorisation of manufacturer type (branded, own brand), product category (natural, flavoured and luxury) and declared nutrition content. Samples (n200) were randomly selected from these weighted groups for the 2018 nutrition label verification study. A subsample (n100) was randomly sampled and checked for presence of nutrition and health claims. Presence of nutrition and health claims was recorded in Microsoft Excel and checked for compliance with Regulation 1924/2006.Of the yoghurts reviewed, 67% (n67) made at least one nutrition claim and 34% (n34) made at least one health claim. Of these, 29% (n29) made a nutrition and a health claim. Branded yoghurts were more likely to make nutrition and health claims than own brand yoghurts (78% (n49) vs. 48% (n18)). Of yoghurts with a health claim, 88% (n30) were branded and 12% (n4) were own brand. Of yoghurts with a nutrition claim, 1.5% (n1) made a nutrition claim which was potentially non-compliant with Regulation 1924/2006. Of yoghurts with a health claim, 74% (n23) made a health claim which was potentially non-compliant with Regulation 1924/2006. The majority of potentially non-compliant health claims were in relation to probiotic strains and ‘live cultures’.In conclusion, yoghurts continue to be a food category which often uses nutrition and health claims. Nutrition and health claims are more frequently used by branded than own brand products. Potentially non-compliant health claims are an issue amongst this food category which will be further investigated and followed up.</jats:p