Identifying susceptibility genes by using joint tests of association and linkage and accounting for epistasis

Simulated Genetic Analysis Workshop14 data were analyzed by jointly testing linkage and association and by accounting for epistasis using a candidate gene approach. Our group was unblinded to the "answers." The 48 single-nucleotide polymorphisms (SNPs) within the six disease loci were analyzed in addition to five SNPs from each of two non-disease-related loci. Affected sib-parent data was extracted from the first 10 replicates for populations Aipotu, Kaarangar, and Danacaa, and analyzed separately for each replicate. We developed a likelihood for testing association and/or linkage using data from affected sib pairs and their parents. Identical-by-descent (IBD) allele sharing between sibs was explicitly modeled using a conditional logistic regression approach and incorporating a covariate that represents expected IBD allele sharing given the genotypes of the sibs and their parents. Interactions were accounted for by performing likelihood ratio tests in stages determined by the highest order interaction term in the model. In the first stage, main effects were tested independently, and in subsequent stages, multilocus effects were tested conditional on significant marginal effects. A reduction in the number of tests performed was achieved by prescreening gene combinations with a goodness-of-fit chi square statistic that depended on mating-type frequencies. SNP-specific joint effects of linkage and association were identified for loci D1, D2, D3, and D4 in multiple replicates. The strongest effect was for SNP B03T3056, which had a median p-value of 1.98 × 10(-34). No two- or three-locus effects were found in more than one replicate

Impact of temperature and precipitation extremes on the flowering dates of four German wildlife shrub species

Ongoing climate change is known to cause an increase in the frequency and amplitude of local temperature and precipitation extremes in many regions of the Earth. While gradual changes in the climatological conditions have already been shown to strongly influence plant flowering dates, the question arises if and how extremes specifically impact the timing of this important phenological phase. Studying this question calls for the application of statistical methods that are tailored to the specific properties of event time series. Here, we employ event coincidence analysis, a novel statistical tool that allows assessing whether or not two types of events exhibit similar sequences of occurrences in order to systematically quantify simultaneities between meteorological extremes and the timing of the flowering of four shrub species across Germany. Our study confirms previous findings of experimental studies by highlighting the impact of early spring temperatures on the flowering of the investigated plants. However, previous studies solely based on correlation analysis do not allow deriving explicit estimates of the strength of such interdependencies without further assumptions, a gap that is closed by our analysis. In addition to direct impacts of extremely warm and cold spring temperatures, our analysis reveals statistically significant indications of an influence of temperature extremes in the autumn preceding the flowering

Interleukin-18: A Mediator of Inflammation and Angiogenesis in Rheumatoid Arthritis

Interleukin-18 (IL-18) is a highly regulated inflammatory cytokine that is elevated in synovial tissues and synovial fluids of patients with rheumatoid arthritis (RA) compared with patients with osteoarthritis (OA) and patients with other arthropathies. Within the RA joint, IL-18 can contribute to the inflammatory process by inducing leukocyte extravasation through upregulation of endothelial cell adhesion molecules, the release of chemokines from RA synovial fibroblasts, and directly as a monocytes, lymphocyte, and neutrophil chemoattractant. IL-18 can also help maintain and develop the inflammatory pannus by inducing endothelial cell migration and angiogenesis. IL-18 does this directly by binding and activating endothelial cells and indirectly by inducing RA synovial fibroblasts to produce angiogenic chemokines and vascular endothelial growth factor. IL-18 is present in RA synovial fluid in high levels, where it functions as an angiogenic mediator and leukocyte chemoattractant. IL-18 mediates all these inflammatory processes by binding to its receptor, IL-18 receptor, and initiating the activation of different signaling cascades leading to changes in target cells gene expression and behavior. IL-18 has been identified as a potential therapeutic target in the treatment of RA.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90485/1/jir-2E2011-2E0050.pd

Particulate Matter, DNA Methylation in Nitric Oxide Synthase, and Childhood Respiratory Disease

Background: Air pollutants have been associated with childhood asthma and wheeze. Epigenetic regulation of nitric oxide synthase—the gene responsible for nitric oxide production—may be affected by air pollutants and contribute to the pathogenesis of asthma and wheeze. Objective: Our goal was to investigate the association between air pollutants, DNA methylation, and respiratory outcomes in children. Methods: Given residential address and buccal sample collection date, we estimated 7-day, 1-month, 6-month, and 1-year cumulative average $PM_{2.5}$ and $PM_{10}$ (particulate matter ≤ 2.5 and ≤ 10 µm aerodynamic diameter, respectively) exposures for 940 participants in the Children’s Health Study. Methylation of 12 CpG sites in three NOS (nitric oxide synthase) genes was measured using a bisulfite-polymerase chain reaction Pyrosequencing assay. Beta regression models were used to estimate associations between air pollutants, percent DNA methylation, and respiratory outcomes. Results: A 5-µg/$m^3$ increase in $PM_{2.5}$ was associated with a 0.20% [95% confidence interval (CI): –0.32, –0.07] to 1.0% (95% CI: –1.61, –0.56) lower DNA methylation at NOS2A position 1, 0.06% (95% CI: –0.18, 0.06) to 0.58% (95% CI: –1.13, –0.02) lower methylation at position 2, and 0.34% (95% CI: –0.57, –0.11) to 0.89% (95% CI: –1.57, –0.21) lower methylation at position 3, depending on the length of exposure and CpG locus. One-year $PM_{2.5}$ exposure was associated with 0.33% (95% CI: 0.01, 0.65) higher in average DNA methylation of 4 loci in the NOS2A CpG island. A 5-µg/$m^3$ increase in 7-day and 1-year $PM_{2.5}$ was associated with 0.6% (95% CI: 0.13, 0.99) and 2.8% (95% CI: 1.77, 3.75) higher NOS3 DNA methylation. No associations were observed for NOS1. $PM_{10}$ showed similar but weaker associations with DNA methylation in these genes. Conclusions: $PM_{2.5}$ exposure was associated with percent DNA methylation of several CpG loci in NOS genes, suggesting an epigenetic mechanism through which these pollutants may alter production of nitric oxide

A high resolution, high frame rate detector based on a microchannel plate read out with the Medipix2 counting CMOS pixel chip.

The future of ground-based optical astronomy lies with advancements in adaptive optics (AO) to overcome the limitations that the atmosphere places on high resolution imaging. A key technology for AO systems on future very large telescopes are the wavefront sensors (WFS) which detect the optical phase error and send corrections to deformable mirrors. Telescopes with >30 m diameters will require WFS detectors that have large pixel formats (512x512), low noise (<3 e-/pixel) and very high frame rates (~1 kHz). These requirements have led to the idea of a bare CMOS active pixel device (the Medipix2 chip) functioning in counting mode as an anode with noiseless readout for a microchannel plate (MCP) detector and at 1 kHz continuous frame rate. First measurement results obtained with this novel detector are presented both for UV photons and beta particles

Impacts of temperature extremes on European vegetation during the growing season

Temperature is a key factor controlling plant growth and vitality in the temperate climates of the mid-latitudes like in vast parts of the European continent. Beyond the effect of average conditions, the timings and magnitudes of temperature extremes play a particularly crucial role, which needs to be better understood in the context of projected future rises in the frequency and/or intensity of such events. In this work, we employ event coincidence analysis (ECA) to quantify the likelihood of simultaneous occurrences of extremes in daytime land surface temperature anomalies (LSTAD) and the normalized difference vegetation index (NDVI). We perform this analysis for entire Europe based upon remote sensing data, differentiating between three periods corresponding to different stages of plant development during the growing season. In addition, we analyze the typical elevation and land cover type of the regions showing significantly large event coincidences rates to identify the most severely affected vegetation types. Our results reveal distinct spatio-temporal impact patterns in terms of extraordinarily large co-occurrence rates between several combinations of temperature and NDVI extremes. Croplands are among the most frequently affected land cover types, while elevation is found to have only a minor effect on the spatial distribution of corresponding extreme weather impacts. These findings provide important insights into the vulnerability of European terrestrial ecosystems to extreme temperature events and demonstrate how event-based statistics like ECA can provide a valuable perspective on environmental nexuses