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At least 145 records · Page 8

Characterization of acute biliary hyperplasia in Fisher 344 Rats administered the Indole-3-Carbinol Analog, NSC-743380

NSC-743380 (1-[(3-chlorophenyl)-methyl]-1H-indole-3-carbinol) is in early stages of development as an anticancer agent. Two metabolites reflect sequential conversion of the carbinol functionality to a carboxaldehyde and the major metabolite, 1-[(3-chlorophenyl)-methyl]-1H-indole-3-carboxylic acid. In an exploratory toxicity study in rats, NSC-743380 induced elevations in liver-associated serum enzymes and biliary hyperplasia. Biliary hyperplasia was observed 2 days after dosing orally for 2 consecutive days at 100 mg/kg/day. Notably, hepatotoxicity and biliary hyperplasia were observed after oral administration of the parent compound, but not when major metabolites were administered. The toxicities of a structurally similar but pharmacologically inactive molecule and a structurally diverse molecule with a similar efficacy profile in killing cancer cells in vitro were compared to NSC-743380 to explore scaffold versus target-mediated toxicity. Following two oral doses of 100 mg/kg/day given once daily on two consecutive days, the structurally unrelated active compound produced hepatic toxicity similar to NSC-743380. The structurally similar inactive compound did not, but, lower exposures were achieved. The weight of evidence implies that the hepatotoxicity associated with NSC-743380 is related to the anticancer activity of the parent molecule. Furthermore, because biliary hyperplasia represents an unmanageable and non-monitorable adverse effect in clinical settings, this model may provide an opportunity for investigators to use a short-duration study design to explore biomarkers of biliary hyperplasia. - Highlights: • NSC-743380 induced biliary hyperplasia in rats. • Toxicity of NSC-743380 appears to be related to its anticancer activity. • The model provides an opportunity to explore biomarkers of biliary hyperplasia.

60 APPLIED LIFE SCIENCES↗

Yes, No, Maybe So: Human Factors Considerations for Fostering Calibrated Trust in Foundation Models Under Uncertainty

High-stakes analytical environments require analysts to evaluate evidence and generate conclusions to inform critical decisions often under conditions of uncertainty. Probabilistic decision-making based on incomplete or inaccurate information can reduce productivity, compromise national interests, and endanger public safety. Researchers are developing expert systems built on foundation models (FMs) to support analysts’ decision-making processes by enabling human-artificial intelligence (AI) teaming, in part through the quantification and expression of uncertainty information. As FMs continue to mature, it is imperative to correspondingly consider analysts’ needs for appropriately interpreting and using uncertainty information. However, prior research indicates that it remains unclear how analysts engage with FM-generated uncertainty information and the extent to which these interactions influence trust in, and reliance on, expert systems. We plan to review the state of the science and conduct an exploratory, qualitative study to (a) understand how properly communicated uncertainty can foster calibrated trust and appropriate reliance and (b) identify approaches for effectively conveying FM-generated uncertainty information during analytical workflows. We will administer semi-structured interviews with analysts from a specific high-stakes analytical environment to collect their current experiences with job-related uncertainty and their impressions when viewing FM-generated uncertainty information. During the interview protocol, participants will be presented with several different FM outputs and invited to discuss their thoughts and beliefs about the uncertainty information displayed. Participants may provide insights into how trust and reliance may be influenced by uncertainty. The results of this study will help us to better understand how analysts currently interpret and use uncertainty information. Our findings may inform human factors recommendations for effectively conveying uncertainty information to foster calibrated trust in, and appropriate reliance on, expert systems. Interaction designers and FM developers can use this knowledge to enhance human-AI teaming and ensure the responsible deployment of FM-based expert systems in analytical workflows.

97 MATHEMATICS AND COMPUTING↗

Glyphosate in Irish adults – A pilot study in 2017

Glyphosate is the highest volume herbicide used globally and has recently been classified as a 2 A 'probably carcinogenic to humans' by the International Agency for Research on Cancer (IARC). There is limited data to evaluate the public health impacts from glyphosate exposure. The objective of this study is to conduct an exploratory glyphosate exposure assessment study among Irish adults, who were non-occupational users of glyphosate.

54 ENVIRONMENTAL SCIENCES↗

Sustainable Development in Basic Education Sciences in Portugal—Perspective of Official Curriculum Documents

This study aims to identify and characterize the understanding of the concept of Sustainable Development in the official scientific educational documents of basic education in Portugal. Methodologically, it is a qualitative study that fits into the interpretive paradigm; its implementation is based on an interpretative-descriptive strategy of exploratory nature. The study involved the organization of the analysis corpus and the subsequent content analysis of the selected documents. The documents included in this corpus are the official educational documents on the teaching and learning of Natural Sciences in Basic Education (1st to 9th grade—ages 6 to 15): the Essential Learning and two transversal documents (the Student Profile on Leaving Compulsory Schooling and the Environmental Education Framework for Sustainability). The obtained results show that these documents frame and guide the implementation of Education for Sustainable Development, in all its dimensions, throughout basic education. However, this does not happen in an equitable way, neither in all documents nor in all years of schooling.

João, Patrícia (ORCID:0000000201021191)↗

Lattice QCD study of the Boer-Mulders effect in a pion

The three-dimensional momenta of quarks inside a hadron are encoded in transverse momentumdependent parton distribution functions (TMDs). Our work presents an exploratory lattice QCD study of a TMD observable in the pion describing the Boer-Mulders effect, which is related to polarized quark transverse momentum in an unpolarized hadron. The primary goal is to gain insight into the behavior of TMDs as a function of a Collins-Soper evolution parameter, $\hat{ζ}$, which quantifies the rapidity difference between the hadron momentum and a vector describing the trajectory of the struck quark, e.g., in a semiinclusive deep-inelastic scattering (SIDIS) process. The lattice calculation, performed at the pion mass m π = 518 MeV, utilizes a definition of TMDs via hadronic matrix elements of a quark bilocal operator with a staple-shaped gauge connection; in this context, the evolution parameter is related to the staple direction. By parametrizing the aforementioned matrix elements in terms of invariant amplitudes, the problem can be cast in a Lorentz frame suited for the lattice calculation. Aided by the lower mass of the pion, compared to the nucleon studied previously, the present investigation of pion TMD observables constitutes an important step towards the quantitative study of the physically important regime of large relative rapidity where the dependence on $\hat{ζ}$ appears to approach a limit. Even though matching to perturbative evolution equations in $\hat{ζ}$ is not yet available, extrapolations based on Ansätze containing inverse powers of $\hat{ζ}$ yield stable results with an uncertainty as low as 20%, and both upper and lower bounds for the asymptotics are obtained. In passing, the similarity between the Boer-Mulders effects extracted in the pion and the nucleon is indicated.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

Social vulnerability indicators as a sustainable planning tool

In the face of global warming and environmental change, the conventional strategy of resource centralization will not be able to cope with a future of increasingly extreme climate events and related disasters. It may even contribute to inter-regional disparities as a result of these events. To promote sustainable development, this study offers a case study of developmental planning in Chiayi, Taiwan and a review of the relevant literature to propose a framework of social vulnerability indicators at the township level. The proposed framework can not only be used to measure the social vulnerability of individual townships in Chiayi, but also be used to capture the spatial developmental of Chiayi. Seventeen social vulnerability indicators provide information in five dimensions. Owing to limited access to relevant data, the values of only 13 indicators were calculated. By simply summarizing indicators without using weightings and by using zero-mean normalization to standardize the indicators, this study calculates social vulnerability scores for each township. To make social vulnerability indicators more useful, this study performs an overlay analysis of social vulnerability and patterns of risk associated with national disasters. The social vulnerability analysis draws on secondary data for 2012 from Taiwan's National Geographic Information System. The second layer of analysis consists of the flood potential ratings of the Taiwan Water Resources Agency as an index of biophysical vulnerability. The third layer consists of township-level administrative boundaries. Analytical results reveal that four out of the 18 townships in Chiayi not only are vulnerable to large-scale flooding during serious flood events, but also have the highest degree of social vulnerability. Administrative boundaries, on which social vulnerability is based, do not correspond precisely to “cross-administrative boundaries,” which are characteristics of the natural environment. This study adopts an exploratory approach that provides Chiayi and other government agencies with a foundation for sustainable strategic planning for environmental change. The final section offers four suggestions concerning the implications of social vulnerability for local development planning. -- Highlights: • This study proposes a framework of social vulnerability indicators at the township level in Chiayi County, Taiwan. • Seventeen social vulnerability indicators are categorized into four dimensions. • This study performs a three-layer overlay analysis of social vulnerability and natural disaster risk patterns. • 4 out of the 18 townships not only have potential for large-scale flooding, but also high degree of social vulnerability. • This study provides a foundation for sustainable strategic planning to deal with environmental change. • Four suggestions are proposed regarding the implications of social vulnerability for local development planning.

54 ENVIRONMENTAL SCIENCES↗

Challenging Common Assumptions of Thick-Wall Chamber Dynamics in Inertial Fusion Systems using MOOSE

As an increasing number of companies look toward commercial Inertial Fusion Energy (IFE) designs, there is a pressing need to understand the physics of thick-wall chamber gas dynamics. The thick liquid wall approach implements a renewable wall to mitigate the fusion target emissions, thereby reducing the radiation damage rate and significantly extending the lifetime of chamber structures, leading to increased plant availability and reduced waste streams in comparison to dry wall chamber designs. It is necessary, however, to assess the critical performance and safety aspects of these systems. For example, it is crucial to predict (1) where the mass ablated from the liquid walls will vent, which determines the placement of condensing surfaces; (2) debris propagation up the beam lines, which provides essential information for design and protection requirements; (3) peak pressures and impulse on chamber walls, which affect chamber structural design; and (4) momentum transfer to the liquid jets, which constrains the shape and positioning of the jets. In turn, the chamber design and its liquid walls affect shielding requirements, material activation, and tritium fuel cycle. Currently available simulation tools, however, are unable to accurately capture key thick-wall chamber dynamics. Significant assumptions are often made to simplify the system and reduce computational cost and modeling capability needs, but the impact of these assumptions on simulation predictions has not been evaluated. For example, no three-dimensional simulations can be found in the open literature to evaluate gas venting and momentum transfer to the jets with simulations using two-dimensional domains to represent complex three-dimensional geometries. Moreover, limited studies have been dedicated to jet breakup due to both turbulence and neutron heating, and no studies have been found that evaluate how jet breakup can impact shock-jet interaction. Furthermore, effects of radiative heat transfer have rarely been included for the hydrodynamic phase of shock propagation, and integration of proper equations of state in shock dynamics codes has been mostly exploratory. In this study, we use the flexible, high-fidelity Multiphysics Object-Oriented Simulation Environment (MOOSE) to model these complex phenomena and inform design and safety studies. Capabilities to model thick-wall chamber gas dynamics are being developed, and the impact of the assumptions listed above (i.e., two-dimensional vs three-dimensional, absence of jet breakout, no radiative heat transfer, and ideal gas behavior) are being quantified.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

Challenging Common Assumptions of Thick-Wall Chamber Dynamics in Inertial Fusion Systems Using MOOSE-based Multiphysics Simulations

As an increasing number of companies look toward commercial Inertial Fusion Energy (IFE) designs, there is a pressing need to understand the physics of thick-wall chamber gas dynamics. The thick liquid wall approach implements a renewable wall to mitigate the fusion target emissions, thereby reducing the radiation damage rate and significantly extending the lifetime of chamber structures, leading to increased plant availability and reduced waste streams in comparison to dry wall chamber designs. It is necessary, however, to assess the critical performance and safety aspects of these systems. For example, it is crucial to predict (1) where the mass ablated from the liquid walls will vent, which determines the placement of condensing surfaces; (2) debris propagation up the beam lines, which provides essential information for design and protection requirements; (3) peak pressures and impulse on chamber walls, which affect chamber structural design; and (4) momentum transfer to the liquid jets, which constrains the shape and positioning of the jets. In turn, the chamber design and its liquid walls affect shielding requirements, material activation, and tritium fuel cycle. Currently available simulation tools, however, are unable to accurately capture key thick-wall chamber dynamics. Significant assumptions are often made to simplify the system and reduce computational cost and modeling capability needs, but the impact of these assumptions on simulation predictions has not been evaluated. For example, no three-dimensional simulations can be found in the open literature to evaluate gas venting and momentum transfer to the jets with simulations using two-dimensional domains to represent complex three-dimensional geometries. Moreover, limited studies have been dedicated to jet breakup due to both turbulence and neutron heating, and no studies have been found that evaluate how jet breakup can impact shock-jet interaction. Furthermore, effects of radiative heat transfer have rarely been included for the hydrodynamic phase of shock propagation, and integration of proper equations of state in shock dynamics codes has been mostly exploratory. In this study, we use the flexible, high-fidelity Multiphysics Object-Oriented Simulation Environment (MOOSE) to model these complex phenomena and inform design and safety studies. Capabilities to model thick-wall chamber gas dynamics are being developed, and the impact of the assumptions listed above (i.e., two-dimensional vs three-dimensional, absence of jet breakout, no radiative heat transfer, and ideal gas behavior) are being quantified.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

Establishing reference ranges for circulating biomarkers of drug‐induced liver injury in healthy human volunteers 1

Aims The potential of mechanistic biomarkers to improve prediction of drug‐induced liver injury (DILI) and hepatic regeneration is widely acknowledged. We sought to determine reference intervals for new biomarkers of DILI and regeneration, as well as to characterize their natural variability and impact of diurnal variation. Methods Serum samples from 227 healthy volunteers were recruited as part of a cross‐sectional study; of these, 25 subjects had weekly serial sampling over 3 weeks, while 23 had intensive blood sampling over a 24h period. Alanine aminotransferase (ALT), MicroRNA‐122 (miR‐122), High Mobility Group Box‐1 (HMGB1), total Keratin‐18 (K18), caspase‐cleaved Keratin‐18 (ccK18), Glutamate Dehydrogenase (GLDH) and Macrophage Colony‐Stimulating Factor‐1 (CSF‐1) were assayed. Results Reference intervals were established for each biomarker based on the 97.5% quantile (90% CI) following the assessment of fixed effects in univariate and multivariable models. Intra‐individual variability was found to be non‐significant, and there was no significant impact of diurnal variation. Conclusion Reference intervals for novel DILI biomarkers have been described. An upper limit of a reference range might represent the most appropriate mechanism to utilize these data. These data can now be used to interpret data from exploratory clinical DILI studies and to assist their further qualification as required by regulatory authorities.

Jorgensen, Andrea L. [Department of Health Data Sc↗

Machine Learning Approaches for Predicting Radiation Therapy Outcomes: A Clinician's Perspective

Radiation oncology has always been deeply rooted in modeling, from the early days of isoeffect curves to the contemporary Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) initiative. In recent years, medical modeling for both prognostic and therapeutic purposes has exploded thanks to increasing availability of electronic data and genomics. One promising direction that medical modeling is moving toward is adopting the same machine learning methods used by companies such as Google and Facebook to combat disease. Broadly defined, machine learning is a branch of computer science that deals with making predictions from complex data through statistical models. These methods serve to uncover patterns in data and are actively used in areas such as speech recognition, handwriting recognition, face recognition, “spam” filtering (junk email), and targeted advertising. Although multiple radiation oncology research groups have shown the value of applied machine learning (ML), clinical adoption has been slow due to the high barrier to understanding these complex models by clinicians. Here, we present a review of the use of ML to predict radiation therapy outcomes from the clinician's point of view with the hope that it lowers the “barrier to entry” for those without formal training in ML. We begin by describing 7 principles that one should consider when evaluating (or creating) an ML model in radiation oncology. We next introduce 3 popular ML methods—logistic regression (LR), support vector machine (SVM), and artificial neural network (ANN)—and critique 3 seminal papers in the context of these principles. Although current studies are in exploratory stages, the overall methodology has progressively matured, and the field is ready for larger-scale further investigation.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Pharmacological inhibition of Polo Like Kinase 2 (PLK2) does not cause chromosomal damage or result in the formation of micronuclei

Polo Like Kinase 2 (PLK2) phosphorylates α-synuclein and is considered a putative therapeutic target for Parkinson's disease. Several lines of evidence indicate that PLK2 is involved with proper centriole duplication and cell cycle regulation, inhibition of which could impact chromosomal integrity during mitosis. The objectives of the series of experiments presented herein were to assess whether specific inhibition of PLK2 is genotoxic and determine if PLK2 could be considered a tractable pharmacological target for Parkinson's disease. Several selective PLK2 inhibitors, ELN 582175 and ELN 582646, and their inactive enantiomers, ELN 582176 and ELN 582647, did not significantly increase the number of micronuclei in the in vitro micronucleus assay. ELN 582646 was administered to male Sprague Dawley rats in an exploratory 14-day study where flow cytometric analysis of peripheral blood identified a dose-dependent increase in the number of micronucleated reticulocytes. A follow-up investigative study demonstrated that ELN 582646 administered to PLK2 deficient and wildtype mice significantly increased the number of peripheral micronucleated reticulocytes in both genotypes, suggesting that ELN 582646-induced genotoxicity is not through the inhibition of PLK2. Furthermore, significant reduction of retinal phosphorylated α-synuclein levels was observed at three non-genotoxic doses, additional data to suggest that pharmacological inhibition of PLK2 is not the cause of the observed genotoxicity. These data, in aggregate, indicate that PLK2 inhibition is a tractable CNS pharmacological target that does not cause genotoxicity at doses and exposures that engage the target in the sensory retina. - Highlights: • Active and inactive enantiomers test negative in the in vitro micronucleus test. • ELN 582646 significantly increased micronuclei at 100 and 300 mg/kg/day doses. • ELN 582646 significantly increased micronuclei in PLK2 knockout mice. • ELN 582646 decreased phosphorylation of alpha-synuclein at non-genotoxic doses.

60 APPLIED LIFE SCIENCES↗

Energy Frontier Research in Extreme Environments (EFree)

The mission of EFree has been to accelerate the discovery and synthesis of new energy materials using extreme conditions. EFree has addressed specific knowledge gaps in the discovery of paradigm-shifting, transformative energy materials. The Center targeted three focus areas, Revolutionary Energy Transport Materials, Advanced Structural Materials and Novel Energy Conversion Materials using a system of Center-wide Projects that fall within each of these focus areas. EFree scientists studied materials under extreme conditions to deepen the understanding of materials behavior, enabling new materials to be discovered and ultimately produced by design for practical use at ambient conditions. In addition, EFree supported a range of exploratory projects as feasibility studies for Center-wide projects as well as technical developments that supported these scientific efforts. Over the period of performance, the Center made significant advancements across all three focus areas. This report summarizes key results from the Center and highlights the most important accomplishments including the discovery of near-room-temperature superconductivity, novel diamond-like carbon nanothread materials and new ‘exotic’ semiconductors.

08 HYDROGEN↗

Lawrence Livermore National Laboratory FY 2016 Laboratory Directed Research and Development Annual Report

The LDRD annual report for FY2016 consists of two parts: The Overview. This section contains a broad description of the LDRD Program, highlights of recent accomplishments and awards, Program statistics, and the LDRD portfolio-management processes. Project Reports. Project reports are submitted by all principal investigators at the end of the fiscal year. The length and depth of the report depends on the project’s lifecycle. For projects that will be continuing the following year, the principal investigator submits a continuing project report, which is a brief update containing descriptions of the goals, scope, motivation, relevance (to DOE/NNSA and Livermore mission areas), and technical progress achieved in FY16, as well as a list of selected publications and presentations that resulted from the research. For projects that concluded in FY16, a more detailed final report is provided that is technical in nature and includes the background, objectives, scientific approach, accomplishments, and impacts on the Laboratory missions, as well as a list of publications and presentations that resulted from the research. Project reports are listed under their research topics and organized by year and type, such as exploratory research (ER), feasibility study (FS), laboratory-wide competition (LW), and strategic initiative (SI). Each project is assigned a unique tracking code, an identifier that consists of three elements. The first is the fiscal year in which the project began, the second represents the project type, and the third identifies the serial number of the project for that fiscal year. For example, 16-ERD-100 means the project is an exploratory research project that began in FY16. The three-digit number (100) represents the serial number for the project.

36 MATERIALS SCIENCE↗

Exploratory analysis of machine learning techniques in the Nevada geothermal play fairway analysis

Play fairway analysis (PFA) is commonly used to generate geothermal potential maps and guide exploration studies, with a particular focus on locating and characterizing blind geothermal systems. This study evaluates the application of machine learning techniques to PFA in the Great Basin region of Nevada. Following the evaluation of various techniques, we identified two approaches to PFA that produced promising results, 1) supervised Bayesian probabilistic neural networks to generate geothermal potential maps with confidence intervals, and 2) unsupervised principal component analysis paired with k-means clustering to generate both cluster maps to help identify spatial patterns, as well as new combined feature inputs. We applied these techniques to perform a comparative analysis between two principal sets of geological and geophysical features related to permeability and heat and a set of positive (known geothermal resources) and negative training sites (known drill sites with unsuitable geothermal conditions). We found that these methods constrain previously unrecognized feature controls on geothermal favorability, many of which are spatially organized within the extent of cluster groups and the major structural-hydrologic domains of the study area. Furthermore, we utilized exploratory unsupervised modeling to highlight spatial relationships between input data and predictive output results of our supervised modeling. As a result, we demonstrate how our models compare to the previous Nevada PFA and how the rapid insights these machine learning techniques offer may support future assessments of both known and undiscovered blind geothermal systems in the Great Basin region of Nevada and beyond.

15 GEOTHERMAL ENERGY↗

Distributary Channel Networks as Moving Boundaries: Causes and Morphodynamic Effects

In this study, we propose an exploratory model to describe the morphodynamics of distributary channel network growth on river deltas. The interface between deep channels and the shallow, unchannelized delta front deposits is modeled as a moving boundary. Steady flow over the unchannelized delta front is friction dominated and modeled by Laplace's equation. Shear stress along the network boundary produces nonlinear erosion rates at the interface, causing the boundary to move and network elements (channels and branches) to form. The model was run for boundary conditions resembling the Wax Lake Delta in coastal Louisiana, 20 parameterizations of sediment transport, and 3 parameterizations of discharge. In each case, the model produced a complex channel network with channel number, width, bifurcation angle, and channel shape depending on the sediment transport formula. For reasonable sediment transport parameters and gradually increasing water discharge, the model produced network characteristics and progradation rates similar to theWax Lake Delta. Lastly, this suggests that the model contains the processes responsible for network growth, despite its abstract formulation.

58 GEOSCIENCES↗

Exploring Water System Vulnerabilities in California's Central Valley Under the Late Renaissance Megadrought and Climate Change

Abstract California faces cycles of drought and flooding that are projected to intensify, but these extremes may impact water users across the state differently due to the region's natural hydroclimate variability and complex institutional framework governing water deliveries. To assess these risks, this study introduces a novel exploratory modeling framework informed by paleo and climate‐change based scenarios to better understand how impacts propagate through the Central Valley's complex water system. A stochastic weather generator, conditioned on tree‐ring data, produces a large ensemble of daily weather sequences conditioned on drought and flood conditions under the Late Renaissance Megadrought period (1550–1580 CE). Regional climate changes are applied to this weather data and drive hydrologic projections for the Sacramento, San Joaquin, and Tulare Basins. The resulting streamflow ensembles are used in an exploratory stress test using the California Food‐Energy‐Water System model, a highly resolved, daily model of water storage and conveyance throughout California's Central Valley. Results show that megadrought conditions lead to unprecedented reductions in inflows and storage at major California reservoirs. Both junior and senior water rights holders experience multi‐year periods of curtailed water deliveries and complete drawdowns of groundwater assets. When megadrought dynamics are combined with climate change, risks for unprecedented depletion of reservoir storage and sustained curtailment of water deliveries across multiple years increase. Asymmetries in risk emerge depending on water source, rights, and access to groundwater banks.

Gupta, Rohini S. [School of Civil and Environmenta↗