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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 235 records · Page 13
All sourcesNASA NTRSDOE OSTI
NASA NTRS2002

Computational Model of the Modulation of Gene Expression Following DNA Damage

High linear energy transfer (LET) radiation, such as heavy ions or neutrons, has an increased biological effectiveness compared to X rays for gene mutation, genomic instability, and carcinogenesis. In the traditional paradigm, mutations or chromosomal aberrations are causative of late effects. However, in recent years experimental evidence has demonstrated the important role of the description of the modification of gene expression by radiation in understanding the mechanisms of radiation action. In this report, approaches are discussed to the mathematical description of mRNA and protein expression kinetics following DNA damage. Several hypotheses for models of radiation modulation of protein expression are discussed including possible non-linear processes that evolve from the linear dose responses that follow the initial DNA damage produced by radiation.

NASA Center JSC↗
DOE OSTI2025

Comparative Performance Evaluation of Large Language Models for Extracting Molecular Interactions and Pathway Knowledge

Understanding the interactions and regulatory relationships among biomolecules is essential for deciphering complex biological systems and elucidating the mechanisms behind diverse biological functions. Traditionally, the collection of such molecular interaction data has relied on expert curation, a process that is both time-consuming and labor-intensive. To address these limitations, this study explores the use of large language models (LLMs) to automate the genome-scale extraction of molecular interaction knowledge. Here, we evaluate the performance of various LLMs on key biological tasks, including the identification of protein-protein interactions, detection of genes associated with pathways influenced by low-dose radiation, and inference of gene regulatory relationships. Our findings demonstrate that larger LLMs tend to perform better, particularly in extracting intricate gene and protein interactions. Despite their strengths, these models face challenges in recognizing functionally diverse gene groups and highly correlated regulatory relationships. Through a comprehensive analysis using established molecular interaction and pathway databases, we show that LLMs possess the potential to identify relevant biomolecules and predict their interactions, offering valuable insights and marking a significant step toward AI-driven biological knowledge discovery.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗
DOE OSTI2024

Covalent labeling of the Arabidopsis plasma membrane H + ‐ ATPase reveals 3D conformational changes involving the C‐terminal regulatory domain

The plasma membrane proton pump is the primary energy transducing, electrogenic ion pump of the plasma membrane in plants and fungi. Compared to its fungal counterpart, the plant plasma membrane proton pump's regulatory C‐terminal domain (CTD) contains an additional regulatory segment that links multiple sensory pathways regulating plant cell length through phosphorylation and recruitment of regulatory 14‐3‐3 proteins. However, a complete structural model of a plant proton pump is lacking. Here, we performed covalent labeling with mass spectrometric analysis (CL‐MS) on the Arabidopsis pump AHA2 to identify potential interactions between the CTD and the catalytic domains. Our results suggest that autoinhibition in the plant enzyme is much more structurally complex than in the fungal enzyme.

Blackburn, Matthew R. [Department of Biochemistry ↗
DOE OSTI2024

Crystallography Reveals Metal‐Triggered Restructuring of β‐Hairpins

Abstract Metal binding to β‐sheets occurs in many metalloproteins and is also implicated in the pathology of Alzheimer's disease. De novo designed metallo‐β‐sheets have been pursued as models and mimics of these proteins. However, no crystal structures of canonical β‐sheet metallopeptides have yet been obtained, in stark contrast to many examples for ɑ‐helical metallopeptides, leading to a poor understanding for their chemistry. To address this, we have engineered tryptophan zippers, stable 12‐residue β‐sheet peptides, to bind Cu(II) ions and obtained crystal structures through single crystal X‐ray diffraction (SC‐XRD). We find that metal binding triggers several unexpected supramolecular assemblies that demonstrate the range of higher‐order structures available to metallo‐β‐sheets. Overall, these findings underscore the importance of crystallography in elucidating the rich structural landscape of metallo‐β‐sheet peptides.

Thuc Dang, Viet↗
DOE OSTI2025

Ticking off Lyme disease: OspA mRNA vaccine halts infection in mouse model

Lyme disease, a condition caused by Borrelia burgdorferi sensu lato and transmitted to humans via ticks, affects approximately 676,000 individuals annually in the United States and Western Europe.1 Currently, there is no approved Lyme vaccine available for human use. A promising study by Tahir et al., published in Molecular Therapy Nucleic Acids, investigated the efficacy of mRNA and subunit vaccines targeting Lyme disease.2 This research demonstrated complete protection from infection in a tick-fed mouse model using an outer surface protein A (OspA) mRNA vaccine. Although mRNA vaccines have shown success against viral pathogens, their clinical application against bacterial diseases has been limited.3 Thus, this study represents an important step toward developing an effective mRNA vaccine against Lyme disease.

He, Wei↗
DOE OSTI2026

Hierarchical Truncations for Many-Body Expansion Potentials

In this work, a new strategy to truncate high-order terms in the many-body expansion (MBE) is proposed. This new approach, which we call a hierarchical many-body expansion (HMBE), is based on a hierarchical partition of the system into multitier fragments and can in principle be applied to any large molecular system. Numerical tests on a series of (H 2 O) 64 structures are presented, demonstrating satisfactory relative energies between the clusters and binding energies of individual clusters compared with full-cluster calculations, with significantly fewer high-order terms computed than conventional MBE. The hierarchical truncation can be augmented by certain many-body terms for fragments at the interface between the partitions (called “Schengen terms”) to further improve accuracy. This work establishes the HMBE scheme as a promising framework to model very large systems (e.g., proteins), which are naturally built on a hierarchical structure.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2024

BRAKER3: Fully automated genome annotation using RNA-seq and protein evidence with GeneMark-ETP, AUGUSTUS, and TSEBRA

Gene prediction has remained an active area of bioinformatics research for a long time. Still, gene prediction in large eukaryotic genomes presents a challenge that must be addressed by new algorithms. The amount and significance of the evidence available from transcriptomes and proteomes vary across genomes, between genes, and even along a single gene. User-friendly and accurate annotation pipelines that can cope with such data heterogeneity are needed. The previously developed annotation pipelines BRAKER1 and BRAKER2 use RNA-seq or protein data, respectively, but not both. A further significant performance improvement integrating all three data types was made by the recently released GeneMark-ETP. We here present the BRAKER3 pipeline that builds on GeneMark-ETP and AUGUSTUS, and further improves accuracy using the TSEBRA combiner. BRAKER3 annotates protein-coding genes in eukaryotic genomes using both short-read RNA-seq and a large protein database, along with statistical models learned iteratively and specifically for the target genome. We benchmarked the new pipeline on genomes of 11 species under an assumed level of relatedness of the target species proteome to available proteomes. BRAKER3 outperforms BRAKER1 and BRAKER2. The average transcript-level F1-score is increased by about 20 percentage points on average, whereas the difference is most pronounced for species with large and complex genomes. BRAKER3 also outperforms other existing tools, MAKER2, Funannotate, and FINDER. The code of BRAKER3 is available on GitHub and as a ready-to-run Docker container for execution with Docker or Singularity. Overall, BRAKER3 is an accurate, easy-to-use tool for eukaryotic genome annotation.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1997

Molecular events underlying skeletal muscle atrophy and the development of effective countermeasures

Skeletal muscle adapts to loading; atrophying when exposed to unloading on Earth or in spaceflight. Significant atrophy (decreases in muscle fiber cross-section of 11-24%) in humans has been noted after only 5 days in space. Since muscle strength is determined both by muscle cross-section and synchronization of motor unit recruitment, a loss in muscle size weakens astronauts, which would increase risks to their safety if an emergency required maximal muscle force. Numerous countermeasures have been tested to prevent atrophy. Resistant exercise together with growth hormone and IGF-I are effective countermeasures to unloading as most atrophy is prevented in animal models. The loss of muscle protein is due to an early decrease in protein synthesis rate and a later increase in protein degradation. The initial decrease in protein synthesis is a result of decreased protein translation, caused by a prolongation in the elongation rate. A decrease in HSP70 by a sight increase in ATP may be the factors prolonging elongation rate. Increases in the activities of proteolytic enzymes and in ubiquitin contribute to the increased protein degradation rate in unloaded muscle. Numerous mRNA concentrations have been shown to be altered in unloaded muscles. Decreases in mRNAs for contractile proteins usually occur after the initial fall in protein synthesis rates. Much additional research is needed to determine the mechanism by which muscle senses the absence of gravity with an adaptive atrophy. The development of effective countermeasures to unloading atrophy will require more research.

Non-NASA Center↗
NASA NTRS1996

Crustaceans as a model for microgravity-induced muscle atrophy

Atrophy of skeletal muscles is a serious problem in a microgravity environment. It is hypothesized that the unloading of postural muscles, which no longer must resist gravity force, causes an accelerated breakdown of contractile proteins, resulting in reduction in muscle mass and strength. A crustacean model using the land crab, Gecarcinus lateralis, to assess the effects of spaceflight on protein meatabolism is presented. The model is compared to a developmentally-regulated atrophy in which a premolt reduction in muscle mass allows the withdrawal of the large claws at molt. The biochemical mechanisms underlying protein breakdown involves both Ca2(+) -dependent and multicatalytic proteolytic enzymes. Crustacean claw muscle can be used to determine the interactions between shortening and unloading at the molecular level.

Mykles, D. L.↗
DOE OSTI2024

APACE: AlphaFold2 and advanced computing as a service for accelerated discovery in biophysics

The prediction of protein 3D structure from amino acid sequence is a computational grand challenge in biophysics and plays a key role in robust protein structure prediction algorithms, from drug discovery to genome interpretation. The advent of AI models, such as AlphaFold, is revolutionizing applications that depend on robust protein structure prediction algorithms. To maximize the impact, and ease the usability, of these AI tools we introduce APACE, AlphaFold2 and advanced computing as a service, a computational framework that effectively handles this AI model and its TB-size database to conduct accelerated protein structure prediction analyses in modern supercomputing environments. We deployed APACE in the Delta and Polaris supercomputers and quantified its performance for accurate protein structure predictions using four exemplar proteins: 6AWO, 6OAN, 7MEZ, and 6D6U. Using up to 300 ensembles, distributed across 200 NVIDIA A100 GPUs, we found that APACE is up to two orders of magnitude faster than off-the-self AlphaFold2 implementations, reducing time-to-solution from weeks to minutes. This computational approach may be readily linked with robotics laboratories to automate and accelerate scientific discovery.

97 MATHEMATICS AND COMPUTING↗
NASA NTRS2003

An Alternative Hypothesis for How Microgravity Improves Macromolecular Crystal Quality

There is a substantial body of experimental evidence, from this and other laboratories, that strongly suggests that for many proteins crystal nucleation and growth is by addition of associated species that are preformed by reversible concentration-driven self association processes in the bulk solution. We have developed a self-association model for the crystal nucleation and growth of the protein chicken egg lysozyme. The model accounts for the obtained crystal symmetry, explains the observed surface structures, and shows the importance of the symmetry obtained by self-association in solution to the process as a whole. This model also offers a possible mechanism for fluid flow effects on the growth process and how microgravity may affect it. While a single lysozyme molecule is relatively small an octamer in the 43 helix configuration (the proposed average sized growth unit) would have a M.W. approx. 115,000 and dimensions of 5.6 x 5.6 x 7.6 nm. Direct AFM measurements of growth unit incorporation indicate that units as wide as 11.2 nm and as long as 11.4 nm (a 24-mer) commonly attach to the crystal. AFM results from Weichmann et al. (Ultramicroscopy 86, 159-166, 2001) suggest that associated species of up to 40-mers in size add to the (101) faces. These measurements reflect the sizes of units that both added and desorbed from the crystal surface. The larger and less isotropic the associated species the more likely that it will be oriented to some degree in a flowing boundary layer, even at the low flow velocities measured about macromolecule crystals. On Earth, concentration gradient driven flow will maintain a high interfacial concentration, i.e., a high level (essentially that of the bulk solution) of solute association at the interface and higher growth rate. Higher growth rates mean an increased probability that misaligned growth units are trapped by subsequent growth layers before they can be desorbed and try again, or that the desorbing species is more likely to be smaller than the adsorbing species. In microgravity the extended diffusive boundary layer will lower the interfacial concentration. This results in a net dissociation of aggregated species that diffuse in from the bulk solution, i.e., smaller associated species, which are more likely able to make multiple attempts to correctly bind, yielding higher quality crystals.

Pusey, Marc↗
DOE OSTI2025

Discovery and Development of a Small-Molecule Inhibitor Targeting the GAS41 YEATS Domain in Nonsmall Cell Lung Cancer

Abstract GAS41 is frequently overexpressed in Non-Small Cell Lung Cancer (NSCLC). GAS41 contains a YEATS domain, which recognizes acetylated lysine residues on histones to recruit protein complexes and facilitate transcription. Suppression of GAS41 in NSCLC models inhibits cellular proliferation and markedly reduces tumor growth in mouse xenografts, justifying the development of small-molecule inhibitors. We have employed structure-based design and medicinal chemistry optimization to discover DLG-41, a submicromolar inhibitor binding to the GAS41 YEATS domain. DLG-41 potently disrupts the association of GAS41 YEATS with chromatin in mammalian cells and inhibits the proliferation of NSCLC cell lines with submicromolar potency without significantly affecting normal lung fibroblasts. DLG-41 induces more effective growth inhibition in A549 versus GAS41-knockout cells, demonstrating on-target activity. DLG-41 treatment upregulates the CDKN1A gene and downregulates pathways associated with lung cancer cell identity, tumor migration, and invasion. DLG-41 is a promising chemical probe for targeting GAS41 protein in NSCLC models and has potential for future development.

Listunov, Dymytrii [University of Michigan , , , ,↗
NASA NTRS2002

Alterations in protein metabolism during space flight and inactivity

Space flight and the accompanying diminished muscular activity lead to a loss of body nitrogen and muscle function. These losses may affect crew capabilities and health in long-duration missions. Space flight alters protein metabolism such that the body is unable to maintain protein synthetic rates. A concomitant hypocaloric intake and altered anabolic/catabolic hormonal profiles may contribute to or exacerbate this problem. The inactivity associated with bedrest also reduces muscle and whole-body protein synthesis. For this reason, bedrest provides a good model for the investigation of potential exercise and nutritional countermeasures to restore muscle protein synthesis. We have demonstrated that minimal resistance exercise preserves muscle protein synthesis throughout bedrest. In addition, ongoing work indicates that an essential amino acid and carbohydrate supplement may ameliorate the loss of lean body mass and muscle strength associated with 28 d of bedrest. The investigation of inactivity-induced alterations in protein metabolism, during space flight or prolonged bedrest, is applicable to clinical populations and, in a more general sense, to the problems associated with the decreased activity that occur with aging.

Non-NASA Center↗
NASA NTRS1995

Prospect redux

The remote estimation of leaf biochemical content from spaceborne platforms has been the subject of many studies aimed at better understanding of terrestrial ecosystem functioning. The major ecological processes involved in exchange of matter and energy, like photosynthesis, primary production, evaportranspiration, respiration, and decomposition can be related to plant properties e.g., chlorophyll, water, protein, cellulose and lignin contents. As leaves represent the most important plant surfaces interacting with solar energy, a top priority has been to relate optical properties to biochemical constituents. Two different approaches have been considered: first, statistical correlations between the leaf reflectance (or transmittance) and biochemical content, and second, physically based models of leaf scattering and absorption developed using the laws of optics. Recently reviewed by Verdebout et al., the development of models of leaf optical properties has resulted in better understanding of the interaction of light with plant leaves. Present radiative transfer models mainly use chlorophyll and/or water contents as input parameters to calculate leaf reflectance. Inversion of these models allows to retrieve these constituents from spectrophotometric measurements. Conel et al. recently proposed a two-stream Kubelka-Munk model to analyze the influence of protein, cellulose, lignin, and starch on leaf reflectance, but in fact, the estimation of leaf biochemistry from remote sensing is still an open question. In order to clarify it, a laboratory experiment associating visible/infrared spectra of plan leaves both with physical measurements and biochemical analyses was conducted at the Joint Research Center during the summer of 1993. This unique data set has been used to upgrade the PROSPECT model, by including leaf biochemistry.

Jacquemoud, S.↗
NASA NTRS2006

Protein Sensors Based on Optical Ring Resonators

Prototype transducers based on integrated optical ring resonators have been demonstrated to be useful for detecting the protein avidin in extremely dilute solutions. In an experiment, one of the transducers proved to be capable of indicating the presence of avidin at a concentration of as little as 300 pM in a buffer solution a detection sensitivity comparable to that achievable by previously reported protein-detection techniques. These transducers are serving as models for the further development of integrated-optics sensors for detecting small quantities of other proteins and protein-like substances. The basic principle of these transducers was described in Chemical Sensors Based on Optical Ring Resonators (NPO-40601), NASA Tech Briefs, Vol. 29, No. 10 (October 2005), page 32. The differences between the present transducers and the ones described in the cited prior article lie in details of implementation of the basic principle. As before, the resonator in a transducer of the present type is a closed-circuit dielectric optical waveguide. The outermost layer of this waveguide, analogous to the optical cladding layer on an optical fiber, consists of a layer comprising sublayers having indices of refraction lower than that of the waveguide core. The outermost sublayer absorbs the chemical of interest (in this case, avidin). The index of refraction of the outermost sublayer changes with the concentration of absorbed avidin. The resonator is designed to operate with relatively strong evanescent-wave coupling between the outer sublayer and the electromagnetic field propagating along the waveguide core. By virtue of this coupling, the chemically induced change in the index of refraction of the outermost sublayer causes a measurable change in the spectrum of the resonator output.

Lin, Ying↗
DOE OSTI2024

NCAP: Noncanonical Amino Acid Parameterization Software for CHARMM Potentials

Noncanonical Amino Acids (NCAAs) provide numerous avenues for introduction of novel functionality to peptides and proteins. NCAAs can be incorporated through solid phase synthesis or genetic code expansion in conjugation with heterologous expression of the encoded protein modification. Due to the difficulty of synthesis, wide chemical space and lack of empirically resolved structures modeling the effects of NCAA mutation is critical for rational protein design. To evaluate the structural and functional perturbations NCAAs introduce we utilize molecular potentials that describe the forces in protein structure. Most potentials such as CHARMM are designed to model canonical residues but can be parameterized in include novel NCAAs. Here, in this work, we introduce NCAP a software package to generate CHARMM compatible parameters from quantum chemical calculation. Unlike currently available tools NCAP is designed to recognize NCAA structure and automatically bridge the gap between DFT calculations and potential parameters. For our software we discuss workflow, validation against canonical parameter sets and comparison to published NCAA-protein structures.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Artificial Intelligence Transforming Post-Translational Modification Research

Post-Translational Modifications (PTMs) are covalent changes to amino acids that occur after protein synthesis, including covalent modifications on side chains and peptide backbones. Many PTMs profoundly impact cellular and molecular functions and structures, and their significance extends to evolutionary studies as well. In light of these implications, we have explored how artificial intelligence (AI) can be utilized in researching PTMs. Initially, rationales for adopting AI and its advantages in understanding the functions of PTMs are discussed. Then, various deep learning architectures and programs, including recent applications of language models, for predicting PTM sites on proteins and the regulatory functions of these PTMs are compared. Finally, our high-throughput PTM-data-generation pipeline, which formats data suitably for AI training and predictions is described. We hope this review illuminates areas where future AI models on PTMs can be improved, thereby contributing to the field of PTM bioengineering.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1993

The mechanosensory calcium-selective ion channel: key component of a plasmalemmal control centre?

Mechanosensory calcium-selective ion channels probably serve to detect not only mechanical stress but also electrical, thermal, and diverse chemical stimuli. Because all stimuli result in a common output, most notably a shift in second messenger calcium concentration, the channels are presumed to serve as signal integrators. Further, insofar as second messenger calcium in turn gives rise to mechanical, electrical, and diverse chemical changes, the channels are postulated to initiate regulatory feedbacks. It is proposed that the channels and the feedback loops play a wide range of roles in regulating normal plant function, as well as in mediating disturbance of normal function by environmental stressors and various pathogens. In developing evidence for the physiological performance of the channel, a model for a cluster of regulatory plasmalemmal proteins and cytoskeletal elements grouped around a set of wall-to-membrane and transmembrane linkers has proved useful. An illustration of how the model might operate is presented. It is founded on the demonstration that several xenobiotics interfere both with normal channel behaviour and with gravitropic reception. Accordingly, the first part of the illustration deals with how the channels and the control system within which they putatively operate might initiate gravitropism. Assuming that gravitropism is an asymmetric expression of growth, the activities of the channels and the plasmalemmal control system are extrapolated to account for regulation of both rate and allometry of cell expansion. Finally, it is discussed how light, hormones, redox agents and herbicides could in principle affect growth via the putative plasmalemmal control cluster or centre.

NASA Program Space Biology↗