Summary and recommendations on nuclear electric propulsion technology for the space exploration initiative

A project in Nuclear Electric Propulsion (NEP) technology is being established to develop the NEP technologies needed for advanced propulsion systems. A paced approach has been suggested which calls for progressive development of NEP component and subsystem level technologies. This approach will lead to major facility testing to achieve TRL-5 for megawatt NEP for SEI mission applications. This approach is designed to validate NEP power and propulsion technologies from kilowatt class to megawatt class ratings. Such a paced approach would have the benefit of achieving the development, testing, and flight of NEP systems in an evolutionary manner. This approach may also have the additional benefit of synergistic application with SEI extraterrestrial surface nuclear power applications

Geomechanics of penetration : experimental and computational approaches : final report for LDRD project 38718.

The purpose of the present work is to increase our understanding of which properties of geomaterials most influence the penetration process with a goal of improving our predictive ability. Two primary approaches were followed: development of a realistic, constitutive model for geomaterials and designing an experimental approach to study penetration from the target's point of view. A realistic constitutive model, with parameters based on measurable properties, can be used for sensitivity analysis to determine the properties that are most important in influencing the penetration process. An immense literature exists that is devoted to the problem of predicting penetration into geomaterials or similar man-made materials such as concrete. Various formulations have been developed that use an analytic or more commonly, numerical, solution for the spherical or cylindrical cavity expansion as a sort of Green's function to establish the forces acting on a penetrator. This approach has had considerable success in modeling the behavior of penetrators, both as to path and depth of penetration. However the approach is not well adapted to the problem of understanding what is happening to the material being penetrated. Without a picture of the stress and strain state imposed on the highly deformed target material, it is not easy to determine what properties of the target are important in influencing the penetration process. We developed an experimental arrangement that allows greater control of the deformation than is possible in actual penetrator tests, yet approximates the deformation processes imposed by a penetrator. Using explosive line charges placed in a central borehole, we loaded cylindrical specimens in a manner equivalent to an increment of penetration, allowing the measurement of the associated strains and accelerations and the retrieval of specimens from the more-or-less intact cylinder. Results show clearly that the deformation zone is highly concentrated near the borehole, with almost no damage occurring beyond 1/2 a borehole diameter. This implies penetration is not strongly influenced by anything but the material within a diameter or so of the penetration. For penetrator tests, target size should not matter strongly once target diameters exceed some small multiple of the penetrator diameter. Penetration into jointed rock should not be much affected unless a discontinuity is within a similar range. Accelerations measured at several points along a radius from the borehole are consistent with highly-concentrated damage and energy absorption; At the borehole wall, accelerations were an order of magnitude higher than at 1/2 a diameter, but at the outer surface, 8 diameters away, accelerations were as expected for propagation through an elastic medium. Accelerations measured at the outer surface of the cylinders increased significantly with cure time for the concrete. As strength increased, less damage was observed near the explosively-driven borehole wall consistent with the lower energy absorption expected and observed for stronger concrete. As it is the energy absorbing properties of a target that ultimately stop a penetrator, we believe this may point the way to a more readily determined equivalent of the S number

Genomic alterations indicate tumor origin and varied metastatic potential of disseminated cells from prostate-cancer patients

Disseminated epithelial cells can be isolated from the bone marrow of a far greater fraction of prostate-cancer patients than the fraction of patients who progress to metastatic disease. To provide a better understanding of these cells, we have characterized their genomic alterations. We first present an array comparative genomic hybridization method capable of detecting genomic changes in the small number of disseminated cells (10-20) that can typically be obtained from bone-marrow aspirates of prostate-cancer patients. We show multiple regions of copy-number change, including alterations common in prostate cancer, such as 8p loss, 8q gain, and gain encompassing the androgen-receptor gene on Xq, in the disseminated cell pools from 11 metastatic patients. We found fewer and less striking genomic alterations in the 48 pools of disseminated cells from patients with organ-confined disease. However, we identify changes shared by these samples with their corresponding primary tumors and prostate-cancer alterations reported in the literature, evidence that these cells, like those in advanced disease, are disseminated tumor cells (DTCs). We also demonstrate that DTCs from patients with advanced and localized disease share several abnormalities, including losses containing cell-adhesion genes and alterations reported to associate with progressive disease. These shared alterations might confer the capability to disseminate or establish secondary disease. Overall, the spectrum of genomic deviations is evidence for metastatic capacity in advanced-disease DTCs and variation in that capacity in DTCs from localized disease. Our analysis lays the foundation for elucidation of the relationship between DTC genomic alterations and progressive prostate cancer

Helping the Working Poor: Employer- vs. Employee-Based Subsidies

In the United States and Europe there has been renewed interest in subsidizing firms that employ disadvantaged workers as a means of addressing poverty and other social problems. In contrast, the prevailing practice is largely to provide social welfare benefits directly to individuals. Which approach is better? We re-examine the relative merits of employee- versus employer-based labor market subsidies and conclude there are good reasons to continue to rely on the direct, employee-based approach. In practice, low-wage workers are seldom either low-skill or low-income workers. Furthermore, workers who might quality for a firm-based subsidy are reluctant to so identify themselves for fear of being stigmatized or labeled as needy. Thus, employer-based subsidy programs have lower participation rates and correspondingly higher per capita expenditures than employee-based subsidy programs

Deletion of individual Ku subunits in mice causes an NHEJ-independent phenotype potentially by altering apurinic/apyrimidinic site repair

Ku70 and Ku80 form a heterodimer called Ku that forms a holoenzyme with DNA dependent-protein kinase catalytic subunit (DNA-PKCS) to repair DNA double strand breaks (DSBs) through the nonhomologous end joining (NHEJ) pathway. As expected mutating these genes in mice caused a similar DSB repair-defective phenotype. However, ku70-/- cells and ku80 -/- cells also appeared to have a defect in base excision repair (BER). BER corrects base lesions, apurinic/apyrimidinic (AP) sites and single stand breaks (SSBs) utilizing a variety of proteins including glycosylases, AP endonuclease 1 (APE1) and DNA Polymerase β (Pol β). In addition, deleting Ku70 was not equivalent to deleting Ku80 in cells and mice. Therefore, we hypothesized that free Ku70 (not bound to Ku80) and/or free Ku80 (not bound to Ku70) possessed activity that influenced BER. To further test this hypothesis we performed two general sets of experiments. The first set showed that deleting either Ku70 or Ku80 caused an NHEJ-independent defect. We found ku80-/- mice had a shorter life span than dna-pkcs-/- mice demonstrating a phenotype that was greater than deleting the holoenzyme. We also found Ku70-deletion induced a p53 response that reduced the level of small mutations in the brain suggesting defective BER. We further confirmed that Ku80-deletion impaired BER via a mechanism that was not epistatic to Pol β. The second set of experiments showed that free Ku70 and free Ku80 could influence BER. We observed that deletion of either Ku70 or Ku80, but not both, increased sensitivity of cells to CRT0044876 (CRT), an agent that interferes with APE1. In addition, free Ku70 and free Ku80 bound to AP sites and in the case of Ku70 inhibited APE1 activity. These observations support a novel role for free Ku70 and free Ku80 in altering BER. © 2014 Choi et al

High quality copy number and genotype data from FFPE samples using Molecular Inversion Probe (MIP) microarrays

BACKGROUND:A major challenge facing DNA copy number (CN) studies of tumors is that most banked samples with extensive clinical follow-up information are Formalin-Fixed Paraffin Embedded (FFPE). DNA from FFPE samples generally underperforms or suffers high failure rates compared to fresh frozen samples because of DNA degradation and cross-linking during FFPE fixation and processing. As FFPE protocols may vary widely between labs and samples may be stored for decades at room temperature, an ideal FFPE CN technology should work on diverse sample sets. Molecular Inversion Probe (MIP) technology has been applied successfully to obtain high quality CN and genotype data from cell line and frozen tumor DNA. Since the MIP probes require only a small (~40 bp) target binding site, we reasoned they may be well suited to assess degraded FFPE DNA. We assessed CN with a MIP panel of 50,000 markers in 93 FFPE tumor samples from 7 diverse collections. For 38 FFPE samples from three collections we were also able to asses CN in matched fresh frozen tumor tissue.RESULTS:Using an input of 37 ng genomic DNA, we generated high quality CN data with MIP technology in 88% of FFPE samples from seven diverse collections. When matched fresh frozen tissue was available, the performance of FFPE DNA was comparable to that of DNA obtained from matched frozen tumor (genotype concordance averaged 99.9%), with only a modest loss in performance in FFPE.CONCLUSION:MIP technology can be used to generate high quality CN and genotype data in FFPE as well as fresh frozen samples.This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at [email protected]

Mitochondrial Oxidative Stress Causes Hyperphosphorylation of Tau

Age-related neurodegenerative disease has been mechanistically linked with mitochondrial dysfunction via damage from reactive oxygen species produced within the cell. We determined whether increased mitochondrial oxidative stress could modulate or regulate two of the key neurochemical hallmarks of Alzheimer's disease (AD): tau phosphorylation, and ß-amyloid deposition. Mice lacking superoxide dismutase 2 (SOD2) die within the first week of life, and develop a complex heterogeneous phenotype arising from mitochondrial dysfunction and oxidative stress. Treatment of these mice with catalytic antioxidants increases their lifespan and rescues the peripheral phenotypes, while uncovering central nervous system pathology. We examined sod2 null mice differentially treated with high and low doses of a catalytic antioxidant and observed striking elevations in the levels of tau phosphorylation (at Ser-396 and other phospho-epitopes of tau) in the low-dose antioxidant treated mice at AD-associated residues. This hyperphosphorylation of tau was prevented with an increased dose of the antioxidant, previously reported to be sufficient to prevent neuropathology. We then genetically combined a well-characterized mouse model of AD (Tg2576) with heterozygous sod2 knockout mice to study the interactions between mitochondrial oxidative stress and cerebral Aß load. We found that mitochondrial SOD2 deficiency exacerbates amyloid burden and significantly reduces metal levels in the brain, while increasing levels of Ser-396 phosphorylated tau. These findings mechanistically link mitochondrial oxidative stress with the pathological features of AD

Narrative theology in Religious Education

This is an Author's Accepted Manuscript of an article published in British Journal of Religious Education, 20 March 2013. Copyright © 2013 Taylor & Francis. Available online at: http://www.tandfonline.com/10.1080/01416200.2013.785931This article advocates a pedagogy of Religious Education (RE) based upon a narratival framework informed by both narrative theology and narrative philosophy. Drawing on the work of narrative theologians including Stanley Hauerwas, the article outlines the nature of the framework, describes the four phases of learning that comprise the pedagogy, and explains how such an approach can overcome existing difficulties in how biblical texts are handled within RE. Working from the narrative assumption that individuals and communities are formed by reading, sharing and living within stories, it suggests that the pedagogy might encourage pupils to think about how the lives of Christians are shaped by their interpretations of biblical narratives, to offer their own interpretations of biblical and other texts, and to consider the stories – religious, non-religious or both – which shape their own lives. In so doing, the article moves away from a ‘proof-texting’ approach to the Bible towards one in which pupils are enabled to think about the significance of biblical narratives for both Christians and themselves