The association of a SNP upstream of INSIG2 with body mass index is reproduced in several but not all cohorts

A SNP upstream of the INSIG2 gene, rs7566605, was recently found to be associated with obesity as measured by body mass index (BMI) by Herbert and colleagues. The association between increased BMI and homozygosity for the minor allele was first observed in data from a genome-wide association scan of 86,604 SNPs in 923 related individuals from the Framingham Heart Study offspring cohort. The association was reproduced in four additional cohorts, but was not seen in a fifth cohort. To further assess the general reproducibility of this association, we genotyped rs7566605 in nine large cohorts from eight populations across multiple ethnicities (total n = 16,969). We tested this variant for association with BMI in each sample under a recessive model using family-based, population-based, and case-control designs. We observed a significant (p < 0.05) association in five cohorts but saw no association in three other cohorts. There was variability in the strength of association evidence across examination cycles in longitudinal data from unrelated individuals in the Framingham Heart Study Offspring cohort. A combined analysis revealed significant independent validation of this association in both unrelated (p = 0.046) and family-based (p = 0.004) samples. The estimated risk conferred by this allele is small, and could easily be masked by small sample size, population stratification, or other confounders. These validation studies suggest that the original association is less likely to be spurious, but the failure to observe an association in every data set suggests that the effect of SNP rs7566605 on BMI may be heterogeneous across population samples.     

Structures of proteins of biomedical interest from the Center for Eukaryotic Structural Genomics

The Center for Eukaryotic Structural Genomics (CESG) produces and solves the structures of proteins from eukaryotes. We have developed and operate a pipeline to both solve structures and to test new methodologies. Both NMR and X-ray crystallography methods are used for structure solution. CESG chooses targets based on sequence dissimilarity to known structures, medical relevance, and nominations from members of the scientific community. Many times proteins qualify in more than one of these categories. Here we review some of the structures that have connections to human health and disease.     

Cells of the synovium in rheumatoid arthritis. T lymphocytes

Recent findings have substantiated the importance of T lymphocytes to the pathogenesis of rheumatoid arthritis (RA). Here, we review emerging data regarding genetic predisposition, spontaneous animal models of arthritis, and cell-cell interactions that implicate T cells as driving synovial inflammation and joint destruction. Information regarding the proinflammatory role of interleukin-17-producing T cells and the functional state of regulatory T cells both in animal models and in patients with RA is also discussed. In light of the overwhelming evidence that disrupted T-cell homeostasis greatly contributes to joint pathology in RA, the therapeutic potential of targeting activators of pro-inflammatory T cells or their products is compelling.     

2'-o-dimethylaminoethoxyuridine and 5-dimethylaminopropargyl deoxyuridine for at base pair recognition in triple helices

The nucleoside analogues 2'-O-dimethylaminoethoxy uridine and 5-dimethylaminopropargyl deoxyuridine have been synthesised and incorporated into oligonucleotides. Their triplex-stabilising properties have been determined in fluorescence melting experiments.     

Microarray blob-defect removal improves array analysis

MOTIVATION: New generation Affymetrix oligonucleotide microarrays often have blob-like image defects that will require investigators to either repeat their hybridization assays or analyze their data with the defects left in place. We investigated the effect of analyzing a spike-in experiment on Affymetrix ENCODE tiling arrays in the presence of simulated blobs covering between 1 and 9% of the array area. Using two different ChIP-chip tiling array analysis programs (Affymetrix tiling array software, TAS, and model-based analysis of tiling arrays, MAT), we found that even the smallest blob defects significantly decreased the sensitivity and increased the false discovery rate (FDR) of the spike-in target prediction. RESULTS: We introduced a new software tool, the microarray blob remover (MBR), which allows rapid visualization, detection and removal of various blob defects from the .CEL files of different types of Affymetrix microarrays. It is shown that using MBR significantly improves the sensitivity and FDR of a tiling array analysis compared to leaving the affected probes in the analysis. AVAILABILITY: The MBR software and the sample array .CEL files used in this article are available at: http://liulab.dfci.harvard.edu/Software/MBR/MBR.htm     

Effects of Urbanization on the Dynamics of Organic Sediments in Temperate Lakes

Residential development of lakeshores affects the structure and function of riparian and littoral habitats. Organic detritus in sediments is a critical component of littoral food webs, but the effects of urbanization on sediment characteristics are unexplored. We characterized the quantity of organic sediments in Pacific Northwest lakes along a development gradient and found a 10-fold decline in the proportion of detritus in littoral sediments associated with density of lakeshore dwellings. In a comparison between two fully developed lakes and two undeveloped reference lakes, we examined several possible controls on sedimentary organic content, including terrestrial inputs, decomposition rates and associated macroinvertebrate communities, and physical retention by coarse wood. The littoral sediments of undeveloped lakes ranged from 34 to 77% organic by mass, whereas the range on urban lakes was an order of magnitude less, ranging from 1 to 3% organic. We found no significant differences in terrestrial litter inputs between the two sets of lakes. Leaf litter decomposition rates did not vary significantly between the two sets of lakes, and we found higher densities of shredder macroinvertebrate taxa in the littoral zones of undeveloped lakes. Sedimentary organic matter on undeveloped lakes accumulated in shallow waters and declined with distance from shore, whereas the opposite pattern existed on urban lakes. Our results suggest that coarse wood physically retains organic matter in littoral zones where it can enter the detrital energy pathway, and the loss of this feature on urban lakes alters littoral sediment characteristics, with potentially far-reaching consequences for lake food webs.     

Environmental fluctuations can stabilize food web dynamics by increasing synchrony

Natural food webs are species-rich, but classical theory suggests that they should be unstable and extinction-prone. Asynchronous fluctuations in the densities of competing consumers can stabilize food web dynamics in constant environments. However, environmental fluctuations often synchronize dynamics in nature. Using the same 'diamond-shape' food web model first used to demonstrate the stabilizing effects of asynchrony in constant environments, we show that weak-to-moderate environmentally induced fluctuations in consumer mortality rates stabilize food webs while disrupting asynchrony. Synchrony actually promotes stability because: (i) synchronous declines in consumer density reduce the maximum abundance of top predators and (ii) resource competition quickly converts synchronous increases in consumer density into synchronous declines. These results are robust to details of food web topology and the implementation of environmental fluctuations. The fluctuation strengths that enhance stability are within the range experienced naturally by many species, suggesting that stabilization via environmental fluctuations is a realistic possibility.