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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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DOE OSTI2020

Hydrogen Risk Assessment Models (HyRAM) (Version 3.0 Technical Reference Manual)

The HyRAM software toolkit provides a basis for conducting quantitative risk assessment and consequence modeling for hydrogen infrastructure and transportation systems. HyRAM is designed to facilitate the use of state-of-the-art science and engineering models to conduct robust, repeatable assessments of hydrogen safety, hazards, and risk. HyRAM includes generic probabilities for hydrogen equipment failures, probabilistic models for the impact of heat flux on humans and structures, and computationally and experimentally validated first-order models of hydrogen release and flame physics. HyRAM integrates deterministic and probabilistic models for quantifying accident scenarios, predicting physical effects, and characterizing hydrogen hazards (thermal effects from jet fires, overpressure effects from deflagrations), and assessing impact on people and structures. HyRAM is developed at Sandia National Laboratories for the U.S. Department of Energy to increase access to technical data about hydrogen safety and to enable the use of that data to support development and revision of national and international codes and standards. HyRAM is a research software in active development and thus the models and data may change. This report will be updated at appropriate developmental intervals. This document provides a description of the methodology and models contained in the HyRAM version 3.0. HyRAM 3.0 includes the new ability to model cryogenic hydrogen releases from liquid hydrogen systems, using a different property calculation method and different equations of state. Other changes include modifications to the ignition probability calculations, component leak frequency calculations, and addition of default impulse data.

08 HYDROGEN↗
DOE OSTI2020

Mild and Selective Hydrogenation of Nitrate to Ammonia in the Absence of Noble Metals

Motivated by increased awareness about nitrate contamination of surface waters and its deleterious effects in human and animal health, we sought an alternative, non-noble metal catalyst for the chemical degradation of nitrate. First row transition metal phosphides recently emerged as excellent alternatives for hydrogen evolution and hydrotreating reactions. We demonstrate that a key member of this family, Ni 2 P, readily hydrogenates nitrate (NO 3 – ) to ammonia (NH 3 ) near ambient conditions with very high selectivity (96%). One of the few non-precious metal-based catalysts for this transformation, and among ca. 1% of catalysts with NH 3 selectivity, Ni 2 P can be recycled multiple times with limited loss of activity. Both nitrite (NO 2 – ) and nitric oxide (NO) intermediates are also hydrogenated. Density functional theory (DFT) indicates that—in the absence of a catalyst—nitrite hydrogenation is the reaction bottleneck. A variety of adsorbates (H, O, N, NO) induce surface reconstruction with top-layer Ni-rich surface stoichiometry. Critically, H saturation coverage on Ni 2 P(001) is only ca. 3 nm –2 , significantly less than that on Pd(111) and Ni(111) of ca. 15–18 nm –2 , which may play a key role in allowing coadsorption of NO x – . Here the ability of Earth-abundant, binary metal phosphides such as Ni 2 P to catalyze nitrate hydrogenation could transform and help us to better understand the basic science behind catalytic hydrogenation and, in turn, advance the next generation of oxyanion removal technologies.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2025

A Deep Learning-Aided Workflow for Decoding the Stress Regime of Southern Nevada

The Rock Valley fault zone in southern Nevada has a notable history of seismic activity and is the site of a future direct comparison experiment of explosion and earthquake sources. This study aims to gain insight into regional tectonic processes by leveraging recent advances in seismic monitoring capabilities to elucidate the local stress regime. A crucial step in this investigation is the accurate determination of P-wave first-motion polarities, which play a vital role in resolving earthquake focal mechanisms of small earthquakes. Here, we deploy a deep learning-based method for automatic determination of first-motion polarities to vastly expand the polarity dataset beyond what has been reviewed by human analysts. By the integrating P-wave polarities with new measurements of S/P amplitude ratios, we obtain robust focal mechanism estimates for 1306 earthquakes with a local magnitude of 1 and above occurring between 2010 and 2023 in southern Nevada. We then use the focal mechanism catalog to examine the regional stress orientation, confirming an overall trans-tensional stress regime with smaller scale complexities illuminated by individual earthquake sequences. These findings demonstrate how detailed analyses of small earthquakes can provide fundamental information for understanding earthquake processes in the region and inform future experiments at the Nevada National Security Site.

58 GEOSCIENCES↗
DOE OSTI2020

Updates to a Preliminary Probabilistic Performance Assessment Model for Radiological and Chemical Contamination at the West Valley Site, New York - 20420

The New York State Energy Research and Development Authority (NYSERDA) is the owner of the Western New York Nuclear Service Center (WNYNSC), a 1,351-ha site located approximately 48 km south of Buffalo, New York. In 1962, Nuclear Fuel Services, Inc. (NFS) entered into agreements with the Atomic Energy Commission and New York State to construct the first commercial reprocessing plant of nuclear fuel in the United States at the WNYNSC. NFS built and operated the spent fuel reprocessing plant and waste disposal facilities, processing 640 Mg (640 metric tons) of spent nuclear fuel from 1966 to 1972 under an Atomic Energy Commission license. Nuclear fuel reprocessing operations halted in 1972 and never restarted, leaving behind radioactive and chemical wastes. The U.S. Department of Energy (DOE) was required to complete certain waste management activities under the West Valley Demonstration Project (WVDP) Act of 1980 including decommissioning of WVDP facilities. As collaborating agencies, NYSERDA and the DOE are tasked with making decisions about decommissioning and risk reduction for the West Valley Site. Neptune and Company, Inc. (Neptune) was contracted to develop a probabilistic performance assessment (PPA) model to assist the agencies in their decision making process for decommissioning the WVDP and WNYNSC. One important tool that is needed in order to inform the decision-making process is a science-based model of the West Valley Site that evaluates potential future consequences for human health and the environment. This forms the core of the spatial domain of the West Valley PPA Model. The PPA Model, developed using the GoldSim system modeling software, is a tool intended to provide support for decision making that evaluates uncertainty, in a manner that is transparent, defensible, and robust. The PPA Model includes contaminant transport and health effects components, and is organized around geographically-grouped contaminated facilities. These include the waste disposal areas licensed by the U.S. Nuclear Regulatory Commission and the State of New York, a waste tank farm for storage of high level radioactive waste resulting from reprocessing operations, and several areas contaminated with radioactive and chemical constituents. The PPA Model evaluates contaminant transport from these sources to points of exposure across the site and into receiving surface waters and sediments. Hypothetical people and wildlife could be exposed to contamination at these locations, and the effects of these exposures are evaluated. Contaminant transport processes to be evaluated in the PPA Model include groundwater and surface water transport, contaminant translocation by plants and animals, diffusion, and erosion. The evaluation of exposures to people in this preliminary model is limited to a resident farmer scenario, and ecological assessment is performed at the level of a screening analysis. The results of these preliminary evaluations inform future model developments. PPA Model results are subjected to sensitivity analysis in order to determine those pathways and parameters that are most significant in influencing the results. This information allows analysts and decision makers to focus on those aspects of Site behavior and processes. With this information, the decision makers can drive informed, defensible decisions regarding decommissioning of the Site. This paper includes an update of the information presented at WM2019 [1]. (authors)

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗
DOE OSTI2023

Human DNA polymerase η promotes RNA-templated error-free repair of DNA double-strand breaks

A growing body of evidence indicates that RNA plays a critical role in orchestrating DNA double-strand break repair (DSBR). Recently, we showed that homologous nascent RNA can be used as a template for error-free repair of double-strand breaks (DSBs) in the transcribed genome and to restore the missing sequence at the break site via the transcription-coupled classical nonhomologous end-joining (TC-NHEJ) pathway. TC-NHEJ is a complex multistep process in which a reverse transcriptase (RT) is essential for synthesizing the DNA strand from template RNA. However, the identity of the RT involved in the TC-NHEJ pathway remained unknown. Here, we report that DNA polymerase eta (Pol η), known to possess RT activity, plays a critical role in TC-NHEJ. We found that Pol η forms a multiprotein complex with RNAP II and other TC-NHEJ factors, while also associating with nascent RNA. Moreover, purified Pol η, along with DSBR proteins PNKP, XRCC4, and Ligase IV can fully repair RNA templated 3'-phosphate-containing gapped DNA substrate. In addition, we demonstrate here that Pol η deficiency leads to accumulation of R-loops and persistent strand breaks in the transcribed genes. Finally, we determined that, in Pol η depleted but not in control cells, TC-NHEJ-mediated repair was severely abrogated when a reporter plasmid containing a DSB with several nucleotide deletion within the E. coli lacZ gene was introduced for repair in lacZ-expressing mammalian cells. Thus, our data strongly suggest that RT activity of Pol η is required in error-free DSBR.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

When Spectral Modeling Meets Convolutional Networks: A Method for Discovering Reionization-era Lensed Quasars in Multiband Imaging Data

Over the last two decades, around 300 quasars have been discovered at z ≳ 6, yet only one has been identified as being strongly gravitationally lensed. We explore a new approach—enlarging the permitted spectral parameter space, while introducing a new spatial geometry veto criterion—which is implemented via image-based deep learning. We first apply this approach to a systematic search for reionization-era lensed quasars, using data from the Dark Energy Survey, the Visible and Infrared Survey Telescope for Astronomy Hemisphere Survey, and the Wide-field Infrared Survey Explorer. Our search method consists of two main parts: (i) the preselection of the candidates, based on their spectral energy distributions (SEDs), using catalog-level photometry; and (ii) relative probability calculations of the candidates being a lens or some contaminant, utilizing a convolutional neural network (CNN) classification. The training data sets are constructed by painting deflected point-source lights over actual galaxy images, to generate realistic galaxy–quasar lens models, optimized to find systems with small image separations, i.e., Einstein radii of θ E ≤ 1''. Visual inspection is then performed for sources with CNN scores of P lens > 0.1, which leads us to obtain 36 newly selected lens candidates, which are awaiting spectroscopic confirmation. These findings show that automated SED modeling and deep learning pipelines, supported by modest human input, are a promising route for detecting strong lenses from large catalogs, which can overcome the veto limitations of primarily dropout-based SED selection approaches.

High-redshift galaxies↗
DOE OSTI2023

Identifying strengths and weaknesses of methods for computational network inference from single-cell RNA-seq data

Single-cell RNA-sequencing (scRNA-seq) offers unparalleled insight into the transcriptional programs of different cellular states by measuring the transcriptome of thousands of individual cells. An emerging problem in the analysis of scRNA-seq is the inference of transcriptional gene regulatory networks and a number of methods with different learning frameworks have been developed to address this problem. Here, we present an expanded benchmarking study of eleven recent network inference methods on seven published scRNA-seq datasets in human, mouse, and yeast considering different types of gold standard networks and evaluation metrics. We evaluate methods based on their computing requirements as well as on their ability to recover the network structure. We find that, while most methods have a modest recovery of experimentally derived interactions based on global metrics such as Area Under the Precision Recall curve, methods are able to capture targets of regulators that are relevant to the system under study. Among the top performing methods that use only expression were SCENIC, PIDC, MERLIN or Correlation. Addition of prior biological knowledge and the estimation of transcription factor activities resulted in the best overall performance with the Inferelator and MERLIN methods that use prior knowledge outperforming methods that use expression alone. We found that imputation for network inference did not improve network inference accuracy and could be detrimental. Comparisons of inferred networks for comparable bulk conditions showed that the networks inferred from scRNA-seq datasets are often better or at par with the networks inferred from bulk datasets. Our analysis should be beneficial in selecting methods for network inference. At the same time, this highlights the need for improved methods and better gold standards for regulatory network inference from scRNAseq datasets.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Low-temperature mineralization of perfluorocarboxylic acids

Per- and polyfluoroalkyl substances (PFAS) are persistent, bioaccumulative pollutants found in water resources at concentrations harmful to human health. Whereas current PFAS destruction strategies use nonselective destruction mechanisms, we found that perfluoroalkyl carboxylic acids (PFCAs) could be mineralized through a sodium hydroxide–mediated defluorination pathway. PFCA decarboxylation in polar aprotic solvents produced reactive perfluoroalkyl ion intermediates that degraded to fluoride ions (78 to ~100%) within 24 hours. The carbon-containing intermediates and products were inconsistent with oft-proposed one-carbon-chain shortening mechanisms, and we instead computationally identified pathways consistent with many experiments. Degradation was also observed for branched perfluoroalkyl ether carboxylic acids and might be extended to degrade other PFAS classes as methods to activate their polar headgroups are identified.

Science & Technology - Other Topics↗
DOE OSTI2021

Complex of human Melanotransferrin and SC57.32 Fab fragment reveals novel interdomain arrangement with ferric N-lobe and open C-lobe

Melanotransferrin (MTf) is an iron-binding member of the transferrin superfamily that can be membrane-anchored or secreted in serum. On cells, it can mediate transferrin-independent iron uptake and promote proliferation. In serum, it is a transcytotic iron transporter across the blood–brain barrier. MTf has been exploited as a drug delivery carrier to the brain and as an antibody-drug conjugate (ADC) target due to its oncogenic role in melanoma and its elevated expression in triple-negative breast cancer (TNBC). For treatment of TNBC, an MTf-targeting ADC completed a phase I clinical trial (NCT03316794). The structure of its murine, unconjugated Fab fragment (SC57.32) is revealed here in complex with MTf. The MTf N-lobe is in an active and iron-bound, closed conformation while the C-lobe is in an open conformation incompatible with iron binding. This combination of active and inactive domains displays a novel inter-domain arrangement in which the C2 subdomain angles away from the N-lobe. The C2 subdomain also contains the SC57.32 glyco-epitope, which comprises ten protein residues and two N-acetylglucosamines. Our report reveals novel features of MTf and provides a point of reference for MTf-targeting, structure-guided drug design.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Stakeholder-Engaged Structured Decision Making for the Los Alamos Legacy Cleanup Mission - 20501

The Los Alamos National Laboratory (LANL) environmental legacy cleanup program requires decisions to be made for environmental remediation, decommissioning and disposal or management of radioactive waste. This legacy cleanup program was established to address groundwater contamination, material disposal areas (MDAs) that have been used to dispose of radioactive and other waste material, and 'aggregate areas' that might produce radioactive or other chemical waste as a result of remediation activities. The LANL site is regulated for environmental concerns under the Resource Conservation and Recovery Act (RCRA). However, some parts of LANL, such as material disposal area G (MDA G), have disposed of radioactive waste under DOE Order 435.1, and are subject to other regulations. For example, decommissioning the remote-handled TRU material stored in 33 shafts at MDA G falls under EPA's 40 CFR 191. Collectively, the regulations are all aimed in the same direction of finding the best solution, either through constructs such as 'as low as reasonably achievable' (ALARA), considering balancing factors as opposed to only cost and human health risk, and, under EPA regulations such as RCRA and NEPA, evaluating impact from all chemicals and both human health and ecological endpoints. Despite the basic goals and objectives of the regulations or their guidance, the main challenge is in their implementation. Arguably perhaps, but really in principle, all of these (and similar) regulations are asking for a decision analysis to be performed. Implementation challenges encountered have included lack of understanding of decision analysis in the industry, lack of effective stakeholder engagement in the decision analysis process, and lack of appreciation of the need to separate value judgments from science, the latter leading to developing conservative, or protective, science-based models. Conservative models lead to poor solutions, lack of effective stakeholder engagement leads to long drawn out protracted approaches to finding a solution (which also might never be found with this approach), and lack of understanding of decision analysis and Bayesian statistics causes poor models to be built, which creates unfortunate situations of 'garbage in, garbage out' becoming the basis for decision making. Stakeholder-engaged structured decision making (SDM) is an approach to solving problems that relies on the theory of decision science to involve stakeholders in the decision-making process. This approach incorporates stakeholder values using a scientifically rigorous methodology that separates value judgments from science in a way that helps avoid the pitfalls of biased, protective, or conservative modeling. This approach has its foundation in Keeney's 1992 treatise on value-focused thinking [1]. Keeney advocated a paradigm shift in decision making based on the idea that the standard way of thinking about decisions is backwards. The standard approach of focusing first on identifying alternatives rather than on articulating values results in a reactive approach with the emphasis on mechanics and fixed choices instead of the core values that have meaning to stakeholders. This paradigm shift effectively engages all stakeholders in the decision-making process while using a values focused thinking approach that can lead to the identification of decision opportunities and the creation of better alternatives. The intent is to be proactive and generate solutions that are related directly to values and objectives as identified by stakeholders. There are, perhaps, two overarching reasons why SDM can be used to benefit LANL's environmental legacy cleanup. Some of LANL's remaining waste management and environmental management problems are challenging and complex (for example, the Cr and RDX plumes, and MDAs) and while the traditional approach has, arguably, worked well for relatively simple risk-based problems, it cannot, or should not, be applied to more complex problems if the most effective and efficient solutions are desired. The second reason is cost. This has perhaps become more critical since publication of the Government Accountability Office (GAO) reports that DoE's environmental liability is considered a high-risk concern for the nation [2]. The focus of SDM is on structuring solutions to decision risk problems by first addressing stakeholder and decision maker values and subsequently developing decision objectives and ways to measure those objectives, preference weighting across objectives, identifying decision alternatives that best achieve those values, and characterizing uncertainty in predictions of the measures. Because a complete decision model is created using SDM, it can be evaluated to find the main elements of the model that drive, or predict, the best solution. This approach creates complete decision models that are transparent, traceable, reproducible and technically defensible. The science behind SDM, or decision analysis, is well founded, yet it is not unusual to see ad hoc approaches to decision making implemented under various environmental regulations that are pertinent to the LANL site, including NEPA, RCRA and DOE Order 435.1. Such ad hoc approaches are often not transparent or traceable, and lack reproducibility and technical defensibility. The LANL legacy cleanup program has embarked on using SDM to address the complex problems that remain. Stakeholder meetings have been held, and a prototype version of the stakeholder value system has been developed. Further meetings are expected in the future to address specific project needs. This is a long-term endeavor considering the complex environmental problems faced by DOE EM in Los Alamos (EM-LA), and careful planning, consideration of stakeholder value systems, and engagement with stakeholders throughout the SDM process is expected to lead to a successful endpoint. (authors)

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗
DOE OSTI2021

Multimodal analysis for human ex vivo studies shows extensive molecular changes from delays in blood processing

Multi-omic profiling of human peripheral blood is increasingly utilized to identify biomarkers and pathophysiologic mechanisms of disease. The importance of these platforms in clinical and translational studies led us to investigate the impact of delayed blood processing on the numbers and state of peripheral blood mononuclear cells (PBMC) and on the plasma proteome. Similar to previous studies, we show minimal effects of delayed processing on the numbers and general phenotype of PBMCs up to 18 hours. In contrast, profound changes in the single-cell transcriptome and composition of the plasma proteome become evident as early as 4 hours after blood draw. These reflect patterns of cellular activation across diverse cell types that lead to progressive distancing of the gene expression state and plasma proteome from native in situ biology. Differences accumulating during an overnight rest (18 hours) would confound relevant biologic variance related to many underlying disease states.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Mutation-driven RRE stem-loop II conformational change induces HIV-1 nuclear export dysfunction

Abstract The Rev response element (RRE) forms an oligomeric complex with the viral protein Rev to facilitate the nuclear export of intron-retaining viral RNAs during the late phase of HIV-1 (human immunodeficiency virus type 1) infection. However, the structures and mechanisms underlying this process remain largely unknown. Here, we determined the crystal structure of the HIV-1 RRE stem-loop II (SLII), revealing a unique three-way junction architecture in which the base stem (IIa) bifurcates into the stem-loops (IIb and IIc) to compose Rev binding sites. The crystal structures of various SLII mutants demonstrated that while some mutants retain the same “compact” fold as the wild type, other single-nucleotide mutants induce drastic conformational changes, forming an “extended” SLII structure. Through in vitro Rev binding assays and Rev activity measurements in HIV-1-infected cells using structure-guided SLII mutants designed to favor specific conformers, we showed that while the compact fold represents a functional SLII, the alternative extended conformation inhibits Rev binding and oligomerization and consequently stimulates HIV-1 RNA nuclear export dysfunction. The propensity of SLII to adopt multiple conformations as captured in crystal structures and their influence on Rev oligomerization illuminate emerging perspectives on RRE structural plasticity-based regulation of HIV-1 nuclear export and provide opportunities for developing anti-HIV drugs targeting specific RRE conformations.

Biochemistry & Molecular Biology↗
DOE OSTI2023

Resilient Inverter-Driven Black Start with Collective Parallel Grid-Forming Operation

As modern power systems are experiencing exceptional changes with increasing penetrations of inverter-based resources (IBRs), system restoration using IBRs has received attention. Using local grid-forming (GFM) assets near consumers, engineered to establish grid voltages in the absence of a stiff grid, i.e., bottom-up restoration, a distribution system could obtain high system resilience by not relying on the bulk power system restoration, which requires significant human intervention and procedure. This paper studies the technical feasibility of the novel approach with detailed electromagnetic transient (EMT) simulations. To thoroughly evaluate the potential of GFM inverters and the technical challenges in IBR-driven black start, a detailed three-phase inverter model is developed, including negative-sequence control for voltage balance and a phase-by- phase current limiter to sustain momentary overloading during the black start. To examine dynamic aspects of the black-start process, the EMT simulation also models transformer and motor dynamics to emulate their inrush and startup behaviors as well as network dynamics. In addition, active involvement of grid- following distributed energy resources is also studied to facilitate the black-start process. By allowing multiple GFM inverters to collectively black start without leader-follower coordination, we demonstrate that a system can achieve high resilience even with a fraction of assets lost. Two test cases of inverter-driven black start, using two and one GFM inverters, respectively, for a heavily unbalanced 2-MVA distribution feeder are demonstrated. Takeaways for further study and field deployment are provided.

grid-forming inverter↗
DOE OSTI2020

Collaborative Research: Natural Organic Matter and Microbial Controls on Mobilization/Immobilization of I and Pu in Soils and Waters Affected by Radionuclide Releases in USA and Japan

In this project, the relationship between natural organic matter (NOM) and two radioactive elements that are relevant to nuclear waste disposal were studied: Plutonium (Pu) and Iodine. The human and environmental risks associated with Pu stem mainly from the very long half-lives of several of its isotopes ( 238 Pu, 88 yr; 239 Pu, 24,100 yr; 240 Pu, 6560 yr) and its radiotoxicity. Understanding Pu biogeochemical behavior in both near-field (>10-11M) and far-field scales (<10-11M) is imperative to the development of approaches for reprocessing Pu, remediation of Pu contamination and accurate assessment of risks posed by disposal practices for Pu-bearing wastes. The environmental mobility of Pu can be affected by redox potential, pH, adsorption, precipitation, complexation, colloid formation, and microbial activity, of which the first characteristic has the most profound influence. Numerous studies have shown high affinity of Pu towards NOM, as well as to mineral phases. NOM is ubiquitous in the environment, e.g., both fulvic and humic acids are able to reduce Pu(V,VI) to Pu(IV) and the redox potential of NOM is positively related to the abundance of phenolic/acidic OH groups. NOM can either facilitate or limit actinide migration, depending on specific biogeochemical conditions including pH, mineral and organic matter characteristics, etc. The other radionuclide of interest is radioiodine ( 129 I). 129I is a major by-product of nuclear fission and of serious concern to the Department of Energy (DOE) as it is among the top risk drivers at existing and potential radiowaste-contaminated sites. The risk of 129 I stems largely from its high bioconcentration factor (90% of the body’s iodine is accumulated in the thyroid), a high inventory at source terms, a very long-half life (16M years), and rapid mobility in the subsurface environment. As a consequence, 129 I has the lowest drinking water standard (1 pCi/L) among all radionuclides in the Federal Register. With a novel and sensitive gas chromatography-mass spectrometry (GC-MS) method developed in our lab, it is possible to quickly and simultaneously determine the distribution of 129 I and stable 127 I forms in environments, as low as 2 pCi/L for 129 I. This method was subsequently validated using accelerator mass spectroscopy, AMS. IO 3 - and organo-I were determined as major species in the groundwater of SRS and the Hanford Site, contrary to thermodynamic predictions that I- should be the dominant species at these sites. Mobility of 129 I was also demonstrated to depend greatly on the I species and its concentration, sediment pH, and redox state, with times to achieve equilibrium taking up to 12 weeks. Along the groundwater pathway in the F-Area of SRS, 129 I- supplied from the seepage basins was transformed to 129 IO 3 - and organo- 129 I with increasing iodine sediment sorption, causing the lower total 127 I and 129 I concentrations along the gradient transect of the waste plume. By contrast, groundwater 129 I concentrations in the wetlands (as high as 1617.3 pCi/L) were greatly elevated with respect to the source term (159.3 pCi/L). While the NOM promoted the uptake of 129 I to the wetland sediment, it also promoted the formation of soluble organic fraction. A small fraction of NOM that is bound to iodine can behave as a mobile organo-I source. Iodide was enzymatically incorporated into NOM, whereas both iodide and iodate were abiotically bound to NOM, under certain conditions. Iodate removal from the mobile aqueous phase can also occur through incorporation into carbonate (e.g., at the Hanford Site, USA). Thus immobilization and re-mobilization of iodine species were influenced by pH, Eh and the presence of NOM and metal oxides, which adds to the complexity of site remediation action. A ground-breaking result was to elucidate the products (i.e. organo-iodine moieties formed via enzymatic and non-enzymatic processes) at the molecular level by nuclear magnetic resonance (NMR) and electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICRMS). We found that iodine-NOM interactions may be influenced by NOM hydrophobic aliphatic moieties. From the perspective of ESI-FTICRMS, organo-iodine formulas were ascribed to the groups of unsaturated hydrocarbons, lignins and proteins. Iodate is likely abiotically reduced to reactive iodine species by lignin- and tannin-like compounds or carboxylic-rich alicyclic molecules (CRAM). We also investigated microbial mechanisms in iodine incorporation into NOM. We established that soil bacteria isolated from F-Area of SRS did not accumulate significant amounts of I- (0.2-2%). Intracellular uptake of I- decreases with increasing pH when pH ranged from 4 to 6. In contrast, 44 out of 84 strains isolated from the F-Area of SRS can transform I- to IO 3 - and organo-iodine. In some cases, oxidation was facilitated in the presence of H 2 O 2 . Microbes can also excrete organic acids that enhance I- oxidation by lowering the ambient pH and reacting with H 2 O 2 to form peroxy carboxylic acids. At lower pH values (≤5), H 2 O 2 hydrolysis was the driving force for iodide-oxidation; whereas, at pH ≥ 6, spontaneous decomposition of peroxy carboxylic acids, originating from H 2 O 2 and organic acids were the primary cause of iodide oxidation. Lastly, it was determined that microbial processes involved in Mn (II) are capable of directly oxidizing I- via enzymatic catalysis (i.e., multicopper oxidases), or indirectly through the formation of reactive oxygen species (ROS) and/or biogenic manganese oxides. ROS-mediated oxidation of I- was found to predominate at pH >5, whereas the enzymatic and Mn oxide pathways were more active at pH < 5. Together, this project has resulted in 9 publications in high-impact journals, and the training of 1 Ph.D and 4 undergraduate students.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2020

Metabolic Signaling Cascades Prompted by Glutaminolysis in Cancer

Aberrant glutamatergic signaling has been implicated in altered metabolic activity and the demand to synthesize biomass in several types of cancer including melanoma. In the last decade, there has been a significant contribution to our understanding of metabolic pathways. An increasing number of studies are now emphasizing the importance of glutamate functioning as a signaling molecule and a building block for cancer progression. To that end, our group has previously illustrated the role of glutamatergic signaling mediated by metabotropic glutamate receptor 1 (GRM1) in neoplastic transformation of melanocytes in vitro and spontaneous development of metastatic melanoma in vivo. Glutamate, the natural ligand of GRM1, is one of the most abundant amino acids in humans and the predominant excitatory neurotransmitter in the central nervous system. Elevated levels of glutaminolytic mitochondrial tricarboxylic acid (TCA) cycle intermediates, especially glutamate, have been reported in numerous cancer cells. Herein, we highlight and critically review metabolic bottlenecks that are prevalent during tumor evolution along with therapeutic implications of limiting glutamate bioavailability in tumors.

Shah, Raj (ORCID:0000000204400189)↗
DOE OSTI2023

A GPT‐4 Reticular Chemist for Guiding MOF Discovery**

Abstract We present a new framework integrating the AI model GPT‐4 into the iterative process of reticular chemistry experimentation, leveraging a cooperative workflow of interaction between AI and a human researcher. This GPT‐4 Reticular Chemist is an integrated system composed of three phases. Each of these utilizes GPT‐4 in various capacities, wherein GPT‐4 provides detailed instructions for chemical experimentation and the human provides feedback on the experimental outcomes, including both success and failures, for the in‐context learning of AI in the next iteration. This iterative human‐AI interaction enabled GPT‐4 to learn from the outcomes, much like an experienced chemist, by a prompt‐learning strategy. Importantly, the system is based on natural language for both development and operation, eliminating the need for coding skills, and thus, make it accessible to all chemists. Our collaboration with GPT‐4 Reticular Chemist guided the discovery of an isoreticular series of MOFs, with each synthesis fine‐tuned through iterative feedback and expert suggestions. This workflow presents a potential for broader applications in scientific research by harnessing the capability of large language models like GPT‐4 to enhance the feasibility and efficiency of research activities.

Chemistry↗
DOE OSTI2023

Cryo-EM analyses of KIT and oncogenic mutants reveal structural oncogenic plasticity and a target for therapeutic intervention

The receptor tyrosine kinase KIT and its ligand stem cell factor (SCF) are required for the development of hematopoietic stem cells, germ cells, and other cells. A variety of human cancers, such as acute myeloid leukemia, gastrointestinal stromal tumor, and mast cell leukemia, are driven by somatic gain-of-function KIT mutations. Here, we report cryo electron microscopy (cryo-EM) structural analyses of full-length wild-type and two oncogenic KIT mutants, which show that the overall symmetric arrangement of the extracellular domain of ligand-occupied KIT dimers contains asymmetric D5 homotypic contacts juxtaposing the plasma membrane. Mutational analysis of KIT reveals in D5 region an “Achilles heel” for therapeutic intervention. A ligand-sensitized oncogenic KIT mutant exhibits a more comprehensive and stable D5 asymmetric conformation. A constitutively active ligand-independent oncogenic KIT mutant adopts a V-shaped conformation solely held by D5-mediated contacts. Binding of SCF to this mutant fully restores the conformation of wild-type KIT dimers, including the formation of salt bridges responsible for D4 homotypic contacts and other hallmarks of SCF-induced KIT dimerization. These experiments reveal an unexpected structural plasticity of oncogenic KIT mutants and a therapeutic target in D5.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Discovery of an ultraspecific triuret hydrolase (TrtA) establishes the triuret biodegradation pathway

Triuret (carbonyldiurea) is an impurity found in industrial urea fertilizer (<0.1% w/w) that is applied, worldwide, around 300 million pounds each year on agricultural lands. In addition to anthropogenic sources, endogenous triuret has been identified in amoeba and human urine, the latter being diagnostic for hypokalemia. The present study is the first to describe the metabolic breakdown of triuret, which funnels into biuret metabolism. We identified the gene responsible for triuret decomposition ( trtA ) in bacterial genomes, clustered with biuH , which encodes biuret hydrolase and has close protein sequence homology. TrtA is a member of the isochorismatase-like hydrolase (IHL) protein family, similarly to BiuH, and has a catalytic efficiency (k cat/ K M ) of 6 x 10 5 M –1 s –1 , a K M for triuret of 20 μM, and exquisite substrate specificity. Indeed, TrtA has four orders of magnitude less activity with biuret. Crystal structures of TrtA in apo and holo form were solved and compared with the BiuH structure. The high substrate selectivity was found to be conveyed by second shell residues around each active site. Mutagenesis of residues conserved in TrtA to the alternate consensus found in BiuHs revealed residues critical to triuret hydrolase activity but no single mutant evolved more biuret activity, and likely a combination of mutations is required to interconvert between TrtA, BiuH functions. TrtA-mediated triuret metabolism is relatively rare in recorded genomes (1–2%), but is largely found in plant-associated, nodulating, and endophytic bacteria. This study suggests functions for triuret hydrolase in certain eukaryotic intermediary processes and prokaryotic intermediary or biodegradative metabolism.

36 MATERIALS SCIENCE↗