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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 55 records · Page 3
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Asymmetric and non-stoichiometric glycoprotein recognition by two distinct antibodies results in broad protection against ebolaviruses

Several ebolaviruses cause outbreaks of severe disease. Vaccines and monoclonal antibody cocktails are available to treat Ebola virus (EBOV) infections, but not Sudan virus (SUDV) or other ebolaviruses. Current cocktails contain antibodies that cross-react with the secreted soluble glycoprotein (sGP) that absorbs virus-neutralizing antibodies. By sorting memory B cells from EBOV infection survivors, we isolated two broadly reactive anti-GP monoclonal antibodies, 1C3 and 1C11, that potently neutralize, protect rodents from disease, and lack sGP cross-reactivity. Both antibodies recognize quaternary epitopes in trimeric ebolavirus GP. 1C11 bridges adjacent protomers via the fusion loop. 1C3 has a tripartite epitope in the center of the trimer apex. One 1C3 antigen-binding fragment anchors simultaneously to the three receptor-binding sites in the GP trimer, and separate 1C3 paratope regions interact differently with identical residues on the three protomers. A cocktail of both antibodies completely protected nonhuman primates from EBOV and SUDV infections, indicating their potential clinical value.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Safety and efficacy of C. muridarum vaccines adjuvanted with CpG-1826 and four concentrations of Montanide-ISA-720-VG

It is recommended that the adjuvant Montanide ISA 720 VG be used at a concentration of 70% v/v. At this concentration, Montanide causes at the site of immunization a local granuloma that can last for several weeks. To determine the safety and protective efficacy of a Chlamydia muridarum MOMP vaccine, formulated with CpG-1826 and four different concentrations of Montanide (70%, 50%, 30% and 10%), BALB/c (H-2 d ) female mice were immunized twice intramuscularly. Local reactogenicity was significant for vaccines formulated with 70% or 50% Montanide but not for those inoculated with 30% or 10% Montanide. Robust humoral and cell mediated memory immune responses were elicited by the 70%, 50% and 30% Montanide formulations. Mice were challenged intranasally with 10 4 C. muridarum inclusion forming units (IFU). Based on changes in body weight, lungs’s weight and number of IFU recovered, mice vaccinated with the 70%, 50% and 30% Montanide formulations were significantly protected, but not mice receiving 10% Montanide. To conclude, we recommend the 30% Montanide concentration to be tested in humans and animal models to determine its safety and efficacy, in comparison to the 70% Montanide concentration currently used. The 30% Montanide formulation could significantly facilitate licensing of this adjuvant for human use.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Broad and potent neutralizing human antibodies to tick-borne flaviviruses protect mice from disease

Tick-borne encephalitis virus (TBEV) is an emerging human pathogen that causes potentially fatal disease with no specific treatment. Mouse monoclonal antibodies are protective against TBEV, but little is known about the human antibody response to infection. Here, we report on the human neutralizing antibody response to TBEV in a cohort of infected and vaccinated individuals. Expanded clones of memory B cells expressed closely related anti-envelope domain III (EDIII) antibodies in both groups of volunteers. However, the most potent neutralizing antibodies, with IC50s below 1 ng/ml, were found only in individuals who recovered from natural infection. These antibodies also neutralized other tick-borne flaviviruses, including Langat, louping ill, Omsk hemorrhagic fever, Kyasanur forest disease, and Powassan viruses. Structural analysis revealed a conserved epitope near the lateral ridge of EDIII adjoining the EDI–EDIII hinge region. Prophylactic or early therapeutic antibody administration was effective at low doses in mice that were lethally infected with TBEV.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

mRNA-LNP HIV-1 trimer boosters elicit precursors to broad neutralizing antibodies

Germline-targeting (GT) HIV vaccine strategies are predicated on deriving broadly neutralizing antibodies (bnAbs) through multiple boost immunogens. However, as the recruitment of memory B cells (MBCs) to germinal centers (GCs) is inefficient and may be derailed by serum antibody–induced epitope masking, driving further B cell receptor (BCR) modification in GC-experienced B cells after boosting poses a challenge. Using humanized immunoglobulin knockin mice, we found that GT protein trimer immunogen N332-GT5 could prime inferred-germline precursors to the V3-glycan–targeted bnAb BG18 and that B cells primed by N332-GT5 were effectively boosted by either of two novel protein immunogens designed to have minimum cross-reactivity with the off-target V1-binding responses. The delivery of the prime and boost immunogens as messenger RNA lipid nanoparticles (mRNA-LNPs) generated long-lasting GCs, somatic hypermutation, and affinity maturation and may be an effective tool in HIV vaccine development.

Science & Technology - Other Topics↗
DOE OSTI2023

Broadly neutralizing antibodies against sarbecoviruses generated by immunization of macaques with an AS03-adjuvanted COVID-19 vaccine

The rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that evade immunity elicited by vaccination has placed an imperative on the development of countermeasures that provide broad protection against SARS-CoV-2 and related sarbecoviruses. Here, we identified extremely potent monoclonal antibodies (mAbs) that neutralized multiple sarbecoviruses from macaques vaccinated with AS03-adjuvanted monovalent subunit vaccines. Longitudinal analysis revealed progressive accumulation of somatic mutation in the immunoglobulin genes of antigen-specific memory B cells (MBCs) for at least 1 year after primary vaccination. Antibodies generated from these antigen-specific MBCs at 5 to 12 months after vaccination displayed greater potency and breadth relative to those identified at 1.4 months. Fifteen of the 338 (about 4.4%) antibodies isolated at 1.4 to 6 months after the primary vaccination showed potency against SARS-CoV-2 BA.1, despite the absence of serum BA.1 neutralization. 25F9 and 20A7 neutralized authentic clade 1 sarbecoviruses (SARS-CoV, WIV-1, SHC014, SARS-CoV-2 D614G, BA.1, and Pangolin-GD) and vesicular stomatitis virus–pseudotyped clade 3 sarbecoviruses (BtKY72 and PRD-0038). 20A7 and 27A12 showed potent neutralization against all SARS-CoV-2 variants and multiple Omicron sublineages, including BA.1, BA.2, BA.3, BA.4/5, BQ.1, BQ.1.1, and XBB. Crystallography studies revealed the molecular basis of broad and potent neutralization through targeting conserved sites within the RBD. Prophylactic protection of 25F9, 20A7, and 27A12 was confirmed in mice, and administration of 25F9 particularly provided complete protection against SARS-CoV-2, BA.1, SARS-CoV, and SHC014 challenge. These data underscore the extremely potent and broad activity of these mAbs against sarbecoviruses.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

A protective and broadly binding antibody class engages the influenza virus hemagglutinin head at its stem interface

ABSTRACT Influenza infection and vaccination impart strain-specific immunity that protects against neither seasonal antigenic variants nor the next pandemic. However, antibodies directed to conserved sites can confer broad protection. Here, we identify and characterize a class of human antibodies that engage a previously undescribed, conserved epitope on the influenza hemagglutinin (HA) protein. Prototype antibody S8V1-157 binds at the normally occluded interface between the HA head and stem. Antibodies to this HA head–stem interface epitope are non-neutralizingin vitrobut protect against lethal influenza infection in mice. These antibodies bind to most influenza A subtypes and seasonal human variants, and are present at low frequencies in the memory B cell populations of multiple human donors. Vaccines designed to elicit these antibodies might contribute to “universal” influenza immunity. IMPORTANCE Antibodies to the influenza virus hemagglutinin (HA) protein confer the strongest protection against infection. Human antibodies elicited by infection and/or vaccination fail to protect against antigenically novel animal, pandemic, or human seasonal viruses. Improved vaccines are needed. We identify a novel class of antibodies that bind most divergent HA subtypes and all seasonal human HA antigenic variants tested. These antibodies confer protection from lethal influenza challenge in animal models. The corresponding epitope on the HA head is occluded by its interaction with the stem and is inaccessible in the well-resolved prefusion state. The immunogenicity of this head–stem interface indicates that poorly understood conformations of HA presenting widely conserved surfaces are explored in biochemical, cell-based, andin vivoassays. Head–stem interface antibodies warrant further investigation as an avenue to improve influenza vaccines and therapeutics.

Microbiology↗
DOE OSTI2023

Antigen pressure from two founder viruses induces multiple insertions at a single antibody position to generate broadly neutralizing HIV antibodies

Vaccination strategies aimed at maturing broadly neutralizing antibodies (bnAbs) from naïve precursors are hindered by unusual features that characterize these Abs, including insertions and deletions (indels). Longitudinal studies of natural HIV infection cases shed light on the complex processes underlying bnAb development and have suggested a role for superinfection as a potential enhancer of neutralization breadth. Here we describe the development of a potent bnAb lineage that was elicited by two founder viruses to inform vaccine design. The V3-glycan targeting bnAb lineage (PC39-1) was isolated from subtype C-infected IAVI Protocol C elite neutralizer, donor PC39, and is defined by the presence of multiple independent insertions in CDRH1 that range from 1-11 amino acids in length. Memory B cell members of this lineage are predominantly atypical in phenotype yet also span the class-switched and antibody-secreting cell compartments. Development of neutralization breadth occurred concomitantly with extensive recombination between founder viruses before each virus separated into two distinct population “arms” that evolved independently to escape the PC39-1 lineage. Ab crystal structures show an extended CDRH1 that can help stabilize the CDRH3. Overall, these findings suggest that early exposure of the humoral system to multiple related Env molecules could promote the induction of bnAbs by focusing Ab responses to conserved epitopes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Total-Ionizing-Dose Effects on Long-term Data Retention Characteristics of Commercial 3-D NAND Memories

This article evaluates the data retention characteristics of irradiated multi-level cell (MLC) 3-D NAND flash memories. We irradiate the memory chips by a Co-60 gamma-ray source for up to 50 krad(Si) and then write a random data pattern on the irradiated chip to find its retention characteristics. The experimental results show that the data retention property of the irradiated chips is significantly degraded compared to the un-irradiated ones. We evaluate two independent strategies to improve the data retention characteristics of the irradiated chips. Furthermore, the first method involves high-temperature annealing of the irradiated chip while the second method suggests pre-programming the memory modules before deploying them in radiation-prone environments.

3-D NAND flash↗
DOE OSTI2020

Dynamic load balancing with enhanced shared-memory parallelism for particle-in-cell codes

Furthering our understanding of many of today’s interesting problems in plasma physics – including plasma based acceleration and magnetic reconnection with pair production due to quantum electrodynamic effects – requires large-scale kinetic simulations using particle-in-cell (PIC) codes. However, these simulations are extremely demanding, requiring that contemporary PIC codes be designed to efficiently use a new fleet of exascale computing architectures. To this end, the key issue of parallel load balance across computational nodes must be addressed. We discuss the implementation of dynamic load balancing by dividing the simulation space into many small, self-contained regions or ‘‘tiles,’’ along with shared-memory (e.g., OpenMP) parallelism both over many tiles and within single tiles. The load balancing algorithm can be used with three different topologies, including two space-filling curves. Here, we tested this implementation in the code Osiris and show low overhead and improved scalability with OpenMP thread number on simulations with both uniform load and severe load imbalance. Compared to other load-balancing techniques, our algorithm gives order-of-magnitude improvement in parallel scalability for simulations with severe load imbalance issues.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2022

Phase IB study of ziv-aflibercept plus pembrolizumab in patients with advanced solid tumors

Background The combination of antiangiogenic agents with immune checkpoint inhibitors could potentially overcome immune suppression driven by tumor angiogenesis. We report results from a phase IB study of ziv-aflibercept plus pembrolizumab in patients with advanced solid tumors. Methods This is a multicenter phase IB dose-escalation study of the combination of ziv-aflibercept (at 2–4 mg/kg) plus pembrolizumab (at 2 mg/kg) administered intravenously every 2 weeks with expansion cohorts in programmed cell death protein 1 (PD-1)/programmed death-ligand 1(PD-L1)-naïve melanoma, renal cell carcinoma (RCC), microsatellite stable colorectal cancer (CRC), and ovarian cancer. The primary objective was to determine maximum tolerated dose (MTD) and recommended dose of the combination. Secondary endpoints included overall response rate (ORR) and overall survival (OS). Exploratory objectives included correlation of clinical efficacy with tumor and peripheral immune population densities. Results Overall, 33 patients were enrolled during dose escalation (n=3) and dose expansion (n=30). No dose-limiting toxicities were reported in the initial dose level. Ziv-aflibercept 4 mg/kg plus pembrolizumab 2 mg/kg every 2 weeks was established as the MTD. Grade ≥3 adverse events occurred in 19/33 patients (58%), the most common being hypertension (36%) and proteinuria (18%). ORR in the dose-expansion cohort was 16.7% (5/30, 90% CI 7% to 32%). Complete responses occurred in melanoma (n=2); partial responses occurred in RCC (n=1), mesothelioma (n=1), and melanoma (n=1). Median OS was as follows: melanoma, not reached (NR); RCC, 15.7 months (90% CI 2.5 to 15.7); CRC, 3.3 months (90% CI 0.6 to 3.4); ovarian, 12.5 months (90% CI 3.8 to 13.6); other solid tumors, NR. Activated tumor-infiltrating CD8 T cells at baseline (CD8+PD1+), high CD40L expression, and increased peripheral memory CD8 T cells correlated with clinical response. Conclusion The combination of ziv-aflibercept and pembrolizumab demonstrated an acceptable safety profile with antitumor activity in solid tumors. The combination is currently being studied in sarcoma and anti-PD-1-resistant melanoma. Trial registration number NCT02298959 .

Rahma, Osama E.↗
DOE OSTI2021

A participant-derived xenograft model of HIV enables long-term evaluation of autologous immunotherapies

HIV-specific CD8+ T cells partially control viral replication and delay disease progression, but they rarely provide lasting protection, largely due to immune escape. Here, we show that engrafting mice with memory CD4+ T cells from HIV+ donors uniquely allows for the in vivo evaluation of autologous T cell responses while avoiding graft-versus-host disease and the need for human fetal tissues that limit other models. Treating HIV-infected mice with clinically relevant HIV-specific T cell products resulted in substantial reductions in viremia. In vivo activity was significantly enhanced when T cells were engineered with surface-conjugated nanogels carrying an IL-15 superagonist, but it was ultimately limited by the pervasive selection of a diverse array of escape mutations, recapitulating patterns seen in humans. By applying mathematical modeling, we show that the kinetics of the CD8+ T cell response have a profound impact on the emergence and persistence of escape mutations. This “participant-derived xenograft” model of HIV provides a powerful tool for studying HIV-specific immunological responses and facilitating the development of effective cell-based therapies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

A Coarse-Grained Model of Affinity Maturation Indicates the Importance of B-Cell Receptor Avidity in Epitope Subdominance

The elicitation of broadly neutralizing antibodies (bnAbs) is a major goal in the design of vaccines against rapidly-mutating viruses. In the case of influenza, many bnAbs that target conserved epitopes on the stem of the hemagglutinin protein (HA) have been discovered. However, these antibodies are rare, are not boosted well upon reinfection, and often have low neutralization potency, compared to strain-specific antibodies directed to the HA head. Different hypotheses have been proposed to explain this phenomenon. We use a coarse-grained computational model of the germinal center reaction to investigate how B-cell receptor binding valency affects the growth and affinity maturation of competing B-cells. We find that receptors that are unable to bind antigen bivalently, and also those that do not bind antigen cooperatively, have significantly slower rates of growth, memory B-cell production, and, under certain conditions, rates of affinity maturation. The corresponding B-cells are predicted to be outcompeted by B-cells that bind bivalently and cooperatively. We use the model to explore strategies for a universal influenza vaccine, e.g., how to boost the concentrations of the slower growing cross-reactive antibodies directed to the stem. The results suggest that, upon natural reinfections subsequent to vaccination, the protectiveness of such vaccines would erode, possibly requiring regular boosts. Collectively, our results strongly support the importance of bivalent antibody binding in immunodominance, and suggest guidelines for developing a universal influenza vaccine.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Error-Free and Current-Driven Synthetic Antiferromagnetic Domain Wall Memory Enabled by Channel Meandering

We propose a new type of energy-efficient multi-bit magnetic memory based on current-driven, field-free, controlled domain wall motion. A meandering domain wall channel with precisely interspersed pinning regions provides the multi-bit capability of a magnetic tunnel junction memory. The magnetic free layer of the memory device has perpendicular magnetic anisotropy (PMA) and interfacial Dzyaloshinskii-Moriya interaction (DMI) so that spin-orbit torques (SOTs) induce efficient domain wall motion. Using micromagnetic simulations, we find two different cell designs: two-way switching and four-way switching. The memory cell design choices and the physics of pinning mechanisms are discussed in detail. Furthermore, we show that switching reliability and speed may be significantly improved by replacing the ferromagnetic free layer with a synthetic antiferromagnetic (SAF) layer. Switching behavior and material choices will be discussed for the two memory implementations.

magnetic domain wall↗
DOE OSTI2023

A nanocryotron memory and logic family

The development of superconducting electronics based on nanocryotrons has been limited so far to few device circuits, in part due to the lack of standard and robust logic cells. Here, we introduce and experimentally demonstrate designs for a set of nanocryotron-based building blocks that can be configured and combined to implement memory and logic functions. The devices were fabricated by patterning a single superconducting layer of niobium nitride and measured in liquid helium on a wide range of operating points. The tests show 10 - 4 bit error rates with above ± 20 % margins up to 50 MHz and the possibility of operating under the effect of an out-of-plane 36 mT magnetic field, with ± 30 % margins at 10 MHz. Additionally, we designed and measured an equivalent delay-flip-flop made of two memory cells to show the possibility of combining multiple building blocks to make larger circuits. These blocks may constitute a solid foundation for the development of nanocryotron logic circuits and finite-state machines with potential applications in the integrated processing and control of superconducting nanowire single-photon detectors.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗
DOE OSTI2022

Total-Ionizing-Dose Effects on Read Noise of MLC 3-D NAND Memories T

This paper analyzes the total ionizing dose (TID) effects on noise characteristics of commercial multi-level-cell (MLC) 3-D NAND memory technology during the read operation. Additionally, the chips were exposed to a Co-60 gamma-ray source for up to 100 krad(Si) of TID. We find that the number of noisy cells in the irradiated chip increases with TID. Bit-flip noise was more dominant for cells in an erased state during irradiation compared to programmed cells.

3-D NAND Flash↗
DOE OSTI2023

Molecular basis of differential HLA class I-restricted T cell recognition of a highly networked HIV peptide

Cytotoxic-T-lymphocyte (CTL) mediated control of HIV-1 is enhanced by targeting highly networked epitopes in complex with human-leukocyte-antigen-class-I (HLA-I). However, the extent to which the presenting HLA allele contributes to this process is unknown. Here we examine the CTL response to QW9, a highly networked epitope presented by the disease-protective HLA-B57 and disease-neutral HLA-B53. Despite robust targeting of QW9 in persons expressing either allele, T cell receptor (TCR) cross-recognition of the naturally occurring variant QW9_S3T is consistently reduced when presented by HLA-B53 but not by HLA-B57. Crystal structures show substantial conformational changes from QW9-HLA to QW9_S3T-HLA by both alleles. The TCR-QW9-B53 ternary complex structure manifests how the QW9-B53 can elicit effective CTLs and suggests sterically hindered cross-recognition by QW9_S3T-B53. We observe populations of cross-reactive TCRs for B57, but not B53 and also find greater peptide-HLA stability for B57 in comparison to B53. These data demonstrate differential impacts of HLAs on TCR cross-recognition and antigen presentation of a naturally arising variant, with important implications for vaccine design.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Entire expressed peripheral blood transcriptome in pediatric severe malarial anemia

Abstract This study on severe malarial anemia (SMA: Hb < 6.0 g/dL), a leading global cause of childhood morbidity and mortality, compares the entire expressed whole blood host transcriptome between Kenyan children (3-48 mos.) with non-SMA (Hb ≥ 6.0 g/dL, n = 39) and SMA ( n = 18). Differential expression analyses reveal 1403 up-regulated and 279 down-regulated transcripts in SMA, signifying impairments in host inflammasome activation, cell death, and innate immune and cellular stress responses. Immune cell profiling shows decreased memory responses, antigen presentation, and immediate pathogen clearance, suggesting an immature/improperly regulated immune response in SMA. Module repertoire analysis of blood-specific gene signatures identifies up-regulation of erythroid genes, enhanced neutrophil activation, and impaired inflammatory responses in SMA. Enrichment analyses converge on disruptions in cellular homeostasis and regulatory pathways for the ubiquitin-proteasome system, autophagy, and heme metabolism. Pathway analyses highlight activation in response to hypoxic conditions [Hypoxia Inducible Factor (HIF)−1 target and Reactive Oxygen Species (ROS) signaling] as a central theme in SMA. These signaling pathways are also top-ranking in protein abundance measures and a Ugandan SMA cohort with available transcriptomic data. Targeted RNA-Seq validation shows strong concordance with our entire expressed transcriptome data. These findings identify key molecular themes in SMA pathogenesis, offering potential targets for new malaria therapies.

60 APPLIED LIFE SCIENCES↗