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At least 343 records · Page 19

Pan-H7 influenza human antibody virus neutralization depends on avidity and steric hindrance

H7N9 avian influenza virus is a zoonotic influenza virus of public health concern, with a 39% mortality rate in humans. H7N9-specific prevention or treatments for humans have not been approved. We previously isolated a human monoclonal antibody (mAb) designated H7-235 that broadly reacts to diverse H7 viruses and neutralizes H7N9 viruses in vitro. Here, we report the crystal structure of H7 HA1 bound to the fragment antigen-binding region (Fab) of recombinant H7-235 (rH7-235). The crystal structure revealed that rH7-235 recognizes residues near but outside of the receptor binding site (RBS). Nevertheless, the rH7-235 IgG potently inhibits hemagglutination mediated by H7N9 viruses due to avidity effect and Fc steric hindrance. This mAb prophylactically protects mice against weight loss and death caused by challenge with lethal H7N9 viruses in vivo. rH7-235 mAb neutralizing activity alone is sufficient for protection when used at a high dose in a prophylactic setting. This study provides insights into mechanisms of viral neutralization by protective, broadly reactive anti-H7 antibodies, informing the rational design of therapeutics and vaccines against H7N9 influenza virus.

Research & Experimental Medicine↗

Reduced Neutralization Feasibility Study for H-Canyon Accelerated Basin De- Inventory (ABD) Program

An alternative approach to Spent Nuclear Fuel (SNF) and Nuclear Material Processing was developed for future H-Canyon (HCAN) and L-Area operations that involves a paradigm shift from current HCAN, Concentrate, Storage, and Transfer Facility (CSTF), and Defense Waste Processing Facility (DWPF) operations. The alternative, referred to as Accelerated Basin De-inventory (ABD), requires that all Domestic and Foreign Research Reactor SNF currently at the Savannah River Site (SRS) will be dissolved, stored, and then transferred to CSTF without recovery of Highly Enriched Uranium (HEU). Concentrated nitric acid is utilized to dissolve aluminum spent nuclear fuel (ASNF) in HCAN. The vessels and piping in HCAN are fabricated from 304L stainless steel and are ideally suited to handle the acidic waste stream. However, as the waste is transferred to the CSTF and DWPF, it will contact the carbon steel waste tanks in CSTF. In order to prevent corrosion of the carbon steel, the acidic waste is neutralized (i.e., pH adjusted over 11) by the addition of sodium hydroxide (NaOH). The NaOH is added until the final solution contains 1.2 M excess -OH. Additionally, if the waste is not neutralized to a pH greater than 11, then aluminum hydroxide (Al(OH) 3 ) would form, and solids may form in the piping as it is transferred to CSTF. This document presents an analysis of the influence of reducing the excess caustic that is added to the neutralization tanks on the corrosion protection scheme primarily for the CSTF waste tanks. The implications to HCAN and DWPF were also assessed.

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗

Computational Modeling To Adapt Neutralizing Antibody

Monoclonal antibodies (mAbs) is the leading therapy for viral infections because it provides immediate protection and can be administered at higher levels than in a natural immune response. Finding mAbs that neutralize a broad spectrum of viral targets has proven difficult because many species and strains exist and blanket targeting is a slow and laborious process to experimentally screen 108 variants. A new method is needed to rapidly redesign mAbs for homologous targets. This project speeds up redesign using structure-based computational design to reduce the mAbs search space to a manageable level and screen mutants at a much higher rate than in experiments. Computation will also provide critical knowledge about the fundamental interactions. The project will adapt S230, a human antibody that neutralizes SARS-CoV, to neutralize SARS-COV-2.

60 APPLIED LIFE SCIENCES↗

Time-resolved measurement of electron beam neutralization

An intense relativistic electron beam (IREB) incident on a target generates positive ions by stimulated and thermal desorption of adsorbed gas, and subsequent electron impact ionization. These ions are accelerated upstream by the beam space-charge potential, thereby partially neutralizing the beam. If there is enough neutralization, the repulsive space-charge force can be overcome by the magnetic-pinch force due to the beam current. This so-called ion focusing is responsible for time dependent defocusing of the radiographic source spot. Since a single monolayer of adsorbed gas has a surface density of about 10 15 /cm 2 and is formed in about one second in a one micro-Torr vacuum, there is always enough adsorbed gas to make this a concern in our accelerators. Therefore, time-resolved measurements of the degree of neutralization are valuable for better understanding of this process with an eye to mitigation for improvement of our radiography. Moreover, these measurements would aid quantification of uncertainties due to these effects when using invasive beam diagnostics, such as OTR imaging targets.

43 PARTICLE ACCELERATORS↗

Science and Technology Review: Getting to Carbon Neutral

At Lawrence Livermore National Laboratory, we focus on science and technology research to ensure our nation’s security. We also apply that expertise to solve other important national problems in energy, bioscience, and the environment. Science & Technology Review is published eight times a year to communicate, to a broad audience, the Laboratory’s scientific and technological accomplishments in fulfilling its primary missions. The publication’s goal is to help readers understand these accomplishments and appreciate their value to the individual citizen, the nation, and the world. Achieving carbon neutrality requires a well-considered combination of technologies, private involvement, and public policies. As described in the article beginning on p. 4, Lawrence Livermore National Laboratory developed the Getting to Neutral: Options for Negative Carbon Emissions in California report, a three-pillared approach to bridge the gap between California’s initial plans to reduce carbon emissions and the state’s goal to achieve net zero emissions by 2045. The cover image represents the network of strategies and stakeholders involved in achieving carbon neutrality for the environment.

29 ENERGY PLANNING, POLICY, AND ECONOMY↗

Pathways to Carbon Neutrality 2050 in Malaysia and Kuala Lumpur

Malaysia has recently set an ambitious target of achieving carbon neutrality as early as 2050. To accomplish this, the country will need to strategically reduce its emissions across all sectors. In 2020, Malaysia emitted approximately 368 MtCO2e, with the largest sources of emissions including electricity (36% of total emissions), transportation (17%), and industry (15%)1. We find that the greatest reductions in emissions can therefore come from decarbonizing power generation and electrifying end-use sectors. Digitalization, smart technologies, and improved energy efficiency will significantly reduce economy-wide energy consumption. By leveraging efficient technologies, both Malaysia and Kuala Lumpur can address the challenges posed by rapid urbanization and climate change. Digitalization is a broad category that includes a variety of measures; for example, the wide adoption of high-efficiency appliances and lighting or improved building energy codes in the buildings sector. Similarly, technological improvements can advance industrial energy efficiency, and for transportation, smart technologies cover a shift from private to public transportation and the greater use of electric vehicles. While renewable energy (RE) will play a crucial role in decarbonization, achieving carbon neutrality in certain sectors will be difficult without emerging technologies like carbon capture and storage (CCS) and innovative fuel sources such as hydrogen. In order for Malaysia to rely on CCS as a mitigation option, early investment and incentives to the private sector will be critical. This holds for the use of hydrogen as well: investing in the necessary technology, infrastructure, and human capital will allow Malaysia to position itself as an innovator in the region and leverage these advanced technologies as a key part of its climate strategy. Another possible carbon removal option other than CCS would be a land-use sink; however, given that Malaysia is still developing and may deforest in the near-term, this report does not focus on the mitigation potential of land-use change. With its innovative and bold climate plans, Kuala Lumpur is primed to be a leader in regional climate change efforts. Kuala Lumpur is also engaged in several international collaborations to ensure sustainable city development such as the C40 network and the ASEAN Smart Cities Partnership. As such, the city will play a critical role in contributing to Malaysia’s overall climate goals and as a policy trendsetter through ambitious, scalable plans. One key factor in these emissions reductions is that Kuala Lumpur has full control over its building guidelines, allowing for ambitious policies resulting in significant emissions reductions. However, in other sectors, Kuala Lumpur has less direct control over regulations; for example, power generation and integration of RE are largely in the hands of the Malaysian government. With limited and primarily light industry, Kuala Lumpur’s contributions to emissions reductions here are curbed. And, while Kuala Lumpur has control over local transportation policies like increasing access to and quality of public transportation, broad shifts in transportation will stem from national-level policies. As such, multi-level governance is an integral component of Malaysia’s climate strategy and coordination between local and national governments will be essential in reducing emissions and achieving other climate goals. This report addresses these and other key challenges and opportunities Malaysia faces on the road to carbon neutrality.

29 ENERGY PLANNING, POLICY, AND ECONOMY↗

Modeling HIV-1 Within-Host Dynamics After Passive Infusion of the Broadly Neutralizing Antibody VRC01

VRC01 is a broadly neutralizing antibody that targets the CD4 binding site of HIV-1 gp120. Passive administration of VRC01 in humans has assessed the safety and the effect on plasma viremia of this monoclonal antibody (mAb) in a phase 1 clinical trial. After VRC01 infusion, the plasma viral load in most of the participants was reduced but had particular dynamics not observed during antiretroviral therapy. In this paper, we introduce different mathematical models to explain the observed dynamics and fit them to the plasma viral load data. Based on the fitting results we argue that a model containing reversible Ab binding to virions and clearance of virus-VRC01 complexes by a two-step process that includes (1) saturable capture followed by (2) internalization/degradation by phagocytes, best explains the data. This model predicts that VRC01 may enhance the clearance of Ab-virus complexes, explaining the initial viral decay observed immediately after antibody infusion in some participants. Because Ab-virus complexes are assumed to be unable to infect cells, i.e., contain neutralized virus, the model predicts a longer-term viral decay consistent with that observed in the VRC01 treated participants. By assuming a homogeneous viral population sensitive to VRC01, the model provides good fits to all of the participant data. However, the fits are improved by assuming that there were two populations of virus, one more susceptible to antibody-mediated neutralization than the other.

60 APPLIED LIFE SCIENCES↗

The molecular basis of the neutralization breadth of the RBD-specific antibody CoV11

SARS-CoV-2, the virus behind the COVID-19 pandemic, has changed over time to the extent that the current virus is substantially different from what originally led to the pandemic in 2019–2020. Viral variants have modified the severity and transmissibility of the disease and continue do so. How much of this change is due to viral fitness versus a response to immune pressure is hard to define. One class of antibodies that continues to afford some level of protection from emerging variants are those that closely overlap the binding site for angiotensin-converting enzyme 2 (ACE2) on the receptor binding domain (RBD). Some members of this class that were identified early in the course of the pandemic arose from the VH 3-53 germline gene (IGHV3-53*01) and had short heavy chain complementarity-determining region 3s (CDR H3s). Here, we describe the molecular basis of the SARS-CoV-2 RBD recognition by the anti-RBD monoclonal antibody CoV11 isolated early in the COVID-19 pandemic and show how its unique mode of binding the RBD determines its neutralization breadth. CoV11 utilizes a heavy chain VH 3-53 and a light chain VK 3-20 germline sequence to bind to the RBD. Two of CoV11’s four heavy chain changes from the VH 3-53 germline sequence, $Thr^{28}_{FWRH1}$ to Ile and $Ser^{31}_{CDRH1}$ to Arg, and some unique features in its CDR H3 increase its affinity to the RBD, while the four light chain changes from the VK 3-20 germline sequence sit outside of the RBD binding site. Antibodies of this type can retain significant affinity and neutralization potency against variants of concern (VOCs) that have diverged significantly from original virus lineage such as the prevalent omicron variant. We also discuss the mechanism by which VH 3-53 encoded antibodies recognize spike antigen and show how minimal changes to their sequence, their choice of light chain, and their mode of binding influence their affinity and impact their neutralization breadth.

60 APPLIED LIFE SCIENCES↗

Zika Virus Infection and Antibody Neutralization in FcRn Expressing Placenta and Engineered Cell Lines

As a developmental toxicant, Zika virus (ZIKV) attacks both the growing nervous system, causing congenital Zika syndrome, and the placenta, resulting in pathological changes and associated adverse fetal outcomes. There are no vaccines, antibodies, or other treatments for ZIKV, despite the potential for its re-emergence. Multiple studies have highlighted the risk of antibodies for enhancing ZIKV infection, including during pregnancy, but the mechanisms for such effects are not fully understood. We have focused on the ability of the neonatal Fc receptor (FcRn) to interact with ZIKV in the presence and absence of relevant antibodies. We found that ZIKV replication was higher in Marvin Darby Canine Kidney (MDCK) cells that overexpress FcRn compared to those that do not, and knocking down FcRn decreased ZIKV RNA production. In the placenta trophoblast BeWo cell line, ZIKV infection itself downregulated FcRn at the mRNA and protein levels. Addition of anti-ZIKV antibodies to MDCK/FcRn cells resulted in non-monotonous neutralization curves with neutralization attenuation and even enhancement of infection at higher concentrations. Non-monotonous neutralization was also seen in BeWo cells at intermediate antibody concentrations. Our studies highlight the underappreciated role FcRn plays in ZIKV infection and may have implications for anti-ZIKV prophylaxis and therapy in pregnant women.

60 APPLIED LIFE SCIENCES↗

Composition of ions and neutral gases during a magnetic storm

Study of the variation in composition of ions and neutral gases on the basis of numerical solutions of a coupled differential equation system describing the fundamental properties of the ionosphere and atmosphere within the range of the thermosphere. It is shown that changes in ion composition observed during a magnetic storm can be represented by changes in neutral gas composition in the lower thermosphere. A reduction of the O/N2 ratio in the lower thermosphere starts a sequence of events that leads to an increase in neutral gas temperature, decrease in O(+) and increase in NO(+) concentration.

Chandra, S.↗

Internal structure of the geomagnetic neutral sheet.

A study of the internal structure of the neutral sheet in the geomagnetic tail has been made from data obtained by the NASA-GSFC magnetic-field experiment on the Explorer 34 spacecraft during its tail passage in the first half of 1968. The data used in the analysis are individual measurements of the vector magnetic field at 2.56-sec intervals. The experimental results consist of statistical studies of relevant properties of the magnetic field as a function of field magnitude. The results do not support nearly one-dimensional field models with characteristic lengths for field variation parallel to the neutral sheet much larger than the neutral-sheet width. The principal conclusion from the data points toward consistency with a quasi-periodic (possibly turbulent) structure with a tendency to formation of magnetic loops as one might expect from stability studies.

Schindler, K.↗

Interaction of the solar wind with the neutral component of the interstellar gas.

A model is constructed to represent the interaction between the solar wind and the neutral component of the interstellar gas. It is found that the neutral gas has several important effects on the solar-wind expansion beyond the orbit of the earth and that it should be possible to infer the presence of the neutral gas from observations of the solar wind made by a space probe traveling into the outer solar system. The effects include a deceleration and heating of the supersonic solar wind, a cooling of and pressure reduction in the subsonic solar wind, and a tightening of the spiral magnetic field in the supersonic solar wind.

Holzer, T. E.↗

Coincidence degree and periodic solutions of neutral equations

The problem of existence of periodic solutions for some nonautonomous neutral functional differential equations is examined. It is an application of a basic theorem on the Fredholm alternative for periodic solutions of some linear neutral equations and of a generalized Leray-Schauder theory. Although proofs are simple, the results are nontrivial extensions to the neutral case of existence theorems for periodic solutions of functional differential equations.

Hale, J. K.↗

The San Marco 3 neutral atmosphere composition experiment

The experimental instrumentation of the San Marco 3 satellite is described along with the calibration and operation. The instrumentation for the following experiments was included: an air density experiment for measuring the instantaneous drag force, and thus the neutral particle total mass density; a neutral atmosphere composition experiment for measuring the densities of helium, atomic and molecular oxygen, molecular nitrogen and argon; and a neutral atmosphere temperature experiment to determine the gas kinetic temperature by measuring molecular nitrogen density variations in an orificed spherical chamber as a function of angle of attack.

Pelz, D. T.↗

Neutral winds above 200 km at high latitudes.

Electrically neutral, luminous clouds are a by-product of chemical releases conducted to create barium ion clouds for the measurement of electric fields. Wind measurements provided by the motions of these clouds are particularly valuable in that the motions can be directly compared with convective ion drift motions to test the importance of ion drag forces. Motion from multiple releases between 200 and 300 km from 15 rockets launched from four high-latitude locations is analyzed in this paper. The observations in the evening and midnight hours at magnetic latitudes above 65 deg strongly suggest that in these regions ion drag is the dominant force in driving neutral winds between 200 and 300 km. In the morning sector, it is evident that neutral wind observations cannot be directly interpreted in terms of ion drag; other factors must be considered.

Meriwether, J. W.↗

Transient ion neutralization by electrons.

The nonlinear initial-boundary-value problems describing the lateral neutralization of ion beams for the cases that (1) an auxiliary electric field accelerates the electrons into the ion space, and (2) the electrons are injected into the ion space at a prescribed current density are treated. Analytical solutions are derived which give the position and speed of the neutralization front as a function of time, and the temporal development of the electron density, velocity, and electric fields during the neutralization process.

Wilhelm, H. E.↗

Calorimetric detection of neutral-atom content of ion beam

Energy deposition technique deduces neutral-beam flux or dose from measured values of incremental resistance increases in platinum wire passed through beam. Steady-state heat balance analysis led to equivalent neutral-beam current. Method was used to detect neutral-atom content of 60-keV argon ion beam.

Roberts, A. S., Jr.↗

Free-free absorption of infrared radiation in collisions of electrons with neutral rare-gas atoms

A relationship between the inverse bremsstrahlung absorption cross section and the electron neutral momentum transfer cross section has been utilized to determine the infrared free-free continuum absorption coefficient for the negative ions of helium, neon, argon, krypton, and xenon. The values of the momentum transfer cross section for this calculation have been obtained from experimental measurements. Analytical expressions for the absorption coefficient have also been developed. From the results of this calculation, it is possible to determine the absorption coefficient per unit electron density per neutral atom for temperatures in the range from 2500 to 25,000 K. The results are compared with those from tabulations of previous calculations and those computed from theoretical values of the phase shifts for the elastic scattering of electrons by neutral atoms.

Stallcop, J. R.↗