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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 271 records · Page 15
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Updated Thermofluid Performance of the Simplified Flat Variant of the HEMJ

Our group has recently developed and studied “finger”-type divertors that are a simplified version of the helium-cooled modular divertor with multiple jets (HEMJ) using coupled computational fluid dynamics and thermal stress simulations. Such a simplified geometry could reduce complexity and cost given the large number of fingers required to cover the total divertor target area. Previous experimental studies for this simplified flat design reported lower heat transfer coefficients and higher pressure drops than the HEMJ, contrary to numerical predictions. Subsequent measurements determined that the original test section had significant dimensional variations in the jet exit holes. A new test section was therefore manufactured and tested in the Georgia Tech (GT) helium loop. The experimental results presented here for this test section at maximum heat flux of 7.1 MW/m 2 are in good agreement with numerical predictions. Correlations developed from these experimental data are extrapolated to predict the maximum heat flux that can be accommodated by the flat design and the coolant pumping power requirements under prototypical conditions. Lastly, numerical simulations are used to estimate the sensitivity of the flat design to geometric variations typical of manufacturing tolerances and variations in the gap width.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
DOE OSTI2021

Density functional study of the variants of inter-Coulombic decay resonances in the photoionization of Cl@C 60

Inter-Coulombic decay (ICD) resonances in the photoionization of Cl@C 60 endofullerene molecule are calculated using a perturbative density functional theory (DFT) method. This is the first ICD study of an open shell atom in a fullerene cage. Here, three classes of resonances are probed: (i) Cl inner vacancies decaying through C 60 outer continua, (ii) C 60 inner vacancies decaying through Cl outer continua, and (iii) inner vacancies of either system decaying through the continua of Cl-C 60 hybrid levels, the hybrid Auger-ICD resonances. Comparisons with Ar@C 60 results reveal that the properties of hybrid Auger-ICD resonances are affected by the extent of level hybridization.

74 ATOMIC AND MOLECULAR PHYSICS↗
DOE OSTI2022

Training neural networks using Metropolis Monte Carlo and an adaptive variant

Abstract We examine the zero-temperature Metropolis Monte Carlo (MC) algorithm as a tool for training a neural network by minimizing a loss function. We find that, as expected on theoretical grounds and shown empirically by other authors, Metropolis MC can train a neural net with an accuracy comparable to that of gradient descent (GD), if not necessarily as quickly. The Metropolis algorithm does not fail automatically when the number of parameters of a neural network is large. It can fail when a neural network’s structure or neuron activations are strongly heterogenous, and we introduce an adaptive Monte Carlo algorithm (aMC) to overcome these limitations. The intrinsic stochasticity and numerical stability of the MC method allow aMC to train deep neural networks and recurrent neural networks in which the gradient is too small or too large to allow training by GD. MC methods offer a complement to gradient-based methods for training neural networks, allowing access to a distinct set of network architectures and principles.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2023

Mechanisms of HIV-1 integrase resistance to dolutegravir and potent inhibition of drug-resistant variants

HIV-1 infection depends on the integration of viral DNA into host chromatin. Integration is mediated by the viral enzyme integrase and is blocked by integrase strand transfer inhibitors (INSTIs), first-line antiretroviral therapeutics widely used in the clinic. Resistance to even the best INSTIs is a problem, and the mechanisms of resistance are poorly understood. Here, we analyze combinations of the mutations E138K, G140A/S, and Q148H/K/R, which confer resistance to INSTIs. The investigational drug 4d more effectively inhibited the mutants compared with the approved drug Dolutegravir (DTG). We present 11 new cryo-EM structures of drug-resistant HIV-1 intasomes bound to DTG or 4d, with better than 3-Å resolution. These structures, complemented with free energy simulations, virology, and enzymology, explain the mechanisms of DTG resistance involving E138K + G140A/S + Q148H/K/R and show why 4d maintains potency better than DTG. These data establish a foundation for further development of INSTIs that potently inhibit resistant forms in integrase.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Maternal Broadly Neutralizing Antibodies Can Select for Neutralization-Resistant, Infant-Transmitted/Founder HIV Variants

Each year, >180,000 infants become infected via mother-to-child transmission (MTCT) of HIV despite the availability of effective maternal antiretroviral treatments, underlining the need for a maternal HIV vaccine. We characterized 224 maternal HIV envelope (Env)-specific IgG monoclonal antibodies (MAbs) from seven nontransmitting and transmitting HIV-infected U.S. and Malawian mothers and examined their neutralization activities against nontransmitted autologous circulating viruses and infant-transmitted founder (infant-T/F) viruses. Only a small subset of maternal viruses, 3 of 72 (4%), were weakly neutralized by maternal linear V3 epitope-specific IgG MAbs, whereas 6 out of 6 (100%) infant-T/F viruses were neutralization resistant to these V3-specific IgG MAbs. We also show that maternal-plasma broadly neutralizing antibody (bNAb) responses targeting the V3 glycan supersite in a transmitting woman may have selected for an N332 V3 glycan neutralization-resistant infant-T/F virus. These data have important implications for bNAb-eliciting vaccines and passively administered bNAbs in the setting of MTCT.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Structural basis for varying drug resistance of SARS-CoV-2 M pro E166 variants

ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M pro ) has an essential role in the virus lifecycle and, accordingly, it is a target for antiviral drugs. Multiple studies have identified an M pro mutation (E166V) that confers strong resistance to clinically relevant inhibitors, including nirmatrelvir, but the underlying mechanism is not fully understood. Here, we report on crystal structures of SARS-CoV-2 M pro E166V in complex with nirmatrelvir, ensitrelvir, and bofutrelvir. The structures suggest that resistance is caused in part by the loss of a direct hydrogen bond and also, especially for nirmatrelvir, by a steric clash with the substituted valine residue. In comparison, the binding of bofutrelvir shows greater flexibility, which may help alleviate this steric effect and allow bofutrelvir to fit the mutant active site despite the loss of a direct polar contact. Thermal stability analyses also corroborate E166V most severely affecting the binding of nirmatrelvir and, to lesser and different extents, ensitrelvir and bofutrelvir. We further show that E166I causes even more severe nirmatrelvir resistance, whereas E166A and E166L have much milder effects. These studies shed light on the molecular mechanisms of a key M pro drug resistance mutation and may help inform the design of next-generation inhibitors. IMPORTANCE Using a combination of high-resolution X-ray crystallographic and biochemical analyses, we reveal the molecular mechanisms by which a mutation in the severe acute respiratory syndrome coronavirus 2 main protease (M pro ) confers strong resistance against clinically relevant antiviral drugs that inhibit M pro activity. The results presented here may help inform the design of next-generation inhibitors to combat the problem of therapy resistance.

Microbiology↗
DOE OSTI2025

Engineered IL-18 variants with half-life extension and improved stability for cancer immunotherapy

Background The pro-inflammatory cytokine, interleukin-18 (IL-18), plays an instrumental role in bolstering anti-tumor immunity. However, the therapeutic application of IL-18 has been limited due to its susceptibility to neutralization by IL-18 binding protein (IL-18BP), short in vivo half-life, and unfavorable physicochemical properties. Methods In order to overcome the poor drug-like properties of IL-18, we installed an artificial disulfide bond, removed the native, unpaired cysteines, and fused the stabilized cytokine to an IgG Fc domain. The stability, potency, pharmacokinetic and pharmacodynamic properties as well as efficacy of disulfide-stabilized IL-18 Fc-fusion (dsIL-18-Fc) were assessed via in vitro and in vivo studies. Results The stability and mammalian host cell production yields of dsIL-18-Fc were improved, compared to the wild-type (WT) cytokine, while maintaining its biological potency and interactions with IL-18 receptor α (IL-18Rα) and IL-18BP. Recombinant fusion of the cytokine to an IgG Fc domain provided extended half-life. Notably, despite maintaining sensitivity to IL-18BP, dsIL-18-Fc was effective at activating both T and natural killer (NK) cells, and elicited a strong anti-tumor response, either as a single agent, or in conjunction with anti-programmed cell death-ligand 1 (anti-PD-L1) therapy. Conclusions We engineered IL-18 for reinforced stability, extended half-life, and improved manufacturability. The therapeutic benefit of dsIL-18-Fc, coupled with a more favorable manufacturability profile and enhanced drug-like properties, underscores the potential utility of this engineered cytokine in cancer immunotherapy.

Immunology↗
DOE OSTI2020

Robust Event Simulation Variants Endowed to Ns-3 for General Exploration

Sandia's ns-3 contributions are modifications to the open source ns-3 network simulator that enable simulation speedup. One improvement, for example, removes the need for simulating the transmission and receipt of packets between nodes that are too distant to actually be able to communicate. In large-scale simulations this optimization has shown significant gains in performance. Additional contributions will pave the way for parallel discrete simulation (PDES) in ns-3. SAND2020-12456 O Sandia National Laboratories is a multimission laboratory managed and operated by National Technology & Engineering Solutions of Sandia, LLC, a wholly owned subsidiary of Honeywell International Inc., for the U.S. Department of Energy’s National Nuclear Security Administration under contract DE-NA0003525.

Dickson, Joseph↗