The Political De-Determination of Legal Rules and the Contested Meaning of the ‘No Bailout’ Clause

Traditional debates on legal theory have devoted a great deal of attention to the question of the determinacy of legal rules. With the aid of social sciences and linguistics, this article suggests a way out of the ‘determinate-indeterminate’ dichotomy that has dominated the academic debate on the topic so far. Instead, a dynamic approach is proposed, in which rules are deemed to undergo processes of political ‘de-determination’ and ‘re-determination’. To illustrate this, the article uses the example of Art. 125 of the Treaty on the Functioning of the European Union, the ‘no bailout’ provision, which played a major role in the management of the Euro-crisis. As will be shown, with the start of the crisis, this provision, whose meaning was once scarcely controversial, became the object of intense interpretative disagreement. As it became politically relevant, the rule also became the site of interpretative competitions, until the intervention of the European Court of Justice disambiguated and redefined its meaning

Cis and Trans Effects of Human Genomic Variants on Gene Expression

This work was funded by the Louis-Jeantet Foundation (http://www.jeantet.ch/), the European Research Council (Grant ID: 260927 http://erc.europa.eu/), the Swiss National Foundation (Grant ID: 130342 http://www.snf.ch), NCCR Frontiers In Genetics (http://www.frontiers-in-genetics.org), the UK Medical Research Council (http://www.mrc.ac.uk) and the Wellcome Trust (Grant ID: 092731).

Detection of regulator genes and eQTLs in gene networks

Genetic differences between individuals associated to quantitative phenotypic traits, including disease states, are usually found in non-coding genomic regions. These genetic variants are often also associated to differences in expression levels of nearby genes (they are "expression quantitative trait loci" or eQTLs for short) and presumably play a gene regulatory role, affecting the status of molecular networks of interacting genes, proteins and metabolites. Computational systems biology approaches to reconstruct causal gene networks from large-scale omics data have therefore become essential to understand the structure of networks controlled by eQTLs together with other regulatory genes, and to generate detailed hypotheses about the molecular mechanisms that lead from genotype to phenotype. Here we review the main analytical methods and softwares to identify eQTLs and their associated genes, to reconstruct co-expression networks and modules, to reconstruct causal Bayesian gene and module networks, and to validate predicted networks in silico.Comment: minor revision with typos corrected; review article; 24 pages, 2 figure

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Clinicopathologic and gene expression parameters predict liver cancer prognosis

<p>Abstract</p> <p>Background</p> <p>The prognosis of hepatocellular carcinoma (HCC) varies following surgical resection and the large variation remains largely unexplained. Studies have revealed the ability of clinicopathologic parameters and gene expression to predict HCC prognosis. However, there has been little systematic effort to compare the performance of these two types of predictors or combine them in a comprehensive model.</p> <p>Methods</p> <p>Tumor and adjacent non-tumor liver tissues were collected from 272 ethnic Chinese HCC patients who received curative surgery. We combined clinicopathologic parameters and gene expression data (from both tissue types) in predicting HCC prognosis. Cross-validation and independent studies were employed to assess prediction.</p> <p>Results</p> <p>HCC prognosis was significantly associated with six clinicopathologic parameters, which can partition the patients into good- and poor-prognosis groups. Within each group, gene expression data further divide patients into distinct prognostic subgroups. Our predictive genes significantly overlap with previously published gene sets predictive of prognosis. Moreover, the predictive genes were enriched for genes that underwent normal-to-tumor gene network transformation. Previously documented liver eSNPs underlying the HCC predictive gene signatures were enriched for SNPs that associated with HCC prognosis, providing support that these genes are involved in key processes of tumorigenesis.</p> <p>Conclusion</p> <p>When applied individually, clinicopathologic parameters and gene expression offered similar predictive power for HCC prognosis. In contrast, a combination of the two types of data dramatically improved the power to predict HCC prognosis. Our results also provided a framework for understanding the impact of gene expression on the processes of tumorigenesis and clinical outcome.</p

The population of Young Stellar Clusters throughout the disk of M33

The properties of young stellar clusters (YSCs) in M33, identified from the center out to about twice the size of the bright star-forming disk,are investigated. We find 915 discrete MIR sources as far as the extent of the warped HI disk, i.e. 16 kpc from the galaxy center. Their surface density has a steep radial decline beyond 4.5 kpc, and flattens out beyond the optical radius at 8.5 kpc. We are able to identify YSCs out to 12 kpc. At large galactocentric radii, the paucity of very luminous clusters and the relevance of hot dust emission become evident from the analysis of the bolometric and MIR luminosity functions. The YSC mass and size are correlated with a log-log slope of 2.09, similar to that measured for giant molecular clouds in M33 and the Milky Way, which represent the protocluster environment. Most of the YSCs in our sample have low extinction and ages between 3 and 10 Myr. In the inner regions of M33 the clusters span a wide range of mass (10^2<M<3 10^5 msun) and luminosity 10^38<L{bol}<3 10^{41}erg/s, while at galactocentric radii larger than 4 kpc we find a deficiency of massive clusters. Beyond 7 kpc, where the Halpha surface brightness drops significantly, the dominant YSC population has M<10^3 msun and a slightly older age (10 Myrs). This implies the occurrence of star formation events about 10 Myr ago as far as 10-12 kpc from the center of M33. The cluster L{FUV}--L{Halpha} relation is non-linear for L{FUV}<10^{39}erg/s, in agreement with randomly sampled models of the IMF which, furthermore, shows no appreciable variation throughout the M33 disk.Comment: Accepted for publication in A&A, 16 pages, 14 figure

The Ethics of Delusional Belief

In this paper we address the ethics of adopting delusional beliefs and we apply consequentialist and deontological considerations to the epistemic evaluation of delusions. Delusions are characterised by their epistemic shortcomings and they are often defined as false and irrational beliefs. Despite this, when agents are overwhelmed by negative emotions due to the effects of trauma or previous adversities, or when they are subject to anxiety and stress as a result of hypersalient experience, the adoption of a delusional belief can prevent a serious epistemic harm from occurring. For instance, delusions can allow agents to remain in touch with their environment overcoming the disruptive effect of negative emotions and anxiety. Moreover, agents are not blameworthy for adopting their delusions if their ability to believe otherwise is compromised. There is evidence suggesting that no evidence-related action that would counterfactually lead them to believe otherwise is typically available to them. The lack of ability to believe otherwise, together with some other conditions, implies that the agents are not blameworthy for their delusions. The examination of the epistemic status of delusions prompts us to acknowledge the complexity and contextual nature of epistemic evaluation, establish connections between consequentialist and deontological frameworks in epistemology, and introduce the notion of epistemic innocence into the vocabulary of epistemic evaluatio

DNA mismatch repair gene MSH6 implicated in determining age at natural menopause

notes: PMCID: PMC3976329This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10(-9)), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.UK Medical Research CouncilWellcome Trus

Genetic Crossovers Are Predicted Accurately by the Computed Human Recombination Map

Hotspots of meiotic recombination can change rapidly over time. This instability and the reported high level of inter-individual variation in meiotic recombination puts in question the accuracy of the calculated hotspot map, which is based on the summation of past genetic crossovers. To estimate the accuracy of the computed recombination rate map, we have mapped genetic crossovers to a median resolution of 70 Kb in 10 CEPH pedigrees. We then compared the positions of crossovers with the hotspots computed from HapMap data and performed extensive computer simulations to compare the observed distributions of crossovers with the distributions expected from the calculated recombination rate maps. Here we show that a population-averaged hotspot map computed from linkage disequilibrium data predicts well present-day genetic crossovers. We find that computed hotspot maps accurately estimate both the strength and the position of meiotic hotspots. An in-depth examination of not-predicted crossovers shows that they are preferentially located in regions where hotspots are found in other populations. In summary, we find that by combining several computed population-specific maps we can capture the variation in individual hotspots to generate a hotspot map that can predict almost all present-day genetic crossovers

Predictive Genes in Adjacent Normal Tissue Are Preferentially Altered by sCNV during Tumorigenesis in Liver Cancer and May Rate Limiting

Background: In hepatocellular carcinoma (HCC) genes predictive of survival have been found in both adjacent normal (AN) and tumor (TU) tissues. The relationships between these two sets of predictive genes and the general process of tumorigenesis and disease progression remains unclear. Methodology/Principal Findings: Here we have investigated HCC tumorigenesis by comparing gene expression, DNA copy number variation and survival using ~250 AN and TU samples representing, respectively, the pre-cancer state, and the result of tumorigenesis. Genes that participate in tumorigenesis were defined using a gene-gene correlation meta-analysis procedure that compared AN versus TU tissues. Genes predictive of survival in AN (AN-survival genes) were found to be enriched in the differential gene-gene correlation gene set indicating that they directly participate in the process of tumorigenesis. Additionally the AN-survival genes were mostly not predictive after tumorigenesis in TU tissue and this transition was associated with and could largely be explained by the effect of somatic DNA copy number variation (sCNV) in cis and in trans. The data was consistent with the variance of AN-survival genes being rate-limiting steps in tumorigenesis and this was confirmed using a treatment that promotes HCC tumorigenesis that selectively altered AN-survival genes and genes differentially correlated between AN and TU. Conclusions/Significance: This suggests that the process of tumor evolution involves rate-limiting steps related to the background from which the tumor evolved where these were frequently predictive of clinical outcome. Additionally treatments that alter the likelihood of tumorigenesis occurring may act by altering AN-survival genes, suggesting that the process can be manipulated. Further sCNV explains a substantial fraction of tumor specific expression and may therefore be a causal driver of tumor evolution in HCC and perhaps many solid tumor types. © 2011 Lamb et al.published_or_final_versio