Modeling and Analysis of AF Depot Business Practices for Supply

This thesis explored the impact of heroic actions on depot maintenance operations in terms of aircraft flow days through programmed depot maintenance and in terms of lost production hours. In an area of fiscal uncertaintly and reducing budgets, an understanding of the impact of heroic actions would lead to efficiency gains for the Air Force. Depots do not routinely report the associated impact of heroic actions on their operations and recent efforts to assess these impacts have not arrived to a definitive conclusion. To assess the impact of heroic actions on depot processes, a discrete event simulation was developed for the KC-135 depot operations and heroic actions. Two scenarios were developed and relative impact of heroics was assessed. A baseline case was created with the intent to model current operations and an alternate scenario was developed based on the premise that additional funds for part procurement would reduce the flow day and production hour impact of heroics. An analysis of these scenarios shows that reducing the frequency of heroic actions does significantly impact KC-135 flow days and lost production hours

Uncertainty and Error in Combat Modeling, Simulation, and Analysis

Due to the infrequent and competitive nature of combat, several challenges present themselves when developing a predictive simulation. First, there is limited data with which to validate such analysis tools. Secondly, there are many aspects of combat modeling that are highly uncertain and not knowable. This research develops a comprehensive set of techniques for the treatment of uncertainty and error in combat modeling and simulation analysis. First, Evidence Theory is demonstrated as a framework for representing epistemic uncertainty in combat modeling output. Next, a novel method for sensitivity analysis of uncertainty in Evidence Theory is developed. This sensitivity analysis method generates marginal cumulative plausibility functions (CPFs) and cumulative belief functions (CBFs) and prioritizes the contribution of each factor by the Wasserstein distance (also known as the Kantorovich or Earth Movers distance) between the CBF and CPF. Using this method, a rank ordering of the simulation input factors can be produced with respect to uncertainty. Lastly, a procedure for prioritizing the impact of modeling choices on simulation output uncertainty in settings where multiple models are employed is developed. This analysis provides insight into the overall sensitivities of the system with respect to multiple modeling choices

Isotopic composition of stratospheric ozone

We present a kinetic calculation for the isotopic composition of stratospheric ozone. The calculated enrichments of ^(49)O_3 and ^(50)O_3 are in agreement with atmospheric measurements made at midlatitudes. Integrating the kinetic fractionation processes in the formation and photolysis of ozone, we obtain enrichments of ∼7.5–10.5 and ∼7.5–12.5% (referenced to atmospheric O_2) for δ^(49)O_3 and δ^(50)O_3, respectively, at altitudes between 20 and 35 km; the photolysis in the Hartley band of ozone is responsible for the observed altitude variation. The overall magnitude of the ozone enrichments (∼10%) is large compared with that commonly known in atmospheric chemistry and geochemistry. The heavy oxygen atom in ozone is therefore useful as a tracer of chemical species and pathways that involve ozone or its derived products. For example, the mass anomalies of oxygen in two greenhouse gases, CO_2 and N_2O, are likely the consequences of the transfer of heavy oxygen atoms from ozone

Profiling human breast epithelial cells using single cell RNA sequencing identifies cell diversity.

Breast cancer arises from breast epithelial cells that acquire genetic alterations leading to subsequent loss of tissue homeostasis. Several distinct epithelial subpopulations have been proposed, but complete understanding of the spectrum of heterogeneity and differentiation hierarchy in the human breast remains elusive. Here, we use single-cell mRNA sequencing (scRNAseq) to profile the transcriptomes of 25,790 primary human breast epithelial cells isolated from reduction mammoplasties of seven individuals. Unbiased clustering analysis reveals the existence of three distinct epithelial cell populations, one basal and two luminal cell types, which we identify as secretory L1- and hormone-responsive L2-type cells. Pseudotemporal reconstruction of differentiation trajectories produces one continuous lineage hierarchy that closely connects the basal lineage to the two differentiated luminal branches. Our comprehensive cell atlas provides insights into the cellular blueprint of the human breast epithelium and will form the foundation to understand how the system goes awry during breast cancer

Lethal Mutagenesis of Poliovirus Mediated by a Mutagenic Pyrimidine Analogue

Lethal mutagenesis is the mechanism of action of ribavirin against poliovirus (PV) and numerous other RNA viruses. However, there is still considerable debate regarding the mechanism of action of ribavirin against a variety of RNA viruses. Here we show by using T7 RNA polymerase mediated production of PV genomic RNA, PV polymerase-catalyzed primer extension and cell-free PV synthesis that a pyrimidine ribonucleoside triphosphate analogue (rPTP) with ambiguous basepairing capacity is an efficient mutagen of the PV genome. The in vitro incorporation properties of rPTP are superior to ribavirin triphosphate. We observed a log-linear relationship between virus titer reduction and the number of rPMP molecules incorporated. A PV genome encoding a high-fidelity polymerase was more sensitive to rPMP incorporation, consistent with diminished mutational robustness of high-fidelity PV. The nucleoside (rP) did not exhibit antiviral activity in cell culture owing to the inability of rP to be converted to rPMP by cellular nucleotide kinases. rP was also a poor substrate for herpes simplex virus thymidine kinase. The block to nucleoside phosphorylation could be bypassed by treatment with the P nucleobase, which exhibited both antiviral activity and mutagenesis, presumably a reflection of rP nucleotide formation by a nucleotide salvage pathway. These studies provide additional support for lethal mutagenesis as an antiviral strategy, suggest that rPMP prodrugs may be highly efficacious antiviral agents, and provide a new tool to determine the sensitivity of RNA virus genomes to mutagenesis as well as interrogation of the impact of mutational load on the population dynamics of these viruses

Lethal Mutagenesis of Picornaviruses with N-6-Modified Purine Nucleoside Analogues

RNA viruses exhibit extraordinarily high mutation rates during genome replication. Nonnatural ribonucleosides that can increase the mutation rate of RNA viruses by acting as ambiguous substrates during replication have been explored as antiviral agents acting through lethal mutagenesis. We have synthesized novel N-6-substituted purine analogues with ambiguous incorporation characteristics due to tautomerization of the nucleobase. The most potent of these analogues reduced the titer of poliovirus (PV) and coxsackievirus (CVB3) over 1,000-fold during a single passage in HeLa cell culture, with an increase in transition mutation frequency up to 65-fold. Kinetic analysis of incorporation by the PV polymerase indicated that these analogues were templated ambiguously with increased efficiency compared to the known mutagenic nucleoside ribavirin. Notably, these nucleosides were not efficient substrates for cellular ribonucleotide reductase in vitro, suggesting that conversion to the deoxyriboucleoside may be hindered, potentially limiting genetic damage to the host cell. Furthermore, a high-fidelity PV variant (G64S) displayed resistance to the antiviral effect and mutagenic potential of these analogues. These purine nucleoside analogues represent promising lead compounds in the development of clinically useful antiviral therapies based on the strategy of lethal mutagenesis

Curating gene sets: challenges and opportunities for integrative analysis.

Genomic data interpretation often requires analyses that move from a gene-by-gene focus to a focus on sets of genes that are associated with biological phenomena such as molecular processes, phenotypes, diseases, drug interactions or environmental conditions. Unique challenges exist in the curation of gene sets beyond the challenges in curation of individual genes. Here we highlight a literature curation workflow whereby gene sets are curated from peer-reviewed published data into GeneWeaver (GW), a data repository and analysis platform. We describe the system features that allow for a flexible yet precise curation procedure. We illustrate the value of curation by gene sets through analysis of independently curated sets that relate to the integrated stress response, showing that sets curated from independent sources all share significant Jaccard similarity. A suite of reproducible analysis tools is provided in GW as services to carry out interactive functional investigation of user-submitted gene sets within the context of over 150 000 gene sets constructed from publicly available resources and published gene lists. A curation interface supports the ability of users to design and maintain curation workflows of gene sets, including assigning, reviewing and releasing gene sets within a curation project context

A spatial dissection of the Arabidopsis floral transcriptome by MPSS

<p>Abstract</p> <p>Background</p> <p>We have further characterized floral organ-localized gene expression in the inflorescence of <it>Arabidopsis thaliana </it>by comparison of massively parallel signature sequencing (MPSS) data. Six libraries of RNA sequence tags from immature inflorescence tissues were constructed and matched to their respective loci in the annotated <it>Arabidopsis </it>genome. These signature libraries survey the floral transcriptome of wild-type tissue as well as the floral homeotic mutants, <it>apetala1, apetala3, agamous</it>, a <it>superman/apetala1 </it>double mutant, and differentiated ovules dissected from the gynoecia of wild-type inflorescences. Comparing and contrasting these MPSS floral expression libraries enabled demarcation of transcripts enriched in the petals, stamens, stigma-style, gynoecia, and those with predicted enrichment within the sepal/sepal-petals, petal-stamens, or gynoecia-stamens.</p> <p>Results</p> <p>By comparison of expression libraries, a total of 572 genes were found to have organ-enriched expression within the inflorescence. The bulk of characterized organ-enriched transcript diversity was noted in the gynoecia and stamens, whereas fewer genes demonstrated sepal or petal-localized expression. Validation of the computational analyses was performed by comparison with previously published expression data, <it>in situ </it>hybridizations, promoter-reporter fusions, and reverse transcription PCR. A number of well-characterized genes were accurately delineated within our system of transcript filtration. Moreover, empirical validations confirm MPSS predictions for several genes with previously uncharacterized expression patterns.</p> <p>Conclusion</p> <p>This extensive MPSS analysis confirms and supplements prior microarray floral expression studies and illustrates the utility of sequence survey-based expression analysis in functional genomics. Spatial floral expression data accrued by MPSS and similar methods will be advantageous in the elucidation of more comprehensive genetic regulatory networks governing floral development.</p

Miniature exoplanet radial velocity array I: design, commissioning, and early photometric results

The MINiature Exoplanet Radial Velocity Array (MINERVA) is a US-based observational facility dedicated to the discovery and characterization of exoplanets around a nearby sample of bright stars. MINERVA employs a robotic array of four 0.7 m telescopes outfitted for both high-resolution spec- troscopy and photometry, and is designed for completely autonomous operation. The primary science program is a dedicated radial velocity survey and the secondary science objective is to obtain high precision transit light curves. The modular design of the facility and the flexibility of our hardware allows for both science programs to be pursued simultaneously, while the robotic control software provides a robust and efficient means to carry out nightly observations. In this article, we describe the design of MINERVA including major hardware components, software, and science goals. The telescopes and photometry cameras are characterized at our test facility on the Caltech campus in Pasadena, CA, and their on-sky performance is validated. New observations from our test facility demonstrate sub-mmag photometric precision of one of our radial velocity survey targets, and we present new transit observations and fits of WASP-52b—a known hot-Jupiter with an inflated radius and misaligned orbit. The process of relocating the MINERVA hardware to its final destination at the Fred Lawrence Whipple Observatory in southern Arizona has begun, and science operations are expected to commence within 2015