2,534 research outputs found

    Quantitative Proteomic and Metabolomic Profiling Reveals Altered Mitochondrial Metabolism and Folate Biosynthesis Pathways in the Aging Drosophila Eye

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    Aging is associated with increased risk of ocular disease, suggesting that age-associated molecular changes in the eye increase its vulnerability to damage. Although there are common pathways involved in aging at an organismal level, different tissues and cell types exhibit specific changes in gene expression with advanced age. Drosophila melanogaster is an established model system for studying aging and neurodegenerative disease that also provides a valuable model for studying age-associated ocular disease. Flies, like humans, exhibit decreased visual function and increased risk of retinal degeneration with age. Here, we profiled the aging proteome and metabolome of the Drosophila eye and compared these data with age-associated transcriptomic changes from both eyes and photoreceptors to identify alterations in pathways that could lead to age-related phenotypes in the eye. Of note, the proteomic and metabolomic changes observed in the aging eye are distinct from those observed in the head or whole fly, suggesting that tissue-specific changes in protein abundance and metabolism occur in the aging fly. Our integration of the proteomic, metabolomic, and transcriptomic data reveals that changes in metabolism, potentially due to decreases in availability of B vitamins, together with chronic activation of the immune response, may underpin many of the events observed in the aging Drosophila eye. We propose that targeting these pathways in the genetically tractable Drosophila system may help to identify potential neuroprotective approaches for neurodegenerative and age-related ocular diseases. Data are available via ProteomeXchange with identifier PXD027090

    Comment on ``the Klein-Gordon Oscillator''

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    The different ways of description of the S=0S=0 particle with oscillator-like interaction are considered. The results are in conformity with the previous paper of S. Bruce and P. Minning.Comment: LaTeX file, 5p

    How do you foresee the requirements for ultrasonic standards changing as NDE evolves from a defect detection mode to a quantitative defect characterization mode?

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    The topic of our panel discussion is: How do you foresee the requirements for ultrasonic standards changing as NDE evolves from a defect detection mode to a defect characterization mode? We\u27ve heard a number of comments yesterday and today about the problem of standards. Our plan for the balance of the day in the panel session is to hear from a group of experts who have had considerable experience, and therefore, have developed varied opinions on the problem of standards. We\u27ll hear briefly from each of them, and then have an open discussion where those in the audience are invited to participate

    1-Alpha, 25-dihydroxyvitamin D3 alters the pharmacokinetics of mycophenolic acid in renal transplant recipients by regulating two extrahepatic UDP-glucuronosyltransferases 1A8 and 1A10

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    Mycophenolic acid (MPA) is an important immunosuppressant broadly used in renal transplantation. However, the large inter-patient variability in mycophenolic acid (MPA) pharmacokinetics (PK) limits its use. We hypothesize that extrahepatic metabolism of MPA may have significant impact on MPA PK variability. Two intestinal UDP-glucuronosyltransferases 1A8 and 1A10 plays critical role in MPA metabolism. Both in silico and previous genome-wide analyses suggested that vitamin D (VD) may regulate intestinal UGT1A expression. We validated the VD response elements (VDREs) across the UGT1A locus with chromatin immunoprecipitation (ChIP) and luciferase reporter assays. The impact of 1-alpha,25-dihydroxyvitamin D3 (D3) on UGT1A8 and UGT1A10 transcription and on MPA glucuronidation was tested in human intestinal cell lines LS180, Caco-2 and HCT-116. The correlation between transcription levels of VD receptor (VDR) and the two UGT genes were examined in human normal colorectal tissue samples (n = 73). PK alterations of MPA following the parent drug, mycophenolate mofetil (MMF), and D3 treatment was assessed among renal transplant recipients (n = 10). Our ChIP assay validate three VDREs which were further demonstrated as transcriptional enhancers with the luciferase assays. D3 treatment significantly increased transcription of both UGT genes as well as MPA glucuronidation in cells. The VDR mRNA level was highly correlated with that of both UGT1A8 and UGT1A10 in human colorectal tissue. D3 treatment in patients led to about 40% reduction in both AUC0-12 and Cmax while over 70% elevation of total clearance of MPA. Our study suggested a significant regulatory role of VD on MPA metabolism and PK via modulating extrahepatic UGT activity

    Association between an Internet-Based Measure of Area Racism and Black Mortality

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    Racial disparities in health are well-documented and represent a significant public health concern in the US. Racism-related factors contribute to poorer health and higher mortality rates among Blacks compared to other racial groups. However, methods to measure racism and monitor its associations with health at the population-level have remained elusive. In this study, we investigated the utility of a previously developed Internet search-based proxy of area racism as a predictor of Black mortality rates. Area racism was the proportion of Google searches containing the “N-word” in 196 designated market areas (DMAs). Negative binomial regression models were specified taking into account individual age, sex, year of death, and Census region and adjusted to the 2000 US standard population to examine the association between area racism and Black mortality rates, which were derived from death certificates and mid-year population counts collated by the National Center for Health Statistics (2004–2009). DMAs characterized by a one standard deviation greater level of area racism were associated with an 8.2% increase in the all-cause Black mortality rate, equivalent to over 30,000 deaths annually. The magnitude of this effect was attenuated to 5.7% after adjustment for DMA-level demographic and Black socioeconomic covariates. A model controlling for the White mortality rate was used to further adjust for unmeasured confounders that influence mortality overall in a geographic area, and to examine Black-White disparities in the mortality rate. Area racism remained significantly associated with the all-cause Black mortality rate (mortality rate ratio = 1.036; 95% confidence interval = 1.015, 1.057; p = 0.001). Models further examining cause-specific Black mortality rates revealed significant associations with heart disease, cancer, and stroke. These findings are congruent with studies documenting the deleterious impact of racism on health among Blacks. Our study contributes to evidence that racism shapes patterns in mortality and generates racial disparities in health

    Drop Formation and Breakup of Low Viscosity Elastic Fluids: Effects of Molecular Weight and Concentration

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    Submitted to Phys. FluidsThe dynamics of drop formation and pinch-off have been investigated for a series of low viscosity elastic fluids possessing similar shear viscosities, but differing substantially in elastic properties. On initial approach to the pinch region, the viscoelastic fluids all exhibit the same global necking behaviour that is observed for a Newtonian fluid of equivalent shear viscosity. For these low viscosity dilute polymer solutions, inertial and capillary forces form the dominant balance in this potential flow regime, with the viscous force being negligible. The approach to the pinch point, which corresponds to the point of rupture for a Newtonian fluid, is extremely rapid in such solutions, with the sudden increase in curvature producing very large extension rates at this location. In this region the polymer molecules are significantly extended, causing a localised increase in the elastic stresses, which grow to balance the capillary pressure. This prevents the necked fluid from breaking off, as would occur in the equivalent Newtonian fluid. Alternatively, a cylindrical filament forms in which elastic stresses and capillary pressure balance, and the radius decreases exponentially with time. A (0+1)-dimensional FENE dumbbell theory incorporating inertial, capillary and elastic stresses is able to capture the basic features of the experimental observations. Before the critical ‘pinch time’ tp , an inertial-capillary balance leads to the expected 2/3-power scaling of the minimum radius with time, Rmin ∌ (tp − t)^2/3. However, the diverging deformation rate results in large molecular deformations and rapid crossover to an elasto-capillary balance for times t > tp. In this region the filament radius decreases exponentially with time Rmin ~exp[(tp - t) / λ1], where λ1 is the characteristic time constant of the polymer molecules. Measurements of the relaxation times of PEO solutions of varying concentrations and molecular weights obtained from high speed imaging of the rate of change of filament radius are significantly higher than the relaxation times estimated from Rouse-Zimm theory, even though the solutions are within the dilute concentration region as determined using intrinsic viscosity measurements. The effective relaxation times exhibit the expected scaling with molecular weight but with an additional dependence on the concentration of the polymer in solution. This is consistent with the expectation that the polymer molecules are in fact highly extended during the approach to the pinch region (i.e. prior to the elasto-capillary filament thinning regime) and subsequently as the filament is formed they are further extended by filament stretching at a constant rate until full extension of the polymer coil is achieved. In this highly-extended state, inter-molecular interactions become significant producing relaxation times far above theoretical predictions for dilute polymer solutions under equilibrium conditions.Australian Research Counci
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