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At least 523 records · Page 29

Metabolic Mechanisms of Naphthalene Toxicity in Lung

The objective of this project at LLNL was to test the hypothesis that naphthalene (NA) metabolites will form covalent adducts with DNA. Demonstration of NA DNA adducts drives the risk estimation because this mechanism of action is not considered to have a threshold and is tightly linked to carcinogenesis. However, proving that NA does NOT stably adduct DNA is equally important because it refocuses the studies on other mechanisms of carcinogenesis. What is critically needed, and is uniquely approachable now with new methods, is a species comparison of NA genotoxicity in the lung to provide clear data on this mode of action that is intimately related to the potential for human risk. Further, these studies provided important methodology and approaches for testing other potential DNA adducting carcinogens in the lung.

59 BASIC BIOLOGICAL SCIENCES↗

Simulated Microgravity Alters Gene Regulation Linked to Immunity and Cardiovascular Disease

Microgravity exposure induces a cephalad fluid shift and an overall reduction in physical activity levels which can lead to cardiovascular deconditioning in the absence of countermeasures. Future spaceflight missions will expose crew to extended periods of microgravity among other stressors, the effects of which on cardiovascular health are not fully known. In this study, we determined cardiac responses to extended microgravity exposure using the rat hindlimb unloading (HU) model. We hypothesized that exposure to prolonged simulated microgravity and subsequent recovery would lead to increased oxidative damage and altered expression of genes involved in the oxidative response. To test this hypothesis, we examined hearts of male (three and nine months of age) and female (3 months of age) Long–Evans rats that underwent HU for various durations up to 90 days and reambulated up to 90 days post-HU. Results indicate sex-dependent changes in oxidative damage marker 8-hydroxydeoxyguanosine (8-OHdG) and antioxidant gene expression in left ventricular tissue. Three-month-old females displayed elevated 8-OHdG levels after 14 days of HU while age-matched males did not. In nine-month-old males, there were no differences in 8-OHdG levels between HU and normally loaded control males at any of the timepoints tested following HU. RNAseq analysis of left ventricular tissue from nine-month-old males after 14 days of HU revealed upregulation of pathways involved in pro-inflammatory signaling, immune cell activation and differential expression of genes associated with cardiovascular disease progression. Taken together, these findings provide a rationale for targeting antioxidant and immune pathways and that sex differences should be taken into account in the development of countermeasures to maintain cardiovascular health in space.

Genetics & Heredity↗

Thermal chains and entrainment in cumulus updrafts, Part 2: Analysis of idealized simulations

Research has suggested that the structure of deep convection often consists of a series of rising thermals, or “thermal chain”, which contrasts with existing conceptual models that are used to construct cumulus parameterizations. In this work, simplified theoretical expressions for updraft properties obtained in Part 1 of this study are used to develop a hypothesis explaining why this structure occurs. In this hypothesis, cumulus updraft structure is strongly influenced by organized entrainment below the updraft’s vertical velocity maximum. In a dry environment, this enhanced entrainment can locally reduce condensation rates and increase evaporation, thus eroding buoyancy. For moderate-to-large initial cloud radius R, this breaks up the updraft into a succession of discrete pulses of rising motion (i.e., a thermal chain). For small R, this leads to the structure of a single, isolated rising thermal. In contrast, moist environments are hypothesized to favor plume-like updrafts for moderate-to-large R. In a series of axisymmetric numerical cloud simulations, R and environmental relative humidity (RH) are systematically varied to test this hypothesis. Vertical profiles of fractional entrainment rate, passive tracer concentration, buoyancy, and vertical velocity from these runs agree well with vertical profiles calculated from the theoretical expressions in Part 1. Analysis of the simulations supports the hypothesized dependency of updraft structure on R and RH, that is, whether it consists of an isolated thermal, a thermal chain, or a plume, and the role of organized entrainment in driving this dependency. Additional 3-dimensional (3-D) turbulent cloud simulations are analyzed, and the behavior of these 3-D runs is qualitatively consistent with the theoretical expressions and axisymmetric simulations.

54 ENVIRONMENTAL SCIENCES↗

Exploring Whether Super-puffs can be Explained as Ringed Exoplanets

An intriguing, growing class of planets are the “super-puffs,” objects with exceptionally large radii for their masses and thus correspondingly low densities (≲0.3 g cm{sup −3}). Here we consider whether they could have large inferred radii because they are in fact ringed. This would naturally explain why super-puffs have thus far only shown featureless transit spectra. We find that this hypothesis can work in some cases but not all. The close proximity of the super-puffs to their parent stars necessitates rings with a rocky rather than icy composition. This limits the radius of the rings, and makes it challenging to explain the large size of Kepler 51b, 51c, 51d, and 79d unless the rings are composed of porous material. Furthermore, the short tidal locking timescales for Kepler 18d, 223d, and 223e mean that these planets may be spinning too slowly, resulting in a small oblateness and rings that are warped by their parent star. Kepler 87c and 177c have the best chance of being explained by rings. Using transit simulations, we show that testing this hypothesis requires photometry with a precision of somewhere between ∼10 ppm and ∼50 ppm, which roughly scales with the ratio of the planet and star’s radii. We conclude with a note about the recently discovered super-puff HIP 41378f.

79 ASTRONOMY AND ASTROPHYSICS↗

Volatile Element Depletion of the Moon – The Roles of Pre-Cursors, Post-Impact Disk Dynamics, and Core Formation

The compositional and isotopic similarity of Earth’s primitive upper mantle (PUM) and the Moon has bolstered the idea that the Moon was derived from the proto-Earth, but the Moon’s inventory of volatile lithophile elements – Na, K, Rb and Cs – are lower than in Earth’s PUM by a factor of 4 to 5. The abundances of fourteen other volatile elements exhibit siderophile behavior (volatile siderophile elements or VSE; P, As, Cu, Ag, Sb, Ga, Ge, Bi, Pb, Zn, Sn, Cd, In, and Tl) that could be used to evaluate whether the Moon was derived from the proto-Earth, and whether their depletion can be attributed to volatility or core formation. In this study, newly available core-mantle partitioning data are used, together with bulk Moon compositions, protolunar disk dynamics modelling to test the hypothesis that the Moon was derived from PUM-like material. At lunar core formation conditions, As, Sb, Ag, Ge, Bi, Sn are siderophile, whereas P, Cu, Ga, Pb, Zn, Cd, In and Tl are all weakly siderophile or lithophile. Most of the VSE can be explained by a combination of known processes – pre-cursor volatile depletion, melt-gas dynamics and equilibria in the protolunar disk, and core formation. Explaining this whole group of volatile elements may require a combination of mixing and separation of the newly formed Moon from remnant gas rich in the highest volatility VSEs. This large group of volatile elements informs a wide temperature range and offers a powerful test of melt-gas segregation mechanisms in the protolunar disk and lunar formation hypotheses.

Righter, K.↗

Extremely accurate sequential verification of RELAP5-3D

Large computer programs like RELAP5-3D solve complex systems of governing, closure and special process equations to model the underlying physics of nuclear power plants. Further, these programs incorporate many other features for physics, input, output, data management, user-interaction, and post-processing. For software quality assurance, the code must be verified and validated before being released to users. For RELAP5-3D, verification and validation are restricted to nuclear power plant applications. Verification means ensuring that the program is built right by checking that it meets its design specifications, comparing coding to algorithms and equations and comparing calculations against analytical solutions and method of manufactured solutions. Sequential verification performs these comparisons initially, but thereafter only compares code calculations between consecutive code versions to demonstrate that no unintended changes have been introduced. Recently, an automated, highly accurate sequential verification method has been developed for RELAP5-3D. The method also provides to test that no unintended consequences result from code development in the following code capabilities: repeating a timestep advancement, continuing a run from a restart file, multiple cases in a single code execution, and modes of coupled/uncoupled operation. In conclusion, mathematical analyses of the adequacy of the checks used in the comparisons are provided.

22 GENERAL STUDIES OF NUCLEAR REACTORS↗

Automatic Imagery Data Analysis for Proactive Computer-Based Workflow Management during Nuclear Power Plant Outages

This report is being submitted for the task “Final Report” of DOE NEUP Project 15-8121 “Automatic Imagery Data Analysis for Proactive Computer-Based Workflow Management during Nuclear Power Plant Outages.” Typical nuclear power plant (NPP) outages always involve thousands of maintenance and refueling activities and a large number of workers in limited workspaces, while having tight schedules and zero-tolerance for accidents. During an outage, thousands of workers will be working in various workspaces across the NPP. High outage costs and expensive delays (approximately 1.5 million dollars of loss per day of delay) in NPP maintenance demand tight outage schedules. In packed workspaces, an automatic system that monitors human behaviors in real-time and provides insights about current and pending schedule deviations from the plan is critical for ensuring: 1) effective collaboration among workers and worker teams from different trades; 2) less waste of time and resources due to the lack of situational awareness; and 3) proactive outage project control. The overall goal of this project is to test the hypothesis that real-time imagery-based object tracking and spatial analysis, as well as human behavior modeling of outage participants, will significantly improve the efficiency of outage control while lowering the rates of accidents and incidents. Three objectives of this project are: 1) Establish real-time object tracking and spatiotemporal analysis methods that automatically assess the productivity of field activities and detect anomalous spatiotemporal relationships among activities that cause inefficiencies and risks; 2) Establish realtime human tracking and human factor modeling methods for automatically diagnosing unexpected actions of and interactions between outage participants, those which cause inefficient collaborations between Advanced Outage Control Center (AOCC), satellite outage centers, NPP workers, and maintenance service providers; and 3) Test the proposed automated object tracking, human behavior modeling, and spatiotemporal analysis methods in outage control case studies in order to characterize the effectiveness of automated imagery-data-driven methods in proactively improving the efficiency and safety of workflows in outage coordination and risk management. Recent studies of detailed human behavior monitoring on construction sites have examined the potential of applying advanced computer vision algorithms in detecting and tracking anomalous workers (i.e., workers who do not wear hard hats or safety vests) for ensuring job site safety. Some studies of human factor studies revealed the importance of modeling detailed interactions between individuals within and across teams in better understanding the impact of human in proactive project control. Other studies in the construction domain have developed computational simulation frameworks that formalize detailed spatiotemporal interactions between tasks in order to simulate the impacts of individual tasks on the performance of workflows. While integrated analyses that combine human factor assessment, as well as image processing and simulation, are in demand for effective decision-making, limited studies have examined the potential of such integrated analyses in NPP outage control. This research project has examined an automatic outage monitoring and control system that integrates human factor analysis, computer vision techniques, and simulation methods in order to enable engineers to better understand the interactions between humans, resources, and workflows during outage processes. The project aims at providing NPP maintenance agencies insights into more efficient use of limited resources in extending the life of a nuclear plant, as well as reducing waste while ensuring sufficient generation of electricity. This study is significant for the safety of nuclear plants, sustainable electricity generation for livable communities, and cost savings for maintaining electricity infrastructures in the United States.

22 GENERAL STUDIES OF NUCLEAR REACTORS↗

Absorptive Weak Plume Detection on Gaussian and Non-Gaussian Background Clutter

For additive signals on Gaussian clutter, the optimal detector is a linear matched filter that is adapted to the known signal and the covariance of the background. This adaptive matched filter is widely used for gas-phase plume detection, even though the effect of the plume on the background is not strictly additive. Here, a derivation of the matched filter for a strictly absorptive plume produces, in the weak plume limit, a quadratic filter. This quadratic matched filter is extended in two ways: an elliptically-contoured multivariate t distribution is used to generalize the Gaussian background clutter, and a generalized likelihood ratio test detector is derived to extend applicability to stronger plumes. In addition to detectors whose purpose is to identify presence versus absence of a plume, expressions are also derived for estimating plume strength. The performance of these various detectors is evaluated by implanting simulated plume into background images that are either real hyperspectral images or simulated images based on different (Gaussian, multivariate t, and lognormal) clutter distributions.

79 ASTRONOMY AND ASTROPHYSICS↗

Changes in peak oxygen uptake and plasma volume in fit and unfit subjects following exposure to a simulation of microgravity

To test the hypothesis that the magnitude of reduction in plasma volume and work capacity following exposure to simulated microgravity is dependent on the initial level of aerobic fitness, peak oxygen uptake (VO2peak) was measured in a group of physically fit subjects and compared with VO2peak in a group of relatively unfit subjects before and after 10 days of continuous 6 degrees head-down tilt (HDT). Ten fit subjects (40 +/- 2 year) with mean +/- SE VO2peak = 48.9 +/- 1.7 mL kg-1 min-1 were matched for age, height, and lean body weight with 10 unfit subjects (VO2peak = 37.7 +/- 1.6 mL kg-1 min-1). Before and after HDT, plasma, blood, and red cell volumes and body composition were measured and all subjects underwent a graded supine cycle ergometer test to determine VO2peak period needed. Reduced VO2peak in fit subjects (-16.2%) was greater than that of unfit subjects (-6.1%). Similarly, reductions in plasma (-18.3%) and blood volumes (-16.0%) in fit subjects were larger than those of unfit subjects (blood volume = -5.6%; plasma volume = -6.6%). Reduced plasma volume was associated with greater negative body fluid balance during the initial 24 h of HDT in the fit group (912 +/- 154 mL) compared with unfit subjects (453 +/- 200 mL). The percentage change for VO2peak correlated with percentage change in plasma volume (r = +0.79). Following exposure to simulated microgravity, fit subjects demonstrated larger reductions in VO2peak than unfit subjects which was associated with larger reductions in plasma and blood volume. These data suggest that the magnitude of physical deconditioning induced by exposure to microgravity without intervention of countermeasures was influenced by the initial fitness of the subjects.

Non-NASA Center↗

Targeting Maturation and Quality Control of Photosynthetic Membrane Proteins

Plsp1 is a type I signal peptidase that is responsible for removing the targeting signal peptide from passenger proteins upon their delivery to the thylakoid lumen. Plsp1 is itself a resident of the thylakoid membrane, with a single membrane anchor and the catalytic domain facing the lumen. Work to uncover the targeting mechanism for this protein has been underway in the Inoue lab from the previous DOE funding period has established that Plsp1 is targeted at the thylakoid by the Sec1 translocase, and that it passes through a high molecular weight intermediate in the stroma en route to the thylakoid membrane. During this funding period we have demonstrated by MS/MS of immunoprecipitated samples that the high molecular weight complex containing Plsp1 in the stroma contains primarily the α1 and β1 forms of Cpn60 in approximately equal amounts. Mixing experiments with overexpressed purified proteins have reproduced the Cpn60/Plsp1 complex. Surprisingly, the co-chaperonins Cpn10 and Cpn20 were not detected in the immunoprecipitated sample, even though they are able to bind to the Cpn60/Plsp1 complex formed in mixing experiments. We have further confirmed that the addition of purified stromal cpSecA1 results in a decrease in the amount of Plsp1 successfully incorporated into the thylakoid membrane. We are currently working on experiments to describe the conditions for the handoff between Cpn60 and cpSec1 in the stroma prior to membrane targeting. The structure of Plsp1 can be inferred by threading its sequence onto the structure of its E. coli homologue LepB to contain a single membrane anchor followed by a soluble structure consisting of ten β strands. In the last DOE funding period it was determined that the transmembrane domain not only acts as the membrane anchor, but probably mediates the interaction with cpSecA1. We have now determined that the binding to Cpn60 is likely mediated by β strands 1 and 2. What is the mechanism and significance of oxidative folding of Plsp1? It was found during the last DOE funding period that Plsp1 purified after overexpression in E. coli loses its peptidase activity upon reduction of its conserved cysteines. We have now determined that Plsp1 undergoes a measurable conformational change upon reduction, both by monitoring susceptibility to protease and by native tryptophan fluorescence. We have also shown that Plsp1 is at least partly, and likely completely, oxidized in the thylakoid lumen. While these results were not unexpected, experiments on Plsp1 in vivo were completely surprising. We have known for years (from work conducted with prior DOE funding) that a Plsp1 knockout is embryo lethal. Accordingly, given that reduction of the isolated protein inactivates it, we expected that plants in which one or both of the cysteine pair were mutated would also lead to a severe mutant phenotype. This was not observed, and in fact, these mutants complemented fully the plsp1 plants. This lead to the hypothesis that either association with an interacting protein or with the membrane preserves Plsp1structure even when the disulfides are reduced. Work performed in the last DOE funding cycle revealed that Pgrl1, a protein reportedly involved in cyclic electron flow, interacts stably with Plsp1. However, the Plsp1 cysteine-less mutants are still able to compliment the plsp1 mutant even in the pgrl1 knockout mutant background. We have also found that in vitro activity of Plsl1 is not abolished by reduction in thylakoids that have been permeabilized by low concentrations of detergent, whereas the activity of fully extracted protein is. This points to membrane association as the condition important to activity, and by extension, structure preservation. We are presently working to isolate Plsp1 in a lipid nanodisk to test this hypothesis.

59 BASIC BIOLOGICAL SCIENCES↗

Evolutionary Effects of Translocations in Bacterial Genomes

It has become clear that different genome regions need not evolve uniformly. This variation is particularly evident in bacterial genomes with multiple chromosomes, in which smaller, secondary chromosomes evolve more rapidly. We previously demonstrated that substitution rates and gene dispensability were greater on secondary chromosomes in many bacterial genomes. In Vibrio, the secondary chromosome is replicated later during the cell cycle, which reduces the effective dosage of these genes and hence their expression. More rapid evolution of secondary chromosomes may therefore reflect weaker purifying selection on less expressed genes. Here, we test this hypothesis by relating substitution rates of orthologs shared by multiple Burkholderia genomes, each with three chromosomes, to a study of gene expression in genomes differing by a major reciprocal translocation. This model predicts that expression should be greatest on chromosome 1 (the largest) and least on chromosome 3 (the smallest) and that expression should tend to decline within chromosomes from replication origin to terminus. Moreover, gene movement to the primary chromosome should associate with increased expression, and movement to secondary chromosomes should result in reduced expression. Our analysis supports each of these predictions, as translocated genes tended to shift expression toward their new chromosome neighbors despite inevitable cis-acting regulation of expression. This study sheds light on the early dynamics of genomes following rearrangement and illustrates how secondary chromosomes in bacteria may become evolutionary test beds.

59 BASIC BIOLOGICAL SCIENCES↗

Phenology of Photosynthesis in Winter‐Dormant Temperate and Boreal Forests: Long‐Term Observations From Flux Towers and Quantitative Evaluation of Phenology Models

Abstract We examined the seasonality of photosynthesis in 46 evergreen needleleaf (evergreen needleleaf forests (ENF)) and deciduous broadleaf (deciduous broadleaf forests (DBF)) forests across North America and Eurasia. We quantified the onset and end (Start GPP and End GPP ) of photosynthesis in spring and autumn based on the response of net ecosystem exchange of CO 2 to sunlight. To test the hypothesis that snowmelt is required for photosynthesis to begin, these were compared with end of snowmelt derived from soil temperature. ENF forests achieved 10% of summer photosynthetic capacity ∼3 weeks before end of snowmelt, while DBF forests achieved that capacity ∼4 weeks afterward. DBF forests increased photosynthetic capacity in spring faster (1.95% d −1 ) than ENF (1.10% d −1 ), and their active season length (End GPP –Start GPP ) was ∼50 days shorter. We hypothesized that warming has influenced timing of the photosynthesis season. We found minimal evidence for long‐term change in Start GPP , End GPP , or air temperature, but their interannual anomalies were significantly correlated. Warmer weather was associated with earlier Start GPP (1.3–2.5 days °C −1 ) or later End GPP (1.5–1.8 days °C −1 , depending on forest type and month). Finally, we tested whether existing phenological models could predict Start GPP and End GPP . For ENF forests, air temperature‐ and daylength‐based models provided best predictions for Start GPP , while a chilling‐degree‐day model was best for End GPP . The root mean square errors (RMSE) between predicted and observed Start GPP and End GPP were 11.7 and 11.3 days, respectively. For DBF forests, temperature‐ and daylength‐based models yielded the best results (RMSE 6.3 and 10.5 days).

Environmental Sciences & Ecology↗

Origin of the Moon: Constraints from volatile elements

Supporting arguments for the lunar fusion hypothesis include the low density of the Moon corresponding to the density of the Earth's mantle and the low volatile content of the lunar rocks vs. those of terrestrial origin. Vapor pressures of the alkali elements and their oxides increase in the following order: Na, K, Rb and Cs. The Moon should, therefore, be more depleted in Cs relative to Rb, Rb relative to K, and K relative to Na than the Earth if the fission model is correct. Analyses of lunar mare basalts and terrestrial mid-ocean ridge and other young basalts indicate that this behavior is not observed. It is possible that monovalent alkali elements might be lost from silicate materials in a different order than that inferred from elemental and oxide vapor pressures, as a result of differences in the way they are bound in silicate materials. To test this hypothesis a series of experiments was conducted to investigate alkali loss at high temperatures. Analyses indicate that the behavior of volatiles dissolved in a silicate melt is similar to that inferred from elemental and oxide vapor pressures. It is concluded that alkali element ratios in the Earth and Moon are not readily interpreted in terms of the fission hypothesis.

Kreutzberger, M. E.↗

Mineral properties, microbes, transport, and plant-input profiles control vertical distribution and age of soil carbon stocks

The role of organo-mineral interactions, microbial dynamics, and vertical plant input profiles are hypothesized to be important in controlling soil organic matter (SOM) stocks and dynamics. In this paper, to test this hypothesis, we enhanced and applied a model (Biotic and Abiotic Model of SOM – BAMS1) that represents microbial dynamics and organo-mineral interactions integrated with a multiphase reactive transport solver for variably saturated porous media. The model represents aqueous chemistry, aqueous advection and diffusion, gaseous diffusion, sorption processes, bacterial and fungal activity, and archetypal monomer- and polymer-carbon substrate groups, including dead cell wall material. This model structure is fundamentally different, and produces different SOM dynamics, than the pseudo-first order relationships that are used in most site- and global-scale terrestrial SOM models. We simulated two grasslands, a seven-site chronosequence (~3.9–240 Ky) in Northern California, and a Russian Chernozem site where soils were sampled 100 years apart. We calibrated the model's vertically-resolved soil bulk specific surface area (SBSSA) using observed bulk SOM content, and then tested the model against observed Δ 14 C profiles. The modeled microbial processes, organo-mineral interactions, and vertical aqueous transport produced realistic vertically-resolved predictions of bulk SOM content, Δ 14 C values of SOM, lignin content, and fungi-to-aerobic bacteria biomass ratios. Using sensitivity analyses, we found that vertical carbon input profiles were important controls over the Δ 14 C depth distribution. Shallower carbon input profiles lead to older carbon at depth. In addition, the SBSSA was the dominant control over the magnitude and vertical distribution of SOM stocks. Finally, the findings of this study demonstrate the value of explicitly incorporating microbial activity, sorption, and vertical transport into land models to predict SOM dynamics.

54 ENVIRONMENTAL SCIENCES↗

Prospective Study of Functional Bone Marrow-Sparing Intensity Modulated Radiation Therapy With Concurrent Chemotherapy for Pelvic Malignancies

Purpose: To test the hypothesis that intensity modulated radiation therapy (IMRT) can reduce radiation dose to functional bone marrow (BM) in patients with pelvic malignancies (phase IA) and estimate the clinical feasibility and acute toxicity associated with this technique (phase IB). Methods and Materials: We enrolled 31 subjects (19 with gynecologic cancer and 12 with anal cancer) in an institutional review board-approved prospective trial (6 in the pilot study, 10 in phase IA, and 15 in phase IB). The mean age was 52 years; 8 of 31 patients (26%) were men. Twenty-one subjects completed {sup 18}F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) simulation and magnetic resonance imaging by use of quantitative IDEAL (IDEAL IQ; GE Healthcare, Waukesha, WI). The PET/CT and IDEAL IQ were registered, and BM subvolumes were segmented above the mean standardized uptake value and below the mean fat fraction within the pelvis and lumbar spine; their intersection was designated as functional BM for IMRT planning. Functional BM-sparing vs total BM-sparing IMRT plans were compared in 12 subjects; 10 were treated with functional BM-sparing pelvic IMRT per protocol. Results: In gynecologic cancer patients, the mean functional BM V{sub 10} (volume receiving {>=}10 Gy) and V{sub 20} (volume receiving {>=}20 Gy) were 85% vs 94% (P<.0001) and 70% vs 82% (P<.0001), respectively, for functional BM-sparing IMRT vs total BM-sparing IMRT. In anal cancer patients, the corresponding values were 75% vs 77% (P=.06) and 62% vs 67% (P=.002), respectively. Of 10 subjects treated with functional BM-sparing pelvic IMRT, 3 (30%) had acute grade 3 hematologic toxicity or greater. Conclusions: IMRT can reduce dose to BM subregions identified by {sup 18}F-fluorodeoxyglucose-PET/CT and IDEAL IQ. The efficacy of BM-sparing IMRT is being tested in a phase II trial.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Complex Chromosomal Rearrangements Induced in Vivo by Heavy Ions

It has been suggested that the ratio complex/simple exchanges can be used as a biomarker of exposure to high-LET radiation. We tested this hypothesis in vivo, by considering data from several studies that measured complex exchanges in peripheral blood from humans exposed to mixed fields of low- and high-LET radiation. In particular, we studied data from astronauts involved in long-term missions in low-Earth-orbit, and uterus cancer patients treated with accelerated carbon ions. Data from two studies of chromosomal aberrations in astronauts used blood samples obtained before and after space flight, and a third study used blood samples from patients before and after radiotherapy course. Similar methods were used in each study, where lymphocytes were stimulated to grow in vitro, and collected after incubation in either colcemid or calyculin A. Slides were painted with whole-chromosome DNA fluorescent probes (FISH), and complex and simple chromosome exchanges in the painted genome were classified separately. Complex-type exchanges were observed at low frequencies in control subjects, and in our test subjects before the treatment. No statistically significant increase in the yield of complex-type exchanges was induced by the space flight. Radiation therapy induced a high fraction of complex exchanges, but no significant differences could be detected between patients treated with accelerated carbon ions or X-rays. Complex chromosomal rearrangements do not represent a practical biomarker of radiation quality in our test subjects. Copyright 2003 S. Karger AG, Basel.

Ions/adverse effects/therapeutic use↗

Predicting the Longitudinally and Radially Varying Gut Microbiota Composition Using Multi-Scale Microbial Metabolic Modeling

Background: The gut microbiota is a heterogeneous group of microbes that is spatially distributed along various sections of the intestines and across the mucosa and lumen in each section. Understanding the dynamics between the spatially differential microbial populations and the driving forces for the observed spatial organization will provide valuable insights into important questions such as the nature of colonization of the infant gut and different types of inflammatory bowel disease localized in different regions of the intestines. However, in most studies, the microbiota is sampled only at a single site (often feces) or from a particular anatomical site of the intestines. Differential oxygen availability is putatively a key factor shaping the spatial organization. Results: To test this hypothesis, we constructed a community genome-scale metabolic model consisting of representative organisms for the major phyla present in the human gut microbiome. By solving step-wise optimization problems embedded in a dynamic framework to predict community metabolism and integrate the mucosally-adherent with the luminal microbiome between consecutive sections along the intestines, we were able to capture (i) the essential features of the spatially differential composition of obligate anaerobes vs. facultative anaerobes and aerobes determined experimentally, and (ii) the accumulation of microbial biomass in the lumen. Sensitivity analysis suggests that the spatial organization depends primarily on the oxygen-per-microbe availability in each region. Oxygen availability is reduced relative to the ~100-fold increase in mucosal microbial density along the intestines, causing the switch between aerobes and anaerobes. Conclusion: The proposed integrated dynamic framework is able to predict spatially differential gut microbiota composition using microbial genome-scale metabolic models and test hypotheses regarding the dynamics of the gut microbiota. It can potentially become a valuable tool for exploring therapeutic strategies for site-specific perturbation of the gut microbiota and the associated metabolic activities.

59 BASIC BIOLOGICAL SCIENCES↗

Process Anomaly Detection for Sparsely Labeled Events in Nuclear Power Plants

An essential aspect of online monitoring, subtle anomaly detection increases the detection lead time for equipment failure and enables a nuclear power plant (NPP) to mitigate unexpected partial or full outages, resulting in significant cost saving to the plant. Once an anomaly is detected by plant staff, its cause and severity are investigated. Because the vast majority of anomalies require some level of investigation, including some that require time-consuming examination, before they are passed over to the engineering organization for further analysis, plants are often equipped with tools to assist the staff in performing anomaly detection. Those tools operate as a black box and are often based on statistical methods that establish sensor correlations using preconfigured mathematical models and flag correlation deviations as anomalies. Due to the number of anomalies detected at a given NPP on a daily basis, a significant number of flagged anomalies usually await examination for days or weeks. A primary cause of this backlog is that the methods used by the tools generate many false positives. Though this is usually attributed to oversensitive model settings due to very narrow normal operation bands, it can also be associated with the model development being inadequate for the process being monitored, or with missing model inputs that could have explained misclassified positives. The performance of anomaly detection tools impacts their plant acceptance and utilization, especially when the effort to address false positives generated by the tool depletes the value or cost saved by using that tool. Thus, means to advance anomaly detection performance have been investigated by the Department of Energy’s Light Water Reactor Sustainability program. Previous and ongoing efforts have targeted unsupervised machine-learning (ML) methods, which do not require the labeling of any data fed into the ML model. By contrast, in supervised anomaly detection methods, every data point is labeled as either a normal or abnormal process condition, and the model is trained to replicate the classification process. Supervised methods usually outperform unsupervised methods, due to the added value in differentiating normal from anomalous states of the monitored process. An NPP’s corrective action program requires it to track and document, via a dedicated report, the resolution of any issues that occur within the plant. Once created, each report is reviewed by a plant screening committee, and several classifications and decisions are made. Recently, a collaborating NPP developed an artificial intelligence and ML-based classifier to categorize a condition report (CR) into classes that can serve to label the data as normal or anomalous. Applying CRs as labels represents a semi-supervised use case. Semi-supervised ML assumes that labels exist for some data points (i.e., labeled anomalies, in this case) but not for the rest. In this effort, semi-supervised ML methods were used to fuse data from CRs with anomaly detection methods in order to test the hypothesis that partially labeled anomalies would improve the accuracy of the anomaly detection methods. Specifically, two methods were used. The first is the deep Semi-supervised Anomaly Detection (deep SAD) method, which can handle labels ranging from fully unsupervised to fully supervised cases. The second is a newly designed ML method developed specifically for this effort and referred to as the high-order feature (HOF)-based method. To evaluate these two methods in controlled environments, synthetic data generators were developed and used. The first datasets used a spring-mass-damper (SMD) system simulator commonly found in mechanical engineering references. This was used to create two use cases: a one- and a three-mass system. Anomalies were introduced by changing the spring and damper coefficients while the system was actuated by random forces. The second datasets used the commercial Dymola-Modelica software to build a simplified nuclear reactor model. Anomalies were added in the form of corrupted sensor readings and/or control commands. The deep SAD method was tested using the SMD system, while the HOF method was tested using both datasets. Application of the deep SAD semi-supervised ML method demonstrated that labels can generate increased confidence in detecting true anomalies. This helped increase the number of true positives and decrease the number of false negatives—something that would aid in addressing the backlog of possible anomalies. Application of the HOF method demonstrated that labels can aid in down selecting from a candidate set of features to a more optimal subset in order to better differentiate between normal and anomalous conditions.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗