The Three-Dimensional Structure of Cassiopeia A

We used the Spitzer Space Telescope's Infrared Spectrograph to map nearly the entire extent of Cassiopeia A between 5-40 micron. Using infrared and Chandra X-ray Doppler velocity measurements, along with the locations of optical ejecta beyond the forward shock, we constructed a 3-D model of the remnant. The structure of Cas A can be characterized into a spherical component, a tilted thick disk, and multiple ejecta jets/pistons and optical fast-moving knots all populating the thick disk plane. The Bright Ring in Cas A identifies the intersection between the thick plane/pistons and a roughly spherical reverse shock. The ejecta pistons indicate a radial velocity gradient in the explosion. Some ejecta pistons are bipolar with oppositely-directed flows about the expansion center while some ejecta pistons show no such symmetry. Some ejecta pistons appear to maintain the integrity of the nuclear burning layers while others appear to have punched through the outer layers. The ejecta pistons indicate a radial velocity gradient in the explosion. In 3-D, the Fe jet in the southeast occupies a "hole" in the Si-group emission and does not represent "overturning", as previously thought. Although interaction with the circumstellar medium affects the detailed appearance of the remnant and may affect the visibility of the southeast Fe jet, the bulk of the symmetries and asymmetries in Cas A are intrinsic to the explosion.Comment: Accepted to ApJ. 54 pages, 21 figures. For high resolution figures and associated mpeg movie and 3D PDF files, see http://homepages.spa.umn.edu/~tdelaney/pape

Locating the most energetic electrons in Cassiopeia A

We present deep ($>$2.4 Ms) observations of the Cassiopeia A supernova remnant with {\it NuSTAR}, which operates in the 3--79 keV bandpass and is the first instrument capable of spatially resolving the remnant above 15 keV. We find that the emission is not entirely dominated by the forward shock nor by a smooth "bright ring" at the reverse shock. Instead we find that the $>$15 keV emission is dominated by knots near the center of the remnant and dimmer filaments near the remnant's outer rim. These regions are fit with unbroken power-laws in the 15--50 keV bandpass, though the central knots have a steeper ($\Gamma \sim -3.35$) spectrum than the outer filaments ($\Gamma \sim -3.06$). We argue this difference implies that the central knots are located in the 3-D interior of the remnant rather than at the outer rim of the remnant and seen in the center due to projection effects. The morphology of $>$15 keV emission does not follow that of the radio emission nor that of the low energy ($<$12 keV) X-rays, leaving the origin of the $>$15 keV emission as an open mystery. Even at the forward shock front we find less steepening of the spectrum than expected from an exponentially cut off electron distribution with a single cutoff energy. Finally, we find that the GeV emission is not associated with the bright features in the {\it NuSTAR} band while the TeV emission may be, suggesting that both hadronic and leptonic emission mechanisms may be at work.Comment: 12 pages, 11 figures, accepted for publication in Ap

Perceived access and barriers to care among illicit drug users and hazardous drinkers: findings from the Seek, Test, Treat, and Retain data harmonization initiative (STTR).

BACKGROUND: Illicit drug use (DU) and hazardous drinking (HD) among marginalized populations may be associated with greater barriers to care. METHODS: We used baseline data on the participants of the Seek, Test, Treat, and Retain data harmonization initiative. DU includes use of any illicit drugs within the past 6 months. HD was defined as scores ≥8 for men and ≥ 7 for women on Alcohol Use Disorders Identification Test within the past 12 months. Social support scores were assigned by summing scores from individual questions related to social support. Two outcomes for multivariable regression models and mediation analysis were perceived access to care and perceived barriers to care scores, calculated from summated points from individual questions within each domain. All models were adjusted for age, gender, race/ethnicity, and social support and stratified by HIV status. RESULTS: Among 1403 illicit drug users and 4984 non-drug users, the mean age was 39.6 ± 12.2 years old, 71% were male, 57% African Americans, and 39% Hispanic/Latinos. Over 25% reported difficulties in covering medical costs and finding transportation to health care facilities and greater proportions of drug users and hazardous drinkers reported these issues than non-DU/non-HD. In multivariable models, DU and HD were both independently associated with having greater barriers to care (β: 0.49 (95% confidence interval: 0.19 to 0.79) p \u3c 0.01; 0.31 (0.18 to 0.45) \u3c 0.01) in HIV-negative participants. Neither DU nor HD was strongly associated with barriers to care for HIV-positive participants. Social support was associated with better perceived access to care and fewer barriers to care in the HIV-negative participants. CONCLUSION: The current study found that financial burdens of care, logistical difficulties in accessing care, and low social support were common challenges among individuals using illicit drugs and/or drinking hazardously. Addressing structural barriers and strengthening social support may be important strategies to improve health care among marginalized populations, regardless of HIV status

The distribution of radioactive 44Ti in Cassiopeia A

The distribution of elements produced in the innermost layers of a supernova explosion is a key diagnostic for studying the collapse of massive stars. Here we present the results of a 2.4 Ms NuSTAR observing campaign aimed at studying the supernova remnant Cassiopeia A (Cas A). We perform spatially resolved spectroscopic analyses of the 44Ti ejecta, which we use to determine the Doppler shift and thus the three-dimensional (3D) velocities of the 44Ti ejecta. We find an initial 44Ti mass of (1.54 ± 0.21) × 10−4 M⊙, which has a present-day average momentum direction of 340° ± 15° projected onto the plane of the sky (measured clockwise from celestial north) and is tilted by 58° ± 20° into the plane of the sky away from the observer, roughly opposite to the inferred direction of motion of the central compact object. We find some 44Ti ejecta that are clearly interior to the reverse shock and some that are clearly exterior to it. Where we observe 44Ti ejecta exterior to the reverse shock we also see shock-heated iron; however, there are regions where we see iron but do not observe 44Ti. This suggests that the local conditions of the supernova shock during explosive nucleosynthesis varied enough to suppress the production of 44Ti by at least a factor of two in some regions, even in regions that are assumed to be the result of processes like α-rich freezeout that should produce both iron and titanium

Effects of CYP3A4 and CYP2C9 genotype on systemic anastrozole and fulvestrant concentrations in SWOG S0226

Objective &amp; methods: This study tested associations of genotype-predicted activity of CYP3A4, other pharmacogenes, SLC28A7 (rs11648166) and ALPPL2 (rs28845026) with systemic concentrations of the endocrine therapies anastrozole and fulvestrant in SWOG S0226 trial participants. Results: Participants in the anastrozole-only arm with low CYP3A4 activity (i.e. CYP3A4*22 carriers) had higher systemic anastrozole concentrations than patients with high CYP3A4 activity (β-coefficient&nbsp;=&nbsp;10.03; 95% CI: 1.42, 18.6; p&nbsp;=&nbsp;0.025). In an exploratory analysis, participants with low CYP2C9 activity had lower anastrozole concentrations and higher fulvestrant concentrations than participants with high CYP2C9 activity. Conclusion: Inherited genetic variation in CYP3A4 and CYP2C9 may affect concentrations of endocrine therapy and may be useful to personalize dosing and improve treatment outcomes

Making 'chemical cocktails' - evolution of urban geochemical processes across the periodic table of elements.

Urbanization contributes to the formation of novel elemental combinations and signatures in terrestrial and aquatic watersheds, also known as 'chemical cocktails.' The composition of chemical cocktails evolves across space and time due to: (1) elevated concentrations from anthropogenic sources, (2) accelerated weathering and corrosion of the built environment, (3) increased drainage density and intensification of urban water conveyance systems, and (4) enhanced rates of geochemical transformations due to changes in temperature, ionic strength, pH, and redox potentials. Characterizing chemical cocktails and underlying geochemical processes is necessary for: (1) tracking pollution sources using complex chemical mixtures instead of individual elements or compounds; (2) developing new strategies for co-managing groups of contaminants; (3) identifying proxies for predicting transport of chemical mixtures using continuous sensor data; and (4) determining whether interactive effects of chemical cocktails produce ecosystem-scale impacts greater than the sum of individual chemical stressors. First, we discuss some unique urban geochemical processes which form chemical cocktails, such as urban soil formation, human-accelerated weathering, urban acidification-alkalinization, and freshwater salinization syndrome. Second, we review and synthesize global patterns in concentrations of major ions, carbon and nutrients, and trace elements in urban streams across different world regions and make comparisons with reference conditions. In addition to our global analysis, we highlight examples from some watersheds in the Baltimore-Washington DC region, which show increased transport of major ions, trace metals, and nutrients across streams draining a well-defined land-use gradient. Urbanization increased the concentrations of multiple major and trace elements in streams draining human-dominated watersheds compared to reference conditions. Chemical cocktails of major and trace elements were formed over diurnal cycles coinciding with changes in streamflow, dissolved oxygen, pH, and other variables measured by high-frequency sensors. Some chemical cocktails of major and trace elements were also significantly related to specific conductance (p<0.05), which can be measured by sensors. Concentrations of major and trace elements increased, peaked, or decreased longitudinally along streams as watershed urbanization increased, which is consistent with distinct shifts in chemical mixtures upstream and downstream of other major cities in the world. Our global analysis of urban streams shows that concentrations of multiple elements along the Periodic Table significantly increase when compared with reference conditions. Furthermore, similar biogeochemical patterns and processes can be grouped among distinct mixtures of elements of major ions, dissolved organic matter, nutrients, and trace elements as chemical cocktails. Chemical cocktails form in urban waters over diurnal cycles, decades, and throughout drainage basins. We conclude our global review and synthesis by proposing strategies for monitoring and managing chemical cocktails using source control, ecosystem restoration, and green infrastructure. We discuss future research directions applying the watershed chemical cocktail approach to diagnose and manage environmental problems. Ultimately, a chemical cocktail approach targeting sources, transport, and transformations of different and distinct elemental combinations is necessary to more holistically monitor and manage the emerging impacts of chemical mixtures in the world's fresh waters

Cellular Growth Kinetics Distinguish a Cyclophilin Inhibitor from an HSP90 Inhibitor as a Selective Inhibitor of Hepatitis C Virus

During antiviral drug discovery, it is critical to distinguish molecules that selectively interrupt viral replication from those that reduce virus replication by adversely affecting host cell viability. In this report we investigate the selectivity of inhibitors of the host chaperone proteins cyclophilin A (CypA) and heat-shock protein 90 (HSP90) which have each been reported to inhibit replication of hepatitis C virus (HCV). By comparing the toxicity of the HSP90 inhibitor, 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) to two known cytostatic compounds, colchicine and gemcitabine, we provide evidence that 17-AAG exerts its antiviral effects indirectly through slowing cell growth. In contrast, a cyclophilin inhibitor, cyclosporin A (CsA), exhibited selective antiviral activity without slowing cell proliferation. Furthermore, we observed that 17-AAG had little antiviral effect in a non-dividing cell-culture model of HCV replication, while CsA reduced HCV titer by more than two orders of magnitude in the same model. The assays we describe here are useful for discriminating selective antivirals from compounds that indirectly affect virus replication by reducing host cell viability or slowing cell growth