Comparison of Effects of p53 Null and Gain-of-Function Mutations on Salivary Tumors in MMTV-Hras Transgenic Mice

p53 is an important tumor suppressor gene which is mutated in ~50% of all human cancers. Some of these mutants appear to have acquired novel functions beyond merely losing wild-type functions. To investigate these gain-of-function effects in vivo, we generated mice of three different genotypes: MMTV-Hras/p53+/+, MMTV-Hras/p53-/-, and MMTV-Hras/p53R172H/R172H. Salivary tumors from these mice were characterized with regard to age of tumor onset, tumor growth rates, cell cycle distribution, apoptotic levels, tumor histopathology, as well as response to doxorubicin treatment. Microarray analysis was also performed to profile gene expression. The MMTV-Hras/p53-/- and MMTV-Hras/p53R172H/R172H mice displayed similar properties with regard to age of tumor onset, tumor growth rates, tumor histopathology, and response to doxorubicin, while both groups were clearly distinct from the MMTV-Hras/p53+/+ mice by these measurements. In addition, the gene expression profiles of the MMTV-Hras/p53-/- and MMTV-Hras/p53R172H/R172H tumors were tightly clustered, and clearly distinct from the profiles of the MMTV-Hras/p53+/+ tumors. Only a small group of genes showing differential expression between the MMTV-Hras/p53-/- and MMTV-Hras/p53R172H/R172H tumors, that did not appear to be regulated by wild-type p53, were identified. Taken together, these results indicate that in this MMTV-Hras-driven salivary tumor model, the major effect of the p53 R172H mutant is due to the loss of wild-type p53 function, with little or no gain-of-function effect on tumorigenesis, which may be explained by the tissue- and tumor type-specific properties of this gain-of-function mutant of p53

Redshift and Shear Calibration: Impact on Cosmic Shear Studies and Survey Design

The cosmological interpretation of weak lensing by large-scale structures requires knowledge of the redshift distribution of the source galaxies. Current lensing surveys are often calibrated using external redshift samples which span a significantly smaller sky area in comparison to the lensing survey, and are thus subject to sample variance. Some future lensing surveys are expected to be calibrated in the same way, in particular the fainter galaxy populations where the entire color coverage, and hence photometric redshift estimate, could be challenging to obtain. Using N-body simulations, we study the impact of this sample variance on cosmic shear analysis and show that, to first approximation, it behaves like a shear calibration error 1+/-epsilon. Using the Hubble Deep Field as a redshift calibration survey could therefore be a problem for current lensing surveys. We discuss the impact of the redshift distribution sampling error and a shear calibration error on the design of future lensing surveys, and find that a lensing survey of area Theta square degrees and limiting magnitude m_lim}, has a minimum shear and redshift calibration accuracy requirements given by epsilon = epsilon_0 10^{beta(m_lim-24.5)} / sqrt(Theta/ 200). Above that limit, lensing surveys would not reach their full potential. Using the galaxy number counts from the Hubble Ultra-Deep Field, we find (epsilon_0,beta)=(0.015,-0.18) and (epsilon_0,beta)=(0.011,-0.23) for ground and space based surveys respectively. Lensing surveys with no or limited redshift information and/or poor shear calibration accuracy will loose their potential to analyse the cosmic shear signal in the sub-degree angular scales, and therefore complete photometric redshift coverage should be a top priority for future lensing surveys.Comment: Accepted version to Astroparticle Physic

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Board) directed staff to convene a team of independent scientific experts to provide input regarding sediment impairment in the Freshwater, Bear, Jordan, Stitz, and Elk River watersheds. The panel was convened in August of 2002, and, produced the above-noted document o

Optical counterpart of HLX-1 during the 2010 outburst

We studied the optical counterpart of the intermediate-mass black hole candidate HLX-1 in ESO 243-49. We used a set of Very Large Telescope imaging observations from 2010 November, integrated by Swift X-ray data from the same epoch. We measured standard Vega brightnesses U = 23.89 +/- 0.18 mag, B = 25.19 +/- 0.30 mag, V = 24.79 +/- 0.34 mag and R = 24.71 +/- 0.40 mag. Therefore, the source was ~1 mag fainter in each band than in a set of Hubble Space Telescope images taken a couple of months earlier, when the X-ray flux was a factor of 2 higher. We conclude that during the 2010 September observations, the optical counterpart was dominated by emission from an irradiated disk (which responds to the varying X-ray luminosity), rather than by a star cluster around the black hole (which would not change). We modelled the Comptonized, irradiated X-ray spectrum of the disk, and found that the optical luminosity and colours in the 2010 November data are still consistent with emission from the irradiated disk, with a characteristic outer radius r_{out} ~ 2800 r_{in} ~ 10^{13} cm and a reprocessing fraction ~ 2 x 10^{-3}. The optical colours are also consistent with a stellar population with age <~ 6 Myr (at solar metallicity) and mass ~ 10^4 M_{sun}; this is only an upper limit to the mass, if there is also a significant contribution from an irradiated disk. We strongly rule out the presence of a young super-star-cluster, which would be too bright. An old globular cluster might be associated with HLX-1, as long as its mass <~ 2 x 10^6 M_{sun} for an age of 10 Gyr, but it cannot significantly contribute to the observed very blue and variable optical/UV emission.Comment: Accepted by MNRAS on Nov 28; 11 pages, 1.3 MB. v2: same paper, same price, now 20% more authors

How penalizing substance use in pregnancy affects treatment and research: A qualitative examination of researchers\u27 perspectives

INTRODUCTION: Laws regulating substance use in pregnancy are changing and may have unintended consequences on scientific efforts to address the opioid epidemic. Yet, how these laws affect care and research is poorly understood. METHODS: We conducted semi-structured qualitative interviews using purposive and snowball sampling of researchers who have engaged pregnant people experiencing substance use. We explored views on laws governing substance use in pregnancy and legal reform possibilities. Interviews were double coded. Data were examined using thematic analysis. RESULTS: We interviewed 22 researchers (response rate: 71 per cent) and identified four themes: (i) harms of punitive laws, (ii) negative legal impacts on research, (iii) proposals for legal reform, and (iv) activism over time. DISCUSSION: Researchers view laws penalizing substance use during pregnancy as failing to treat addiction as a disease and harming pregnant people and families. Respondents routinely made scientific compromises to protect participants. While some have successfully advocated for legal reform, ongoing advocacy is needed. CONCLUSION: Adverse impacts from criminalizing substance use during pregnancy extend to research on this common and stigmatized problem. Rather than penalizing substance use in pregnancy, laws should approach addiction as a medical issue and support scientific efforts to improve outcomes for affected families

The COSMOS Survey: Hubble Space Telescope / Advanced Camera for Surveys (HST/ACS) Observations and Data Processing

We describe the details of the Hubble Space Telescope (HST) Advanced Camera for Surveys / Wide Field Channel (ACS/WFC) observations of the COSMOS field, including the data calibration and processing procedures. We obtained a total of 583 orbits of HST ACS/WFC imaging in the F814W filter, covering a field that is 1.64 square degrees in area, the largest contiguous field ever imaged with HST. The median exposure depth across the field is 2028 seconds (one HST orbit), achieving a limiting point-source depth AB(F814W) = 27.2 (5 sigma). We also present details about the astrometric image registration, distortion removal and image combination using MultiDrizzle, as well as motivating the choice of our final pixel scale (30 milliarcseconds per pixel), based on the requirements for weak lensing science. The final set of images are publicly available through the archive sites at IPAC and STScI, along with further documentation on how they were produced.Comment: Accepted for ApJ COSMOS Special Issue, 17 pages, 4 figures, aastex. A version with higher resolution figures is available at: http://www.stsci.edu/~koekemoe

New constraints on dark energy from the observed growth of the most X-ray luminous galaxy clusters

We present constraints on the mean matter density, Omega_m, the normalization of the density fluctuation power spectrum, sigma_8, and the dark-energy equation-of-state parameter, w, obtained from measurements of the X-ray luminosity function of the largest known galaxy clusters at redshifts z<0.7, as compiled in the Massive Cluster Survey (MACS) and the local BCS and REFLEX galaxy cluster samples. Our analysis employs an observed mass-luminosity relation, calibrated by hydrodynamical simulations, including corrections for non-thermal pressure support and accounting for the presence of intrinsic scatter. Conservative allowances for all known systematic uncertainties are included, as are standard priors on the Hubble constant and mean baryon density. We find Omega_m=0.28 +0.11 -0.07 and sigma_8=0.78 +0.11 -0.13 for a spatially flat, cosmological-constant model, and Omega_m=0.24 +0.15 -0.07, sigma_8=0.85 +0.13 -0.20 and w=-1.4 +0.4 -0.7 for a flat, constant-w model. Future work improving our understanding of redshift evolution and observational biases affecting the mass--X-ray luminosity relation have the potential to significantly tighten these constraints. Our results are consistent with those from recent analyses of type Ia supernovae, cosmic microwave background anisotropies, the X-ray gas mass fraction of relaxed galaxy clusters, baryon acoustic oscillations and cosmic shear. Combining the new X-ray luminosity function data with current supernova, cosmic microwave background and cluster gas fraction data yields the improved constraints Omega_m=0.269 +- 0.016, sigma_8=0.82 +- 0.03 and w=-1.02 +- 0.06. (Abridged)Comment: Submitted to MNRAS. 15 pages, 15 figures. v2: Improved modeling of the mass-luminosity relation, including additional systematic allowances for evolution in the scatter and non-thermal pressure support. Constraints are somewhat weaker, but overall conclusions are unchanged

Bringing democracy back home: Community localism and the domestication of political space

Strategies of localism have constituted the community as a metaphor for democracy and empowerment as part of a wider reordering of state institutions and state power. In conflating the smallest scale with increased participation, however, community localism provides a framework through which the power of sociospatial positioning might be made vulnerable to resistance and change. This paper identifies four spatial practices through which marginalised communities apply the technology of localism to challenge the limitations of their positioning and imprint promises of empowerment and democracy on space. Drawing on the work of Judith Butler, the paper theorises these practices as the incursion into the public realm of regulatory norms related to domestic and private spaces, rendering political space familiar and malleable, and suggesting that power and decision making can be brought within reach. It is argued that these spatial practices of community rehearse a more fundamental transformation of the political ordering of space than that authorised by the state strategies of localism. © 2014 Pion and its Licensors

'To live and die [for] Dixie': Irish civilians and the Confederate States of America

Around 20,000 Irishmen served in the Confederate army in the Civil War. As a result, they left behind, in various Southern towns and cities, large numbers of friends, family, and community leaders. As with native-born Confederates, Irish civilian support was crucial to Irish participation in the Confederate military effort. Also, Irish civilians served in various supporting roles: in factories and hospitals, on railroads and diplomatic missions, and as boosters for the cause. They also, however, suffered in bombardments, sieges, and the blockade. Usually poorer than their native neighbours, they could not afford to become 'refugees' and move away from the centres of conflict. This essay, based on research from manuscript collections, contemporary newspapers, British Consular records, and Federal military records, will examine the role of Irish civilians in the Confederacy, and assess the role this activity had on their integration into Southern communities. It will also look at Irish civilians in the defeat of the Confederacy, particularly when they came under Union occupation. Initial research shows that Irish civilians were not as upset as other whites in the South about Union victory. They welcomed a return to normalcy, and often 'collaborated' with Union authorities. Also, Irish desertion rates in the Confederate army were particularly high, and I will attempt to gauge whether Irish civilians played a role in this. All of the research in this paper will thus be put in the context of the Drew Gilpin Faust/Gary Gallagher debate on the influence of the Confederate homefront on military performance. By studying the Irish civilian experience one can assess how strong the Confederate national experiment was. Was it a nation without a nationalism