Constitutional Analogies in the International Legal System

This Article explores issues at the frontier of international law and constitutional law. It considers five key structural and systemic challenges that the international legal system now faces: (1) decentralization and disaggregation; (2) normative and institutional hierarchies; (3) compliance and enforcement; (4) exit and escape; and (5) democracy and legitimacy. Each of these issues raises questions of governance, institutional design, and allocation of authority paralleling the questions that domestic legal systems have answered in constitutional terms. For each of these issues, I survey the international legal landscape and consider the salience of potential analogies to domestic constitutions, drawing upon and extending the writings of international legal scholars and international relations theorists. I also offer some preliminary thoughts about why some treaties and institutions, but not others, more readily lend themselves to analysis in constitutional terms. And I distinguish those legal and political issues that may generate useful insights for scholars studying the growing intersections of international and constitutional law from other areas that may be more resistant to constitutional analogies

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis

Comparison of genotyping using pooled DNA samples (allelotyping) and individual genotyping using the affymetrix genome-wide human SNP array 6.0

Background: Genome-wide association studies (GWAS) using array-based genotyping technology are widely used to identify genetic loci associated with complex diseases or other phenotypes. The costs of GWAS projects based on individual genotyping are still comparatively high and increase with the size of study populations. Genotyping using pooled DNA samples, as also being referred as to allelotyping approach, offers an alternative at affordable costs. In the

Troponin I and cardiovascular risk prediction in the general population: the BiomarCaRE consortium

Our aims were to evaluate the distribution of troponin I concentrations in population cohorts across Europe, to characterize the association with cardiovascular outcomes, to determine the predictive value beyond the variables used in the ESC SCORE, to test a potentially clinically relevant cut-off value, and to evaluate the improved eligibility for statin therapy based on elevated troponin I concentrations retrospectively

Towards a Holistic Approach to Technology and Climate Change:What Would Form Part of an Answer?

This multi-authored piece conducts an interdisciplinary analysis of the fields and principles which could be relevant to securing access to climate change technologies, while at the same time encouraging the initial development of the technologies. The paper is the first part of a project funded by the British Academy, ‘Obtaining, protecting and using essential environmental technologies: a holistic analysis’

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Cell Specific eQTL Analysis without Sorting Cells

The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohn’s disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus

Does periodontitis affect diabetes incidence and haemoglobin A1c change? An 11-year follow-up study

Aim: As periodontitis may contribute to the pathogenesis of diabetes, the effects of periodontitis on diabetes incidence and HbA1c change was quantified in a prospective cohort.Methods: Data from an 11-year follow-up of the Study of Health in Pomerania were analyzed to evaluate the effects of periodontitis on incident diabetes and long-term HbA1c changes in 2047 subjects aged 20–81 years. Diabetes was based on self-reported physician diagnoses, antidiabetic medication use, or HbA1c ≥ 6.5% or non-fasting blood glucose levels ≥ 11.1 mmol/L. To assess periodontal status, periodontal pockets were probed, and their depth and clinical attachment levels measured. For both measures, means and percentages of sites ≥ 3 mm were calculated. In addition, all probing depths ≥ 4 mm were summed (cumulative probing depth). Modified Poisson and multivariable linear models were applied, adjusted for age, gender, highest level of general education, marital status, waist circumference, physical activity, smoking status and follow-up time.Results: Over a mean follow-up period of 11.1 years, 207 subjects developed diabetes. Baseline mean clinical attachment levels (CAL) and probing depths (PPD) were not significantly associated with either diabetes incidence [mean CALs, fourth quartile, incidence rate ratio = 0.819, 95% confidence interval (CI): 0.489–1.370; P = 0.446] or long-term changes in HbA1c (mean CAL, fourth quartile, β = −0.086, 95% CI: −0.187, −0.016; P = 0.098). Sensitivity analyses using alternative exposure definitions confirmed these results.Conclusion: Contrary to the currently available literature, no convincing evidence was found of any potential association between periodontitis and diabetes incidence or HbA1c change