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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 1,351 records · Page 75
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Novel fold of rotavirus glycan-binding domain predicted by AlphaFold2 and determined by X-ray crystallography

The VP8* domain of spike protein VP4 in group A and C rotaviruses, which cause epidemic gastroenteritis in children, exhibits a conserved galectin-like fold for recognizing glycans during cell entry. In group B rotavirus, which causes significant diarrheal outbreaks in adults, the VP8* domain (VP8*B) surprisingly lacks sequence similarity with VP8* of group A or group C rotavirus. Here, by using the recently developed AlphaFold2 for ab initio structure prediction and validating the predicted model by determining a 1.3-Å crystal structure, we show that VP8*B exhibits a novel fold distinct from the galectin fold. This fold with a β-sheet clasping an α-helix represents a new fold for glycan recognition based on glycan array screening, which shows that VP8*B recognizes glycans containing N-acetyllactosamine moiety. Although uncommon, our study illustrates how evolution can incorporate structurally distinct folds with similar functionality in a homologous protein within the same virus genus.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Human antibodies to SARS-CoV-2 with a recurring YYDRxG motif retain binding and neutralization to variants of concern including Omicron

Studying the antibody response to SARS-CoV-2 informs on how the human immune system can respond to antigenic variants as well as other SARS-related viruses. Here, we structurally identified a YYDRxG motif encoded by IGHD3-22 in CDR H3 that facilitates antibody targeting to a functionally conserved epitope on the SARS-CoV-2 receptor binding domain. A computational search for a YYDRxG pattern in publicly available sequences uncovered 100 such antibodies, many of which can neutralize SARS-CoV-2 variants and SARS-CoV. Thus, the YYDRxG motif represents a common convergent solution for the human humoral immune system to target sarbecoviruses including the Omicron variant. These findings suggest an epitope-targeting strategy to identify potent and broadly neutralizing antibodies for design of pan-sarbecovirus vaccines and antibody therapeutics.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Achieving strength-ductility synergy in hierarchical aluminum metal matrix composites via friction extrusion

We report the fabrication of aluminum metal matrix composites (Al-MMCs) with hierarchical architectures via friction extrusion (FE), a scalable, single-step, solid-phase processing technique. Precursor pucks containing 0–15 vol% Al₂O₃ particles were extruded into fully dense AA6061-based composite rods. The FE induced a tree-ring-like architecture of concentric particle-rich and particle-lean bands, yielding refined grains in particle-rich regions and coarser grains elsewhere. At the nanoscale, magnesium in AA6061 selectively reacted with Al₂O₃ particles to form virus-like nodes, improving particle–matrix bonding. This multi-scale design strategy, combining mesoscale architecture, microscale grain refinement, and nanoscale interface engineering overcome the conventional strength–ductility trade-off. Tensile testing showed substantial increases in yield and ultimate tensile strengths while retaining high ductility ( > 20%). Enhanced strain hardening, driven by the accumulation of geometrically necessary dislocations at interfaces, contributed to the performance. The hierarchical microstructure produced by FE demonstrates a promising pathway for scalable fabrication of lightweight MMCs for structural applications requiring a combined high strength and ductility.

Kalsar, Rajib [Pacific Northwest National Laborato↗
DOE OSTI2025

Host cell and viral protease targets of human SERPINs identified by in silico docking

Serine protease inhibitors (SERPINs) are involved in various physiological processes and diseases, such as inflammation, cancer metastasis, and neurodegeneration. Their role in viral infections is poorly understood, as their expression patterns during infection and the range of proteases they target have yet to be fully characterized. Here, we show widespread expression of human SERPINs in response to respiratory virus infections, both in bronchioalveolar lavages from COVID-19 patients and in polarized human airway epithelial cultures. Using in silico docking of 10 SERPINs to 48 host proteases, we confirm known targets and predict new interactions. Protease activity assays validated selected interactions, confirming the newly predicted host targets for PAI-1 (SERPINE1) and PAI-2 (SERPINB2). PAI-1 inhibits cathepsin L, essential for SARS-CoV-2 maturation, and suppresses multi-cycle replication of both ancestral SARS-CoV-2 WA-1 and its variant Omicron BA.1. In addition, we identify PAI-2 as an antiviral SERPIN that reduces infectivity of human adenovirus 5 by directly inhibiting the adenoviral protease. Our study leverages in silico docking using full-length 3D protein structures to uncover new SERPIN targets, offering a range of candidate targets for therapeutic interventions.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

The nanocaterpillar's random walk: diffusion with ligand–receptor contacts

Particles with ligand–receptor contacts bind and unbind fluctuating “legs” to surfaces, whose fluctuations cause the particle to diffuse. Quantifying the diffusion of such “nanoscale caterpillars” is a challenge, since binding events often occur on very short time and length scales. Here, in this work, we derive an analytical formula, validated by simulations, for the long time translational diffusion coefficient of an overdamped nanocaterpillar, under a range of modeling assumptions. We demonstrate that the effective diffusion coefficient, which depends on the microscopic parameters governing the legs, can be orders of magnitude smaller than the background diffusion coefficient. Furthermore it varies rapidly with temperature, and reproduces the striking variations seen in existing data and our own measurements of the diffusion of DNA-coated colloids. Our model gives insight into the mechanism of motion, and allows us to ask: when does a nanocaterpillar prefer to move by sliding, where one leg is always linked to the surface, and when does it prefer to move by hopping, which requires all legs to unbind simultaneously? We compare a range of systems (viruses, molecular motors, white blood cells, protein cargos in the nuclear pore complex, bacteria such as Escherichia coli, and DNA-coated colloids) and present guidelines to control the mode of motion for materials design.

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

Selecting XFEL single-particle snapshots by geometric machine learning

A promising new route for structural biology is single-particle imaging with an X-ray Free-Electron Laser (XFEL). This method has the advantage that the samples do not require crystallization and can be examined at room temperature. However, high-resolution structures can only be obtained from a sufficiently large number of diffraction patterns of individual molecules, so-called single particles. Here, we present a method that allows for efficient identification of single particles in very large XFEL datasets, operates at low signal levels, and is tolerant to background. This method uses supervised Geometric Machine Learning (GML) to extract low-dimensional feature vectors from a training dataset, fuse test datasets into the feature space of training datasets, and separate the data into binary distributions of “single particles” and “non-single particles.” As a proof of principle, we tested simulated and experimental datasets of the Coliphage PR772 virus. We created a training dataset and classified three types of test datasets: First, a noise-free simulated test dataset, which gave near perfect separation. Second, simulated test datasets that were modified to reflect different levels of photon counts and background noise. These modified datasets were used to quantify the predictive limits of our approach. Third, an experimental dataset collected at the Stanford Linear Accelerator Center. The single-particle identification for this experimental dataset was compared with previously published results and it was found that GML covers a wide photon-count range, outperforming other single-particle identification methods. Moreover, a major advantage of GML is its ability to retrieve single particles in the presence of structural variability.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2021

Direct numerical simulation of turbulent dispersion of evaporative aerosol clouds produced by an intense expiratory event

Airborne particles are a major route for transmission of COVID-19 and many other infectious diseases. When a person talks, sings, coughs, or sneezes, nasal and throat secretions are spewed into the air. After a short initial fragmentation stage, the expelled material is mostly composed of spherical particles of different sizes. While the dynamics of the largest droplets are dominated by gravitational effects, the smaller aerosol particles, mostly transported by means of hydrodynamic drag, form clouds that can remain afloat for long times. In subsaturated air environments, the dependence of pathogen-laden particle dispersion on their size is complicated due to evaporation of the aqueous fraction. Particle dynamics can significantly change when ambient conditions favor rapid evaporation rates that result in a transition from buoyancyto-drag dominated dispersion regimes. To investigate the effect of particle size and evaporation on pathogen-laden cloud evolution, a direct numerical simulation of a mild cough was coupled with an evaporative Lagrangian particle advection model. The results suggest that while the dispersion of cough particles in the tails of the size distribution are unlikely to be disrupted by evaporative effects, preferential aerosol diameters (30-40 μm) may exhibit significant increases in the residence time and horizontal range under typical ambient conditions. Using estimations of the viral concentration in the spewed fluid and the number of ejected particles in a typical respiratory event, we obtained a map of viral load per volume of air at the end of the cough and the number of virus copies per inhalation in the emitter vicinity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Viricidal and bactericidal exciplex barrier-discharge lamps

A brief review is presented of investigations performed in 2002 – 2020 on ultraviolet inactivation of bacteria, vital cells, and viruses by using excilamps. The excilamp models that have been developed at the Institute of High-Current Electronics, SB RAS are briefly described. Scientific data acquired by now show that excilamps on KrCl{sup *}, KrBr{sup *}, and XeBr{sup *} molecules are an alternative to low-pressure mercury lamps with respect to optical parameters. These sources of optical radiation exhibit a bactericidal effect, and emission of KrCl and KrBr excilamps demonstrates viricidal action. The latter is actual due to expansion of coronavirus disease. (paper)

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

How cholesterol stiffens unsaturated lipid membranes

Cholesterol is an integral component of eukaryotic cell membranes and a key molecule in controlling membrane fluidity, organization, and other physicochemical parameters. It also plays a regulatory function in antibiotic drug resistance and the immune response of cells against viruses, by stabilizing the membrane against structural damage. While it is well understood that, structurally, cholesterol exhibits a densification effect on fluid lipid membranes, its effects on membrane bending rigidity are assumed to be nonuniversal; i.e., cholesterol stiffens saturated lipid membranes, but has no stiffening effect on membranes populated by unsaturated lipids, such as 1,2-dioleoyl- sn -glycero-3-phosphocholine (DOPC). This observation presents a clear challenge to structure–property relationships and to our understanding of cholesterol-mediated biological functions. Here, using a comprehensive approach—combining neutron spin-echo (NSE) spectroscopy, solid-state deuterium NMR ( 2 H NMR) spectroscopy, and molecular dynamics (MD) simulations—we report that cholesterol locally increases the bending rigidity of DOPC membranes, similar to saturated membranes, by increasing the bilayer’s packing density. All three techniques, inherently sensitive to mesoscale bending fluctuations, show up to a threefold increase in effective bending rigidity with increasing cholesterol content approaching a mole fraction of 50%. Our observations are in good agreement with the known effects of cholesterol on the area-compressibility modulus and membrane structure, reaffirming membrane structure–property relationships. The current findings point to a scale-dependent manifestation of membrane properties, highlighting the need to reassess cholesterol’s role in controlling membrane bending rigidity over mesoscopic length and time scales of important biological functions, such as viral budding and lipid–protein interactions.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Attaining the promise of plant gene editing at scale

Crop improvement relies heavily on genetic variation that arises spontaneously through mutation. Modern breeding methods are very adept at combining this genetic variation in ways that achieve remarkable improvements in plant performance. Novel traits have also been created through mutation breeding and transgenesis. The advent of gene editing, however, marks a turning point: With gene editing, synthetic variation will increasingly supplement and, in some cases, supplant the genetic variation that occurs naturally. We are still in the very early stages of realizing the opportunity provided by plant gene editing. At present, typically only one or a few genes are targeted for mutation at a time, and most mutations result in loss of gene function. New technological developments, however, promise to make it possible to perform gene editing at scale. RNA virus vectors, for example, can deliver gene-editing reagents to the germ line through infection and create hundreds to thousands of diverse mutations in the progeny of infected plants. With developmental regulators, edited somatic cells can be induced to form meristems that yield seed-producing shoots, thereby increasing throughput and shrinking timescales for creating edited plants. As these approaches are refined and others developed, they will allow for accelerated breeding, the domestication of orphan crops and the reengineering of metabolism in a more directed manner than has ever previously been possible.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface

The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells. The recognition mode is unprecedented in that the targeted domain of CEP250 is a coiled coil and is topologically featureless, embodying both a structural motif and surface topology previously considered on the extreme limits of “undruggability” for an intracellular target. Structural studies reveal extensive protein–WDB002 and protein–protein contacts, with the latter being distinct from those seen in FKBP12 ternary complexes formed by FK506 and rapamycin. Outward-facing structural changes in a bound small molecule can thus reprogram FKBP12 to engage diverse, otherwise “undruggable” targets. The flat-targeting modality demonstrated here has the potential to expand the druggable target range of small-molecule therapeutics. As CEP250 was recently found to be an interaction partner with the Nsp13 protein of the SARS-CoV-2 virus that causes COVID-19 disease, it is possible that WDB002 or an analog may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV neutralizing antibody

Significance Neutralizing antibodies (NAbs) against HIV-1 are under clinical development. Despite demonstrated antiviral activity when used as treatment in HIV-infected people, the mechanism of action of NAbs remains controversial. Quantification of the relative contribution of Fab-mediated (neutralization of free virus) and Fc-mediated functions such as antibody-dependent cellular cytotoxicity (ADCC), phagocytosis, and complement fixation is essential to develop better therapies. Here, we treated chronically SHIV-infected rhesus macaques with a single dose of NAb VRC07-523LS with or without Fc modifications. Fc function contributes 21% to the antiviral activity of VRC07-523LS with an unmodified Fc region, when compared to NAb with Fc knockout mutations. However, NAbs with improved ADCC function in vitro did not show enhanced antiviral activity in vivo.

Asokan, Mangaiarkarasi↗
DOE OSTI2021

Design and proof of concept for targeted phage-based COVID-19 vaccination strategies with a streamlined cold-free supply chain

Significance The COVID-19 pandemic has had an unprecedented impact. Although several vaccines have received emergency use authorization, demand has created enormous logistical challenges—including supply, access, and distribution—that justify research for alternative strategies. Phage are viruses that only infect bacteria and can be safely administered to humans. Here, as a proof-of-concept study, we demonstrate that aerosol vaccination with lung-targeted phage particles displaying short SARS-CoV-2 S protein epitopes and subcutaneous vaccination with targeted AAVP particles carrying the entire S protein gene both elicit systemic and specific immune responses in immunocompetent mice. Given their unique attributes, including sturdiness, simple-to-engineer platform, cost-effectiveness for rapid large-scale production, and stability at room temperature, these phage-based approaches may become attractive tools for COVID-19 vaccine development.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Multiple spillovers from humans and onward transmission of SARS-CoV-2 in white-tailed deer

Many animal species are susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and could act as reservoirs; however, transmission in free-living animals has not been documented. White-tailed deer, the predominant cervid in North America, are susceptible to SARS-CoV-2 infection, and experimentally infected fawns can transmit the virus. To test the hypothesis that SARS-CoV-2 is circulating in deer, 283 retropharyngeal lymph node (RPLN) samples collected from 151 free-living and 132 captive deer in Iowa from April 2020 through January of 2021 were assayed for the presence of SARS-CoV-2 RNA. Ninety-four of the 283 (33.2%) deer samples were positive for SARS-CoV-2 RNA as assessed by RT-PCR. Notably, following the November 2020 peak of human cases in Iowa, and coinciding with the onset of winter and the peak deer hunting season, SARS-CoV-2 RNA was detected in 80 of 97 (82.5%) RPLN samples collected over a 7-wk period. Whole genome sequencing of all 94 positive RPLN samples identified 12 SARS-CoV-2 lineages, with B.1.2 (n = 51; 54.5%) and B.1.311 (n = 19; 20%) accounting for ~75% of all samples. The geographic distribution and nesting of clusters of deer and human lineages strongly suggest multiple human-to-deer transmission events followed by subsequent deer-to-deer spread. These discoveries have important implications for the long-term persistence of the SARS-CoV-2 pandemic. Our findings highlight an urgent need for a robust and proactive “One Health” approach to obtain enhanced understanding of the ecology, molecular evolution, and dissemination of SARS-CoV-2.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Proof-of-concept studies with a computationally designed M pro inhibitor as a synergistic combination regimen alternative to Paxlovid

As the SARS-CoV-2 virus continues to spread and mutate, it remains important to focus not only on preventing spread through vaccination but also on treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a SARS-CoV-2 main protease (M pro ) DAA, has been significant for treatment of patients. A limitation of this DAA, however, is that the antiviral component, nirmatrelvir, is rapidly metabolized and requires inclusion of a CYP450 3A4 metabolic inhibitor, ritonavir, to boost levels of the active drug. Serious drug–drug interactions can occur with Paxlovid for patients who are also taking other medications metabolized by CYP4503A4, particularly transplant or otherwise immunocompromised patients who are most at risk for SARS-CoV-2 infection and the development of severe symptoms. Developing an alternative antiviral with improved pharmacological properties is critical for treatment of these patients. By using a computational and structure-guided approach, we were able to optimize a 100 to 250 μM screening hit to a potent nanomolar inhibitor and lead compound, Mpro61. In this study, we further evaluate Mpro61 as a lead compound, starting with examination of its mode of binding to SARS-CoV-2 M pro . In vitro pharmacological profiling established a lack of off-target effects, particularly CYP450 3A4 inhibition, as well as potential for synergy with the currently approved alternate antiviral, molnupiravir. Development and subsequent testing of a capsule formulation for oral dosing of Mpro61 in B6-K18-hACE2 mice demonstrated favorable pharmacological properties, efficacy, and synergy with molnupiravir, and complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

An essential and highly selective protein import pathway encoded by nucleus-forming phage

Targeting proteins to specific subcellular destinations is essential in prokaryotes, eukaryotes, and the viruses that infect them. Chimalliviridae phages encapsulate their genomes in a nucleus-like replication compartment composed of the protein chimallin (ChmA) that excludes ribosomes and decouples transcription from translation. These phages selectively partition proteins between the phage nucleus and the bacterial cytoplasm. Currently, the genes and signals that govern selective protein import into the phage nucleus are unknown. Here, we identify two components of this protein import pathway: a species-specific surface-exposed region of a phage intranuclear protein required for nuclear entry and a conserved protein, PicA (Protein importer of chimalliviruses A), that facilitates cargo protein trafficking across the phage nuclear shell. We also identify a defective cargo protein that is targeted to PicA on the nuclear periphery but fails to enter the nucleus, providing insight into the mechanism of nuclear protein trafficking. Using CRISPRi-ART protein expression knockdown of PicA, we show that PicA is essential early in the chimallivirus replication cycle. Together, our results allow us to propose a multistep model for the Protein Import Chimallivirus pathway, where proteins are targeted to PicA by amino acids on their surface and then licensed by PicA for nuclear entry. The divergence in the selectivity of this pathway between closely related chimalliviruses implicates its role as a key player in the evolutionary arms race between competing phages and their hosts.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Cross-reactive sarbecovirus antibodies induced by mosaic RBD nanoparticles

Broad immune responses are needed to mitigate viral evolution and escape. To induce antibodies against conserved receptor-binding domain (RBD) regions of SARS-like betacoronavirus (sarbecovirus) spike proteins that recognize SARS-CoV-2 variants of concern and zoonotic sarbecoviruses, we developed mosaic-8b RBD nanoparticles presenting eight sarbecovirus RBDs arranged randomly on a 60-mer nanoparticle. Mosaic-8b immunizations protected animals from challenges from viruses whose RBDs were matched or mismatched to those on nanoparticles. Here, we describe neutralizing mAbs isolated from mosaic-8b-immunized rabbits, some on par with Pemgarda, the only currently FDA-approved therapeutic mAb. Deep mutational scanning, in vitro selection of spike resistance mutations, and single-particle cryo-electron microscopy structures of spike–antibody complexes demonstrated targeting of conserved RBD epitopes. Rabbit mAbs included critical D-gene segment RBD-recognizing features in common with human anti-RBD mAbs, despite rabbit genomes lacking an equivalent human D-gene segment, thus demonstrating that the immune systems of humans and other mammals can utilize different antibody gene segments to arrive at similar modes of antigen recognition. These results suggest that animal models can be used to elicit anti-RBD mAbs with similar properties to those raised in humans, which can then be humanized for therapeutic use, and that mosaic RBD nanoparticle immunization coupled with multiplexed screening represents an efficient way to generate and select broadly cross-reactive therapeutic pan-sarbecovirus and pan-SARS-CoV-2 variant mAbs.

Science & Technology - Other Topics↗
DOE OSTI2020

Unusual zwitterionic catalytic site of SARS–CoV-2 main protease revealed by neutron crystallography

The main protease (3CL M pro ) from SARS–CoV-2, the etiological agent of COVID-19, is an essential enzyme for viral replication. 3CL M pro possesses an unusual catalytic dyad composed of Cys 145 and His 41 residues. A critical question in the field has been what the protonation states of the ionizable residues in the substrate-binding active-site cavity are; resolving this point would help understand the catalytic details of the enzyme and inform rational drug development against this pernicious virus. Here, we present the room-temperature neutron structure of 3CL M pro , which allowed direct determination of hydrogen atom positions and, hence, protonation states in the protease. We observe that the catalytic site natively adopts a zwitterionic reactive form in which Cys 145 is in the negatively charged thiolate state and His 41 is doubly protonated and positively charged, instead of the neutral unreactive state usually envisaged. The neutron structure also identified the protonation states, and thus electrical charges, of all other amino acid residues and revealed intricate hydrogen-bonding networks in the active-site cavity and at the dimer interface. The fine atomic details present in this structure were made possible by the unique scattering properties of the neutron, which is an ideal probe for locating hydrogen positions and experimentally determining protonation states at near-physiological temperature. Our observations provide critical information for structure-assisted and computational drug design, allowing precise tailoring of inhibitors to the enzyme's electrostatic environment.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗