TGFβ1 single-nucleotide polymorphism C-509T alters mucosal cell function in pediatric eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a chronic Th2 antigen-driven disorder associated with tissue remodeling. Inflammation and remodeling lead to esophageal rigidity, strictures, and dysphagia. TGFβ1 drives esophageal remodeling including epithelial barrier dysfunction and subepithelial fibrosis. A functional SNP in the TGFβ1 gene that increases its transcription (C-509T) is associated with elevated numbers of esophageal TGFβ1-expressing cells. We utilized esophageal biopsies and fibroblasts from TT-genotype EoE children to understand if TGFβ1 influenced fibroblast and epithelial cell function in vivo. Genotype TT EoE esophageal fibroblasts had higher baseline TGFβ1, collagen1α1, periostin, and MMP2 (p < 0.05) gene expression and distinct contractile properties compared with CC genotype (n = 6 subjects per genotype). In vitro TGFβ1 exposure caused greater induction of target gene expression in genotype CC fibroblasts (p < 0.05). Esophageal biopsies from TT-genotype subjects had significantly less epithelial membrane-bound E-cadherin (p < 0.01) and wider cluster distribution at nanometer resolution. TGFβ1 treatment of stratified primary human esophageal epithelial cells and spheroids disrupted transepithelial resistance (p < 0.001) and E-cadherin localization (p < 0.0001). A TGFβ1-receptor-I inhibitor improved TGFβ1-mediated E-cadherin mislocalization. These data suggest that EoE severity can depend on genotypic differences that increase in vivo exposure to TGFβ1. TGFβ1 inhibition may be a useful therapy in subsets of EoE patients

The distribution of effective tax burdens in four EU countries

National policymakers are increasingly aware that their tax policy options are constrained by international tax competition. Important features of national tax systems - notably the tax mix, tax rates and rules which define the tax base - will influence decisions of firms and individuals regarding the location and (re)structuring of economic activities. The aim of the present paper is twofold: Firstly, we detail the tax mix of four member states of the European Union (Germany, The Netherlands, Spain and United Kingdom). Secondly, the paper aims to trace the distribution of the tax burden over rich and poor households in these four countries. Although tax mix and tax rates differ considerably among the four countries included in the study, the distribution of tax burdens proves to be amazingly similar.Distribution of tax burden, European Union; tax mix of Germany, the Netherlands, Spain and United Kingdom

The distribution of effective tax burdens in four EU countries

National policymakers are increasingly aware that their tax policy options are constrained by international tax competition. Important features of national tax systems - notably the tax mix, tax rates and rules which define the tax base - will influence decisions of firms and individuals regarding the location and (re)structuring of economic activities. The aim of the present paper is twofold: Firstly, we detail the tax mix of four member states of the European Union (Germany, The Netherlands, Spain and United Kingdom). Secondly, the paper aims to trace the distribution of the tax burden over rich and poor households in these four countries. Although tax mix and tax rates differ considerably among the four countries included in the study, the distribution of tax burdens proves to be amazingly similar.Distribution of tax burden, European Union; tax mix of Germany, the Netherlands, Spain and United Kingdom

Employing Channel Probing to Derive End-of-Life Service Margins for Optical Spectrum Services

Optical Spectrum as a Service (OSaaS) spanning over multiple transparent optical network domains, can significantly reduce the investment and operational costs of the end-to-end service. Based on the black-link approach, these services are empowered by reconfigurable transceivers and the emerging disaggregation trend in optical transport networks. This work investigates the accuracy aspects of the channel probing method used in Generalized Signal to Noise Ratio (GSNR)-based OSaaS characterization in terrestrial brownfield systems. OSaaS service margins to accommodate impacts from enabling neighboring channels and end-of-life channel loads are experimentally derived in a systematic lab study carried out in the Open Ireland testbed. The applicability of the lab-derived margins is then verified in the HEAnet production network using a 400 GHz wide OSaaS. Finally, the probing accuracy is tested by depleting the GSNR margin through power adjustments utilizing the same 400 GHz OSaaS in the HEAnet live network. A minimum of 0.92 dB and 1.46 dB of service margin allocation is recommended to accommodate the impacts of enabling neighboring channels and end-of-life channel loads. Further 0.6 dB of GSNR margin should be allocated to compensate for probing inaccuracies

Gamma Oscillations in the Mouse Primary Visual Cortex as an Endophenotype of Schizophrenia

Gamma oscillations (20-50 Hz) are a robust component of brain activity associated with information processing, but are also part of the background spontaneous activity during various brain states including sleep and anesthesia. Our goal was to examine the changes in gamma oscillations that result from pharmacological and genetic manipulations of glutamatergic transmission which produce endophenotypes of schizophrenia. We recorded local field potentials (LFP) and single units through the depth of the mouse primary visual cortex in vivo and examined the alterations in gamma frequency activity under both normal and pathological conditions. Our results indicate that both in awake and anesthetized animals, baseline gamma frequency power in the LFP is increased throughout the cortical lamina, and the signal-to-noise ratio of gamma oscillations produced by a visual stimulus is diminished, most notably in the superficial layers. In addition, the entrainment of single units to the local oscillations in the LFP is reduced in the supragranular (L2/3) and infragranular (L5/6) layers. This work supports the hypothesis that alterations in glutamatergic transmission result in changes to gamma oscillations in primary sensory areas and is consistent with the hypothesis that these changes are associated with disrupted sensory perception

The distribution of effective tax burdens in four EU countries

National policymakers are increasingly aware that their tax policy options are constrained by international tax competition. Important features of national tax systems - notably the tax mix, tax rates and rules which define the tax base - will influence decisions of firms and individuals regarding the location and (re)structuring of economic activities. The aim of the present paper is twofold: Firstly, we detail the tax mix of four member states of the European Union (Germany, The Netherlands, Spain and United Kingdom). Secondly, the paper aims to trace the distribution of the tax burden over rich and poor households in these four countries. Although tax mix and tax rates differ considerably among the four countries included in the study, the distribution of tax burdens proves to be amazingly similar

The distribution of effective tax burdens in four EU countries

National policymakers are increasingly aware that their tax policy options are constrained by international tax competition. Important features of national tax systems - notably the tax mix, tax rates and rules which define the tax base - will influence decisions of firms and individuals regarding the location and (re)structuring of economic activities. The aim of the present paper is twofold: Firstly, we detail the tax mix of four member states of the European Union (Germany, The Netherlands, Spain and United Kingdom). Secondly, the paper aims to trace the distribution of the tax burden over rich and poor households in these four countries. Although tax mix and tax rates differ considerably among the four countries included in the study, the distribution of tax burdens proves to be amazingly similar

Social foundations of the mathematics curriculum: a rationale for change

The nature of educational aims as criteria for worthwhile curriculum practice is explored and a cross-section of aims for mathematics education is discussed. An aim for mathematics education which emphasises the social aspect of the subject in its being, its conduct and its applications is identified and epistemological foundations for such a view of the nature of the subject are explored. It is argued that such an epistemological perspective of mathematics would be reflected in the social context of the mathematics classroom, arising from a methodology in which the subject would become more problematic and open to change, investigation and hypothesis. The aims of two major mathematics curriculum development projects (the Nuffield Mathematics Project and the School Mathematics Project) are examined to determine the extent to which their aims may take the 'social' nature of mathematics into account. The probable social context of mathematics classrooms using their materials is postulated in an attempt to characterise the nature of the subject as it is reflected in these materials. A view of the nature of mathematics held by practising teachers and by pupils is then established by drawing upon, and extrapolating from, evidence relating to the social context of mathematics classrooms at primary and secondary level. Conclusions follow, which suggest that fundamental change in mathematics education requires, as a first step, the adoption of a new epistemological perspective of the subject in order that the pursuit of the aim which emphasises the social nature of mathematics is achieved. It is suggested that this, in turn, ultimately could lead to the desired balance in the mathematics curriculum which hitherto has been lacking

Genetic variants associated with fasting blood lipids in the U.S. population: Third National Health and Nutrition Examination Survey

<p>Abstract</p> <p>Background</p> <p>The identification of genetic variants related to blood lipid levels within a large, population-based and nationally representative study might lead to a better understanding of the genetic contribution to serum lipid levels in the major race/ethnic groups in the U.S. population.</p> <p>Methods</p> <p>Using data from the second phase (1991-1994) of the Third National Health and Nutrition Examination Survey (NHANES III), we examined associations between 22 polymorphisms in 13 candidate genes and four serum lipids: high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG). Univariate and multivariable linear regression and within-gene haplotype trend regression were used to test for genetic associations assuming an additive mode of inheritance for each of the three major race/ethnic groups in the United States (non-Hispanic white, non-Hispanic black, and Mexican American).</p> <p>Results</p> <p>Variants within <it>APOE </it>(rs7412, rs429358), <it>PON1 </it>(rs854560), <it>ITGB3 </it>(rs5918), and <it>NOS3 </it>(rs2070744) were found to be associated with one or more blood lipids in at least one race/ethnic group in crude and adjusted analyses. In non-Hispanic whites, no individual polymorphisms were associated with any lipid trait. However, the <it>PON1 </it>A-G haplotype was significantly associated with LDL-C and TC. In non-Hispanic blacks, <it>APOE </it>variant rs7412 and haplotype T-T were strongly associated with LDL-C and TC; whereas, rs5918 of <it>ITGB3 </it>was significantly associated with TG. Several variants and haplotypes of three genes were significantly related to lipids in Mexican Americans: <it>PON1 </it>in relation to HDL-C; <it>APOE </it>and <it>NOS3 </it>in relation to LDL-C; and <it>APOE </it>in relation to TC.</p> <p>Conclusions</p> <p>We report the significant associations of blood lipids with variants and haplotypes in <it>APOE</it>, <it>ITGB3, NOS3</it>, and <it>PON1 </it>in the three main race/ethnic groups in the U.S. population using a large, nationally representative and population-based sample survey. Results from our study contribute to a growing body of literature identifying key determinants of plasma lipoprotein concentrations and could provide insight into the biological mechanisms underlying serum lipid and cholesterol concentrations.</p