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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 487 records · Page 27
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Translating dosimetry of Dibenzo[ def,p ]chrysene (DBC) and metabolites across dose and species using physiologically based pharmacokinetic (PBPK) modeling

We report that Dibenzo[def,p]chrysene (DBC) is an environmental polycyclic aromatic hydrocarbon (PAH) that causes tumors in mice and has been classified as a probable human carcinogen by the International Agency for Research on Cancer. Animal toxicity studies often utilize higher doses than are found in relevant human exposures. Additionally, like many PAHs, DBC requires metabolic bioactivation to form the ultimate toxicant, and species differences in DBC and DBC metabolite metabolism have been observed. To understand the implications of dose and species differences, a physiologically based pharmacokinetic model (PBPK) for DBC and major metabolites was developed in mice and humans. Metabolism parameters used in the model were obtained from experimental in vitro metabolism assays using mice and human hepatic microsomes. PBPK model simulations were evaluated against mice dosed with 15 mg/kg DBC by oral gavage and human volunteers orally microdosed with 29 ng of DBC. DBC and its primary metabolite DBC-11,12-diol were measured in blood of mice and humans, while in urine, the majority of DBC metabolites were obeserved as conjugated DBC-11,12-diol, conjugated DBC tetrols, and unconjugated DBC tetrols. The PBPK model was able to predict the time course concentrations of DBC, DBC-11,12-diol, and other DBC metabolites in blood and urine of human volunteers and mice with reasonable accuracy. Agreement between model simulations and measured pharmacokinetic data in mice and human studies demonstrate the success and versatility of our model for interspecies extrapolation and applicability for different doses. Furthermore, our simulations show that internal dose metrics used for risk assessment do not necessarily scale allometrically, and that PBPK modeling provides a reliable approach to appropriately account for interspecies differences in metabolism and physiology.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Benzo[$\mathcal{a}$]pyrene toxicokinetics in humans following dietary supplementation with 3,3'-diindolylmethane (DIM) or Brussels sprouts

Utilizing the atto-zeptomole sensitivity of UPLC-accelerator mass spectrometry (UPLC-AMS), we previously demonstrated significant first-pass metabolism following escalating (25–250 ng) oral micro-dosing in humans of [ 14 C]-benzo[a]pyrene ([ 14 C]-BaP). The present study examines the potential for supplementation with Brussels sprouts (BS) or 3,3' -diindolylmethane (DIM) to alter plasma levels of [ 14 C]-BaP and metabolites over a 48-h period following micro-dosing with 50 ng (5.4 nCi) [ 14 C]-BaP. Volunteers were dosed with [ 14 C]-BaP following fourteen days on a cruciferous vegetable restricted diet, or the same diet supplemented for seven days with 50 g of BS or 300 mg of BR-DIM ® prior to dosing. BS or DIM reduced total [ 14 C] recovered from plasma by 56–67% relative to nonintervention. Dietary supplementation with DIM markedly increased T max and reduced C max for [ 14 C]-BaP indicative of slower absorption. Further, both dietary treatments significantly reduced C max values of four downstream BaP metabolites, consistent with delaying BaP absorption. Dietary treatments also appeared to reduce the T 1/2 and the plasma AUC( 0,$\infty$ ) for Unknown Metabolite C, indicating some effect in accelerating clearance of this metabolite. Toxicokinetic constants for other metabolites followed the pattern for [ 14 C]-BaP (metabolite profiles remained relatively consistent) and non-compartmental analysis did not indicate other significant alterations. Significant amounts of metabolites in plasma were at the bay region of [ 14 C]-BaP irrespective of treatment. Although the number of subjects and large interindividual variation are limitations of this study, it represents the first human trial showing dietary intervention altering toxicokinetics of a defined dose of a known human carcinogen.

3,3'-diindolylmethane↗
DOE OSTI2023

Chemical separation and measurement of platinum activation products

Here, a method has been developed to purify and measure platinum radioisotopes in the presence of fission products and environmental constituents. The method uses a combination of cation exchange and anion exchange chromatography and selective precipitation steps to remove other radioisotopes from the sample. The addition of stable platinum carrier allows for a gravimetric determination of the chemical yield of the procedure. Overall, the method is fast, simple, and potentially applicable for rapid turnaround of unknown samples. Using this method, multiple platinum radioisotopes were measured in two different irradiation experiments. The measured ratios of the platinum radioisotopes clearly reflect the neutron spectrum of the irradiation, suggesting that platinum radioisotopes could be valuable signatures in nuclear forensic analyses.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2021

Genotoxicity evaluation using primary hepatocytes isolated from rhesus macaque ( Macaca mulatta )

Non-human primates (NHPs) have played a vital role in fundamental, pre-clinical, and translational studies because of their high physiological and genetic similarity to humans. We report a method to isolate primary hepatocytes from the livers of rhesus macaques (Macaca mulatta) after in situ whole liver perfusion. Isolated primary macaque hepatocytes (PMHs) were treated with various compounds known to have different pathways of genotoxicity/carcinogenicity and the resulting DNA damage was evaluated using the high-throughput CometChip assay. The comet data were quantified using benchmark dose (BMD) modeling and the BMD50 values for treatments of PMHs were compared with those generated from primary human hepatocytes (PHHs) in our previous study. The results showed that despite varying CYP450 enzyme activities, PMHs had the same sensitivity and specificity as PHHs in detecting four indirect-acting (i.e., requiring metabolic activation) and seven direct-acting genotoxicants/carcinogens, as well as five non-carcinogens that are negative or equivocal for genotoxicity in vivo. The BMD50 estimates and their confidence intervals revealed species differences for DNA damage potency, especially for direct-acting compounds. The present study provides a practical method for maximizing the use of animal tissues by isolating primary hepatocytes from NHPs. Our data support the use of PMHs as a reliable surrogate of PHHs for evaluating the genotoxic hazards of chemical substances for humans.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Building a predictive model for polycyclic aromatic hydrocarbon dosimetry in organotypically cultured human bronchial epithelial cells using benzo[ a ]pyrene

The airway epithelium is a primary route of exposure for inhaled toxicants, and organotypic culture models represent an important advancement for toxicity testing compared to simple in vitro models that may lack metabolic capability and multicellular structure/communication associated with the bronchial epithelium in vivo. A quantitative understanding of chemical dosimetry is key for interpreting and extrapolating study results; however, dosimetry is understudied in organotypic models limiting ability to predict toxicity. We developed a dosimetry model for primary human bronchial epithelial cells (HBECs) cultured at the air-liquid interface (ALI) using benzo[a]pyrene (BAP), a representative polycyclic aromatic hydrocarbon. Dose and time course evaluation of metabolite formation and enzyme activity and expression were utilized to parameterize a cellular dosimetry model to improve the utility of ALI-HBECs for assessing chemical risk. Dosimetry analysis demonstrated absorption of BAP into cells and an increase in Phase 1 and 2 metabolites over time that correlated with regulation of metabolizing enzymes. BAP was cleared from cells by 48 h after exposure, and the primary metabolites generated in ALI-HBECs were BAP-3-phenol, BAP-4,5-dihydrodiol, BAP-7,8-dihydrodiol, BAP-9,10-dihydrodiol, BAP-7,8,9,10-tetrol, BAP-3-phenol-glucuronide, BAP-4,5-dihydrodiol-glucuronide, and BAP-9,10-dihydrodiol-glucuronide. The resulting dosimetry model described BAP and 7,8-dihydrodiol toxicokinetics in ALI-HBECs and suggested active excretion of 7,8-dihydrodiol. Overall, this study demonstrates metabolic competency of ALI-HBECs for BAP metabolism, demonstrates the usefulness of complex in vitro systems for human-relevant toxicity data, and exhibits how in silico models can be utilized for understanding the dosimetry of test compounds to aid in in vitro to human extrapolation of toxicity data for risk assessments.

Benzo[a]pyrene↗
DOE OSTI2022

Future changes in extreme precipitation over the San Francisco Bay Area: Dependence on atmospheric river and extratropical cyclone events

Extreme precipitation poses a major challenge for local governments, including the City and County of San Francisco, California, as flooding can damage and destroy infrastructure and property. As the climate continues to warm, reliable future precipitation projections are needed to provide the best possible information to decision makers. However, future changes in the magnitude of extreme precipitation are uncertain, as current state-of-the-art global climate models are typically run at relatively coarse horizontal resolutions that require the use of convective parameterization and have difficulty simulating observed extreme rainfall rates. Here, we performed ensembles of convection-permitting regional climate model simulations to investigate how five historically impactful extreme precipitation events over the San Francisco Bay Area could change if similar events occurred in future climates. We found that changes in storm-total precipitation depend strongly on storm type. Precipitation associated with an atmospheric river (AR) accompanied by an extratropical cyclone (ETC) is projected to increase at a rate exceeding (by up to 1.5 times) the theoretical Clausius Clapeyron scaling of 6–7% per °C warming. On the other hand, future precipitation changes are weak or negative for events characterized by an AR only, despite increases in precipitable water and integrated vapor transport that are similar to those of the co-occurring AR and ETC events. The differences in the sign of future precipitation change between AR-only events and co-occurring AR and ETC events is instead linked with changes in mid-tropospheric vertical velocity. Given that the majority of observed ARs are associated with an ETC, this research has important implications for future precipitation impacts over the Bay Area, as it indicates that storm-total precipitation associated with the most common type of storm event may increase by up to 26–37% in 2100 relative to historical.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2023

Inhibition of polyamine biosynthesis preserves β cell function in type 1 diabetes

In preclinical models, α-difluoromethylornithine (DFMO), an ornithine decarboxylase (ODC) inhibitor, delays the onset of type 1 diabetes (T1D) by reducing β cell stress. However, the mechanism of DFMO action and its human tolerability remain unclear. In this study, we show that mice with β cell ODC deletion are protected against toxin-induced diabetes, suggesting a cell-autonomous role of ODC during β cell stress. In a randomized controlled trial (ClinicalTrials.gov: NCT02384889) involving 41 recent-onset T1D subjects (3:1 drug:placebo) over a 3-month treatment period with a 3-month follow-up, DFMO (125–1,000 mg/m 2 ) is shown to meet its primary outcome of safety and tolerability. DFMO dose-dependently reduces urinary putrescine levels and, at higher doses, preserves C-peptide area under the curve without apparent immunomodulation. Transcriptomics and proteomics of DFMO-treated human islets exposed to cytokine stress reveal alterations in mRNA translation, nascent protein transport, and protein secretion. These findings suggest that DFMO may preserve β cell function in T1D through islet cell-autonomous effects.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Multivariate prognosis of battery advanced state of health via transformers

De-risking energy storage investments necessary to meet CO 2 reduction targets requires a deep understanding of the connections between battery health, design, and use. The historical definition of the battery state of health (SOH) as the percentage of current versus initial capacity is inadequate for this purpose, motivating an expanded SOH consisting of an interrelated set of descriptors including capacity, energy, ionic and electronic impedances, open-circuit voltages, and microstructure metrics. In this work, we introduce deep transformer networks for the simultaneous prognosis of 28 battery SOH descriptors using two cycling datasets representing six lithium-ion cathode chemistries, multiple electrolyte/anode compositions, and different charge-discharge scenarios. The accuracy of these predictions for battery life (with an unprecedented mean absolute error of 19 cycles in predicting end of life for a lithium-iron-phosphate fast-charging dataset) illustrates the promise of deep learning toward providing enhanced understanding and control of battery health.

25 ENERGY STORAGE↗
DOE OSTI2024

Catalyzing deep decarbonization with federated battery diagnosis and prognosis for better data management in energy storage systems

Industrial data analytics methods play a central role in improving energy storage performance and efficiency, impacting the future of electrified transportation and renewable electricity generation. However, significant challenges hinder the large-scale deployment of batteries. Conventional methods rely on centralized collection and processing of fleet-level data, leading to database size issues and privacy concerns due to potential data breaches. To enable scalable deployment of battery management systems, this article proposes a federated battery diagnosis and prognosis model, which distributes the processing of battery standard current-voltage-time-usage data in a privacy-preserving manner. Instead of transferring the raw data, this approach communicates only the locally processed parameters, thus reducing communication load and preserving data confidentiality. The federated model offers a paradigm shift in battery health management through privacy-preserving distributed methods for battery data processing and lifetime prediction, ensuring the reliable and sustainable deployment of lithium-ion batteries in a rapidly evolving world.

asset health management↗
DOE OSTI2021

Efficient production of oxidized terpenoids via engineering fusion proteins of terpene synthase and cytochrome P450

The functionalization of terpenes using cytochrome P450 enzymes is a versatile route to the production of useful derivatives that can be further converted to value-added products. Many terpenes are hydrophobic and volatile making their availability as a substrate for P450 enzymes significantly limited during microbial production. In this study, we developed a strategy to improve the accessibility of terpene molecules for the P450 reaction by linking terpene synthase and P450 together. As a model system, fusion proteins of 1,8-cineole synthase (CS) and P450 cin were investigated and it showed an improved hydroxylation of the monoterpenoid 1,8-cineole up to 5.4-fold. Structural analysis of the CS-P450 cin fusion proteins by SEC-SAXS indicated a dimer formation with preferred orientations of the active sites of the two domains. We also applied the enzyme fusion strategy to the oxidation of a sesquiterpene epi-isozizaene and the fusion enzymes significantly improved albaflavenol production in engineered E. coli. From the analysis of positive and negative examples of the fusion strategy, we proposed key factors in structure-based prediction and evaluation of fusion enzymes. Developing fusion enzymes for terpene synthase and P450 presents an efficient strategy toward oxidation of hydrophobic terpene compounds. This strategy could be widely applicable to improve the biosynthetic titer of the functionalized products from hydrophobic terpene intermediates.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Evaluation of 1,2-diacyl-3-acetyl triacylglycerol production in Yarrowia lipolytica

Plants produce many high-value oleochemical molecules. While oil-crop agriculture is performed at industrial scales, suitable land is not available to meet global oleochemical demand. Worse, establishing new oil-crop farms often comes with the environmental cost of tropical deforestation. The field of metabolic engineering offers tools to transplant oleochemical metabolism into tractable hosts while simultaneously providing access to molecules produced by non-agricultural plants. Here, we evaluate strategies for rewiring metabolism in the oleaginous yeast Yarrowia lipolytica to synthesize a foreign lipid, 3-acetyl-1,2-diacyl-sn-glycerol (acTAG). Oils made up of acTAG have a reduced viscosity and melting point relative to traditional triacylglycerol oils making them attractive as low-grade diesels, lubricants, and emulsifiers. Furthermore, this manuscript describes a metabolic engineering study that established acTAG production at g/L scale, exploration of the impact of lipid bodies on acTAG titer, and a techno-economic analysis that establishes the performance benchmarks required for microbial acTAG production to be economically feasible.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Long-term trends in urban NO 2 concentrations and associated paediatric asthma incidence: estimates from global datasets

Combustion-related nitrogen dioxide (NO 2 ) air pollution is associated with paediatric asthma incidence. We aimed to estimate global surface NO 2 concentrations consistent with the Global Burden of Disease study for 1990-2019 at a 1 km resolution, and the concentrations and attributable paediatric asthma incidence trends in 13 189 cities from 2000 to 2019. We scaled an existing annual average NO 2 concentration dataset for 2010-12 from a land use regression model (based on 5220 NO 2 monitors in 58 countries and land use variables) to other years using NO 2 column densities from satellite and reanalysis datasets. We applied these concentrations in an epidemiologically derived concentration-response function with population and baseline asthma rates to estimate NO 2 -attributable paediatric asthma incidence. We estimated that 1.85 million (95% uncertainty interval [UI] 0.93-2.80 million) new paediatric asthma cases were attributable to NO 2 globally in 2019, two thirds of which occurred in urban areas (1.22 million cases; 95% UI 0.60-1.8 million). The proportion of paediatric asthma incidence that is attributable to NO 2 in urban areas declined from 19.8% (1.22 million attributable cases of 6.14 million total cases) in 2000 to 16.0% (1.24 million attributable cases of 7.73 million total cases) in 2019. Urban attributable fractions dropped in high-income countries (-41%), Latin America and the Caribbean (-16%), central Europe, eastern Europe, and central Asia (-13%), and southeast Asia, east Asia, and Oceania (-6%), and rose in south Asia (+23%), sub-Saharan Africa (+11%), and north Africa and the Middle East (+5%). The contribution of NO 2 concentrations, paediatric population size, and asthma incidence rates to the change in NO 2 -attributable paediatric asthma incidence differed regionally. Despite improvements in some regions, combustion-related NO 2 pollution continues to be an important contributor to paediatric asthma incidence globally, particularly in cities. Mitigating air pollution should be a crucial element of public health strategies for children.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

A high-resolution record of Late Holocene drought in the eastern Sierra Nevada (California, USA) from June Lake carbonate geochemistry

As historic drought conditions become more common in western North America, Late Quaternary hydroclimate records become vital for putting present anthropogenic conditions into a longer-term context. Here, we establish a high-resolution record of drought for the eastern Sierra Nevada (California) using lacustrine carbonates from well-dated sediment cores. We used oxygen and carbon stable-isotope ratios, combined with high-resolution scanning X-ray fluorescence counts of calcium (Ca) and titanium (Ti), to reconstruct the drought record over the last 4600 years in June Lake. We found elevated δ 18 O and δ 13 C carbonate isotope values coinciding with peaks in both total inorganic carbon and Ca/Ti, suggesting enhanced carbonate precipitation in response to evaporative concentration of lake water. At least six intervals of prolonged (centennial-scale) carbonate deposition were identified, including three pulses during the Late Holocene Dry Period (LHDP; ~3500–2000 cal yr BP), the Medieval Climate Anomaly (~1200–800 cal yr BP), and the Current Warm Period, which began around 100 cal yr BP. This record highlights the complexities of the LHDP, an interval that was more variable at June Lake than has been previously described in regional records.

54 ENVIRONMENTAL SCIENCES↗