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At least 937 records · Page 52
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

In vitro enhancement of Zika virus infection by preexisting West Nile virus antibodies in human plasma-derived immunoglobulins revealed after P2 binding site-specific enrichment

ABSTRACT Human immunoglobulin preparations contain a diverse range of polyclonal antibodies that reflect past immune responses against pathogens encountered by the blood donor population. In this study, we examined a panel of intravenous immunoglobulins (IGIVs) manufactured over the past two decades (1998–2020) for their capacity to neutralize or enhance Zika virus (ZIKV) infectionin vitro. These IGIVs were selected specifically based on their production dates in relation to the occurrences of two flavivirus outbreaks in the U.S.: the West Nile virus (WNV) outbreak in 1999 and the ZIKV outbreak in 2015. As demonstrated by enzyme-linked immunosorbent assay (ELISA) experiments, IGIVs made before the ZIKV outbreak already harbored antibodies that bind to various peptides across the envelope protein of ZIKV because of the WNV outbreak. Using phage display, the most dominant binding site was mapped precisely to the P2 peptide between residues 211 and 230 within domain II, where BF1176-56, an anti-ZIKV monoclonal antibody, also binds. When tested in permissive Vero E6 cells for ZIKV neutralization, the IGIVs, even after undergoing rigorous enrichment for P2 binding specificity, failed, as did BF1176-56. Meanwhile, BF1176-56 enhanced ZIKV infection in both FcγRII-expressing K562 cells and human peripheral blood mononuclear cells. However, for enhancement by the IGIVs to be detected in these cells, a substantial increase in their P2 binding specificity was required, thus linking the P2 site with ZIKV enhancementin vitro. Our findings warrant further study of the significance of elevated levels of anti-WNV antibodies in IGIVs, considering that various mechanisms operatingin vivomay modulate ZIKV infection outcomes. IMPORTANCE We investigated the capacity of intravenous immunoglobulins manufactured previously over two decades (1998–2020) to neutralize or enhance Zika virus infectionin vitro. West Nile virus antibodies in IGIVs could not neutralize Zika virus initially; however, once the IGIVs were concentrated further, they enhanced its infection. These findings lay the groundwork for exploring how preexisting WNV antibodies in IGIVs could impact Zika infection, bothin vitroandin vivo. Our observations are historically significant, since we tested a panel of IGIV lots that were carefully selected based on their production dates which covered two major flavivirus outbreaks in the U.S.: the WNV outbreak in 1999 and the ZIKV outbreak in 2015. These findings will facilitate our understanding of the interplay among closely related viral pathogens, particularly from a historical perspective regarding large blood donor populations. They should remain relevant for future outbreaks of emerging flaviviruses that may potentially affect vulnerable populations.

Microbiology↗
DOE OSTI2024

A Theory for the Balance between Warm Rain and Ice Crystal Processes of Precipitation in Mixed-Phase Clouds

Abstract Mixed-phase clouds contain both supercooled cloud liquid and ice crystals. In principle, precipitation may be initiated either by the liquid phase or by the ice phase. Ice crystals may grow by vapor diffusion to become snow (“ice crystal process”), forming “cold” precipitation. Equally, cloud droplets, when large enough, coalesce to form “warm” precipitation by the “warm rain process.” Warm rain could be supercooled and freeze as “warm” graupel. In the present paper, a new simplified theoretical analysis is provided to examine the microphysical system consisting of three species of hydrometeor, namely, cloud liquid, “cold ice” (crystals, snow), and “warm rain” (frozen or supercooled). This is obtained by nondimensionalizing and simplifying the evolution equations for the mass of each species. Analytical formulas are given for equilibria. Feedback analysis shows that the sign of the feedback is linked to the abundance of precipitation, with a neutral surface in the 3D phase space. The system’s precipitation amount explodes while in the initial unstable regime, crossing the neutral surface and approaching the equilibrium point that is a stable attractor. Positive and negative feedbacks are elucidated. In a standard case, the cold ice mass is about 1000 times larger than the warm rain mass. To illustrate the physical behavior of the theory, sensitivity tests are performed with respect to environmental conditions (e.g., aerosol, updraft speed) and microphysical parameters (e.g., riming and sedimentation rates for cold ice). Cold ice prevails, especially in fast ascent, due to its low bulk density, favoring slow sedimentation and a wide cross-sectional area for riming. Significance Statement The theory elucidates how the ice phase can prevail in the precipitation from any mixed-phase clouds with supercooled cloud liquid and crystals. The ice phase radically suppresses cloud liquid by riming when active and “wins” the competition against coalescence. This prevalence of ice is shown to arise from the low bulk density of snow. The cloud is viewed as a system of negative and positive feedbacks that prevail in realms of stability and instability in a 3D phase space.

Meteorology & Atmospheric Sciences↗
DOE OSTI2022

Clean Condensing Gas Furnace

Natural gas furnaces are the most common space heating equipment in the U.S. residential and commercial building markets. However, current residential natural gas condensing furnaces generate substantial acidic condensate as well as significant emissions of sulfur oxides (SOx), nitrogen oxides (NOx), carbon monoxide (CO), hydrocarbons (HC), and methane (CH 4 ) contributing to environmental degradation of air, water, and soil. This report describes a novel solution to reduce the environmental impact of natural gas condensing furnaces based on the technology of a monolithic acidic gas reduction (AGR) catalyst for SOx trapping, NOx redox to nitrogen, and oxidation of formic acid, CO, HC, and CH 4 . The AGR technology offers the following benefits: (1) a neutral furnace condensate with a pH of ~7, allowing its safe release into the sewer system thus eliminating a second drainage system; (2) trapping and removing nearly all SOx emissions; (3) NOx emissions nearly at nearly 1-2 ng/J, more than 95% lower than new emissions standards in California; (4) the use of a low-cost heat exchanger as a condensing heat exchanger (HX) since the condensate is not acidic, avoiding the need for expensive stainless steel alloys; and (5) unburnt fuel energy recovery to boost efficiency.The AGR component and AGR-enabled furnace performance were broadly tested to determine their effects on long-term reliability and durability, as well as SOx storage and regeneration activity. The AGR regeneration does not impair the performance in achieving neutral condensate and ultra-low NOx emissions, and the AGR catalyst subjected to regeneration activities continued to function well and achieved slightly better annual fuel utilization efficiency (AFUE). The 400-hour reliability and durability test of the retrofitted condensing furnace with the AGR component shows that the furnace unit still achieves a neutral furnace condensate with a pH of ~7 and enables 0~3 ng/J of NOx emissions. However, the 400-hour operation slightly degraded the AFUE because of soot particle accumulation caused by frequent incomplete combustion owing to inappropriate condensate drainage during testing. Thus, proper condensate drainage is critical for AGR-enabled furnaces. Furthermore, neutron computed tomography was employed to survey the aged AGR component and demonstrate high-resolution 2D and 3D representations for the nondestructive diagnosis of the AGR component. The tomography showed that the AGR component did not deform or suffer broken AGR channels. A new AGR catalyst with low precious metal loading was preliminarily explored to identify a pathway of optimizing AGR material loading and maximizing acidic gas reduction at low cost. The new AGR component can reduce precious metal loading by 38% and still achieve neutral condensate and ultralow NOx emissions. The furnace with the AGR component of low Pt/Rh loading enables a maximum AFUE of 97%, which is meaningfully higher than the original furnace. Long-duration testing for the furnace enabled with the low precious metal loading AGR component will be vital in future research. Although the current work demonstrates a proof of concept for the AGR-enabled furnace, the AGR assembly needs to be optimized and integrated into the design of new OEM furnace products. Furthermore, the AGR technology can be applied not only for residential gas furnaces, but also for commercial rooftop units, gas heat pumps, gas-fired water heaters, combustion boilers, and other systems.

03 NATURAL GAS↗
DOE OSTI2023

Building a Computational and Experimental Rapid Response Pipeline to Counter the Coronavirus Disease 2019 Outbreak and Emerging Biothreats

The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs, especially where protective candidates can be rapidly identified or developed for emerging biothreats and escape variants. Current cutting-edge technologies for this purpose still rely on pathogen-exposed convalescent volunteers and a large screening effort to find a proverbial needle in a haystack. Computational design of protective antibodies based on pre-existing templates skips those requirements and allows for greater control over the breadth and target epitope, while also co-optimizing for potency and developability or other biophysical characteristics. We approached this problem by building and expanding an in vitro experimental rapid antibody production and characterization pipeline to support development of an autonomous, closed loop, active learning software system based on structural simulation and ground truth experimental data to design and evaluate antibody antigen interactions. Starting from early in the pandemic, we targeted SARS-CoV-2, the causative agent of COVID-19, by re-purposing neutralizing antibodies against SARS-CoV-1 that had been identified in the wake of that outbreak in the early 2000’s. We successfully re-targeted three different anti-SARS-CoV-1 antibodies to neutralize SARS-CoV-2 in vitro, where the antibodies were generated externally and tested through conventional binding and neutralization assays internally or with collaborators. As antibodies were identified from the blood of humans infected with SARS-CoV-2, we shifted to collaborate with academic partners to develop improved versions of their human-derived antibodies. This work reached its most important stage in rapid response to the emergence of the Omicron variant of concern (VOC) in late 2021. In a matter of weeks, enabled by on demand innovation to our screening pipeline, we computationally designed and experimentally characterized derivative antibodies of COV2-2130, one of two antibodies from Vanderbilt that form the basis of the AstraZeneca Evusheld prophylactic drug product. This drug product suffers a serious loss of efficacy against Omicron BA.1 and BA.1.1, the first Omicron strains. Due to tight integration of computational design and experimental evaluation, we were able to identify a pair of designs with potent neutralization of the main targets Omicron BA.1 and BA.1.1; but also the earlier Delta variant, and subsequent Omicron strains including BA.2, BA.4, BA.5, and BA.2.75, demonstrating that our multi-target design process can, by its nature, produce robust antibody designs that strictly improve over the parental antibody. These results, recognized by a 2022 Director’s Science and Technology award, have enabled the follow-on GUIDE program, to commence in FY23. While earlier design campaigns were substantially outsourced, we have engineered better and faster processes internally to better compliment, calibrate, and speed computational designs. As part of the follow-on GUIDE program, we will stand up a rapid and high-throughput antibody production and characterization facility staffed with the expertise and capabilities to foster our current collaboration across PLS and ENG as well as other partnerships toward computational design of biologics.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Quantum Calculations of VX Ammonolysis and Hydrolysis Pathways via Hydrated Lithium Nitride

Recently, lithium nitride (Li 3 N) has been proposed as a chemical warfare agent (CWA) neutralization reagent for its ability to produce nucleophilic ammonia molecules and hydroxide ions in aqueous solution. Quantum chemical calculations can provide insight into the Li 3 N neutralization process that has been studied experimentally. Here, we calculate reaction-free energies associated with the Li3N-based neutralization of the CWA VX using quantum chemical density functional theory and ab initio methods. We find that alkaline hydrolysis is more favorable to either ammonolysis or neutral hydrolysis for initial P-S and P-O bond cleavages. Reaction-free energies of subsequent reactions are calculated to determine the full reaction pathway. Notably, products predicted from favorable reactions have been identified in previous experiments.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

[C ιι] Map of the Molecular Ring and Arms of the Spiral Galaxy NGC 7331*

We present the [C ιι] 157.7 μm map of galaxy NGC 7331 obtained with the Field-Imaging Far-Infrared Line Spectrometer on board the Stratospheric Observatory for Infrared Astronomy (SOFIA). This map extends an existent Herschel/Photodetector Array Camera and Spectrometer observation of the central strip of the galaxy to encompass the entire molecular ring and much of the disk, including multiple spiral arms with intense far-IR emission. We also present Herschel archival data of the [N ιι] 205 μm line, which covers a substantial part of the [C ιι] SOFIA observations and allows us to estimate the neutral fraction of the [C ιι] emission along the ring and disk of the galaxy. We find that the neutral fraction rises with the distance from the center. In addition, by tracing the azimuthal variation of the neutral fraction, we are able to see how our observing perspective affects this measurement. The high inclination of NGC 7331 allows us to glimpse the internal walls of the molecular ring. There, young bright stars emit UV radiation causing more [C ιι] emission to be produced in the ionized gas. On the outer walls, opaque dust shrouds the rest of the ring, making the neutral medium the dominant source of [C ιι] emission. Through spatial analysis comparing the [C ιι] emission to tracers of gas heating, we are able to investigate how the photoelectric heating efficiency varies throughout NGC 7331 and extend global measurements of the [C ιι] deficit to local environments. Since the origin of [C ιι] emission has typically been studied in face-on galaxies, our results shed a new light on the interpretation of [C ιι] emission, especially when studying distant galaxies with unknown inclination.

79 ASTRONOMY AND ASTROPHYSICS↗
DOE OSTI2022

Discovery of a Damped Lyα Absorber Originating in a Spectacular Interacting Dwarf Galaxy Pair at z = 0.026

We present the discovery of neutral gas detected in both damped Lyα absorption (DLA) and H I 21 cm emission outside of the stellar body of a galaxy, the first such detection in the literature. A joint analysis between the Cosmic Ultraviolet Baryon Survey and the MeerKAT Absorption Line Survey reveals an H I bridge connecting two interacting dwarf galaxies (log (M star /M ⊙ ) = 8.5 ± 0.2) that host a z = 0.026 DLA with log[N(H I )/cm –2 ] = 20.60 ± 0.05 toward the QSO J2339–5523 (z QSO = 1.35). At impact parameters of d = 6 and 33 kpc, the dwarf galaxies have no companions more luminous than ≈0.05L * within at least Δv = ±300 km s –1 and d ≈ 350 kpc. The H I 21 cm emission is spatially coincident with the DLA at the 2σ–3σ level per spectral channel over several adjacent beams. However, H I 21 cm absorption is not detected against the radio-bright QSO; if the background UV and radio sources are spatially aligned, the gas is either warm or clumpy (with a spin temperature to covering factor ratio T s /f c > 1880 K). Observations with VLT-MUSE demonstrate that the α-element abundance of the ionized interstellar medium (ISM) is consistent with the DLA (≈10% solar), suggesting that the neutral gas envelope is perturbed ISM gas. This study showcases the impact of dwarf–dwarf interactions on the physical and chemical state of neutral gas outside of star-forming regions. In the SKA era, joint UV and H I 21 cm analyses will be critical for connecting the cosmic neutral gas content to galaxy environments.

79 ASTRONOMY AND ASTROPHYSICS↗
DOE OSTI2023

Measurement of the pion charge exchange differential cross section on Argon with the ProtoDUNE-SP detector

The Deep Underground Neutrino Experiment (DUNE) utilizes Liquid Argon Time Projection Chamber (LArTPC) technology in its pursuit of uncovering the origins of matter. As a crucial prototype for the DUNE far detector (FD) module, ProtoDUNE-SP at CERN Neutrino Platform Facility employs a hadron test beam with a momentum range of 0.3 to 7 GeV/c to study the detector response to particles that could be produced in the neutrino interactions at the DUNE FD. Furthermore, ProtoDUNE-SP is dedicated to testing event reconstruction and performing detector calibration under controlled conditions. Neutral pion reconstruction performance is an important benchmark of the calorimetric and tracking capability of LArTPC, and understanding neutral pion in LArTPC is crucial to characterize backgrounds to oscillation measurements and rare searches. To improve neutral pion reconstruction in LArTPC, a kinematic fitting algorithm is developed, achieving a 12% resolution in neutral pion energy in ProtoDUNE-SP. This enhancement enables the first measurements of the pion-argon charge exchange differential cross-section. By comparing these results with the current model, valuable constraints can be made to improve generator simulations in the future DUNE experiment.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗
DOE OSTI2023

Assessing mechanisms for microbial taxa and community dynamics using process models

Disentangling the assembly mechanisms controlling community composition, structure, distribution, functions, and dynamics is a central issue in ecology. Although various approaches have been proposed to examine community assembly mechanisms, quantitative characterization is challenging, particularly in microbial ecology. Here, we present a novel approach for quantitatively delineating community assembly mechanisms by combining the consumer–resource model with a neutral model in stochastic differential equations. Using time-series data from anaerobic bioreactors that target microbial 16S rRNA genes, we tested the applicability of three ecological models: the consumer–resource model, the neutral model, and the combined model. Our results revealed that model performances varied substantially as a function of population abundance and/or process conditions. The combined model performed best for abundant taxa in the treatment bioreactors where process conditions were manipulated. In contrast, the neutral model showed the best performance for rare taxa. Our analysis further indicated that immigration rates decreased with taxa abundance and competitions between taxa were strongly correlated with phylogeny, but within a certain phylogenetic distance only. The determinism underlying taxa and community dynamics were quantitatively assessed, showing greater determinism in the treatment bioreactors that aligned with the subsequent abnormal system functioning. Given its mechanistic basis, the framework developed here is expected to be potentially applicable beyond microbial ecology.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Economic and operational investigation of CO 2 sequestration through enhanced oil recovery in unconventional reservoirs in Colorado, USA

The ongoing CCUS commercial projects are highly relied on the support of government incentives due to massive capital investment. Here, this study analyzes the economics of carbon capture utilization and sequestration (CCUS) projects, shows a state-wide CCUS deployment exercise, followed by simulation results of enhanced oil recovery (EOR) based CO 2 storage in unconventional reservoirs. The comprehensive economic analysis of capture, transportation, sequestration costs, enhanced 45Q tax credits, and EOR revenue implies the practicality of CO 2 -EOR to offset the high CCUS costs. With the economics understanding, we study the top CO 2 sources, existing CO 2 pipelines, and sequestration sinks in the state of Colorado, USA. This paper next presents results from EOR simulation in one section of the unconventional Denver-Julesburg (DJ) Basin Niobrara and Codell reservoirs. The simulation model is based on a geological static model, incorporated with hydraulic fracture stimulation, history matched to production, and calibrated to the microseismic and time-lapse surface seismic data. The CO 2 -EOR simulation results show that oil production can be increased and more CO 2 stored with: a longer primary production period; the presence of a shut-in period; higher injection rates; and multi-well injectors. The modeling results show that about 7–10 Mscf of CO 2 will be stored when recovering 1 stb of EOR oil. By adding the enhanced oil revenue and the carbon credits together, it is estimated that the most economic case can generate $\$13$ MM when oil price is assumed to be $\$80$/stb, and the EOR oil revenue is 3.4 times greater than that generated from 45Q incentives. It corresponds to the scenario that a five-year primary production is followed by CO 2 injection into four wells with the sequence of injection (4 MMscf/day for 6 months), shut-in (6 months) and production (12 months). The best practices in this study will provide valuable insights for similar CCUS projects in other unconventional fields. Furthermore, this study defines a term named “Carbon Neutrality Index (CNI)” by comparing the amount of CO 2 stored with that burned by EOR oil. The CNI value of 0 indicates the enhanced oil is carbon neutral; a negative CNI value implies there is a net reduction in carbon emission. The 4-year huff-n-puff (HnP) simulation leads to a positive CNI value, indicating that the EOR oil generated in this process is not carbon neutral yet.

03 NATURAL GAS↗
DOE OSTI2020

Laser-assisted high-energy proton pulse extraction for feasibility study of co-located muon source at the SNS

Here, we have experimentally demonstrated the first non-intrusive 1-GeV proton beam extraction for the generation of muons with a temporal structure optimized for Muon Spin Relaxation/Rotation/Resonance (μSR) applications. The proton pulses are extracted based on the laser neutralization of 1 GeV hydrogen ion (H - ) beam in the high energy beam transport of the Spallation Neutron Source (SNS) accelerator. The maximum flux of the extracted proton beam based on laser neutralization causes only 0.2% reduction of the total proton beam used for neutron production, a marked difference from the 20% reduction at other co-located muon and neutron facilities, and thus the proposed method will result in negligible impact on the SNS operation. This paper describes the development of a fiber/solid-state hybrid laser system that has high flexibility of pulse structure and output power, initial experiments on laser neutralization of beam and separation of H 0 beam from the existing SNS accelerator beam line, conversion of H 0 to proton at the SNS linac dump, and measurement results of 30 ns/50 kHz proton pulses. This system conclusively demonstrates the feasibility of laser-based proton beam extraction to power a world-leading μSR facility at the SNS.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗
DOE OSTI2026

A novel conditional formulation of the Vlasov–Ampère equations: a conservative, positivity, asymptotic and Gauss law preserving scheme

We propose a novel reformulation of the Vlasov–Ampère equations for plasmas that reveals discrete symmetries that enables simultaneous conservation of mass, momentum and energy; preservation of Gauss’s law; positivity of the distribution function; and consistency with quasi-neutral asymptotics. The approach employs variable and coordinate transformations to yield a coupled system comprising a modified Vlasov equation and associated moment–field equations. The modified Vlasov equation advances a conditional distribution function that excludes mass, momentum and energy densities, which are instead evolved through moment equations enforcing the relevant symmetries, conservation laws and involution constraints. This reformulation aligns naturally with a recent slow-manifold reduction technique, which separates fast electron time scales and simplifies the treatment of the quasi-neutral limit within the reduced moment–field subsystem. Using this framework, we develop a numerical method for the reduced 1D1V subsystem that, for the first time in the literature, satisfies all key physical constraints while maintaining a quasi-neutral asymptotic behaviour. The advantages of the method are demonstrated on canonical electrostatic test problems, including the multiscale ion acoustic shock wave.

1D1V↗
DOE OSTI2020

The impact of long-range dispersal on gene surfing

Range expansions lead to distinctive patterns of genetic variation in populations, even in the absence of selection. These patterns and their genetic consequences have been well studied for populations advancing through successive short-ranged migration events. However, most populations harbor some degree of long-range dispersal, experiencing rare yet consequential migration events over arbitrarily long distances. Although dispersal is known to strongly affect spatial genetic structure during range expansions, the resulting patterns and their impact on neutral diversity remain poorly understood. Here, we systematically study the consequences of long-range dispersal on patterns of neutral variation during range expansion in a class of dispersal models which spans the extremes of local (effectively short-ranged) and global (effectively well-mixed) migration. We find that sufficiently long-ranged dispersal leaves behind a mosaic of monoallelic patches, whose number and size are highly sensitive to the distribution of dispersal distances. We develop a coarse-grained model which connects statistical features of these spatial patterns to the evolution of neutral diversity during the range expansion. We show that growth mechanisms that appear qualitatively similar can engender vastly different outcomes for diversity: Depending on the tail of the dispersal distance distribution, diversity can be either preserved (i.e., many variants survive) or lost (i.e., one variant dominates) at long times. Our results highlight the impact of spatial and migratory structure on genetic variation during processes as varied as range expansions, species invasions, epidemics, and the spread of beneficial mutations in established populations.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Quantifying the contribution of Fc-mediated effector functions to the antiviral activity of anti–HIV-1 IgG1 antibodies in vivo

In combating viral infections, the Fab portion of an antibody could mediate virus neutralization, whereas Fc engagement of Fc-γ receptors (FcγRs) could mediate an array of effector functions. Evidence abounds that effector functions are important in controlling infections by influenza, Ebola, or HIV-1 in animal models. However, the relative contribution of virus neutralization versus effector functions to the overall antiviral activity of an antibody remains unknown. To address this fundamental question in immunology, here we utilized our knowledge of HIV-1 dynamics to compare the kinetics of the viral load decline (ΔVL) in infected animals given a wild-type (WT) anti–HIV-1 immunoglobulin G1 (IgG1) versus those given a Fc-Null variant of the same antibody. In three independent experiments in HIV-1–infected humanized mice and one pivotal experiment in simian–human immunodeficiency virus (SHIV)-infected rhesus macaques, an earlier and sharper decline in viral load was consistently detected for the WT antibody. Quantifications of the observed differences indicate that Fc-mediated effector functions accounted for 25–45% of the total antiviral activity in these separate experiments. In this study, Fc-mediated effector functions have been quantified in vivo relative to the contribution of virus neutralization mediated by the Fab.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

The scoping, design, and plasma physics optimization of the Eos neutron source stellarator

On the path to a fusion pilot plant, Thea Energy plans to build Eos, a sub-breakeven, deuterium-deuterium, beam-target fusion, stellarator neutron source facility for producing tritium and other valuable radioisotopes. In this paper, a set of 1D plasma physics models are coupled and used to design the operating point of the facility and predict performance. At this foundational stage of the design, analytic and approximate models are sufficient to capture the leading-order effects, and fast enough to run in the inner loop of an optimizer. Higher-fidelity analyses will follow. Models of 1D profile-dependent neutral beam stopping, ion beam slowing down, beam-target fusion, electron-ion classical heat transfer, energy confinement (ISS04), beam pressure, beam heating of ions and electrons, beam-beam fusion fraction, and neutral beam injection and gyrotron heating electrical efficiencies are included. A numerical optimizer is used to determine the minimum required facility electric power to generate tritium at a given rate. A potentially advantageous regime is described in which modern precisely-quasisymmetric stellarators, new high-temperature superconductors, ITER-derived neutral beam injection, and new high-frequency gyrotrons enable a suitible target plasma with hot electrons, cold ions, peaked density and temperature profiles, and high beam-injected ion density. It appears possible at this time for a facility with a medium-scale and medium-strength stellarator whose required facility electric power is less than 40 MW to produce $2.5\times 10^{17}$ neutrons s -1 for the production of radioisotopes. With the addition of a tritium breeding blanket, such a facility could produce 0.2 grams d -1 or 70 grams yr -1 of tritium.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
DOE OSTI2021

Structures of Two Human Astrovirus Capsid/Neutralizing Antibody Complexes Reveal Distinct Epitopes and Inhibition of Virus Attachment to Cells

Human astrovirus is an important cause of viral gastroenteritis worldwide. Young children, the elderly, and the immunocompromised are especially at risk for contracting severe disease. However, no vaccines exist to combat human astrovirus infection. Evidence points to the importance of antibodies in protecting healthy adults from reinfection. To develop an effective subunit vaccine that broadly protects against diverse astrovirus serotypes, we must understand how neutralizing antibodies target the capsid surface at the molecular level. Here, we report the structures of the human astrovirus capsid spike domain bound to two neutralizing monoclonal antibodies. These antibodies bind two distinct conformational epitopes on the spike surface. We add to existing evidence that the human astrovirus capsid spike contains a receptor-binding domain and demonstrate that both antibodies neutralize human astrovirus by blocking virus attachment to host cells. We identify patches of conserved amino acids which overlap or border the antibody epitopes and may constitute a receptor-binding site. Our findings provide a basis for developing therapies to prevent and treat human astrovirus gastroenteritis.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Targeting the Spike Receptor Binding Domain Class V Cryptic Epitope by an Antibody with Pan-Sarbecovirus Activity

Novel therapeutic monoclonal antibodies (MAbs) must accommodate comprehensive breadth of activity against diverse sarbecoviruses and high neutralization potency to overcome emerging variants. Here, in this study, we report the crystal structure of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain (RBD) in complex with MAb WRAIR-2063, a moderate-potency neutralizing antibody with exceptional sarbecovirus breadth, that targets the highly conserved cryptic class V epitope. This epitope overlaps substantially with the spike protein N-terminal domain (NTD) -interacting region and is exposed only when the spike is in the open conformation, with one or more RBDs accessible. WRAIR-2063 binds the RBD of SARS-CoV-2 WA-1, all variants of concern (VoCs), and clade 1 to 4 sarbecoviruses with high affinity, demonstrating the conservation of this epitope and potential resiliency against variation. We compare structural features of additional class V antibodies with their reported neutralization capacity to further explore the utility of the class V epitope as a pan-sarbecovirus vaccine and therapeutic target.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Interchangeability of the Assays Used to Assess the Activity of Anti-SARS-CoV-2 Monoclonal Antibodies

The recent global COVID-19 pandemic caused by SARS-CoV-2 lasted for over three years. A key measure in combatting this pandemic involved the measurement of the monoclonal antibody (mAb)-mediated inhibition of binding between the spike receptor-binding domain (RBD) and hACE2 receptor. Potency assessments of therapeutic anti-SARS-CoV-2 mAbs typically include binding or cell-based neutralization assays. We assessed the inhibitory activity of five anti-SARS-CoV-2 mAbs using ELISA, surface plasmon resonance (SPR), and four cell-based neutralization assays using different pseudovirus particles and 293T or A549 cells expressing hACE2 with or without TMPRSS2. We assessed the interchangeability between cell-based and binding assays by applying the Bland–Altman method under certain assumptions. Our data demonstrated that the IC50 [nM] values determined by eight neutralization assays are independent of the cell line, presence of TMPRSS2 enzyme on the cell surface, and pseudovirus backbone used. Moreover, the Bland–Altman analysis showed that the IC50 [nM] and KD [nM] values determined by neutralization/ELISA or by SPR are equivalent and that the anti-spike mAb activity can be attributed to one variable directly related to its tertiary conformational structure conformation, rate dissociation constant Koff. This parameter is independent from the concentrations of the components of the mAb:RBD:hACE2 complexes and can be used for a comparison between the activities of the different mAbs.

60 APPLIED LIFE SCIENCES↗