Evidence of Differential Allelic Effects between Adolescents and Adults for Plasma High-Density Lipoprotein

A recent meta-analysis of genome-wide association (GWA) studies identified 95 loci that influence lipid traits in the adult population and found that collectively these explained about 25–30% of heritability for each trait. Little is known about how these loci affect lipid levels in early life, but there is evidence that genetic effects on HDL- and LDL-cholesterol (HDL-C, LDL-C) and triglycerides vary with age. We studied Australian adults (N = 10,151) and adolescents (N = 2,363) who participated in twin and family studies and for whom we have lipid phenotypes and genotype information for 91 of the 95 genetic variants. Heterogeneity tests between effect sizes in adult and adolescent cohorts showed an excess of heterogeneity for HDL-C (pHet<0.05 at 5 out of 37 loci), but no more than expected by chance for LDL-C (1 out of 14 loci), or trigycerides (0 out 24). There were 2 (out of 5) with opposite direction of effect in adolescents compared to adults for HDL-C, but none for LDL-C. The biggest difference in effect size was for LDL-C at rs6511720 near LDLR, adolescents (0.021±0.033 mmol/L) and adults (0.157±0.023 mmol/L), pHet = 0.013; followed by ZNF664 (pHet = 0.018) and PABPC4 (pHet = 0.034) for HDL-C. Our findings suggest that some of the previously identified variants associate differently with lipid traits in adolescents compared to adults, either because of developmental changes or because of greater interactions with environmental differences in adults

Structural and biochemical characterization of the exopolysaccharide deacetylase Agd3 required for Aspergillus fumigatus biofilm formation

The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Deletion of a gene encoding a putative deacetylase, Agd3, leads to defects in GAG deacetylation, biofilm formation, and virulence. Here, we show that Agd3 deacetylates GAG in a metal-dependent manner, and is the founding member of carbohydrate esterase family CE18. The active site is formed by four catalytic motifs that are essential for activity. The structure of Agd3 includes an elongated substrate-binding cleft formed by a carbohydrate binding module (CBM) that is the founding member of CBM family 87. Agd3 homologues are encoded in previously unidentified putative bacterial exopolysaccharide biosynthetic operons and in other fungal genomes. The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Here, the authors study an A. fumigatus enzyme that deacetylates GAG in a metal-dependent manner and constitutes a founding member of a new carbohydrate esterase family.Bio-organic Synthesi

Model-independent source imaging using two-pion correlations in 2 to 8A GeV Au + Au collisions

We report a particle source imaging analysis based on two-pion correlations in high multiplicity Au + Au collisions at beam energies between 2 and 8A GeV. We apply the imaging technique introduced by Brown and Danielewicz, which allows a model-independent extraction of source functions with useful accuracy out to relative pion separations of about 20 fm. The extracted source functions have Gaussian shapes. Values of source functions at zero separation are almost constant across the energy range under study. Imaging results are found to be consistent with conventional source parameters obtained from a multidimensional HBT analysis.Comment: 4 pages, 3 figure

Longitudinal Flow of Protons from 2-8 AGeV Central Au+Au Collisions

Rapidity distributions of protons from central $^{197}$Au + $^{197}$Au collisions measured by the E895 Collaboration in the energy range from 2 to 8 AGeV at the Brookhaven AGS are presented. Longitudinal flow parameters derived using a thermal model including collective longitudinal expansion are extracted from these distributions. The results show an approximately linear increase in the longitudinal flow velocity, $_{L}$, as a function of the logarithm of beam energy.Comment: 5 Pages, including 3 figures, 1 tabl

Charged Pion Production in 2 to 8 AGeV Central Au+Au Collisions

Momentum spectra of charged pions over nearly full rapidity coverage from target to beam rapidity have been measured in the 0-5% most central Au+Au collisions in the beam energy range from 2 to 8 AGeV by the E895 Experiment. Using a thermal parameterization to fit the transverse mass spectra, rapidity density distributions are extracted. The observed spectra are compared with predictions from the RQMD v2.3 cascade model and also to a thermal model including longitudinal flow. The total 4$\pi$ yields of the charged pions are used to infer an initial state entropy produced in the collisions.Comment: 13 pgs, 19 figs, accepted by Phys. Rev. C. Data tables available at http://nuclear.ucdavis.edu/~e895/published_spectra.htm

Laying the groundwork at the AGS: Recent results from experiment E895

The E895 Collaboration at the Brookhaven AGS has performed a systematic investigation of Au+Au collisions at 2-8 AGeV, using a large-acceptance Time Projection Chamber. In addition to extensive measurements of particle flow, spectra, two-particle interferometry, and strangeness production, we have performed novel hybrid analyses, including azimuthally-sensitive pion HBT, extraction of the six-dimensional pion phasespace density, and a first measurement of the Lambda-proton correlation function.Comment: Presented at Quark Matter 2001, 8 pages, 5 figure

Near-threshold production of the multi-strange Ξ−\Xi^- hyperon

The yield for the multi-strange $\Xi^{-}$ hyperon has been measured in 6 AGeV Au+Au collisions via reconstruction of its decay products $\pi^{-}$ and $\Lambda$, the latter also being reconstructed from its daughter tracks of $\pi^{-}$ and p. The measurement is rather close to the threshold for $\Xi^{-}$ production and therefore provides an important test of model predictions. The measured yield for $\Xi^{-}$ and $\Lambda$ are compared for several centralities. In central collisions the $\Xi^{-}$ yield is found to be in excellent agreement with statistical and transport model predictions, suggesting that multi-strange hadron production approaches chemical equilibrium in high baryon density nuclear matter.Comment: Submitted to PR

Comparison of Source Images for protons, π−\pi^-'s and Λ\Lambda's in 6 AGeV Au+Au collisions

Source images are extracted from two-particle correlations constructed from strange and non-strange hadrons produced in 6 AGeV Au + Au collisions. Very different source images result from pp vs p$\Lambda$ vs $\pi^-\pi^-$ correlations. These observations suggest important differences in the space-time emission histories for protons, pions and neutral strange baryons produced in the same events

PPAR? Downregulation by TGF in Fibroblast and Impaired Expression and Function in Systemic Sclerosis: A Novel Mechanism for Progressive Fibrogenesis

The nuclear orphan receptor peroxisome proliferator-activated receptor-gamma (PPAR-γ) is expressed in multiple cell types in addition to adipocytes. Upon its activation by natural ligands such as fatty acids and eicosanoids, or by synthetic agonists such as rosiglitazone, PPAR-γ regulates adipogenesis, glucose uptake and inflammatory responses. Recent studies establish a novel role for PPAR-γ signaling as an endogenous mechanism for regulating transforming growth factor-ß (TGF-ß)- dependent fibrogenesis. Here, we sought to characterize PPAR-γ function in the prototypic fibrosing disorder systemic sclerosis (SSc), and delineate the factors governing PPAR-γ expression. We report that PPAR-γ levels were markedly diminished in skin and lung biopsies from patients with SSc, and in fibroblasts explanted from the lesional skin. In normal fibroblasts, treatment with TGF-ß resulted in a time- and dose-dependent down-regulation of PPAR-γ expression. Inhibition occurred at the transcriptional level and was mediated via canonical Smad signal transduction. Genome-wide expression profiling of SSc skin biopsies revealed a marked attenuation of PPAR-γ levels and transcriptional activity in a subset of patients with diffuse cutaneous SSc, which was correlated with the presence of a ''TGF-ß responsive gene signature'' in these biopsies. Together, these results demonstrate that the expression and function of PPAR-γ are impaired in SSc, and reveal the existence of a reciprocal inhibitory cross-talk between TGF-ß activation and PPAR-γ signaling in the context of fibrogenesis. In light of the potent anti-fibrotic effects attributed to PPAR-γ, these observations lead us to propose that excessive TGF-ß activity in SSc accounts for impaired PPAR-γ function, which in turn contributes to unchecked fibroblast activation and progressive fibrosis. © 2010 Wei et al