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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 505 records · Page 28
All sourcesNASA NTRSDOE OSTI
DOE OSTI2026

Discovery of BBO-11818, a Potent and Selective Noncovalent Inhibitor of (ON) and (OFF) KRAS with Activity against Multiple Oncogenic Mutants

Although KRAS G12C -specific inhibitors have been introduced, no approved targeted therapies exist for other clinically significant KRAS mutants, including KRAS G12D and KRAS G12V . We discovered BBO-11818, a potent, selective, orally bioavailable noncovalent pan-KRAS inhibitor capable of targeting multiple KRAS mutants in both the inactive GDP-bound (OFF) and active GTP-bound (ON) states. BBO-11818 binds in the Switch-II/Helix 3 pocket, inducing conformational changes incompatible with effector binding, and demonstrates high-affinity binding to mutant KRAS with strong selectivity over NRAS and HRAS. BBO-11818 potently inhibited MAPK signaling and cellular viability specifically in KRAS-driven lines and produced tumor regressions in KRAS-mutant xenograft models. Combination studies with anti–PD-1, anti-EGFR antibodies, and a RAS:PI3Kα breaker compound showed enhanced efficacy. BBO-11818 has entered phase I clinical trials for patients with various KRAS mutations in colorectal, pancreatic, and lung cancers (NCT06917079).

Stahlhut, Carlos [BridgeBio Oncology Therapeutics,↗
DOE OSTI2026

DLK1 is a GATA1s-driven dependency and therapeutic target in Down syndrome–associated myeloid leukemia

Children with Down syndrome have a markedly increased risk of developing myeloid leukemia. Although having an excellent prognosis, 10% to 20% develop relapsed or refractory disease with poor survival, highlighting the need for new targeted approaches. The pathogenesis of myeloid leukemia of Down syndrome (ML-DS) is tightly linked to fetal hematopoiesis and mutations in GATA1, generating the truncated GATA1 short (GATA1s) isoform. We identified Delta-like noncanonical Notch ligand 1 (DLK1) as a direct GATA1s target. DLK1, a paternally imprinted transmembrane protein, is highly expressed in fetal liver CD34 + cells but absent in adult hematopoiesis, making it an attractive immunotherapeutic target. Chromatin profiling revealed GATA1s occupancy at a distal enhancer within the DLK1-DIO3 locus, driving aberrant DLK1 upregulation in ML-DS. Functional studies demonstrated that DLK1 is a leukemia dependency, as its genetic ablation impaired proliferation and engraftment, induced apoptosis, and altered Notch and β-catenin signaling. Therapeutically, a DLK1-directed antibody-drug conjugate–induced selective cytotoxicity, abrogated colony formation, and significantly prolonged survival in refractory ML-DS patient-derived xenograft (PDX) models, achieving durable remissions at higher doses. These findings establish DLK1 as a leukemia-specific vulnerability and provide preclinical proof-of-concept for DLK1-targeted therapies in ML-DS and other leukemias with fetal-like expression programs.

Biological and medical sciences↗
DOE OSTI2025

Conformational heterogeneity in the dGsw purine riboswitch: role of Mg²⁺ and 2’-dG in aptamer folding

Recent advancements in RNA structural biology have focused on unraveling the complexities of non-coding mRNA elements like riboswitches. These cis-acting regulatory regions undergo structural changes in response to specific cellular metabolites, leading to up or downregulation of downstream genes. The purine riboswitch family regulates many prokaryotic genes involved in purine degradation and biosynthesis. They feature an aptamer domain organized around a 3-way helical junction, where ligand encapsulation occurs at the junctional core. In our study, we chemically probed the aptamer domain of the 2’-dG-sensing purine riboswitch from Mesoplasma florum (dGsw) under various solution conditions to understand how Mg²⁺ and 2’-dG influence riboswitch folding. Here, we find that efficient 2’-dG binding strongly depends on Mg²⁺, indicating that Mg²⁺ is essential for priming dGsw for ligand interactions. We identified a previously undescribed sequence in the 5’ tail of dGsw that is complementary to a conserved helix. The inclusion of this region in a construct led to intramolecular competition between the alternate helix, Palt, and P1. Mutational analysis confirmed that 5’ flanking end of the aptamer domain forms an alternate helix in the absence of ligand. Molecular dynamics simulations revealed that this alternative conformation is stable. This helix may, therefore, facilitate the formation of an anti-terminator helix by opening the 3-way junction surrounding the 2’-dG binding site. Our study further establishes the importance of a closed terminal P1 helix conformation for metabolite binding and suggests that the delicate interplay between P1 and Palt may fine-tune downstream gene regulation. These insights offer a new perspective on riboswitch structure and enhance our understanding of the role that a conformational ensemble plays in riboswitch activity and regulation.

Biochemistry & Molecular Biology↗
DOE OSTI2025

Data for "Enhancing Lipid Production in Plant Cells through Automated High-Throughput Genome Engineering and Phenotyping"

Plant bioengineering is a time-consuming and labor-intensive process with no guarantee of achieving desired traits. Here, we present a fast, automated, scalable, high-throughput pipeline for plant bioengineering (FAST-PB) in maize (Zea mays) and Nicotiana benthamiana. FAST-PB enables genome editing and product characterization by integrating automated biofoundry engineering of callus and protoplast cells with single-cell matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). We first demonstrated that FAST-PB could streamline Golden Gate cloning, with the capacity to construct 96 vectors in parallel. Using FAST-PB in protoplasts, we found that PEG2050 increased transfection efficiency by over 45%. For proof-of-concept, we established a reporter-gene-free method for CRISPR editing and phenotyping via mutation of high chlorophyll fluorescence 136. We show that diverse lipids were enhanced up to 6-fold using CRISPR activation of lipid controlling genes. In callus cells, an automated transformation platform was employed to regenerate plants with enhanced lipid traits through introducing multigene cassettes. Lastly, FAST-PB enabled high-throughput single-cell lipid profiling by integrating MALDI-MS with the biofoundry, protoplast, and callus cells, differentiating engineered and unengineered cells using single-cell lipidomics. These innovations massively increase the throughput of synthetic biology, genome editing, and metabolic engineering and change what is possible using single-cell metabolomics in plants.

AI/ML↗
DOE OSTI2024

Data for Rapid and Efficient in planta Genome Editing in Sorghum Using Foxtail Mosaic Virus-mediated sgRNA Delivery

The requirement of in vitro tissue culture for the delivery of gene editing reagents limits the application of gene editing to commercially relevant varieties of many crop species. To overcome this bottleneck, plant RNA viruses have been deployed as versatile tools for in planta delivery of recombinant RNA. Viral delivery of single-guide RNAs (sgRNAs) to transgenic plants that stably express CRISPR-associated (Cas) endonuclease has been successfully used for targeted mutagenesis in several dicotyledonous and few monocotyledonous plants. Progress with this approach in monocotyledonous plants is limited so far by the availability of effective viral vectors. We engineered a set of foxtail mosaic virus (FoMV) and barley stripe mosaic virus (BSMV) vectors to deliver the fluorescent protein AmCyan to track viral infection and movement in Sorghum bicolor . We further used these viruses to deliver and express sgRNAs to Cas9 and Green Fluorescent Protein (GFP) expressing transgenic sorghum lines, targeting Phytoene desaturase (PDS), Magnesium-chelatase subunit I (MgCh), 4-hydroxy-3-methylbut-2-enyl diphosphate reductase, orthologs of maize Lemon white1 (Lw1) or GFP. The recombinant BSMV did neither infect sorghum nor deliver or express AmCyan and sgRNAs. In contrast, the recombinant FoMV systemically spread throughout sorghum plants and induced somatic mutations with frequencies reaching up to 60%. This mutagenesis led to visible phenotypic changes, demonstrating the potential of FoMV for in planta gene editing and functional genomics studies in sorghum.

Feedstock Production↗
DOE OSTI2026

Machine learning identifies novel signatures of antifungal drug resistance in Saccharomycotina yeasts

Antifungal drug resistance is a major challenge in fungal infection management. Numerous genomic changes are known to contribute to acquired drug resistance in clinical isolates of specific pathogens, but whether they broadly explain natural resistance across entire lineages is unknown. We leveraged genomic, ecological, and phenotypic trait data from naturally sampled strains from nearly all known species in subphylum Saccharomycotina to examine the evolution of resistance to eight antifungal drugs. The phylogenetic distribution of drug resistance varied by drug; fluconazole resistance was widespread, while 5-fluorocytosine resistance was rare, except in Lipomycetales. A random forest algorithm trained on genomic data predicted drug-resistant yeasts with 54–75% accuracy. Fluconazole resistance was consistently predicted with the highest accuracy (75.2%). Furthermore, fluconazole resistance prediction accuracy was similar between models trained on genome-wide variation in the presence and number of InterPro protein annotations across Saccharomycotina (75.2%) and those trained on amino acid sequence alignment data of Erg11, a protein known to be involved in fluconazole resistance (74.3-74.9%). Interestingly, the top Erg11 residues for predicting fluconazole resistance across Saccharomycotina do not overlap with, are not spatially close to, and are less conserved than those previously linked to resistance in clinical isolates of Candida albicans. In silico deep mutational scanning of the C. albicans Erg11 protein reveals that amino acid variants implicated in clinical cases of resistance are almost universally destabilizing while variants in our most informative residues are energetically more neutral, explaining why the latter are much more common than the former in natural populations. Importantly, previous experimental analyses of C. albicans Erg11 have shown that amino acid variation in our most informative residues, despite having never been directly implicated in clinical cases, can directly contribute to resistance. Our results suggest that studies of natural resistance in yeast species never encountered in the clinic will yield a fuller understanding of antifungal drug resistance.

Harrison, Marie-Claire [Vanderbilt Univ., Nashvill↗
DOE OSTI2025

Biophysical and biochemical evidence for the role of acetate kinases (AckAs) in an acetogenic pathway in pathogenic spirochetes

Unraveling the metabolism of Treponema pallidum is a key component to understanding the pathogenesis of the human disease that it causes, syphilis. For decades, it was assumed that glucose was the sole carbon/energy source for this parasitic spirochete. But the lack of citric-acid-cycle enzymes suggested that alternative sources could be utilized, especially in microaerophilic host environments where glycolysis should not be robust. Recent bioinformatic, biophysical, and biochemical evidence supports the existence of an acetogenic energy-conservation pathway in T . pallidum and related treponemal species. In this hypothetical pathway, exogenous D-lactate can be utilized by the bacterium as an alternative energy source. Herein, we examined the final enzyme in this pathway, acetate kinase (named TP0476), which ostensibly catalyzes the generation of ATP from ADP and acetyl-phosphate. We found that TP0476 was able to carry out this reaction, but the protein was not suitable for biophysical and structural characterization. We thus performed additional studies on the homologous enzyme (75% amino-acid sequence identity) from the oral pathogen Treponema vincentii , TV0924. This protein also exhibited acetate kinase activity, and it was amenable to structural and biophysical studies. We established that the enzyme exists as a dimer in solution, and then determined its crystal structure at a resolution of 1.36 Å, showing that the protein has a similar fold to other known acetate kinases. Mutation of residues in the putative active site drastically altered its enzymatic activity. A second crystal structure of TV0924 in the presence of AMP (at 1.3 Å resolution) provided insight into the binding of one of the enzyme’s substrates. On balance, this evidence strongly supported the roles of TP0476 and TV0924 as acetate kinases, reinforcing the hypothesis of an acetogenic pathway in pathogenic treponemes.

Deka, Ranjit K.↗
DOE OSTI2024

Using intrahost single nucleotide variant data to predict SARS-CoV-2 detection cycle threshold values

Over the last four years, each successive wave of the COVID-19 pandemic has been caused by variants with mutations that improve the transmissibility of the virus. Despite this, we still lack tools for predicting clinically important features of the virus. In this study, we show that it is possible to predict the PCR cycle threshold (Ct) values from clinical detection assays using sequence data. Ct values often correspond with patient viral load and the epidemiological trajectory of the pandemic. Using a collection of 36,335 high quality genomes, we built models from SARS-CoV-2 intrahost single nucleotide variant (iSNV) data, computing XGBoost models from the frequencies of A, T, G, C, insertions, and deletions at each position relative to the Wuhan-Hu-1 reference genome. Our best model had an R 2 of 0.604 [0.593–0.616, 95% confidence interval] and a Root Mean Square Error (RMSE) of 5.247 [5.156–5.337], demonstrating modest predictive power. Overall, we show that the results are stable relative to an external holdout set of genomes selected from SRA and are robust to patient status and the detection instruments that were used. This study highlights the importance of developing modeling strategies that can be applied to publicly available genome sequence data for use in disease prevention and control.

COVID19↗
DOE OSTI2024

Lineage frequency time series reveal elevated levels of genetic drift in SARS-CoV-2 transmission in England

Genetic drift in infectious disease transmission results from randomness of transmission and host recovery or death. The strength of genetic drift for SARS-CoV-2 transmission is expected to be high due to high levels of superspreading, and this is expected to substantially impact disease epidemiology and evolution. However, we don’t yet have an understanding of how genetic drift changes over time or across locations. Furthermore, noise that results from data collection can potentially confound estimates of genetic drift. To address this challenge, we develop and validate a method to jointly infer genetic drift and measurement noise from time-series lineage frequency data. Our method is highly scalable to increasingly large genomic datasets, which overcomes a limitation in commonly used phylogenetic methods. We apply this method to over 490,000 SARS-CoV-2 genomic sequences from England collected between March 2020 and December 2021 by the COVID-19 Genomics UK (COG-UK) consortium and separately infer the strength of genetic drift for pre-B.1.177, B.1.177, Alpha, and Delta. We find that even after correcting for measurement noise, the strength of genetic drift is consistently, throughout time, higher than that expected from the observed number of COVID-19 positive individuals in England by 1 to 3 orders of magnitude, which cannot be explained by literature values of superspreading. Our estimates of genetic drift suggest low and time-varying establishment probabilities for new mutations, inform the parametrization of SARS-CoV-2 evolutionary models, and motivate future studies of the potential mechanisms for increased stochasticity in this system.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2026

Directed evolution of a stem-helix–targeting antibody enables MERS-CoV cross-neutralization through enhanced binding affinity

Broadly neutralizing antibodies (bnAbs) targeting conserved regions of the betacoronavirus spike are important for pan-betacoronavirus protection and pandemic preparedness. Here, we report the isolation of a human monoclonal antibody, CC65.1, from a SARS-CoV-2 convalescent donor that targets the conserved S2 stem helix region. CC65.1 neutralizes various sarbecoviruses, including SARS-CoV-2, and binds to the MERS-CoV spike but lacks MERS-CoV-neutralizing activity due to insufficient binding affinity. We utilized directed evolution to enhance the binding affinity of CC65.1 for the MERS-CoV S2 stem helix, yielding engineered antibody variants with newly acquired MERS-CoV-neutralizing activity. High-resolution structural analysis reveals key paratope mutations that enhance binding and stabilize epitope engagement. Our findings demonstrate the potential of in vitro affinity maturation to expand the neutralization breadth of stem-helix-targeting antibodies across divergent betacoronaviruses. This work supports the development of engineered bnAbs for broadly protective betacoronavirus countermeasures and provides a strategy for achieving cross-lineage neutralization.

Zhou, Panpan↗
DOE OSTI2024

Domestication of Algae for Increasing Biomass Productivity

Microalgae cultivation processes have been developed for the production of a variety of bioproducts, however currently only a few species are used in commercial applications. Their domestication, that is strain improvements, is still in its infancy, with major advances required, specifically to maximize biomass productivity a limiting factor in microalgae production. This requires a deep understanding of algal biology, in particular to develop superior strains without the need of genetic technologies that would require lengthy regulatory permits, and often limit consumer acceptance. Adaptive Laboratory Evolution techniques, alone or in conjunction with sexual recombination, can allow for rapid develop of improved strains and their industrial production. Light harvesting antenna reduction has been a major approach to achieve increased photon utilization efficiency by cultures operating under full sunlight conditions due to higher light saturation levels, allowing for higher productivities under outdoor conditions. Decades of research yielded some promising results under controlled conditions with a few specific mutant strains. However, these failed to achieve the anticipated higher productivities in actual algal mass cultures, in part due to the inability of single mutations to overcome photoinhibition, reactive oxygen species, and other pleiotropic impacts on the complex metabolic processes of photosynthesis. Higher productivity strains will require multiple genetic improvements. We report on recent Adaptive Laboratory Evolution with the green alga Scenedesmus obliquus resulting in higher biomass productivity in open pond cultivation. Coupling our approach with sexual recombination and genome sequencing provides a path to algal domestication suitable for large-scale, low-cost biomass production.

09 BIOMASS FUELS↗
DOE OSTI2024

Hardware Fuzzing with An Emulator

Bugs in digital logic have led to some significant security vulnerabilities. Hardware bugs are particularly troublesome since they cannot be easily patched. Additionally, if the bug is in the root of trust, all trust built upon it can be vulnerable. Traditional testing either require a deep knowledge of the system, creative attack vectors and lots of human interaction. This is not scalable as there are very few engineers that can wear the hat of a designer, a verification engineer, and a cybersecurity expert. Hardware fuzzing is a relatively new research area in dynamic hardware testing. It has proven to be an effective method for discovering bugs, unexpected behaviors, and security vulnerabilities in software. While hardware fuzzing is new to the hardware domain, it has a strong track record in software testing. Fuzzing is a testing technique that randomly mutates the input data to uncover bugs or vulnerabilities in the design. It is especially good at finding corner cases that test engineers can not envision. Another advantage over other dynamic testing techniques is that, if done well, deep knowledge of the design is not required. Additionally, fuzzing scales well. If the system is set up correctly, it can run unsupervised for weeks if necessary. In this work, we propose using hardware fuzzing to improve the input vector generation for an information flow tracking tool. To get reasonable throughput of test vectors, an emulator is targeted as the execution platform. Efficient emulator execution has some specific requirements.

42 ENGINEERING↗
DOE OSTI2024

Domesticating the green alga Scenedesmus obliquus

Microalgae cultivation processes exist only for a few species used in commercial applications. Their domestication is still in its infancy, with major advances required, specifically to overcome limiting factors in microalgae production. The goal is to develop superior strains without the need of genetic technologies that would require lengthy regulatory permits, and often limit consumer acceptance. Adaptive Laboratory Evolution techniques, alone or in conjunction with sexual recombination, can allow for rapid develop of improved strains and their industrial production. Approaches include increased photon utilization efficiency by cultures operating under full sunlight conditions due to higher light saturation levels, allowing for higher productivities under outdoor conditions. Decades of research yielded some promising results under controlled conditions with a few specific mutant strains. However, these failed to achieve the anticipated higher productivities in actual algal mass cultures, in part due to the inability of mutations to overcome photoinhibition, reactive oxygen species, and other pleiotropic impacts on photosynthesis.

09 BIOMASS FUELS↗
DOE OSTI2025

Enhancing Developer Productivity - L2 Milestone (Final Report)

This report documents the work done as part of the “Enhancing Developer Productivity” level 2 milestone. The team surveyed developers about impediments and successes; improved our CI pipeline monitoring and reporting; developed tools for line coverage reporting and analysis; improved compiler warning adherence in SIERRA; prototyped static analysis, AI, and mutation testing tooling in SIERRA; and developed a 3-5 year SIERRA plan document to help these initiatives continue past this milestone.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2026

Use of Digital Real-Time Simulation and Optimization to Identify Maximum Real Power Injection on Banshee Distribution Network

This study investigates the hosting capacity of the Banshee Distribution Network by optimizing the real power injection at carefully selected Distributed Energy Resource (DER) locations. The analysis is conducted within the framework of power system operational constraints, including bus voltage ranges, thermal line ratings, and transformer loading limits. A Python-based Genetic Algorithm (GA), implemented using the PyGAD library, is employed to iteratively identify the optimal power injection configuration that maximizes network utilization while preserving system reliability. The methodology integrates a real-time simulation environment using the Real-Time Digital Simulator (RTDS), allowing high-fidelity evaluation of power flow and voltage behavior under each proposed injection scenario. By coupling the optimization algorithm with real-time simulation feedback, this approach ensures that both static and dynamic constraints are enforced during the evaluation process. The GA leverages evolutionary operators such as selection, crossover, and mutation to navigate the nonlinear search space efficiently. The results of the study delineate the feasible hosting capacity at three targeted buses, reflecting maximum real power levels that can be injected without causing voltage violations, transformer overloading, or line congestion. These findings provide a decision- support tool for distribution planners and utilities aiming to integrate higher penetrations of DERs in existing infrastructure. Additionally, the work lays the foundation for extending such optimization techniques to multi-objective formulations, including economic dispatch and reactive power coordination, in future studies.

24 POWER TRANSMISSION AND DISTRIBUTION↗
DOE OSTI2026

pACB112

For recombinant expression of fghA (PP_1617 from Pseudomonas putida) with the S11R mutation and a C-terminal His tag

Adaptive laboratory evolution↗
DOE OSTI2026

pACB113

For recombinant expression of fghA (PP_1617 from Pseudomonas putida) with the W15C mutation and a C-terminal His tag

Adaptive laboratory evolution↗