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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 1,531 records · Page 85
All sourcesNASA NTRSDOE OSTI
DOE OSTI2023

Genome-scale metabolic reconstruction of 7,302 human microorganisms for personalized medicine

The human microbiome influences the efficacy and safety of a wide variety of commonly prescribed drugs. Designing precision medicine approaches that incorporate microbial metabolism would require strain- and molecule-resolved, scalable computational modeling. Here, we extend our previous resource of genome-scale metabolic reconstructions of human gut microorganisms with a greatly expanded version. AGORA2 (assembly of gut organisms through reconstruction and analysis, version 2) accounts for 7,302 strains, includes strain-resolved drug degradation and biotransformation capabilities for 98 drugs, and was extensively curated based on comparative genomics and literature searches. The microbial reconstructions performed very well against three independently assembled experimental datasets with an accuracy of 0.72 to 0.84, surpassing other reconstruction resources and predicted known microbial drug transformations with an accuracy of 0.81. We demonstrate that AGORA2 enables personalized, strain-resolved modeling by predicting the drug conversion potential of the gut microbiomes from 616 patients with colorectal cancer and controls, which greatly varied between individuals and correlated with age, sex, body mass index and disease stages. AGORA2 serves as a knowledge base for the human microbiome and paves the way to personalized, predictive analysis of host–microbiome metabolic interactions.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Comprehensive characterization of protein–protein interactions perturbed by disease mutations

Technological and computational advances in genomics and interactomics have made it possible to identify how disease mutations perturb protein–protein interaction (PPI) networks within human cells. Here, we show that disease-associated germline variants are significantly enriched in sequences encoding PPI interfaces compared to variants identified in healthy participants from the projects 1000 Genomes and ExAC. Somatic missense mutations are also significantly enriched in PPI interfaces compared to noninterfaces in 10,861 tumor exomes. We computationally identified 470 putative oncoPPIs in a pan-cancer analysis and demonstrate that oncoPPIs are highly correlated with patient survival and drug resistance/sensitivity. Further, we experimentally validate the network effects of 13 oncoPPIs using a systematic binary interaction assay, and also demonstrate the functional consequences of two of these on tumor cell growth. In summary, this human interactome network framework provides a powerful tool for prioritization of alleles with PPI-perturbing mutations to inform pathobiological mechanism- and genotype-based therapeutic discovery.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Structural basis of colibactin activation by the ClbP peptidase

Abstract Colibactin, a DNA cross-linking agent produced by gut bacteria, is implicated in colorectal cancer. Its biosynthesis uses a prodrug resistance mechanism: a non-toxic precursor assembled in the cytoplasm is activated after export to the periplasm. This activation is mediated by ClbP, an inner-membrane peptidase with an N-terminal periplasmic catalytic domain and a C-terminal three-helix transmembrane domain. Although the transmembrane domain is required for colibactin activation, its role in catalysis is unclear. Our structure of full-length ClbP bound to a product analog reveals an interdomain interface important for substrate binding and enzyme stability and interactions that explain the selectivity of ClbP for the N -acyl- d -asparagine prodrug motif. Based on structural and biochemical evidence, we propose that ClbP dimerizes to form an extended substrate-binding site that can accommodate a pseudodimeric precolibactin with its two terminal prodrug motifs in the two ClbP active sites, thus enabling the coordinated activation of both electrophilic warheads.

Biochemistry & Molecular Biology↗
DOE OSTI2022

A small molecule inhibitor prevents gut bacterial genotoxin production

Abstract The human gut bacterial genotoxin colibactin is a possible key driver of colorectal cancer (CRC) development. Understanding colibactin’s biological effects remains difficult owing to the instability of the proposed active species and the complexity of the gut microbiota. Here, we report small molecule boronic acid inhibitors of colibactin biosynthesis. Designed to mimic the biosynthetic precursor precolibactin, these compounds potently inhibit the colibactin-activating peptidase ClbP. Using biochemical assays and crystallography, we show that they engage the ClbP binding pocket, forming a covalent bond with the catalytic serine. These inhibitors reproduce the phenotypes observed in a clbP deletion mutant and block the genotoxic effects of colibactin on eukaryotic cells. The availability of ClbP inhibitors will allow precise, temporal control over colibactin production, enabling further study of its contributions to CRC. Finally, application of our inhibitors to related peptidase-encoding pathways highlights the power of chemical tools to probe natural product biosynthesis.

Biochemistry & Molecular Biology↗
DOE OSTI2023

Biosynthesis of natural and halogenated plant monoterpene indole alkaloids in yeast

Monoterpenoid indole alkaloids (MIAs) represent a large class of plant natural products with marketed pharmaceutical activities against a wide range of indications, including cancer, malaria and hypertension. Halogenated MIAs have shown improved pharmaceutical properties; however, synthesis of new-to-nature halogenated MIAs remains a challenge. Here we demonstrate a platform for de novo biosynthesis of two MIAs, serpentine and alstonine, in baker’s yeast Saccharomyces cerevisiae and deploy it to systematically explore the biocatalytic potential of refactored MIA pathways for the production of halogenated MIAs. From this, we demonstrate conversion of individual haloindole derivatives to a total of 19 different new-to-nature haloserpentine and haloalstonine analogs. Furthermore, by process optimization and heterologous expression of a modified halogenase in the microbial MIA platform, we document de novo halogenation and biosynthesis of chloroalstonine. Together, this study highlights a microbial platform for enzymatic exploration and production of complex natural and new-to-nature MIAs with therapeutic potential.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Mitochondrial ATP generation is more proteome efficient than glycolysis

Metabolic efficiency profoundly influences organismal fitness. Nonphotosynthetic organisms, from yeast to mammals, derive usable energy primarily through glycolysis and respiration. Although respiration is more energy efficient, some cells favor glycolysis even when oxygen is available (aerobic glycolysis, Warburg effect). A leading explanation is that glycolysis is more efficient in terms of ATP production per unit mass of protein (that is, faster). Through quantitative flux analysis and proteomics, we find, however, that mitochondrial respiration is actually more proteome efficient than aerobic glycolysis. This is shown across yeast strains, T cells, cancer cells, and tissues and tumors in vivo. Instead of aerobic glycolysis being valuable for fast ATP production, it correlates with high glycolytic protein expression, which promotes hypoxic growth. Aerobic glycolytic yeasts do not excel at aerobic growth but outgrow respiratory cells during oxygen limitation. Here, we accordingly propose that aerobic glycolysis emerges from cells maintaining a proteome conducive to both aerobic and hypoxic growth.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2023

Risk of hematological malignancies from CT radiation exposure in children, adolescents and young adults

Over one million European children undergo computed tomography (CT) scans annually. Although moderate- to high-dose ionizing radiation exposure is an established risk factor for hematological malignancies, risks at CT examination dose levels remain uncertain. Here we followed up a multinational cohort (EPI-CT) of 948,174 individuals who underwent CT examinations before age 22 years in nine European countries. Radiation doses to the active bone marrow were estimated on the basis of body part scanned, patient characteristics, time period and inferred CT technical parameters. We found an association between cumulative dose and risk of all hematological malignancies, with an excess relative risk of 1.96 (95% confidence interval 1.10 to 3.12) per 100 mGy (790 cases). Similar estimates were obtained for lymphoid and myeloid malignancies. Results suggest that for every 10,000 children examined today (mean dose 8 mGy), 1–2 persons are expected to develop a hematological malignancy attributable to radiation exposure in the subsequent 12 years. Our results strengthen the body of evidence of increased cancer risk at low radiation doses and highlight the need for continued justification of pediatric CT examinations and optimization of doses.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Structure of the human SAGA coactivator complex

The SAGA complex is a regulatory hub involved in gene regulation, chromatin modification, DNA damage repair and signaling. While structures of yeast SAGA (ySAGA) have been reported, there are noteworthy functional and compositional differences for this complex in metazoans. Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA) and show how the arrangement of distinct structural elements results in a globally divergent organization from that of yeast, with a different interface tethering the core module to the TRRAP subunit, resulting in a dramatically altered geometry of functional elements and with the integration of a metazoan-specific splicing module. Our hSAGA structure reveals the presence of an inositol hexakisphosphate (InsP 6 ) binding site in TRRAP and an unusual property of its pseudo-(Ψ)PIKK. Finally, we map human disease mutations, thus providing the needed framework for structure-guided drug design of this important therapeutic target for human developmental diseases and cancer.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

The CNK–HYP scaffolding complex promotes RAF activation by enhancing KSR–MEK interaction

The RAS–MAPK pathway regulates cell proliferation, differentiation and survival, and its dysregulation is associated with cancer development. The pathway minimally comprises the small GTPase RAS and the kinases RAF, MEK and ERK. Activation of RAF by RAS is notoriously intricate and remains only partially understood. There are three RAF isoforms in mammals (ARAF, BRAF and CRAF) and two related pseudokinases (KSR1 and KSR2). RAS-mediated activation of RAF depends on an allosteric mechanism driven by the dimerization of its kinase domain. Recent work on human RAFs showed that MEK binding to KSR1 promotes KSR1–BRAF heterodimerization, which leads to the phosphorylation of free MEK molecules by BRAF. Similar findings were made with the single Drosophila RAF homolog. Here we show that the fly scaffold proteins CNK and HYP stabilize the KSR–MEK interaction, which in turn enhances RAF–KSR heterodimerization and RAF activation. The cryogenic electron microscopy structure of the minimal KSR–MEK–CNK–HYP complex reveals a ring-like arrangement of the CNK–HYP complex allowing CNK to simultaneously engage KSR and MEK, thus stabilizing the binary interaction. Together, these results illuminate how CNK contributes to RAF activation by stimulating the allosteric function of KSR and highlight the diversity of mechanisms impacting RAF dimerization as well as the regulatory potential of the KSR–MEK interaction.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

An interphase pool of KIF11 localizes at the basal bodies of primary cilia and a reduction in KIF11 expression alters cilia dynamics

KIF11 is a homotetrameric kinesin that peaks in protein expression during mitosis. It is a known mitotic regulator, and it is well-described that KIF11 is necessary for the formation and maintenance of the bipolar spindle. However, there has been a growing appreciation for non-mitotic roles for KIF11. KIF11 has been shown to function in such processes as axon growth and microtubule polymerization. We previously demonstrated that there is an interphase pool of KIF11 present in glioblastoma cancer stem cells that drives tumor cell invasion. Here, we identified a previously unknown association between KIF11 and primary cilia. We confirmed that KIF11 localized to the basal bodies of primary cilia in multiple cell types, including neoplastic and non-neoplastic cells. Further, we determined that KIF11 has a role in regulating cilia dynamics. Upon the reduction of KIF11 expression, the number of ciliated cells in asynchronously growing populations was significantly increased. We rescued this effect by the addition of exogenous KIF11. Lastly, we found that depleting KIF11 resulted in an increase in cilium length and an attenuation in the kinetics of cilia disassembly. These findings establish a previously unknown link between KIF11 and the dynamics of primary cilia and further support non-mitotic functions for this kinesin.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Direct evidence for low-energy electron emission following O LVV Auger transitions at oxide surfaces

Abstract Oxygen, the third most abundant element in the universe, plays a key role in the chemistry of condensed matter and biological systems. Here, we report evidence for a hitherto unexplored Auger transition in oxides, where a valence band electron fills a vacancy in the 2s state of oxygen, transferring sufficient energy to allow electron emission. We used a beam of positrons with kinetic energies of $$\sim 1$$ ∼ 1 eV to create O 2s holes via matter-antimatter annihilation. This made possible the elimination of the large secondary electron background that has precluded definitive measurements of the low-energy electrons emitted through this process. Our experiments indicate that low-energy electron emission following the Auger decay of O 2s holes from adsorbed oxygen and oxide surfaces are very efficient. Specifically, our results indicate that the low energy electron emission following the Auger decay of O 2s hole is nearly as efficient as electron emission following the relaxation of O 1s holes in $$\hbox {TiO}_2$$ TiO 2 . This has important implications for the understanding of Auger-stimulated ion desorption, Coulombic decay, photodynamic cancer therapies, and may yield important insights into the radiation-induced reactive sites for corrosion and catalysis.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2021

Megavolt bremsstrahlung measurements from linear induction accelerators demonstrate possible use as a FLASH radiotherapy source to reduce acute toxicity

Abstract Recent studies indicate better efficacy and healthy tissue sparing with high dose-rate FLASH radiotherapy (FLASH-RT) cancer treatment. This technique delivers a prompt high radiation dose rather than fractional doses over time. While some suggest thresholds of > 40 Gy s −1 with a maximal effect at > 100 Gy s −1 , accumulated evidence shows that instantaneous dose-rate and irradiation time are critical. Mechanisms are still debated, but toxicity is minimized while inducing apoptosis in malignant tissue. Delivery technologies to date show that a capability gap exists with clinic scale, broad area, deep penetrating, high dose rate systems. Based on these trends, if FLASH-RT is adopted, it may become a dominant approach except in the least technologically advanced countries. The linear induction accelerator (LIA) developed for high instantaneous and high average dose-rate, species independent charged particle acceleration, has yet to be considered for this application. We review the status of LIA technology, explore the physics of bremsstrahlung-converter-target interactions and our work on stabilizing the electron beam. While the gradient of the LIA is low, we present our preliminary work to improve the gradient by an order of magnitude, presenting a point design for a multibeam FLASH-RT system using a single accelerator for application to conformal FLASH-RT.

42 ENGINEERING↗
DOE OSTI2022

A new platform for ultra-high dose rate radiobiological research using the BELLA PW laser proton beamline

Abstract Radiotherapy is the current standard of care for more than 50% of all cancer patients. Improvements in radiotherapy (RT) technology have increased tumor targeting and normal tissue sparing. Radiations at ultra-high dose rates required for FLASH-RT effects have sparked interest in potentially providing additional differential therapeutic benefits. We present a new experimental platform that is the first one to deliver petawatt laser-driven proton pulses of 2 MeV energy at 0.2 Hz repetition rate by means of a compact, tunable active plasma lens beamline to biological samples. Cell monolayers grown over a 10 mm diameter field were exposed to clinically relevant proton doses ranging from 7 to 35 Gy at ultra-high instantaneous dose rates of 10 7 Gy/s. Dose-dependent cell survival measurements of human normal and tumor cells exposed to LD protons showed significantly higher cell survival of normal-cells compared to tumor-cells for total doses of 7 Gy and higher, which was not observed to the same extent for X-ray reference irradiations at clinical dose rates. These findings provide preliminary evidence that compact LD proton sources enable a new and promising platform for investigating the physical, chemical and biological mechanisms underlying the FLASH effect.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
DOE OSTI2022

Epidermal growth factor receptor cascade prioritizes the maximization of signal transduction

Many studies have been performed to quantify cell signaling. Cell signaling molecules are phosphorylated in response to extracellular stimuli, with the phosphorylation sequence forming a signal cascade. The information gain during a signal event is given by the logarithm of the phosphorylation molecule ratio. The average information gain can be regarded as the signal transduction quantity (ST), which is identical to the Kullback–Leibler divergence (KLD), a relative entropy. We previously reported that if the total ST value in a given signal cascade is maximized, the ST rate (STR) of each signaling molecule per signal duration (min) approaches a constant value. To experimentally verify this theoretical conclusion, we measured the STR of the epidermal growth factor (EGF)-related cascade in A431 skin cancer cells following stimulation with EGF using antibody microarrays against phosphorylated signal molecules. The results were consistent with those from the theoretical analysis. Thus, signaling transduction systems may adopt a strategy that prioritizes the maximization of ST. Furthermore, signal molecules with similar STRs may form a signal cascade. In conclusion, ST and STR are promising properties for quantitative analysis of signal transduction.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Multicolor multifocal 3D microscopy using in-situ optimization of a spatial light modulator

Abstract Multifocal microscopy enables high-speed three-dimensional (3D) volume imaging by using a multifocal grating in the emission path. This grating is typically designed to afford a uniform illumination of multifocal subimages for a single emission wavelength. Using the same grating for multicolor imaging results in non-uniform subimage intensities in emission wavelengths for which the grating is not designed. This has restricted multifocal microscopy applications for samples having multicolored fluorophores. In this paper, we present a multicolor multifocal microscope implementation which uses a Spatial Light Modulator (SLM) as a single multifocal grating to realize near-uniform multifocal subimage intensities across multiple wavelength emission bands. Using real-time control of an in-situ-optimized SLM implemented as a multifocal grating, we demonstrate multicolor multifocal 3D imaging over three emission bands by imaging multicolored particles as well as Escherichia coli ( E. coli ) interacting with human liver cancer cells, at $$\sim 2.5$$ ∼ 2.5 multicolor 3D volumes per second acquisition speed. Our multicolor multifocal method is adaptable across SLM hardware, emission wavelength band locations and number of emission bands, making it particularly suited for researchers investigating fast processes occurring across a volume where multiple species are involved.

47 OTHER INSTRUMENTATION↗
DOE OSTI2026

Quantifying mean, variability, and uncertainty in indoor radon exposure in Pennsylvania using random forest and quantile regression forest models

Radon is a naturally occurring radioactive gas that poses a serious health risk as the primary cause of lung cancer in non-smokers. Despite the well-known adverse association with health outcomes, current radon exposure assessments are limited to county-level or average-level estimates, which fail to capture regional variability. This study uses Machine Learning models, including Random Forest (RF) and Quantile Regression Forest (QRF), to estimate the indoor radon concentrations at the ZCTA (Zip code tabulation area)-level and characterize uncertainties in model estimates. Incorporating geological, meteorological, and building-specific data, the models aim to improve radon risk assessment by capturing mean exposure, variability, and extreme concentration levels. Processed radon test data (n = 718,111) were analyzed using average, variability, and quantile prediction methods. Models that estimate the average radon exposure at the ZCTA-level can yield promising model-fit results, but they do not capture the underlying variability of indoor radon exposure within a ZCTA. We utilize volatility analyses to identify characteristics indicative of high variability of indoor radon exposure. We also show that a QRF model can be used to estimate upper quantiles of residential radon exposure, thereby uncovering localized areas of elevated exposure that were not apparent in mean estimates. The results highlighted the need for a deep characterization of exposure risk and show that regions with moderate average exposure levels could still harbor extreme outliers with implications for evaluating health risks. Utilizing multiple radon exposure models allows for a deeper characterization of radon risk within a geographic area and can better identify high-risk areas. The results from this study provide a foundation for developing mitigation strategies and examining associations between radon exposure and health outcomes at fine scales. Future research should extend the geographic scope and incorporate additional environmental risk factors to establish a comprehensive framework for risk assessment.

Lee, Heechan [ORNL]↗
DOE OSTI2021

Tipiracil binds to uridine site and inhibits Nsp15 endoribonuclease NendoU from SARS-CoV-2

SARS-CoV-2 Nsp15 is a uridine-specific endoribonuclease with C-terminal catalytic domain belonging to the EndoU family that is highly conserved in coronaviruses. As endoribonuclease activity seems to be responsible for the interference with the innate immune response, Nsp15 emerges as an attractive target for therapeutic intervention. Here we report the first structures with bound nucleotides and show how the enzyme specifically recognizes uridine moiety. In addition to a uridine site we present evidence for a second base binding site that can accommodate any base. The structure with a transition state analog, uridine vanadate, confirms interactions key to catalytic mechanisms. In the presence of manganese ions, the enzyme cleaves unpaired RNAs. This acquired knowledge was instrumental in identifying Tipiracil, an FDA approved drug that is used in the treatment of colorectal cancer, as a potential anti-COVID-19 drug. Using crystallography, biochemical, and whole-cell assays, we demonstrate that Tipiracil inhibits SARS-CoV-2 Nsp15 by interacting with the uridine binding pocket in the enzyme’s active site. Our findings provide new insights for the development of uracil scaffold-based drugs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Surfactant-assisted one-pot sample preparation for label-free single-cell proteomics

Large numbers of cells are generally required for quantitative global proteome profiling due to surface adsorption losses associated with sample processing. Such bulk measurement obscures important cell-to-cell variability (cell heterogeneity) and makes proteomic profiling impossible for rare cell populations (e.g., circulating tumor cells (CTCs)). Here we report a surfactant-assisted one-pot sample preparation coupled with mass spectrometry (MS) method termed SOP-MS for label-free global single-cell proteomics. SOP-MS capitalizes on the combination of a MS-compatible nonionic surfactant, n-Dodecyl-β-D-maltoside, and hydrophobic surface-based low-bind tubes or multi-well plates for ‘all-in-one’ one-pot sample preparation. This ‘all-in-one’ method including elimination of all sample transfer steps maximally reduces surface adsorption losses for effective processing of single cells, thus improving detection sensitivity for single-cell proteomics. This method allows convenient label-free quantification of hundreds of proteins from single human cells and ~1200 proteins from small tissue sections (close to ~20 cells). When applied to a patient CTC-derived xenograft (PCDX) model at the single-cell resolution, SOP-MS can reveal distinct protein signatures between primary tumor cells and early metastatic lung cells, which are related to the selection pressure of anti-tumor immunity during breast cancer metastasis. The approach paves the way for routine, precise, quantitative single-cell proteomics.

36 MATERIALS SCIENCE↗