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TU-FG-201-01: 18-Month Clinical Experience of a Linac Daily Quality Assurance (QA) Solution Using Only EPID and OBI

Purpose: To describe the clinical use of a Linear Accelerator (Linac) DailyQA system with only EPID and OBI. To assess the reliability over an 18-month period and improve the robustness of this system based on QA failure analysis. Methods: A DailyQA solution utilizing an in-house designed phantom, combined EPID and OBI image acquisitions, and a web-based data analysis and reporting system was commissioned and used in our clinic to measure geometric, dosimetry and imaging components of a Varian Truebeam Linac. During an 18-month period (335 working days), the Daily QA results, including the output constancy, beam flatness and symmetry, uniformity, TPR20/10, MV and KV imaging quality, were collected and analyzed. For output constancy measurement, an independent monthly QA system with an ionization chamber (IC) and annual/incidental TG51 measurements with ADCL IC were performed and cross-compared to Daily QA system. Thorough analyses were performed on the recorded QA failures to evaluate the machine performance, optimize the data analysis algorithm, adjust the tolerance setting and improve the training procedure to prevent future failures. Results: A clinical workflow including beam delivery, data analysis, QA report generation and physics approval was established and optimized to suit daily clinical operation. The output tests over the 335 working day period cross-correlated with the monthly QA system within 1.3% and TG51 results within 1%. QA passed with one attempt on 236 days out of 335 days. Based on the QA failures analysis, the Gamma criteria is revised from (1%, 1mm) to (2%, 1mm) considering both QA accuracy and efficiency. Data analysis algorithm is improved to handle multiple entries for a repeating test. Conclusion: We described our 18-month clinical experience on a novel DailyQA system using only EPID and OBI. The long term data presented demonstrated the system is suitable and reliable for Linac daily QA.

60 APPLIED LIFE SCIENCES↗

TEAL

TEAL is a financial performance calculator plugin for the RAVEN code, framework, resolving around the computation of Net Present Value and associated financial metrics. TEAL can make use of inflation rates, taxation, escalation factors, capital expenditure economy of scale scaling factors. The unique feature of TEAL is the capability to be linked with RAVEN external models and build corresponding cash flows using the variables computed by those external models. In addition to be able to use the capability to generate cash flows derived from complex physical models generated by RAVEN, another distinctive feature of TEAL is the capability to provide financial risk/probabilistic metrics that can empower RAVEN to perform optimization/analysis driven by financial risk augmentations. Optimization, robust optimization, parametric studies, large parallel simulations, sensitivity analysis, data mining, etc. are just some of the capabilities that can be leveraged.

Alfonsi, Andrea↗

Understanding Hailstone Temporal Variability and Contributing Factors over the U.S. Southern Great Plains

Abstract Hailstones are a natural hazard that pose a significant threat to property and are responsible for significant economic losses each year in the United States. Detailed understanding of their characteristics is essential to mitigate their impact. Identifying the dynamic and physical factors contributing to hail formation and hailstone sizes is of great importance to weather and climate prediction and policymakers. In this study, we have analyzed the temporal and spatial variabilities of severe hail occurrences over the U.S. southern Great Plains (SGP) states from 2004 to 2016 using two hail datasets: hail reports from the Storm Prediction Center and the newly developed radar-retrieved maximum expected size of hail (MESH). It is found that severe and significant severe hail occurrences have a considerable year-to-year temporal variability in the SGP region. The interannual variabilities have a strong correspondence with sea surface temperature anomalies over the northern Gulf of Mexico and there is no outlier. The year 2016 is identified as an outlier for the correlations with both El Niño–Southern Oscillation (ENSO) and aerosol loading. The correlations with ENSO and aerosol loading are not statistically robust to inclusion of the outlier 2016. Statistical analysis without the outlier 2016 shows that 1) aerosols that may be mainly from northern Mexico have the largest correlation with hail interannual variability among the three factors and 2) meteorological covariation does not significantly contribute to the high correlation. These analyses warrant further investigations of aerosol impacts on hail occurrence.

54 ENVIRONMENTAL SCIENCES↗

Proteogenomic characterization of difficult-to-treat breast cancer with tumor cells enriched through laser microdissection

Abstract Background Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer death among women globally. Despite advances, there is considerable variation in clinical outcomes for patients with non-luminal A tumors, classified as difficult-to-treat breast cancers (DTBC). This study aims to delineate the proteogenomic landscape of DTBC tumors compared to luminal A (LumA) tumors. Methods We retrospectively collected a total of 117 untreated primary breast tumor specimens, focusing on DTBC subtypes. Breast tumors were processed by laser microdissection (LMD) to enrich tumor cells. DNA, RNA, and protein were simultaneously extracted from each tumor preparation, followed by whole genome sequencing, paired-end RNA sequencing, global proteomics and phosphoproteomics. Differential feature analysis, pathway analysis and survival analysis were performed to better understand DTBC and investigate biomarkers. Results We observed distinct variations in gene mutations, structural variations, and chromosomal alterations between DTBC and LumA breast tumors. DTBC tumors predominantly had more mutations inTP53,PLXNB3, Zinc finger genes, and fewer mutations inSDC2,CDH1,PIK3CA,SVIL, andPTEN. Notably, Cytoband 1q21, which contains numerous cell proliferation-related genes, was significantly amplified in the DTBC tumors. LMD successfully minimized stromal components and increased RNA–protein concordance, as evidenced by stromal score comparisons and proteomic analysis. Distinct DTBC and LumA-enriched clusters were observed by proteomic and phosphoproteomic clustering analysis, some with survival differences. Phosphoproteomics identified two distinct phosphoproteomic profiles for high relapse-risk and low relapse-risk basal-like tumors, involving several genes known to be associated with breast cancer oncogenesis and progression, includingKIAA1522,DCK,FOXO3,MYO9B,ARID1A,EPRS,ZC3HAV1, andRBM14. Lastly, an integrated pathway analysis of multi-omics data highlighted a robust enrichment of proliferation pathways in DTBC tumors. Conclusions This study provides an integrated proteogenomic characterization of DTBC vs LumA with tumor cells enriched through laser microdissection. We identified many common features of DTBC tumors and the phosphopeptides that could serve as potential biomarkers for high/low relapse-risk basal-like BC and possibly guide treatment selections.

Oncology↗

Viral Nuclease Inhibitors: Small molecule disruptors of the UL12 alkaline nuclease display broad anti-herpes virus activity

Herpes simplex virus 1 (HSV-1) UL12 encodes a highly conserved 5′ → 3′ alkaline exonuclease that is essential for the production of infectious virus. Together with the viral single-stranded DNA-binding/annealing protein ICP8, UL12 functions as a two-component recombinase that mediates recombination-dependent viral DNA replication. Here, we present the crystal structure of the catalytic domain of the HSV alkaline nuclease (UL12), which provides the first view of an α-herpesvirus alkaline nuclease. Using this structure, we optimized a series of small-molecule viral nuclease inhibitors (VNIs) that target the UL12 active site and potently inhibit UL12 exonuclease activity in vitro. We have thus established a robust platform for structure-based docking, SAR analysis and rational inhibitor design. Because UL12 orthologs are conserved across all human herpesviruses, we examined the activity of these compounds against the β- and γ-herpesvirus alkaline nucleases UL98 and SOX and found that they inhibit all three enzymes. The VNIs also exhibit antiviral activity against HSV-1 and HCMV in cell culture. EC 50 and IC 50 values were in the nanomolar to low micromolar range. Together, these findings establish herpesvirus alkaline nucleases as conserved, druggable antiviral targets and provide a foundation for the development of broad-spectrum anti-herpesvirus therapeutics, either as standalone agents or in combination with existing nucleoside analogs.

Sharma, Nidhi↗

Systems Level Regulation of Rhythmic Growth Rate and Biomass Accumulation in Grasses

Objectives: Several breakthroughs have been recently made in our understanding of plant growth and biomass accumulation. It was found that plant growth is rhythmically controlled throughout the day by the circadian clock through a complex interplay of light and phytohormone signaling pathways. While plants such as the C4 energy crop sorghum (Sorghum bicolor (L.) Moench) and possibly the C3 grass Brachypodium distachyon also exhibit daily rhythms in growth rate, the molecular details of its regulation remain to be explored. A better understanding of diurnally regulated growth behavior in grasses may lead to species-specific mechanisms highly relevant to future strategies to optimize energy crop biomass yield. Here we propose to devise a systems approach to identify, in parallel, regulatory hubs associated with rhythmic growth in C3 and C4 plants. We propose to use rhythmicity in daily growth patterns to drive the discovery of regulatory network modules controlling biomass accumulation. Description: The project is divided in three main parts: 1) Performing time-lapse imaging and growth measurement in B. distachyon and S. bicolor to determine growth rate dynamic during the day/night cycle. Identifying growth-associated genes whose expression patterns follow the observed growth dynamics using deep sequencing technology, 2) identifying regulators of these genes by screening for DNA-binding proteins interacting with the growth-associated gene promoters identified in Aim 1. Screens will be performed using a validated yeast-one hybrid strategy paired with a specifically designed B. distachyon and S. bicolor transcription factor libraries (1000 clones each), and 3) Selecting 50 potential growth regulators from the screen for downstream characterization. The selection will be made by using a sytems biology approach by calculating the connectivity between growth rate, rhythmic gene expression profiles and TF expression profile and determine which TF is likely part of a hub and a potential regulator of plant growth. We will confirme the 50 DNA-protein interactions using transient transcriptional assays in B. distachyon and S. bicolor, and perform further testing in vivo by measuring growth parameters in transgenic loss- or gain-of-function lines for the selected transcription factors (25 B. distachyon and 3 S. bicolor lines). In 2016 the Principal Investigator relocated the laboratory to The Scripps Research Institute (TSRI) where the project has continued with an end date of 08/31/17. Accomplishments: We successfully collected large datasets of gene expression form the model grass Brachypodium. We used and developed bioinformatics analysis tools to investigate the structure, dynamics and robustness of circadian regulated gene expression in Brachypodium. Relevant Discoveries: We were able to determine that the endogenous circadian clock appears to play a much more subdued role in growth regulation in Brachypodium, that has been demonstrated in either Arabidopsis, or crop plants like Rice, Corn and Soybean. This led to our conclusion that Brachypodium unfortunately is unlikely to serve as an informative model for understanding how growth regulation in plants is under the control of circadian network circuitry. However, we were able to leverage our datasets in Brachypodium to inform us and reinforce a large collaborative study on gene networks governing cell wall deposition in Arabidopsis. This led to a major and highly cited publication relevant to improving biomass production.

09 BIOMASS FUELS↗

Total Moisture Analysis of Salts by Dissolution

This report discusses recent efforts within TA-48 in developing a robust, defensible, and straightforward procedure for determining the moisture content of alkali and alkaline metal halide salts utilizing a total dissolution Karl-Fischer titration method. Utilizing statistical analysis of blank and dissolved salt samples, we determine a (3 sigma) detection limit of 67 micrograms H 2 O/g salt, and a (10 sigma) quantification limit of 160 micrograms H 2 O/g salt. Several salts are analyzed, and suggestions for future efforts are given.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

STELLAR VARIABILITY AND FLARE RATES FROM DOME A, ANTARCTICA, USING 2009 AND 2010 CSTAR OBSERVATIONS

The Chinese Small Telescope Array (CSTAR) carried out high-cadence time-series observations of ∼20.1 square degrees centered on the South Celestial Pole during the 2008, 2009, and 2010 winter seasons from Dome A in Antarctica. The nearly continuous six months of dark conditions during each observing season allowed for >10{sup 6} images to be collected through gri and clear filters, resulting in the detection of >10{sup 4} sources over the course of three years of operation. The nearly space-like conditions in the Antarctic plateau are an ideal testbed for the suitability of very small-aperture (<20 cm) telescopes to detect transient events, variable stars, and stellar flares. We present the results of a robust search for such objects using difference image analysis of the data obtained during the 2009 and 2010 winter seasons. While no transients were found, we detected 29 flaring events and find a normalized flaring rate of 5 ± 4 × 10{sup −7} flare hr{sup −1} for late-K dwarfs, 1 ± 1 × 10{sup −6} flare hr{sup −1} for M dwarfs and 7 ± 1 × 10{sup −7} flare hr{sup −1} for all other stars in our sample. We suggest future small-aperture telescopes planned for deployment at Dome A would benefit from a tracking mechanism, to help alleviate effects from ghosting, and a finer pixel scale, to increase the telescope's sensitivity to faint objects. We find that the light curves of non-transient sources have excellent photometric qualities once corrected for systematics, and are limited only by photon noise and atmospheric scintillation.

79 ASTRONOMY AND ASTROPHYSICS↗

Cosmic evolution of long gamma-ray burst luminosity

The cosmic evolution of gamma-ray burst (GRB) luminosity is essential for revealing the GRB physics and for using GRBs as cosmological probes. We investigate the luminosity evolution of long GRBs with a large sample of 258 Swift/BAT GRBs. By describing the peak luminosity evolution of individual GRBs as L{sub p}∝(1+z){sup k}, we get k=1.49±0.19 using the nonparametric τ statistics method without considering observational biases of GRB trigger and redshift measurement. By modeling these biases with the observed peak flux and characterizing the peak luminosity function of long GRBs as a smoothly broken power law with a break that evolves as L{sub b}∝(1+z){sup k{sub b}}, we obtain k{sub b}=1.14{sub −0.47}{sup +0.99} through simulations based on the assumption that the long GRB rate follows the star formation rate incorporating the cosmic metallicity history. The derived k and k{sub b} values are systematically smaller than those reported in previous papers. By removing the observational biases of the GRB trigger and redshift measurement based on our simulation analysis, we generate mock complete samples of 258 and 1000 GRBs to examine how these biases affect the τ statistics method. We get k=0.94±0.14 and k=0.80±0.09 for the two samples, indicating that these observational biases may lead to overestimating the k value. With the large uncertainty of k{sub b} derived from our simulation analysis, one cannot even convincingly argue for a robust evolution feature of the GRB luminosity.

79 ASTRONOMY AND ASTROPHYSICS↗

MASSIVE GALAXIES ARE LARGER IN DENSE ENVIRONMENTS: ENVIRONMENTAL DEPENDENCE OF MASS–SIZE RELATION OF EARLY-TYPE GALAXIES

Under the Λ cold dark matter (ΛCDM) cosmological models, massive galaxies are expected to be larger in denser environments through frequent hierarchical mergers with other galaxies. Yet, observational studies of low-redshift early-type galaxies have shown no such trend, standing as a puzzle to solve during the past decade. We analyzed 73,116 early-type galaxies at 0.1 ≤ z < 0.15, adopting a robust nonparametric size measurement technique and extending the analysis to many massive galaxies. We find for the first time that local early-type galaxies heavier than 10{sup 11.2} M {sub ⊙} show a clear environmental dependence in mass–size relation, in such a way that galaxies are as much as 20%–40% larger in the densest environments than in underdense environments. Splitting the sample into the brightest cluster galaxies (BCGs) and non-BCGs does not affect the result. This result agrees with the ΛCDM cosmological simulations and suggests that mergers played a significant role in the growth of massive galaxies in dense environments as expected in theory.

79 ASTRONOMY AND ASTROPHYSICS↗

Toward Accurate Modeling of Galaxy Clustering on Small Scales: Constraining the Galaxy-halo Connection with Optimal Statistics

Applying halo models to analyze the small-scale clustering of galaxies is a proven method for characterizing the connection between galaxies and their host halos. Such works are often plagued by systematic errors or limited to clustering statistics that can be predicted analytically. In this work, we employ a numerical mock-based modeling procedure to examine the clustering of Sloan Digital Sky Survey DR7 galaxies. We apply a standard halo occupation distribution (HOD) model to dark matter only simulations with a ΛCDM cosmology. To constrain the theoreStical models, we utilize a combination of galaxy number density and selected scales of the projected correlation function, redshift-space correlation function, group multiplicity function, average group velocity dispersion, mark correlation function, and counts-in-cells statistics. We design an algorithm to choose an optimal combination of measurements that yields tight and accurate constraints on our model parameters. Compared to previous work using fewer clustering statistics, we find a significant improvement in the constraints on all parameters of our halo model for two different luminosity-threshold galaxy samples. Most interestingly, we obtain unprecedented high-precision constraints on the scatter in the relationship between galaxy luminosity and halo mass. However, our best-fit model results in significant tension (>4σ) for both samples, indicating the need to add second-order features to the standard HOD model. To guarantee the robustness of these results, we perform an extensive analysis of the systematic and statistical errors in our modeling procedure, including a first of its kind study of the sensitivity of our constraints to changes in the halo mass function due to baryonic physics.

79 ASTRONOMY AND ASTROPHYSICS↗

Global Framework for Emulation of Nuclear Calculations

We introduce a hierarchical framework that combines ab initio many-body calculations with a Bayesian neural network, developing emulators capable of accurately predicting nuclear properties across isotopic chains simultaneously and being applicable to different regions of the nuclear chart. We benchmark our developments using the oxygen isotopic chain, achieving accurate results for ground-state energies and nuclear charge radii, while providing robust uncertainty quantification. Our framework enables global sensitivity analysis of nuclear binding energies and charge radii with respect to the low-energy constants that describe the nuclear force.

FOS: Computer and information sciences↗

Conic sectors for sampled-data feedback systems

The conic-sector analysis of the closed-loop stability and robustness of a multivariable-analog-system controller based on sampled-data feedback compensation is investigated. Conic sectors and sampled-data feedback systems are defined, and the existence of a conic sector containing a sampled-data operator is established mathematically. An example is presented to prove that the conic sector is computable and gives sufficient conditions of closed-loop stability. A procedure for determining sampled-data-operator gain is also derived.

Thompson, P. M.↗

Modeling clear-air turbulence with vortices using parameter-identification techniques

A vortex model of winds associated with clear-air turbulence (CAT) is shown to be useful for characterizing actual airline CAT encounters. The model consists of an array of vortices with solid-body cores embedded in a potential flow field. Parameters such as the size and strength of the vortices and their locations are identified using a modified Newton-Raphson algorithm. A manual identification start-up scheme is used to minimize errors in the initial parameter estimates, and the identification algorithm is found to be robust in regard to the remaining errors. The analysis of a CAT encounter involving a commercial airliner demonstrates the success of the model and estimation procedure. The analysis finds vortices with core diameters of 1000 ft and tangential velocities of 87 ft/sec in this encounter.

Mehta, R. S.↗

Expanded envelope concepts for aircraft control-element failure detection and identification

The purpose of this effort was to develop and demonstrate concepts for expanding the envelope of failure detection and isolation (FDI) algorithms for aircraft-path failures. An algorithm which uses analytic-redundancy in the form of aerodynamic force and moment balance equations was used. Because aircraft-path FDI uses analytical models, there is a tradeoff between accuracy and the ability to detect and isolate failures. For single flight condition operation, design and analysis methods are developed to deal with this robustness problem. When the departure from the single flight condition is significant, algorithm adaptation is necessary. Adaptation requirements for the residual generation portion of the FDI algorithm are interpreted as the need for accurate, large-motion aero-models, over a broad range of velocity and altitude conditions. For the decision-making part of the algorithm, adaptation may require modifications to filtering operations, thresholds, and projection vectors that define the various hypothesis tests performed in the decision mechanism. Methods of obtaining and evaluating adequate residual generation and decision-making designs have been developed. The application of the residual generation ideas to a high-performance fighter is demonstrated by developing adaptive residuals for the AFTI-F-16 and simulating their behavior under a variety of maneuvers using the results of a NASA F-16 simulation.

Weiss, Jerold L.↗

A geometric approach to regulator and tracker design for an aerospace plane

The paper presents a nonlinear design approach drawing from singular perturbations, feedback linearization, and variable structure control, that leads to regulators with automatic gain scheduling which exhibit similar dynamic behavior over the entire flight envelope of the aerospace plane. Additionally, design approach provides for a systematic way to counter disturbance effects as well as modeling uncertainties. The unifying feature of the three nonlinear feedback control methodologies is that they all have a geometric interpretation. First, the translational dynamics are decomposed into reduced-order slow and fast dynamics by way of a formal singular perturbation analysis. After feedback linearization the fast dynamics are robustly stabilized via a variable structure control approach. The slow dynamics are stabilized using conventional proportional-integral compensation based on the nominal slow dynamics. A number of sample command and disturbance responses at opposite ends of the flight envelope are presented for a nonlinear aerospace plane model.

Van Buren, Mark A.↗

Sensitivity of wildlife habitat models to uncertainties in GIS data

Decision makers need to know the reliability of output products from GIS analysis. For many GIS applications, it is not possible to compare these products to an independent measure of 'truth'. Sensitivity analysis offers an alternative means of estimating reliability. In this paper, we present a CIS-based statistical procedure for estimating the sensitivity of wildlife habitat models to uncertainties in input data and model assumptions. The approach is demonstrated in an analysis of habitat associations derived from a GIS database for the endangered California condor. Alternative data sets were generated to compare results over a reasonable range of assumptions about several sources of uncertainty. Sensitivity analysis indicated that condor habitat associations are relatively robust, and the results have increased our confidence in our initial findings. Uncertainties and methods described in the paper have general relevance for many GIS applications.

Stoms, David M.↗

Design and fabrication of an autonomous rendezvous and docking sensor using off-the-shelf hardware

NASA Marshall Space Flight Center (MSFC) has developed and tested an engineering model of an automated rendezvous and docking sensor system composed of a video camera ringed with laser diodes at two wavelengths and a standard remote manipulator system target that has been modified with retro-reflective tape and 830 and 780 mm optical filters. TRW has provided additional engineering analysis, design, and manufacturing support, resulting in a robust, low cost, automated rendezvous and docking sensor design. We have addressed the issue of space qualification using off-the-shelf hardware components. We have also addressed the performance problems of increased signal to noise ratio, increased range, increased frame rate, graceful degradation through component redundancy, and improved range calibration. Next year, we will build a breadboard of this sensor. The phenomenology of the background scene of a target vehicle as viewed against earth and space backgrounds under various lighting conditions will be simulated using the TRW Dynamic Scene Generator Facility (DSGF). Solar illumination angles of the target vehicle and candidate docking target ranging from eclipse to full sun will be explored. The sensor will be transportable for testing at the MSFC Flight Robotics Laboratory (EB24) using the Dynamic Overhead Telerobotic Simulator (DOTS).

Grimm, Gary E.↗