System model development for nuclear thermal propulsion

A critical enabling technology in the evolutionary development of nuclear thermal propulsion (NTP) is the ability to predict the system performance under a variety of operating conditions. This is crucial for mission analysis and for control subsystem testing as well as for the modeling of various failure modes. Performance must be accurately predicted during steady-state and transient operation, including startup, shutdown, and post operation cooling. The development and application of verified and validated system models has the potential to reduce the design, testing, and cost and time required for the technology to reach flight-ready status. Since Oct. 1991, the U.S. Department of Energy (DOE), Department of Defense (DOD), and NASA have initiated critical technology development efforts for NTP systems to be used on Space Exploration Initiative (SEI) missions to the Moon and Mars. This paper presents the strategy and progress of an interagency NASA/DOE/DOD team for NTP system modeling. It is the intent of the interagency team to develop several levels of computer programs to simulate various NTP systems. The first level will provide rapid, parameterized calculations of overall system performance. Succeeding computer programs will provide analysis of each component in sufficient detail to guide the design teams and experimental efforts. The computer programs will allow simulation of the entire system to allow prediction of the integrated performance. An interagency team was formed for this task to use the best capabilities available and to assure appropriate peer review

Classifying Complications: Assessing Adult Spinal Deformity 2-Year Surgical Outcomes.

STUDY DESIGN: Retrospective review of prospective database. OBJECTIVE: Complication rates for adult spinal deformity (ASD) surgery vary widely because there is no accepted system for categorization. Our objective was to identify the impact of complication occurrence, minor-major complication, and Clavien-Dindo complication classification (Cc) on clinical variables and patient-reported outcomes. METHODS: Complications in surgical ASD patients with complete baseline and 2-year data were considered intraoperatively, perioperatively (\u3c6 \u3eweeks), and postoperatively (\u3e6 weeks). Primary outcome measures were complication timing and severity according to 3 scales: complication presence (yes/no), minor-major, and Cc score. Secondary outcomes were surgical outcomes (estimated blood loss [EBL], length of stay [LOS], reoperation) and health-related quality of life (HRQL) scores. Univariate analyses determined complication presence, type, and Cc grade impact on operative variables and on HRQL scores. RESULTS: Of 167 patients, 30.5% (n = 51) had intraoperative, 48.5% (n = 81) had perioperative, and 58.7% (n = 98) had postoperative complications. Major intraoperative complications were associated with increased EBL ( CONCLUSION: The Cc Scale was most useful in predicting changes in patient outcomes; at 2 years, patients with raised perioperative Cc scores and postoperative complications saw reduced HRQL improvement. Intraoperative and perioperative complications were associated with worse short-term surgical and inpatient outcomes

A high-resolution map of human evolutionary constraint using 29 mammals.

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease

Convergent evolution of the genomes of marine mammals

Marine mammals from different mammalian orders share several phenotypic traits adapted to the aquatic environment and are therefore a classic example of convergent evolution. To investigate convergent evolution at the genomic level, we sequenced and de novo assembled the genomes of three species of marine mammals (the killer whale, walrus and manatee) from three mammalian orders that share independently evolved phenotypic adaptations to a marine existence. Our comparative genomic analyses found that convergent amino acid substitutions were widespread throughout the genome, and that a subset were in genes evolving under positive selection and putatively associated with a marine phenotype. However, we found higher levels of convergent amino acid substitutions in a control set of terrestrial sister taxa to the marine mammals. Our results suggest that while convergent molecular evolution is relatively common, adaptive molecular convergence linked to phenotypic convergence is comparatively rare

Tumor-induced STAT3 activation in monocytic myeloid-derived suppressor cells enhances stemness and mesenchymal properties in human pancreatic cancer

Pancreatic cancer (PC) mobilizes myeloid cells from the bone marrow to the tumor where they promote tumor growth and proliferation. Cancer stem cells (CSCs) are a population of tumor cells that are responsible for tumor initiation. Aldehyde dehydrogenase-1 activity in PC identifies CSCs, and its activity has been correlated with poor overall prognosis in human PC. Myeloid cells have been shown to impact tumor stemness, but the impact of immunosuppressive tumor-infiltrating granulocytic and monocytic myeloid-derived suppressor cells (Mo-MDSC) on ALDH1(Bright) CSCs and epithelial to mesenchymal transition is not well understood. In this study, we demonstrate that Mo-MDSC (CD11b(+)/Gr1(+)/Ly6G(−)/Ly6C(hi)) significantly increase the frequency of ALDH1(Bright) CSCs in a mouse model of PC. Additionally, there was significant upregulation of genes associated with epithelial to mesenchymal transition. We also found that human PC converts CD14(+) peripheral blood monocytes into Mo-MDSC (CD14(+)/HLA-DR(low/−)) in vitro, and this transformation is dependent on the activation of the STAT3 pathway. In turn, these Mo-MDSC increase the frequency of ALDH1(Bright) CSCs and promote mesenchymal features of tumor cells. Finally, blockade of STAT3 activation reversed the increase in ALDH1(Bright) CSCs. These data suggest that the PC tumor microenvironment transforms monocytes to Mo-MDSC by STAT3 activation, and these cells increase the frequency of ALDH1(Bright) CSCs. Therefore, targeting STAT3 activation may be an effective therapeutic strategy in targeting CSCs in PC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00262-014-1527-x) contains supplementary material, which is available to authorized users