OBJECTIVES/GOALS: Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatologic disease childhood and a cause of pain and potential disability. JIA has a strong genetic component and no known cure. The goal of this study is to evaluate allele-dependent effects of a novel JIA risk variant at 1q24.3. METHODS/STUDY POPULATION: JIA patients meeting criteria for the two most common disease subtypes (oligoarticular and RF neg polyarthritis) were genotyped using the Immunochip, an Illumina array with dense coverage of the HLA region and 186 other loci previously reported in autoimmune diseases. Phase I association findings (Hinks, 2013) and Phase II analysis (unpublished) of an expanded cohort (4,271 JIA and 14,390 controls) identified new risk loci, including rs78037977 at 1q24.3. We prioritized rs78037977 and predicted possible impacted mechanisms based on Bayesian predictions of attributable risk, the surrounding chromatin landscape, and transcription factor binding data. A luciferase reporter assay was used to assess allele-dependent enhancer activity. RESULTS/ANTICIPATED RESULTS: rs78037977 is located between FASLG and TNFSF18 at chromosome 1q24.3 is associated with JIA (p = 6.3x10−09), and explains 94% of the posterior probability at this locus; no other SNPs in linkage disequilibrium (r2>0.6). The chromatin landscape around rs78037977 contains H3K4Me1 and H3K27Ac marks, which are indicative of enhancer activity. Further, >160 transcription factors have chromatin immunoprecipitation followed by sequencing (ChIP-seq) peaks overlapping rs78037977 in various cellular contexts. In luciferase reporter assays, the region around rs78037977 containing the reference A allele had ~2-fold increased enhancer activity compared to the non-reference allele. DISCUSSION/SIGNIFICANCE OF IMPACT: This work provides in vitro evidence to support allele-dependent enhancer activity of a novel JIA-risk variant at 1q24.3. Our ongoing work investigates the effect of the DNA-containing region of rs78037977 on gene expression and differential transcription factor binding at rs78037977.

Bastin et al. propose a dual-process model to understand memory deficits. However, results from state-trace analysis have suggested a single underlying variable in behavioral and neural data. We advocate the usage of unidimensional models that are supported by data and have been successful in understanding memory deficits and in linking to neural data.

Epidemiological studies have established an association between obesity, insulin resistance, type 2 diabetes and a number of cancer types. Research has focused predominantly on altered endocrine factors, growth factors and signalling pathways, with little known in man about the immune involvement in the relevant pathophysiological processes. Moreover, in an era of exciting new breakthroughs in cancer immunotherapy, there is also a need to study the safety and efficacy of immunotherapeutics in the complex setting of inflammatory-driven obesity-associated cancer. This review addresses key immune cell subsets underpinning obesity-associated inflammation and describes how such immune compartments might be targeted to prevent and treat obesity-associated cancer. We propose that the modulation, metabolism, migration and abundance of pro- and anti-inflammatory cells and tumour-specific T cells might be therapeutically altered to both restore immune balance, alleviating pathological inflammation, and to improve anti-tumour immune responses in obesity-associated cancer.

George H. Butler was a Gilded Age writer, diplomat, and soldier, who was also a poster boy for what Richard Stott identifies as the “jolly fellow.” Butler parlayed a witty writing style to enter journalism, and with the help of his influencial uncle, Benjamin Butler, he obtained a diplomatic posting as consul general to Egypt. Overly fond of alcohol, George Butler participated in several newsworthy fights, often involving deadly force. His life serves as an archetype for out-of-control manliness, which was contrary to gender expectations of polite society in 1870s America.

This article addresses the so-called ‘apocalyptic reading of Paul’, taking the representative work of J. Louis Martyn and Martinus C. de Boer as its primary focus. The chief contention is that the ‘apocalyptic reading’ does not resemble the historical phenomenon of Jewish apocalyptic literature, although the scope of this article has been intentionally limited to Galatians. The present study is composed of two halves. The first half offers a critique of what it means for Paul to be an apocalyptic thinker according to Martyn and de Boer. Their emphasis is on discontinuity, duality and dichotomy, which coheres neither with first-century apocalyptic literature and its antecedents, nor with the letter to the Galatians. Their nuanced notion of apocalyptic has led to an unnecessary bifurcation between apocalyptic and covenant (not to mention Heilsgeschichte) in the interpretation of Paul. However, this article suggests that the dichotomy has been misplaced, both in relation to the discontinuity that Paul does articulate (i.e. with the law), and the dichotomy reflected in apocalyptic literature, namely, the division between the present evil age and the glorious age to come. Thus, it is argued that Martyn and de Boer's focus on discontinuity hardly constitutes apocalyptic in a first-century historical sense. Rather, their specific emphasis owes its articulation to the theology of Karl Barth. After arguing that the ‘apocalyptic reading’ lacks historical precision (and possibly theological forthrightness), the second half of the study argues that some neglected features of Galatians, such as suffering and persecution, cohere with the apocalyptic character of the letter, and are common features of apocalyptic broadly. In fact, the division between apocalyptic and covenant in scholarship on Galatians is bridged by the themes of conflict and crisis. This is because apocalyptic hope often arises in the absence of the realisation of covenantal promises and expectations; a covenantal disconnect is created and aggravated by crises and hardships of various sorts, hence the need for apocalyptic hope. Suffering therefore ties together the strands of apocalyptic and covenant in Galatians. If Martyn and de Boer's ‘apocalyptic reading’ was truly apocalyptic in a first-century historical sense, it would have integrated the imagery of suffering and persecution found in the letter.

This article establishes the significance of elections held in the annexed departments of the Napoleonic Empire from 1802 to 1813. It thus represents an original, and perhaps surprising, contribution to recent debate on the nature of Napoleonic imperialism, in which attention has shifted from core to periphery, and away from purely military matters. The electoral process under this authoritarian regime has been alternately neglected or derided, especially where the newly created departments of the Low Countries and parts of Germany and Italy are concerned. However, extensive archival research demonstrates that it was taken extremely seriously by both regime and voters, especially outside metropolitan France. These ‘First European Elections', as they may be dubbed, took place in regular fashion right across the Empire and are studied here on a transnational basis, which also involves the metropolitan departments. Though open to all adult males at the primary level, they were not exercises in democracy, but they did create some rare political space which local people were not slow to exploit for their own purposes. Above all, they served as a means of integrating ‘new Frenchmen’, particularly members of indigenous elites, into the Napoleonic system.

This article presents results from the first 3 rounds of an international intercomparison of measurements of Δ14CO2 in liter-scale samples of whole air by groups using accelerator mass spectrometry (AMS). The ultimate goal of the intercomparison is to allow the merging of Δ14CO2 data from different groups, with the confidence that differences in the data are geophysical gradients and not artifacts of calibration. Eight groups have participated in at least 1 round of the intercomparison, which has so far included 3 rounds of air distribution between 2007 and 2010. The comparison is intended to be ongoing, so that: a) the community obtains a regular assessment of differences between laboratories; and b) individual laboratories can begin to assess the long-term repeatability of their measurements of the same source air. Air used in the intercomparison was compressed into 2 high-pressure cylinders in 2005 and 2006 at Niwot Ridge, Colorado (USA), with one of the tanks “spiked” with fossil CO2, so that the 2 tanks span the range of Δ14CO2 typically encountered when measuring air from both remote background locations and polluted urban ones. Three groups show interlaboratory comparability within l% for ambient level Δ14CO2. For high CO2/low Δ14CO2 air, 4 laboratories showed comparability within 2%. This approaches the goals set out by the World Meteorological Organization (WMO) CO2 Measurements Experts Group in 2005. One important observation is that single-sample precisions typically reported by the AMS community cannot always explain the observed differences within and between laboratories. This emphasizes the need to use long-term repeatability as a metric for measurement precision, especially in the context of long-term atmospheric monitoring.