Carriers of a novel frame-shift insertion in WNT16a possess elevated pancreatic expression of TCF7L2

BACKGROUND: The discovery of TCF7L2 as a global type 2 diabetes (T2D) gene has sparked investigations to explore the clinical utility of its variants for guiding the development of new diagnostic and therapeutic strategies. However, interpreting the resulting associations into function still remains unclear. Canonical Wnt signaling regulates β-catenin and its binding with TCF7L2, which in turn is critical for the production of glucagon-like peptide-1 (GLP-1). This study examines the role of a novel frame-shift insertion discovered in a conserved region of WNT16a, and it is proposed that this mutation affects T2D susceptibility in conjunction with gene variants in TCF7L2. RESULTS: Our results predicted that the insertion would convert the upstream open reading frame in the Wnt16a mRNA to an alternative, in-frame translation initiation site, resulting in the prevention of nonsense-mediated decay, leading to a consequent stabilization of the mutated WNT16a message. To examine the role of Wnt16a in the Wnt signaling pathway, DNA and serum samples from 2,034 individuals (48% with T2D) from the Sikh Diabetes Study were used in this investigation. Prevalence of Wnt16a insertion did not differ among T2D cases (33%) and controls (32%). However, there was a 3.2 fold increase in Wnt16a mRNA levels in pancreatic tissues from the insertion carriers and a significant increase (70%, p < 0.0001) in luciferase activity in the constructs carrying the insertion. The expression of TCF7L2 mRNA in pancreas was also elevated (~23-fold) among the insertion carriers (p=0.003). CONCLUSIONS: Our results suggest synergistic effects of WNT16a insertion and the at-risk ‘T’ allele of TCF7L2 (rs7903146) for elevating the expression of TCF7L2 in human pancreas which may affect the regulation of downstream target genes involved in the development of T2D through Wnt/β-catenin/TCF7L2 signaling pathway. However, further studies would be needed to mechanistically link the two definitively

HARP/ACSIS: A submillimetre spectral imaging system on the James Clerk Maxwell Telescope

This paper describes a new Heterodyne Array Receiver Programme (HARP) and Auto-Correlation Spectral Imaging System (ACSIS) that have recently been installed and commissioned on the James Clerk Maxwell Telescope (JCMT). The 16-element focal-plane array receiver, operating in the submillimetre from 325 to 375 GHz, offers high (three-dimensional) mapping speeds, along with significant improvements over single-detector counterparts in calibration and image quality. Receiver temperatures are $\sim$120 K across the whole band and system temperatures of $\sim$300K are reached routinely under good weather conditions. The system includes a single-sideband filter so these are SSB figures. Used in conjunction with ACSIS, the system can produce large-scale maps rapidly, in one or more frequency settings, at high spatial and spectral resolution. Fully-sampled maps of size 1 square degree can be observed in under 1 hour. The scientific need for array receivers arises from the requirement for programmes to study samples of objects of statistically significant size, in large-scale unbiased surveys of galactic and extra-galactic regions. Along with morphological information, the new spectral imaging system can be used to study the physical and chemical properties of regions of interest. Its three-dimensional imaging capabilities are critical for research into turbulence and dynamics. In addition, HARP/ACSIS will provide highly complementary science programmes to wide-field continuum studies, and produce the essential preparatory work for submillimetre interferometers such as the SMA and ALMA.Comment: MNRAS Accepted 2009 July 2. 18 pages, 25 figures and 6 table

The ArDM experiment

The aim of the ArDM project is the development and operation of a one ton double-phase liquid argon detector for direct Dark Matter searches. The detector measures both the scintillation light and the ionization charge from ionizing radiation using two independent readout systems. This paper briefly describes the detector concept and presents preliminary results from the ArDM R&D program, including a 3 l prototype developed to test the charge readout system.Comment: Proceedings of the Epiphany 2010 Conference, to be published in Acta Physica Polonica

The ZEPLIN-III dark matter detector: instrument design, manufacture and commissioning

We present details of the technical design and manufacture of the ZEPLIN-III dark matter experiment. ZEPLIN-III is a two-phase xenon detector which measures both the scintillation light and the ionisation charge generated in the liquid by interacting particles and radiation. The instrument design is driven by both the physics requirements and by the technology requirements surrounding the use of liquid xenon. These include considerations of key performance parameters, such as the efficiency of scintillation light collection, restrictions placed on the use of materials to control the inherent radioactivity levels, attainment of high vacuum levels and chemical contamination control. The successful solution has involved a number of novel design and manufacturing features which will be of specific use to future generations of direct dark matter search experiments as they struggle with similar and progressively more demanding requirements.Comment: 25 pages, 19 figures. Submitted to Astropart. Phys. Some figures down sampled to reduce siz

The ZEPLIN II dark matter detector: data acquisition system and data reduction

ZEPLIN-II is a two-phase (liquid/gas) xenon dark matter detector searching for WIMP-nucleon interactions. In this paper we describe the data acquisition system used to record the data from ZEPLIN-II and the reduction procedures which parameterise the data for subsequent analysis.Comment: 11 pages, 10 figure

The LAGUNA design study- towards giant liquid based underground detectors for neutrino physics and astrophysics and proton decay searches

The feasibility of a next generation neutrino observatory in Europe is being considered within the LAGUNA design study. To accommodate giant neutrino detectors and shield them from cosmic rays, a new very large underground infrastructure is required. Seven potential candidate sites in different parts of Europe and at several distances from CERN are being studied: Boulby (UK), Canfranc (Spain), Fr\'ejus (France/Italy), Pyh\"asalmi (Finland), Polkowice-Sieroszowice (Poland), Slanic (Romania) and Umbria (Italy). The design study aims at the comprehensive and coordinated technical assessment of each site, at a coherent cost estimation, and at a prioritization of the sites within the summer 2010.Comment: 5 pages, contribution to the Workshop "European Strategy for Future Neutrino Physics", CERN, Oct. 200

The ZEPLIN II dark matter detector: data acquisition system and data reduction

ZEPLIN-II is a two-phase (liquid/gas) xenon dark matter detector searching for WIMP-nucleon interactions. In this paper we describe the data acquisition system used to record the data from ZEPLIN-II and the reduction procedures which parameterise the data for subsequent analysis.Comment: 11 pages, 10 figure

Household networks and emergent territory: a GIS study of Chumash households, villages and rock-art in South-Central California

Elite households of the Californian Chumash have been studied in order to understand the development of Late Holocene hunter-gatherer alliance networks. Equally, models of what has been termed ‘tribelet territories’ have been used to describe land ownership within larger Californian concepts. Surprisingly little research has explicitly addressed issues of how such territories may have developed. In this article, we turn to DeLanda’s philosophy of social complexity to consider how Chumash households may have underpinned the development of tribelet territories and the political implications for their articulation with wider alliances. Importantly, utilizing Geographic Information Systems (GIS), we analyse potential mobility patterns in relation to households, villages and rock-art locales in a case from the Emigdiano Chumash. The results suggest that the painting of rock art was imbricated within processes of territorialization, and that the local placement of art reflects which villages were home to particularly high-status households