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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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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

COVID-19 Evidence Accelerator: A parallel analysis to describe the use of Hydroxychloroquine with or without Azithromycin among hospitalized COVID-19 patients

Background: The COVID-19 pandemic remains a significant global threat. However, despite urgent need, there remains uncertainty surrounding best practices for pharmaceutical interventions to treat COVID-19. In particular, conflicting evidence has emerged surrounding the use of hydroxychloroquine and azithromycin, alone or in combination, for COVID-19. The COVID-19 Evidence Accelerator convened by the Reagan-Udall Foundation for the FDA, in collaboration with Friends of Cancer Research, assembled experts from the health systems research, regulatory science, data science, and epidemiology to participate in a large parallel analysis of different data sets to further explore the effectiveness of these treatments. Methods: Electronic health record (EHR) and claims data were extracted from seven separate databases. Parallel analyses were undertaken on data extracted from each source. Each analysis examined time to mortality in hospitalized patients treated with hydroxychloroquine, azithromycin, and the two in combination as compared to patients not treated with either drug. Cox proportional hazards models were used, and propensity score methods were undertaken to adjust for confounding. Frequencies of adverse events in each treatment group were also examined. Results: Neither hydroxychloroquine nor azithromycin, alone or in combination, were significantly associated with time to mortality among hospitalized COVID-19 patients. No treatment groups appeared to have an elevated risk of adverse events. Conclusion: Administration of hydroxychloroquine, azithromycin, and their combination appeared to have no effect on time to mortality in hospitalized COVID-19 patients. Continued research is needed to clarify best practices surrounding treatment of COVID-19.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

A computational modeling framework for pre-clinical evaluation of cardiac mapping systems

There are a variety of difficulties in evaluating clinical cardiac mapping systems, most notably the inability to record the transmembrane potential throughout the entire heart during patient procedures which prevents the comparison to a relevant “gold standard”. Cardiac mapping systems are comprised of hardware and software elements including sophisticated mathematical algorithms, both of which continue to undergo rapid innovation. The purpose of this study is to develop a computational modeling framework to evaluate the performance of cardiac mapping systems. The framework enables rigorous evaluation of a mapping system’s ability to localize and characterize (i.e., focal or reentrant) arrhythmogenic sources in the heart. The main component of our tool is a library of computer simulations of various dynamic patterns throughout the entire heart in which the type and location of the arrhythmogenic sources are known. Our framework allows for performance evaluation for various electrode configurations, heart geometries, arrhythmias, and electrogram noise levels and involves blind comparison of mapping systems against a “silver standard” comprised of computer simulations in which the precise transmembrane potential patterns throughout the heart are known. A feasibility study was performed using simulations of patterns in the human left atria and three hypothetical virtual catheter electrode arrays. Activation times (AcT) and patterns (AcP) were computed for three virtual electrode arrays: two basket arrays with good and poor contact and one high-resolution grid with uniform spacing. The average root mean squared difference of AcTs of electrograms and those of the nearest endocardial action potential was less than 1 ms and therefore appears to be a poor performance metric. In an effort to standardize performance evaluation of mapping systems a novel performance metric is introduced based on the number of AcPs identified correctly and those considered spurious as well as misclassifications of arrhythmia type; spatial and temporal localization accuracy of correctly identified patterns was also quantified. This approach provides a rigorous quantitative analysis of cardiac mapping system performance. Proof of concept of this computational evaluation framework suggests that it could help safeguard that mapping systems perform as expected as well as provide estimates of system accuracy.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Deep mutational scanning reveals the molecular determinants of RNA polymerase-mediated adaptation and tradeoffs

RNA polymerase (RNAP) is emblematic of complex biological systems that control multiple traits involving trade-offs such as growth versus maintenance. Laboratory evolution has revealed that mutations in RNAP subunits, including RpoB, are frequently selected. However, we lack a systems view of how mutations alter the RNAP molecular functions to promote adaptation. We, therefore, measured the fitness of thousands of mutations within a region of rpoB under multiple conditions and genetic backgrounds, to find that adaptive mutations cluster in two modules. Mutations in one module favor growth over maintenance through a partial loss of an interaction associated with faster elongation. Mutations in the other favor maintenance over growth through a destabilized RNAP-DNA complex. The two molecular handles capture the versatile RNAP-mediated adaptations. Combining both interaction losses simultaneously improved maintenance and growth, challenging the idea that growth-maintenance tradeoff resorts only from limited resources, and revealing how compensatory evolution operates within RNAP.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Parallel evaluation of alternative skin barrier models and excised human skin for dermal absorption studies in vitro

Skin permeation is a primary consideration in the safety assessment of cosmetic ingredients, topical drugs, and human users handling veterinary medicinal products. While excised human skin (EHS) remains the ‘gold standard’ for in vitro permeation testing (IVPT) studies, unreliable supply and high cost motivate the search for alternative skin barrier models. In this study, a standardized dermal absorption testing protocol was developed to evaluate the suitability of alternative skin barrier models to predict skin absorption in humans. Under this protocol, side-by-side assessments of a commercially available reconstructed human epidermis (RhE) model (EpiDerm-200-X, MatTek), a synthetic barrier membrane (Strat-M, Sigma-Aldrich), and EHS were performed. The skin barrier models were mounted on Franz diffusion cells and the permeation of caffeine, salicylic acid, and testosterone was quantified. Transepidermal water loss (TEWL) and histology of the biological models were also compared. EpiDerm-200-X exhibited native human epidermis-like morphology, including a characteristic stratum corneum, but had an elevated TEWL as compared to EHS. The mean 6 h cumulative permeation of a finite dose (6 nmol/cm2) of caffeine and testosterone was highest in EpiDerm-200-X, followed by EHS and Strat-M. Salicylic acid permeated most in EHS, followed by EpiDerm-200-X and Strat-M. Altogether, evaluating novel alternative skin barrier models in the manner outlined herein has the potential to reduce the time from basic science discovery to regulatory impact.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Regulatory Research Planning for Micro-Reactor Development

A limited-scope Regulatory Research Development Plan (RRDP) is being developed to link important advanced non light water nuclear microreactor technology research and development (R&D) activities sponsored by the U.S. Department of Energy’s Office of Nuclear Energy (DOE NE), Science, and Technology to regulatory requirements and critical licensing needs likely to impact the deployment of a domestic commercial microreactor fleet. This document is a precursor to that forthcoming limited scope microreactor RRDP. This report is being published to aid in the identification of key fiscal year (FY) 2022 topical research opportunities (as conveyed to the RRDP development team) by respondent microreactor developers and suppliers in consideration of micro-reactor regulatory needs and challenges noted by industry, DOE, and Nuclear Regulatory Commission (NRC) stakeholders. Although this document does not contain the regulatory effects analysis and R&D recommendations that is expected in the final RRDP, this document is being released now to assist DOE researchers and investigators in FY22 research planning activities.

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS↗
DOE OSTI2023

The trans-regulatory landscape of gene networks in plants

The transcriptional effector domains of transcription factors play a key role in controlling gene expression; however, their functional nature is poorly understood, hampering our ability to explore this fundamental dimension of gene regulatory networks. To map the trans-regulatory landscape in a complex eukaryote, we systematically characterized the putative transcriptional effector domains of over 400 Arabidopsis thaliana transcription factors for their capacity to modulate transcription. We demonstrate that transcriptional effector activity can be integrated into gene regulatory networks capable of elucidating the functional dynamics underlying gene expression patterns. We further show how our characterized domains can enhance genome engineering efforts and reveal how plant transcriptional activators share regulatory features conserved across distantly related eukaryotes. Our results provide a framework to systematically characterize the regulatory role of transcription factors at a genome-scale in order to understand the transcriptional wiring of biological systems.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Stage-resolved gene regulatory network analysis reveals developmental reprogramming and genes with robust stem-preferred expression in sorghum

Sorghum bicolor is a deep-rooted, heat- and drought-tolerant crop that thrives on marginal lands and is increasingly valued for its applications in biofuel, bioenergy, and biopolymer production. The sorghum stem, which can reach 4–5 m in length, serves as the primary reservoir of both lignocellulosic biomass and soluble sugars, making it a promising bioenergy feedstock. Although recent advances in genetic, genomic, and transcriptomic resources have improved our understanding of sorghum biology, comprehensive genome-wide analyses of functional dynamics across diverse organ types and developmental stages remain limited. In particular, candidate genes with stem preferred expression pattern or their associated cis-regulatory elements, which may program key stem-related functions and enable organ- or tissue-specific engineering, have not yet been identified.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Organ-delimited gene regulatory networks provide high accuracy in candidate transcription factor selection across diverse processes

Organ-specific gene expression datasets that include hundreds to thousands of experiments allow the reconstruction of organ-level gene regulatory networks (GRNs). However, creating such datasets is greatly hampered by the requirements of extensive and tedious manual curation. Here, we trained a supervised classification model that can accurately classify the organ-of-origin for a plant transcriptome. This K-Nearest Neighbor-based multiclass classifier was used to create organ-specific gene expression datasets for the leaf, root, shoot, flower, and seed in Arabidopsis thaliana . A GRN inference approach was used to determine the: i. influential transcription factors (TFs) in each organ and, ii. most influential TFs for specific biological processes in that organ. These genome-wide, organ-delimited GRNs (OD-GRNs), recalled many known regulators of organ development and processes operating in those organs. Importantly, many previously unknown TF regulators were uncovered as potential regulators of these processes. As a proof-of-concept, we focused on experimentally validating the predicted TF regulators of lipid biosynthesis in seeds, an important food and biofuel trait. Of the top 20 predicted TFs, eight are known regulators of seed oil content, e.g., WRI1, LEC1, FUS3. Importantly, we validated our prediction of MybS2, TGA4, SPL12, AGL18, and DiV2 as regulators of seed lipid biosynthesis. We elucidated the molecular mechanism of MybS2 and show that it induces purple acid phosphatase family genes and lipid synthesis genes to enhance seed lipid content. This general approach has the potential to be extended to any species with sufficiently large gene expression datasets to find unique regulators of any trait-of-interest.

09 BIOMASS FUELS↗
DOE OSTI2024

Dynamics of ER stress-induced gene regulation in plants

Endoplasmic reticulum (ER) stress is a potentially lethal condition that is induced by the abnormal accumulation of unfolded or misfolded secretory proteins in the ER. In eukaryotes, ER stress is managed by the unfolded protein response (UPR) through a tightly regulated, yet highly dynamic, reprogramming of gene transcription. Although the core principles of the UPR are similar across eukaryotes, unique features of the plant UPR reflect the adaptability of plants to their ever-changing environments and the need to balance the demands of growth and development with the response to environmental stressors. Here, the past decades have seen notable progress in understanding the mechanisms underlying ER stress sensing and signaling transduction pathways, implicating the UPR in the effects of physiological and induced ER stress on plant growth and crop yield. Facilitated by sequencing technologies and advances in genetic and genomic resources, recent efforts have driven the discovery of transcriptional regulators and elucidated the mechanisms that mediate the dynamic and precise gene regulation in response to ER stress at the systems level.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Naval Reactors Facility Environmental Monitoring Report (CY2020)

This report presents the results of the radiological and non-radiological environmental monitoring programs for 2020 at the Naval Reactors Facility (NRF). Current operations at NRF are in compliance with applicable regulations governing use, emission, and disposal of solid, liquid, and gaseous materials. The results obtained from the environmental monitoring programs verify that releases to the environment from operations at NRF did not have any adverse effect on human health or the environment. Evaluation of the environmental data confirms that the operation of NRF continues to have no adverse effect on the environment or the health and safety of the general public. Furthermore, a conservative assessment of radiation exposure to the general public as a result of NRF operations demonstrated that the maximum potential dose received by any member of the public was well below the most restrictive dose limits prescribed by the US Environmental Protection Agency (EPA), the US Department of Energy (DOE), and the Nuclear Regulatory Commission.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2022

Naval Reactors Facility Environmental Monitoring Report (CY2019)

This report presents the results of the radiological and non-radiological environmental monitoring programs for 2019 at the Naval Reactors Facility (NRF). Current operations at NRF are in compliance with applicable regulations governing use, emission, and disposal of solid, liquid, and gaseous materials. The results obtained from the environmental monitoring programs verify that releases to the environment from operations at NRF did not have any adverse effect on human health or the environment. Evaluation of the environmental data confirms that the operation of NRF continues to have no adverse effect on the environment or the health and safety of the general public. Furthermore, a conservative assessment of radiation exposure to the general public as a result of NRF operations demonstrated that the maximum potential dose received by any member of the public was well below the most restrictive dose limits prescribed by the US Department of Energy (DOE) and the Nuclear Regulatory Commission.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2020

Transcriptional Regulatory Networks Involved in C3–C4 Alcohol Stress Response and Tolerance in Yeast

Alcohol toxicity significantly impacts the titer and productivity of industrially produced biofuels. To overcome this limitation, we must find and use strategies to improve stress tolerance in production strains. Previously, we developed a multiplex navigation of a global regulatory network (MINR) library that targeted 25 regulatory genes that are predicted to modify global regulation in yeast under different stress conditions. Herein, we expanded this concept to target the active sites of 47 transcriptional regulators using a saturation mutagenesis library. The 47 targeted regulators interact with more than half of all yeast genes. We then screened and selected for C3–C4 alcohol tolerance. We identified specific mutants that have resistance to isopropanol and isobutanol. Notably, the WAR1_K110N variant improved tolerance to both isopropanol and isobutanol. In addition, we investigated the mechanisms for improvement of isopropanol and isobutanol stress tolerance and found that genes related to glycolysis play a role in tolerance to isobutanol, while changes in ATP synthesis and mitochondrial respiration play a role in tolerance to both isobutanol and isopropanol. Overall, this work sheds light on basic mechanisms for isopropanol and isobutanol toxicity and demonstrates a promising strategy to improve tolerance to C3–C4 alcohols by perturbing the transcriptional regulatory network.

09 BIOMASS FUELS↗
DOE OSTI2024

Report on the Integration of Experimental and Modeling Data for Initial Equivalence Study of Microstructural Evolution in Irradiated LPBF 316SS

Advanced materials and manufacturing technologies are poised to improve the safety and design characteristics of nuclear technologies and meet US energy, environmental, and economic needs. In particular, metal additive manufacturing (AM) provides an opportunity to produce novel materials and component geometries, but their use is not without hurdles arising from the inherent microstructure variability that can result from the layer-by-layer build approach. Given the greater possible microstructure variability in AM materials—and the dearth of materials test reactors—it is impractical to rely solely on neutron irradiation studies to produce data for materials qualification for every possibility. This work within the Advanced Materials and Manufacturing Technologies (AMMT) Environmental Effects technical area contributes to the rapid qualification framework by developing a science-driven framework for the accelerated qualification of materials for nuclear environments. A key product of the Environmental Effects technical area of the AMMT program is the Licensing Approach with Ions and Neutrons (LAIN). This approach recognizes that whether using existing materials in new environments, newly developed materials tailored for these environments, or new manufacturing methods, the traditional decades-long approach for materials qualification does not facilitate rapid deployment. In FY 2023, the AMMT program presented a conceptual framework of specific steps to fulfill several technical challenges associated with qualifying materials for performance in radiation environments on an accelerated time frame informed by the state of the art in materials science and a review of the current regulatory landscape. The objective of this section of the Environmental Effects technical area is to critically evaluate and refine the proposed qualification framework presented under AMMT by integrating the research results of the neutron irradiations, the ion irradiations, and modeling efforts. These ongoing efforts span across Argonne National Laboratory (ANL), Idaho National Laboratory (INL), and Oak Ridge National Laboratory (ORNL) and are closely coordinated.

36 MATERIALS SCIENCE↗
DOE OSTI2021

Towards a dynamic photosynthesis model to guide yield improvement in C4 crops

Summary The most productive C4 food and biofuel crops, such as Saccharum officinarum (sugarcane), Sorghum bicolor (sorghum) and Zea mays (maize), all use NADP‐ME‐type C4 photosynthesis. Despite high productivities, these crops fall well short of the theoretical maximum solar conversion efficiency of 6%. Understanding the basis of these inefficiencies is key for bioengineering and breeding strategies to increase the sustainable productivity of these major C4 crops. Photosynthesis is studied predominantly at steady state in saturating light. In field stands of these crops light is continually changing, and often with rapid fluctuations. Although light may change in a second, the adjustment of photosynthesis may take many minutes, leading to inefficiencies. We measured the rates of CO 2 uptake and stomatal conductance of maize, sorghum and sugarcane under fluctuating light regimes. The gas exchange results were combined with a new dynamic photosynthesis model to infer the limiting factors under non‐steady‐state conditions. The dynamic photosynthesis model was developed from an existing C4 metabolic model for maize and extended to include: (i) post‐translational regulation of key photosynthetic enzymes and their temperature responses; (ii) dynamic stomatal conductance; and (iii) leaf energy balance. Testing the model outputs against measured rates of leaf CO 2 uptake and stomatal conductance in the three C4 crops indicated that Rubisco activase, the pyruvate phosphate dikinase regulatory protein and stomatal conductance are the major limitations to the efficiency of NADP‐ME‐type C4 photosynthesis during dark‐to‐high light transitions. We propose that the level of influence of these limiting factors make them targets for bioengineering the improved photosynthetic efficiency of these key crops.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Alternative splicing: transcriptional regulatory network in agroforestry

Alternative splicing (AS) in plants plays a key role in regulating the expression of numerous transcripts from a single gene in a regulatory pathway. Variable concentrations of growth regulatory hormones and external stimuli trigger alternative splicing to switch among different growth stages and adapt to environmental stresses. In the AS phenomenon, a spliceosome causes differential transcriptional modifications in messenger RNA (mRNAs), resulting in partial or complete retention of one or more introns as compared to fully spliced mRNA. Differentially expressed proteins translated from intron-retaining messenger RNA (mRNA ir ) perform vital functions in the feedback mechanism. At the post-transcriptional level, AS causes the remodeling of transcription factors (TFs) by the addition or deletion of binding domains to activate and/or repress transcription. In this study, we have summarized the specific role of AS in the regulation of gene expression through repression and activation of the transcriptional regulatory network under external stimuli and switch among developmental stages.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Molecular dissection of the glutamine synthetase-GlnR nitrogen regulatory circuitry in Gram-positive bacteria

How bacteria sense and respond to nitrogen levels are central questions in microbial physiology. In Gram-positive bacteria, nitrogen homeostasis is controlled by an operon encoding glutamine synthetase (GS), a dodecameric machine that assimilates ammonium into glutamine, and the GlnR repressor. GlnR detects nitrogen excess indirectly by binding glutamine-feedback-inhibited-GS (FBI-GS), which activates its transcription-repression function. The molecular mechanisms behind this regulatory circuitry, however, are unknown. Here we describe biochemical and structural analyses of GS and FBI-GS-GlnR complexes from pathogenic and non-pathogenic Gram-positive bacteria. The structures show FBI-GS binds the GlnR C-terminal domain within its active-site cavity, juxtaposing two GlnR monomers to form a DNA-binding-competent GlnR dimer. The FBI-GS-GlnR interaction stabilizes the inactive GS conformation. Strikingly, this interaction also favors a remarkable dodecamer to tetradecamer transition in some GS, breaking the paradigm that all bacterial GS are dodecamers. These data thus unveil unique structural mechanisms of transcription and enzymatic regulation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

A Systems Biology Approach to Identify Essential Epigenetic Regulators for Specific Biological Processes in Plants

Upon sensing developmental or environmental cues, epigenetic regulators transform the chromatin landscape of a network of genes to modulate their expression and dictate adequate cellular and organismal responses. Knowledge of the specific biological processes and genomic loci controlled by each epigenetic regulator will greatly advance our understanding of epigenetic regulation in plants. To facilitate hypothesis generation and testing in this domain, we present EpiNet, an extensive gene regulatory network (GRN) featuring epigenetic regulators. EpiNet was enabled by (i) curated knowledge of epigenetic regulators involved in DNA methylation, histone modification, chromatin remodeling, and siRNA pathways; and (ii) a machine-learning network inference approach powered by a wealth of public transcriptome datasets. We applied GENIE3, a machine-learning network inference approach, to mine public Arabidopsis transcriptomes and construct tissue-specific GRNs with both epigenetic regulators and transcription factors as predictors. The resultant GRNs, named EpiNet, can now be intersected with individual transcriptomic studies on biological processes of interest to identify the most influential epigenetic regulators, as well as predicted gene targets of the epigenetic regulators. We demonstrate the validity of this approach using case studies of shoot and root apical meristem development.

root apical meristem↗
DOE OSTI2021

Single Cell RNA-Seq and Machine Learning Reveal Novel Subpopulations in Low-Grade Inflammatory Monocytes With Unique Regulatory Circuits

Subclinical doses of LPS (SD-LPS) are known to cause low-grade inflammatory activation of monocytes, which could lead to inflammatory diseases including atherosclerosis and metabolic syndrome. Sodium 4-phenylbutyrate is a potential therapeutic compound which can reduce the inflammation caused by SD-LPS. To understand the gene regulatory networks of these processes, we have generated scRNA-seq data from mouse monocytes treated with these compounds and identified 11 novel cell clusters. We have developed a machine learning method to integrate scRNA-seq, ATAC-seq, and binding motifs to characterize gene regulatory networks underlying these cell clusters. Using guided regularized random forest and feature selection, our method achieved high performance and outperformed a traditional enrichment-based method in selecting candidate regulatory genes. Our method is particularly efficient in selecting a few candidate genes to explain observed expression pattern. In particular, among 531 candidate TFs, our method achieves an auROC of 0.961 with only 10 motifs. Finally, we found two novel subpopulations of monocyte cells in response to SD-LPS and we confirmed our analysis using independent flow cytometry experiments. Our results suggest that our new machine learning method can select candidate regulatory genes as potential targets for developing new therapeutics against low grade inflammation.

60 APPLIED LIFE SCIENCES↗