Effect of treatment with a Nrf2 activator on in vivo proteostasis in mice

2019 Summer.Includes bibliographical references.Aging is characterized by progressive declines in cellular function, often resulting from oxidative stress. Redox homeostasis is perturbed when the production of reactive oxygen species (ROS) exceeds the capacity of antioxidant defenses to eliminate ROS. Chronic imbalances in ROS production and clearance can lead to disruptions in proteostasis by causing unrepairable damage to proteins. Nuclear factor erythroid-derived 2-like 2 (Nrf2) exerts transcriptional regulation over endogenous antioxidant defenses by regulating the transcription of antioxidant enzymes and a myriad of cytoprotective proteins. Nrf2 activation has received attention as a therapeutic intervention to preserve cellular function. Our lab has characterized the treatment effects of Protandim and PB125, phytochemical compounds known to activate Nrf2. The collective findings from our group using both in vitro and in vivo experiments suggest that both compounds are effective for improving proteostasis; however, compared to Protandim, PB125 is more efficacious for sustained Nrf2 activation due to its ability to inhibit mechanisms of the Nrf2 shutdown pathway. We speculate that PB125 may have additional benefits on mechanism of proteostasis in vivo; thus, the purpose of the present study was to examine the effects of two doses of PB125 supplementation on proteostasis. We randomly assigned 51 male C57BL6/J mice aged 15-16 months to diets with 0 ppm (CON), 100 ppm (LOW), or 300 ppm (HIGH) doses of PB125 n=18/group during a 5-week feeding study. Mice were isotopically labeled with 8% deuterium oxide (D2O) administered in the drinking water to simultaneously measure protein and DNA synthesis rates in mitochondrial (mito), cytosolic (cyto), and mixed (mixed) subcellular fractions of heart, liver, and skeletal muscle tissues. We hypothesized that mice treated with PB125 would have enhanced proteostasis outcomes; however, our results indicate that PB125 supplementation did not affect mechanisms of proteostasis. No significant differences were found in protein or DNA synthesis rates between treatment groups, and our secondary measures further support that PB125 did not affect the proteostatic network, as there were no significant differences observed in Nrf2-regulated protein expression or protein aggregation. From our data we were able to confirm that oral administration of PB125 is safe; however, further in vivo investigations are warranted in order to confirm the role of PB125 in modulating mechanisms of proteostasis

Addressing Youth Perceptions of Harm in Marijuana Prevention Programming

The inverse relationship between perception of harm and substance use is clearly supported by decades of research – youth are less likely to engage in substance use when it is seen as harmful. However, despite strong theoretical and practical reasons to focus on perception of harm as a change-producer in prevention programming, little is known about what is effective in impacting perception of harm for youth marijuana use. To investigate the impact of existing prevention efforts designed to influence youth perception of harm and, consequently, youth marijuana use, we reviewed seven privately- or federally-funded online registries (e.g., Blueprints for Healthy Youth Development, Substance Abuse and Mental Health Administration’s National Registry of Evidence Based Programs and Practices) to identify evidence-based programs with marijuana-related outcomes for youth. We found 36 registry-identified programs with demonstrated impact on youth marijuana use. Although many of these programs may have actively or passively sought to alter perception of harm, only ten measured marijuana- or drug-related perception of harm as an intermediate outcome. Drawing on the commonalities of evidence-based programs with significant impacts on youth marijuana perception of harm, as well as lessons learned from other health behavior change efforts, we recommend best practices to provide state and local decision-makers with information on altering youth perception of harm for marijuana and on evaluating the impact of these efforts

About Being Accessible: Your Communication from a Universal Design Perspective

This session will touch on several aspects of universal design for accessibility, including multiple means of representation, the use of at-tags, and captioning and transcription. Some of the hardware and software tools that help make content more widely accessible will be described, including browse plug-ins that render web site pages in a dyslexia-friendly font. We will touch on the proposed 508 Standards refresh, and offer links to content describing the nature of these changes. Several resources for improving document accessibility will be offered

Near-Infrared Properties of Metal-poor Globular Clusters in the Galactic Bulge Direction

Aims. J, H, and K' images obtained from the near-infrared imager CFHTIR on the Canada-France-Hawaii Telescope are used to derive the morphological parameters of the red giant branch (RGB) in the near-infrared color-magnitude diagrams for 12 metal-poor globular clusters in the Galactic bulge direction. Using the compiled data set of the RGB parameters for the observed 12 clusters, in addition to the previously studied 5 clusters, we discuss the properties of the RGB morphology for the clusters and compare them with the calibration relations for the metal-rich bulge clusters and the metal-poor halo clusters. Methods. The photometric RGB shape indices such as colors at fixed magnitudes of MK = MH = (-5.5, -5, -4, and -3), magnitudes at fixed colors of (J - K)o = (J - H)o = 0.7, and the RGB slope are measured from the fiducial normal points defined in the near- infrared color-magnitude diagrams for each cluster. The magnitudes of RGB bump and tip are also estimated from the differential and cumulative luminosity functions of the selected RGB stars. The derived RGB parameters have been used to examine the overall behaviors of the RGB morphology as a function of cluster metallicity. Results. The correlations between the near-infrared photometric RGB shape indices and the cluster metallicity for the programme clusters compare favorably with the previous observational calibration relations for metal-rich clusters in the Galactic bulge and the metal-poor halo clusters. The observed near-infrared magnitudes of the RGB bump and tip for the investigated clusters are also in accordance with the previous calibration relations for the Galactic bulge clusters.Comment: 12 pages, 9 figures, accepted for publication in Astronomy & Astrophysic

The Far-Ultraviolet Spectra of TW Hya. II. Models of H2 Fluorescence in a Disk

We measure the temperature of warm gas at planet-forming radii in the disk around the classical T Tauri star (CTTS) TW Hya by modelling the H2 fluorescence observed in HST/STIS and FUSE spectra. Strong Ly-alpha emission irradiates a warm disk surface within 2 AU of the central star and pumps certain excited levels of H2. We simulate a 1D plane-parallel atmosphere to estimate fluxes for the 140 observed H2 emission lines and to reconstruct the Ly-alpha emission profile incident upon the warm H2. The excitation of H2 can be determined from relative line strengths by measuring self-absorption in lines with low-energy lower levels, or by reconstructing the Ly-alpha profile incident upon the warm H2 using the total flux from a single upper level and the opacity in the pumping transition. Based on those diagnostics, we estimate that the warm disk surface has a column density of log N(H2)=18.5^{+1.2}_{-0.8}, a temperature T=2500^{+700}_{-500} K, and a filling factor of H2, as seen by the source of Ly-alpha emission, of 0.25\pm0.08 (all 2-sigma error bars). TW Hya produces approximately 10^{-3} L_\odot in the FUV, about 85% of which is in the Ly-alpha emission line. From the H I absorption observed in the Ly-alpha emission, we infer that dust extinction in our line of sight to TW Hya is negligible.Comment: Accepted by ApJ. 26 pages, 17 figures, 6 table

Numerically Modeling the First Peak of the Type IIb SN 2016gkg

Many Type IIb supernovae (SNe) show a prominent additional early peak in their light curves, which is generally thought to be due to the shock cooling of extended hydrogen-rich material surrounding the helium core of the exploding star. The recent SN 2016gkg was a nearby Type IIb SN discovered shortly after explosion, which makes it an excellent candidate for studying this first peak. We numerically explode a large grid of extended envelope models and compare these to SN 2016gkg to investigate what constraints can be derived from its light curve. This includes exploring density profiles for both a convective envelope and an optically thick steady-state wind, the latter of which has not typically been considered for Type IIb SNe models. We find that roughly $\sim0.02\,M_\odot$ of extended material with a radius of $\approx180-260\,R_\odot$ reproduces the photometric light curve data, consistent with pre-explosion imaging. These values are independent of the assumed density profile of this material, although a convective profile provides a somewhat better fit. We infer from our modeling that the explosion must have occurred within $\approx2-3\,{\rm hrs}$ of the first observed data point, demonstrating that this event was caught very close to the moment of explosion. Nevertheless, our best-fitting one-dimensional models overpredict the earliest velocity measurements, which suggests that the hydrogen-rich material is not distributed in a spherically symmetric manner. We compare this to the asymmetries seen in the SN IIb remnant Cas A, and we discuss the implications of this for Type IIb SN progenitors and explosion models.Comment: 8 pages, 8 figures, updated version accepted for publication in The Astrophysical Journa