2′-O Methylation of the Viral mRNA Cap by West Nile Virus Evades Ifit1-Dependent and -Independent Mechanisms of Host Restriction In Vivo

Prior studies have shown that 2′-O methyltransferase activity of flaviviruses, coronaviruses, and poxviruses promotes viral evasion of Ifit1, an interferon-stimulated innate immune effector protein. Viruses lacking 2′-O methyltransferase activity exhibited attenuation in primary macrophages that was rescued in cells lacking Ifit1 gene expression. Here, we examined the role of Ifit1 in restricting pathogenesis in vivo of wild type WNV (WNV-WT) and a mutant in the NS5 gene (WNV-E218A) lacking 2′-O methylation of the 5′ viral RNA cap. While deletion of Ifit1 had marginal effects on WNV-WT pathogenesis, WNV-E218A showed increased replication in peripheral tissues of Ifit1−/− mice after subcutaneous infection, yet this failed to correlate with enhanced infection in the brain or lethality. In comparison, WNV-E218A was virulent after intracranial infection as judged by increased infection in different regions of the central nervous system (CNS) and a greater than 16,000-fold decrease in LD50 values in Ifit1−/− compared to wild type mice. Ex vivo infection experiments revealed cell-type specific differences in the ability of an Ifit1 deficiency to complement the replication defect of WNV-E218A. In particular, WNV-E218A infection was impaired in both wild type and Ifit1−/− brain microvascular endothelial cells, which are believed to participate in blood-brain barrier (BBB) regulation of virus entry into the CNS. A deficiency of Ifit1 also was associated with increased neuronal death in vivo, which was both cell-intrinsic and mediated by immunopathogenic CD8+ T cells. Our results suggest that virulent strains of WNV have largely evaded the antiviral effects of Ifit1, and viral mutants lacking 2′-O methylation are controlled in vivo by Ifit1-dependent and -independent mechanisms in different cell types

Genetic variation at CYP3A is associated with age at menarche and breast cancer risk : a case-control study

Abstract Introduction We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years. Methods We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics. Results We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (P trend = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (P trend = 0.005) but not cases (P trend = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (P het = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (ORhet = 0.84, 95% CI 0.75, 0.94; ORhom = 0.81, 95% CI 0.51, 1.30; P trend = 0.002) but not for those who had their menarche age ≤11 years (ORhet = 1.06, 95% CI 0.95, 1.19, ORhom = 1.07, 95% CI 0.67, 1.72; P trend = 0.29). Conclusions To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels

Thresholds for sampled Sloan letters are smaller than sample spacing

Purpose: Although the effect of spatial sampling on the visibility of grating stimuli is well described and well understood, little research has been conducted into the effects of spatial sampling on the visibility of letter optotypes. The purpose of this study was to investigate whether thresholds for spatially sampled Sloan letters were equal to or significantly smaller than the spacing between spatial samples.----- Methods: For four visually normal subjects, we measured Sloan letter acuity thresholds, presented on a computer monitor, after the letters had been sampled by sampling arrays with 6.285 elements per square degree, (23.9 min of arc between samples for a square packed array). We used four different sampling arrays: square packed; hexagonally packed; a cone-like array with positive contrast; and a cone-like array with negative contrast. Thresholds were assessed using letter-counting rules and also Probit analysis.----- Results: Although results depended on array type, and the definition of sample spacing, letter acuity thresholds were substantially less than estimates of sample spacing by between 0.290 log units (49% less) (hexagonally sampled Probit thresholds compared with spacing between hexagonal samples) to 0.136 log units (27% less) (positive contrast cone-like sampled letter-counting thresholds compared with spacing between rows of hexagonal samples).----- Conclusions: Sample spacing is not an absolute limit for Sloan letter thresholds. By comparison with previous measurements of human foveal cone sampling of space, our findings suggest that cone sampling limits for Sloan letters could be as small as 20/4

Wildfires in Bamboo-Dominated Amazonian Forest: Impacts on Above-Ground Biomass and Biodiversity

Fire has become an increasingly important disturbance event in south-western Amazonia. We conducted the first assessment of the ecological impacts of these wildfires in 2008, sampling forest structure and biodiversity along twelve 500 m transects in the Chico Mendes Extractive Reserve, Acre, Brazil. Six transects were placed in unburned forests and six were in forests that burned during a series of forest fires that occurred from August to October 2005. Normalized Burn Ratio (NBR) calculations, based on Landsat reflectance data, indicate that all transects were similar prior to the fires. We sampled understorey and canopy vegetation, birds using both mist nets and point counts, coprophagous dung beetles and the leaf-litter ant fauna. Fire had limited influence upon either faunal or floral species richness or community structure responses, and stems <10 cm DBH were the only group to show highly significant (p = 0.001) community turnover in burned forests. Mean aboveground live biomass was statistically indistinguishable in the unburned and burned plots, although there was a significant increase in the total abundance of dead stems in burned plots. Comparisons with previous studies suggest that wildfires had much less effect upon forest structure and biodiversity in these south-western Amazonian forests than in central and eastern Amazonia, where most fire research has been undertaken to date. We discuss potential reasons for the apparent greater resilience of our study plots to wildfire, examining the role of fire intensity, bamboo dominance, background rates of disturbance, landscape and soil conditions