Association of the tumour necrosis factor alpha -308 but not the interleukin 10 -627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis

BACKGROUND AND AIMS Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology. Abnormalities in immune regulation and genetic associations suggest that PSC is an immune mediated disease. Several polymorphisms within the tumour necrosis factor α (TNF-α) and interleukin 10 (IL-10) promoter genes have been described which influence expression of these cytokines. This study examines the possible association between polymorphisms at the −308 and −627 positions in the TNF-α and IL-10 promoter genes, respectively, and susceptibility to PSC. METHODS TNF-α −308 genotypes were studied by polymerase chain reaction (PCR) in 160 PSC patients from Norway and the UK compared with 145 ethnically matched controls. IL-10 −627 genotypes were studied by PCR in 90 PSC patients compared with 84 ethnically matched controls. RESULTS A total of 16% of Norwegian PSC patients and 12% of British PSC patients were homozygous for the TNF2 allele compared with 3% and 6% of respective controls. The TNF2 allele was present in 60% of PSC patients versus 30% of controls (ORcombined data=3.2 (95% confidence intervals (CI) 1.8–4.5); pcorr=10−5). The association between the TNF2 allele and susceptibility to PSC was independent of the presence of concurrent inflammatory bowel disease (IBD) in the PSC patients; 61% of PSC patients without IBD had TNF2 compared with 30% of controls (ORcombined data=3.2 (95% CI 1.2–9.0); pcorr=0.006 ). There was no difference in the −627 IL-10 polymorphism distributions between patients and controls in either population. The increase in TNF2 allele in PSC patients only occurs in the presence of DRB1*0301 (DR3) and B8. In the combined population data, DRB1*0301 showed a stronger association with susceptibility to PSC than both the TNF2 and B8 alleles (ORcombined data=3.8, pcorr=10−6 v ORcombined data=3.2, pcorr=10−5 vORcombined data =3.41, pcorr=10−4, respectively). CONCLUSIONS This study identified a significant association between possession of the TNF2 allele, a G→A substitution at position −308 in the TNF-α promoter, and susceptibility to PSC. This association was secondary to the association of PSC with the A1-B8-DRB1*0301-DQA1*0501-DQB1*0201 haplotype. No association was found between the IL-10 −627 promoter polymorphism and PSC

MKID development for SuperSpec: an on-chip, mm-wave, filter-bank spectrometer

SuperSpec is an ultra-compact spectrometer-on-a-chip for millimeter and submillimeter wavelength astronomy. Its very small size, wide spectral bandwidth, and highly multiplexed readout will enable construction of powerful multibeam spectrometers for high-redshift observations. The spectrometer consists of a horn-coupled microstrip feedline, a bank of narrow-band superconducting resonator filters that provide spectral selectivity, and Kinetic Inductance Detectors (KIDs) that detect the power admitted by each filter resonator. The design is realized using thin-film lithographic structures on a silicon wafer. The mm-wave microstrip feedline and spectral filters of the first prototype are designed to operate in the band from 195-310 GHz and are fabricated from niobium with at Tc of 9.2K. The KIDs are designed to operate at hundreds of MHz and are fabricated from titanium nitride with a Tc of 2K. Radiation incident on the horn travels along the mm-wave microstrip, passes through the frequency-selective filter, and is finally absorbed by the corresponding KID where it causes a measurable shift in the resonant frequency. In this proceedings, we present the design of the KIDs employed in SuperSpec and the results of initial laboratory testing of a prototype device. We will also briefly describe the ongoing development of a demonstration instrument that will consist of two 500-channel, R=700 spectrometers, one operating in the 1-mm atmospheric window and the other covering the 650 and 850 micron bands.Comment: As submitted, except that "in prep" references have been update

SuperSpec: design concept and circuit simulations

SuperSpec is a pathfinder for future lithographic spectrometer cameras, which promise to energize extra-galactic astrophysics at (sub)millimeter wavelengths: delivering 200–500 km s^(-1) spectral velocity resolution over an octave bandwidth for every pixel in a telescope’s field of view. We present circuit simulations that prove the concept, which enables complete millimeter-band spectrometer devices in just a few square-millimeter footprint. We evaluate both single-stage and two-stage channelizing filter designs, which separate channels into an array of broad-band detectors, such as bolometers or kinetic inductance detector (KID) devices. We discuss to what degree losses (by radiation or by absorption in the dielectric) and fabrication tolerances affect the resolution or performance of such devices, and what steps we can take to mitigate the degradation. Such design studies help us formulate critical requirements on the materials and fabrication process, and help understand what practical limits currently exist to the capabilities these devices can deliver today or over the next few years

Identifier mapping performance for integrating transcriptomics and proteomics experimental results

Background\ud Studies integrating transcriptomic data with proteomic data can illuminate the proteome more clearly than either separately. Integromic studies can deepen understanding of the dynamic complex regulatory relationship between the transcriptome and the proteome. Integrating these data dictates a reliable mapping between the identifier nomenclature resultant from the two high-throughput platforms. However, this kind of analysis is well known to be hampered by lack of standardization of identifier nomenclature among proteins, genes, and microarray probe sets. Therefore data integration may also play a role in critiquing the fallible gene identifications that both platforms emit.\ud \ud Results\ud We compared three freely available internet-based identifier mapping resources for mapping UniProt accessions (ACCs) to Affymetrix probesets identifications (IDs): DAVID, EnVision, and NetAffx. Liquid chromatography-tandem mass spectrometry analyses of 91 endometrial cancer and 7 noncancer samples generated 11,879 distinct ACCs. For each ACC, we compared the retrieval sets of probeset IDs from each mapping resource. We confirmed a high level of discrepancy among the mapping resources. On the same samples, mRNA expression was available. Therefore, to evaluate the quality of each ACC-to-probeset match, we calculated proteome-transcriptome correlations, and compared the resources presuming that better mapping of identifiers should generate a higher proportion of mapped pairs with strong inter-platform correlations. A mixture model for the correlations fitted well and supported regression analysis, providing a window into the performance of the mapping resources. The resources have added and dropped matches over two years, but their overall performance has not changed.\ud \ud Conclusions\ud The methods presented here serve to achieve concrete context-specific insight, to support well-informed decisions in choosing an ID mapping strategy for "omic" data merging

Caveolin-1 protects B6129 mice against Helicobacter pylori gastritis.

Caveolin-1 (Cav1) is a scaffold protein and pathogen receptor in the mucosa of the gastrointestinal tract. Chronic infection of gastric epithelial cells by Helicobacter pylori (H. pylori) is a major risk factor for human gastric cancer (GC) where Cav1 is frequently down-regulated. However, the function of Cav1 in H. pylori infection and pathogenesis of GC remained unknown. We show here that Cav1-deficient mice, infected for 11 months with the CagA-delivery deficient H. pylori strain SS1, developed more severe gastritis and tissue damage, including loss of parietal cells and foveolar hyperplasia, and displayed lower colonisation of the gastric mucosa than wild-type B6129 littermates. Cav1-null mice showed enhanced infiltration of macrophages and B-cells and secretion of chemokines (RANTES) but had reduced levels of CD25+ regulatory T-cells. Cav1-deficient human GC cells (AGS), infected with the CagA-delivery proficient H. pylori strain G27, were more sensitive to CagA-related cytoskeletal stress morphologies ("humming bird") compared to AGS cells stably transfected with Cav1 (AGS/Cav1). Infection of AGS/Cav1 cells triggered the recruitment of p120 RhoGTPase-activating protein/deleted in liver cancer-1 (p120RhoGAP/DLC1) to Cav1 and counteracted CagA-induced cytoskeletal rearrangements. In human GC cell lines (MKN45, N87) and mouse stomach tissue, H. pylori down-regulated endogenous expression of Cav1 independently of CagA. Mechanistically, H. pylori activated sterol-responsive element-binding protein-1 (SREBP1) to repress transcription of the human Cav1 gene from sterol-responsive elements (SREs) in the proximal Cav1 promoter. These data suggested a protective role of Cav1 against H. pylori-induced inflammation and tissue damage. We propose that H. pylori exploits down-regulation of Cav1 to subvert the host's immune response and to promote signalling of its virulence factors in host cells

Researching AI Legibility Through Design

Everyday interactions with computers are increasingly likely to involve elements of Artificial Intelligence (AI). Encompassing a broad spectrum of technologies and applications, AI poses many challenges for HCI and design. One such challenge is the need to make AI’s role in a given system legible to the user in a meaningful way. In this paper we employ a Research through Design (RtD) approach to explore how this might be achieved. Building on contemporary concerns and a thorough exploration of related research, our RtD process reflects on designing imagery intended to help increase AI legibility for users. The paper makes three contributions. First, we thoroughly explore prior research in order to critically unpack the AI legibility problem space. Second, we respond with design proposals whose aim is to enhance the legibility, to users, of systems using AI. Third, we explore the role of design-led enquiry as a tool for critically exploring the intersection between HCI and AI research

Sharing Detailed Research Data Is Associated with Increased Citation Rate

BACKGROUND: Sharing research data provides benefit to the general scientific community, but the benefit is less obvious for the investigator who makes his or her data available. PRINCIPAL FINDINGS: We examined the citation history of 85 cancer microarray clinical trial publications with respect to the availability of their data. The 48% of trials with publicly available microarray data received 85% of the aggregate citations. Publicly available data was significantly (p = 0.006) associated with a 69% increase in citations, independently of journal impact factor, date of publication, and author country of origin using linear regression. SIGNIFICANCE: This correlation between publicly available data and increased literature impact may further motivate investigators to share their detailed research data