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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 343 records · Page 19
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Bifunctional Janus Particles as Multivalent Synthetic Nanoparticle Antibodies (SNAbs) for Selective Depletion of Target Cells

Monoclonal antibodies (mAb) have had a transformative impact on treating cancers and immune disorders. SNAbs However, their use is limited by high development time and monetary cost, manufacturing complexities, suboptimal pharmacokinetics, and availability of disease-specific targets. To address some of these challenges, we developed an entirely synthetic, multivalent, Janus nanotherapeutic platform, called Synthetic Nanoparticle Antibodies (SNAbs). SNAbs, with phage-display-identified cell-targeting ligands on one "face" and Fc-mimicking ligands on the opposite "face", were synthesized using a custom, multistep, solid-phase chemistry method. SNAbs efficiently targeted and depleted myeloid-derived immune-suppressor cells (MDSCs) from mouse-tumor and rat-trauma models, ex vivo. Systemic injection of MDSC-targeting SNAbs efficiently depleted circulating MDSCs in a mouse triple-negative breast cancer model, enabling enhanced T cell and Natural Killer cell infiltration into tumors. Finally, our results demonstrate that SNAbs are a versatile and effective functional alternative to mAbs, with advantages of a plug- and-play, cell-free manufacturing process, and high-throughput screening (HTS)-enabled library of potential targeting ligands.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Utilizing Machine Learning to Improve Neutralization Potency of an HIV-1 Antibody Targeting the gp41 N-Heptad Repeat

The N-heptad repeat (NHR) of the HIV-1 gp41 prehairpin intermediate (PHI) is an attractive potential vaccine target with high sequence conservation across diverse strains. However, despite the potency of NHR-targeting peptides and clinical efficacy of the NHR-targeting entry inhibitor enfuvirtide, no potently neutralizing NHR-directed monoclonal antibodies (mAbs) nor antisera have been identified or elicited to date. The lack of potent NHR-binding mAbs both dampens enthusiasm for vaccine development efforts at this target and presents a barrier to performing passive immunization experiments with NHR-targeting antibodies. To address this challenge, we previously developed an improved variant of the NHR-directed mAb D5, called D5_AR, which is capable of neutralizing diverse tier-2 viruses. Building on that work, here we present the 2.7Å-crystal structure of D5_AR bound to NHR mimetic peptide IQN17. We then utilize protein language models and supervised machine learning to generate small (n < 100) libraries of D5_AR variants that are subsequently screened for improved neutralization potency. We identify a variant with 5-fold improved neutralization potency, D5_FI, which is the most potent NHR-directed monoclonal antibody characterized to date and exhibits broad neutralization of tier-2 and −3 pseudoviruses as well as replicating R5 and X4 challenge strains. Additionally, our work highlights the ability of protein language models to efficiently identify improved mAb variants from relatively small libraries.

Biopolymers↗
DOE OSTI2020

Marker-free carotenoid-enriched rice generated through targeted gene insertion using CRISPR-Cas9

Targeted insertion of transgenes at pre-determined plant genomic safe harbors provides a desirable alternative to insertions at random sites achieved through conventional methods. Most existing cases of targeted gene insertion in plants have either relied on the presence of a selectable marker gene in the insertion cassette or occurred at low frequency with relatively small DNA fragments (<1.8 kb). Here, we report the use of an optimized CRISPR-Cas9-based method to achieve the targeted insertion of a 5.2 kb carotenoid biosynthesis cassette at two genomic safe harbors in rice. We obtain marker-free rice plants with high carotenoid content in the seeds and no detectable penalty in morphology or yield. Whole-genome sequencing reveals the absence of off-target mutations by Cas9 in the engineered plants. These results demonstrate targeted gene insertion of marker-free DNA in rice using CRISPR-Cas9 genome editing, and offer a promising strategy for genetic improvement of rice and other crops.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Design of diverse, functional mitochondrial targeting sequences across eukaryotic organisms using variational autoencoder

Mitochondria play a key role in energy production and metabolism, making them a promising target for metabolic engineering and disease treatment. However, despite the known influence of passenger proteins on localization efficiency, only a few protein-localization tags have been characterized for mitochondrial targeting. To address this limitation, we leverage a Variational Autoencoder to design novel mitochondrial targeting sequences. In silico analysis reveals that a high fraction of the generated peptides (90.14%) are functional and possess features important for mitochondrial targeting. We characterize artificial peptides in four eukaryotic organisms and, as a proof-of-concept, demonstrate their utility in increasing 3-hydroxypropionic acid titers through pathway compartmentalization and improving 5-aminolevulinate synthase delivery by 1.62-fold and 4.76-fold, respectively. Moreover, we employ latent space interpolation to shed light on the evolutionary origins of dual-targeting sequences. Overall, our work demonstrates the potential of generative artificial intelligence for both fundamental research and practical applications in mitochondrial biology.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Targeting of intracellular oncoproteins with peptide-centric CARs

The majority of oncogenic drivers are intracellular proteins, constraining their immunotherapeutic targeting to mutated peptides (neoantigens) presented by individual human leukocyte antigen (HLA) allotypes. However, most cancers have a modest mutational burden that is insufficient for generating responses using neoantigen-based therapies. Neuroblastoma is a paediatric cancer that harbours few mutations and is instead driven by epigenetically deregulated transcriptional networks. Here we show that the neuroblastoma immunopeptidome is enriched with peptides derived from proteins essential for tumorigenesis. We focused on targeting the unmutated peptide QYNPIRTTF discovered on HLA-A*24:02, which is derived from the neuroblastoma-dependency gene and master transcriptional regulator PHOX2B. To target QYNPIRTTF, we developed peptide-centric chimeric antigen receptors (PC-CARs) through a counter panning strategy using predicted potentially cross-reactive peptides. We further proposed that PC-CARs can recognize peptides on additional HLA allotypes when presenting a similar overall molecular surface. Informed by our computational modelling results, we show that PHOX2B PC-CARs also recognize QYNPIRTTF presented by HLA-A*23:01, the most common non-A2 allele in people with African ancestry. Finally, we demonstrate potent and specific killing of neuroblastoma cells expressing these HLAs in vitro and complete tumour regression in mice. These data suggest that PC-CARs have the potential to expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins and allow targeting through additional HLA allotypes in a clinical setting.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Template and target-site recognition by human LINE-1 in retrotransposition

The long interspersed element-1 (LINE-1, hereafter L1) retrotransposon has generated nearly one-third of the human genome and serves as an active source of genetic diversity and human disease. L1 spreads through a mechanism termed target-primed reverse transcription, in which the encoded enzyme (ORF2p) nicks the target DNA to prime reverse transcription of its own or non-self RNAs. Here we purified full-length L1 ORF2p and biochemically reconstituted robust target-primed reverse transcription with template RNA and target-site DNA. We report cryo-electron microscopy structures of the complete human L1 ORF2p bound to structured template RNAs and initiating cDNA synthesis. The template polyadenosine tract is recognized in a sequence-specific manner by five distinct domains. Among them, an RNA-binding domain bends the template backbone to allow engagement of an RNA hairpin stem with the L1 ORF2p C-terminal segment. Moreover, structure and biochemical reconstitutions demonstrate an unexpected target-site requirement: L1 ORF2p relies on upstream single-stranded DNA to position the adjacent duplex in the endonuclease active site for nicking of the longer DNA strand, with a single nick generating a staggered DNA break. Our research provides insights into the mechanism of ongoing transposition in the human genome and informs the engineering of retrotransposon proteins for gene therapy.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Targeting colorectal cancer with small-molecule inhibitors of ALDH1B1

Aldehyde dehydrogenases (ALDHs) are promising cancer drug targets, as certain isoforms are required for the survival of stem-like tumor cells. We have discovered selective inhibitors of ALDH1B1, a mitochondrial enzyme that promotes colorectal and pancreatic cancer. We describe bicyclic imidazoliums and guanidines that target the ALDH1B1 active site with comparable molecular interactions and potencies. Both pharmacophores abrogate ALDH1B1 function in cells; however, the guanidines circumvent an off-target mitochondrial toxicity exhibited by the imidazoliums. Our lead isoform-selective guanidinyl antagonists of ALDHs exhibit proteome-wide target specificity, and they selectively block the growth of colon cancer spheroids and organoids. Finally, we have used genetic and chemical perturbations to elucidate the ALDH1B1-dependent transcriptome, which includes genes that regulate mitochondrial metabolism and ribosomal function. Our findings support an essential role for ALDH1B1 in colorectal cancer, provide molecular probes for studying ALDH1B1 functions and yield leads for developing ALDH1B1-targeting therapies.

36 MATERIALS SCIENCE↗
DOE OSTI2020

Focussing Protons from a Kilojoule Laser for Intense Beam Heating using Proximal Target Structures

Proton beams driven by chirped pulse amplified lasers have multi-picosecond duration and can isochorically and volumetrically heat material samples, potentially providing an approach for creating samples of warm dense matter with conditions not present on Earth. Envisioned on a larger scale, they could heat fusion fuel to achieve ignition. We have shown in an experiment that a kilojoule-class, multi-picosecond short pulse laser is particularly effective for heating materials. The proton beam can be focussed via target design to achieve exceptionally high flux, important for the applications mentioned. The laser irradiated spherically curved diamond-like-carbon targets with intensity 4 × 10 18 W/cm 2 , producing proton beams with 3 MeV slope temperature. A Cu witness foil was positioned behind the curved target, and the gap between was either empty or spanned with a structure. With a structured target, the total emission of Cu Kα fluorescence was increased 18 fold and the emission profile was consistent with a tightly focussed beam. Transverse proton radiography probed the target with ps order temporal and 10 μm spatial resolution, revealing the fast-acting focussing electric field. Complementary particle-in-cell simulations show how the structures funnel protons to the tight focus. Here, the beam of protons and neutralizing electrons induce the bright Kα emission observed and heat the Cu to 100 eV.

47 OTHER INSTRUMENTATION↗
DOE OSTI2022

A laser parameter study on enhancing proton generation from microtube foil targets

Abstract The interaction of an intense laser with a solid foil target can drive $$\sim$$ ∼ TV/m electric fields, accelerating ions to MeV energies. In this study, we experimentally observe that structured targets can dramatically enhance proton acceleration in the target normal sheath acceleration regime. At the Texas Petawatt Laser facility, we compared proton acceleration from a $$1\, {\upmu }\hbox {m}$$ 1 μ m flat Ag foil, to a fixed microtube structure 3D printed on the front side of the same foil type. A pulse length (140–450 fs) and intensity ((4–10) $$\times 10^{20}$$ × 10 20 W/cm $$^2$$ 2 ) study found an optimum laser configuration (140 fs, 4 $$\times 10^{20}$$ × 10 20 W/cm $$^2$$ 2 ), in which microtube targets increase the proton cutoff energy by 50% and the yield of highly energetic protons ( $$>10$$ > 10 MeV) by a factor of 8 $$\times$$ × . When the laser intensity reaches $$10^{21}$$ 10 21 W/cm $$^2$$ 2 , the prepulse shutters the microtubes with an overcritical plasma, damping their performance. 2D particle-in-cell simulations are performed, with and without the preplasma profile imported, to better understand the coupling of laser energy to the microtube targets. The simulations are in qualitative agreement with the experimental results, and show that the prepulse is necessary to account for when the laser intensity is sufficiently high.

43 PARTICLE ACCELERATORS↗
DOE OSTI2025

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

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

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Tritium targets for use in solenoidal spectrometers

Nucleon adding and removing reactions are an ideal probe to study the single-particle foundations of nuclear structure. For experiments far away from the valley of stability, one needs to use radioactive beams in inverse kinematics. To maintain excellent resolution, solenoidal spectrometers like HELIOS at Argonne National Laboratory (ANL), ISS at CERN or SOLARIS at the Facility for Rare Isotope Beams (FRIB) are used. Typically, deuterated plastic foils are the targets of choice. Depending on the energy deposited, these targets might degrade quickly in beam. The potential of using tritium-implanted targets in conjunction with the solenoidal spectrometers was realized for access to even more exotic nuclei with outstanding resolving power. While no tritiated polyethylene is commercially available at the moment, tritium-containing titanium targets have been produced in the past. Unfortunately the loading fraction of tritium for the latter was often very low and not reproducible. The progress in the production of tritium-containing targets is presented, including the characterization of the foils.

Müller-Gatermann, Claus↗
DOE OSTI2020

Design of target irradiation and diagnostic chamber to study ps-laser generated plasma as a source of singly charged ions for external injection into an electron beam ion source

High repetition-rate (~10 kHz) ps-lasers are becoming available on the market with reasonable cost and may offer several advantages compared to ns-lasers by generating nearly continuous beams of singly charged ions appropriate for the “slow” injection mode into the Electron Beam Ion Source (EBIS). To evaluate these advantages, we will perform studies of a ps-laser generated plasma using a laser with a pulse duration of 8 ps and energy up to 5 mJ per pulse. A vacuum chamber equipped with a 3D target positioner, a focusing lens, and a Faraday Cup has been designed and built for this study. Lens-to-target distance variations have been measured using a laser tracker over the whole range of horizontal and vertical translation for all five targets we will use. The variations were found to be within ±150 µm. This level of “target flatness” should be acceptable for our experimental conditions. Ion currents and ion pulse durations of various elements (from Al to Ta) will be measured for different target irradiation conditions (focal spot size and laser pulse energy). The results obtained will allow us to specify all parameters and geometry of a laser ion source based on a ps-laser to provide external ion injection into the relativistic heavy ion collider EBIS

43 PARTICLE ACCELERATORS↗
DOE OSTI2020

Thermomechanical response of thickly tamped targets and diamond anvil cells under pulsed hard x-ray irradiation

In the laboratory study of extreme conditions of temperature and density, the exposure of matter to high intensity radiation sources has been of central importance. Here, we interrogate the performance of multi-layered targets in experiments involving high intensity, hard x-ray irradiation, motivated by the advent of extremely high brightness hard x-ray sources, such as free electron lasers and 4th-generation synchrotron facilities. Intense hard x-ray beams can deliver significant energy in targets having thick x-ray transparent layers (tampers) around samples of interest for the study of novel states of matter and materials’ dynamics. Heated-state lifetimes in such targets can approach the microsecond level, regardless of radiation pulse duration, enabling the exploration of conditions of local thermal and thermodynamic equilibrium at extreme temperature in solid density matter. The thermal and mechanical responses of such thick layered targets following x-ray heating, including hydrodynamic relaxation and heat flow on picosecond to millisecond timescales, are modeled using radiation hydrocode simulation, finite element analysis, and thermodynamic calculations. Assessing the potential for target survival over one or more exposures and resistance to damage arising from heating and resulting mechanical stresses, this study doubles as an investigation into the performance of diamond anvil high pressure cells under high x-ray fluences. Long used in conjunction with synchrotron x-ray radiation and high power optical lasers, the strong confinement afforded by such cells suggests novel applications at emerging high intensity x-ray facilities and new routes to studying thermodynamic equilibrium states of warm, very dense matter.

Meza-Galvez, J. (ORCID:000000032699849X)↗
DOE OSTI2021

Enhancing positron production using front surface target structures

We report a target design which produced a substantial gain in relativistic electron-positron pair production using high-intensity lasers and targets with large-scale micro-structures on their surface. Comparing to an unstructured target, a selected Si microwire array target yielded a near 100% increase in the laser-to-positron conversion efficiency and produced a 10MeV increase in the average emitted positron energy under nominally the same experimental conditions. We had established a multi-scale particle-in-cell simulation scheme to simulate both the laser absorption and the subsequent pair productions in a thick metal target. Here, the experimental results are supported by the simulations demonstrating the performance increase is due to a higher conversion efficiency of laser energy into electrons with kinetic energies greater than 10 MeV due to enhanced direct laser acceleration of electrons enabled by the microwire array.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
DOE OSTI2021

Developing “inverted-corona” fusion targets as high-fluence neutron sources

We present experimental studies of inverted-corona targets as neutron sources at the OMEGA Laser Facility and the National Ignition Facility (NIF). Laser beams are directed onto the inner walls of a capsule via laser-entrance holes (LEHs), heating the target interior to fusion conditions. The fusion fuel is provided either as a wall liner, e.g., deuterated plastic (CD), or as a gas fill, e.g., D 2 gas. Such targets are robust to low-mode drive asymmetries, allowing for single-sided laser drive. On OMEGA, 1.8-mm-diameter targets with either a 10-μm CD liner or up to 2 atm of D 2 -gas fill were driven with up to 18 kJ of laser energy in a 1-ns square pulse. Neutron yields of up to 1.5 × 1010 generally followed expected trends with fill pressure or laser energy, although the data imply some mix of the CH wall into the fusion fuel for either design. Comparable performance was observed with single-sided (1x LEH) or double-sided (2x LEH) drive. NIF experiments tested the platform at scaled up dimensions and energies, combining a 15-μm CD liner and a 3-atm D2-gas fill in a 4.5-mm diameter target, laser-driven with up to 330 kJ. Neutron yields up to 2.6 × 10 12 were measured, exceeding the scaled yield expectation from the OMEGA data. The observed energy scaling on the NIF implies that the neutron production is gas dominated, suggesting a performance boost from using deuterium–tritium (DT) gas. In this work, we estimate that neutron yields exceeding 10 14 should be readily achievable using a modest laser drive of ~300 kJ with a DT fill.

47 OTHER INSTRUMENTATION↗
DOE OSTI2021

Estimate of pre-thermal quench non-thermal electron density profile during Ar pellet shutdowns of low-density target plasmas in DIII-D

The radial density profile of pre-thermal quench (pre-TQ) early-time runaway electrons (REs) is estimated by combining electron cyclotron emission (ECE) and soft x-ray (SXR) data during rapid shutdown of low-density (n e ≲ 10 13 cm -3 ) DIII-D target plasmas with cryogenic argon pellet injection. This technique is limited in these experiments to the pre-TQ phase and quickly loses validity during the TQ. Two different cases are studied: a high (10 keV) temperature target and a lower (4 keV) temperature target. The results indicate that early-time, low-energy (~10 keV) REs form ahead of the argon pellet as it enters the plasma, affecting the pellet ablation rate; it is hypothesized that this may be caused by rapid cross-field transport of argon ions ahead of the pellet. Fokker-Planck modeling of the two shots suggests that the RE current is quite significant during the pre-TQ phase (up to 50% of the total current). Comparison between modeled pre-TQ RE current and post-TQ RE current inferred from avalanche theory suggests that RE current increases during the high temperature target TQ but decreases during the low temperature target TQ. Here, the uncertainties in this estimate are large; but, if true, this suggests that TQ loss of REs can be larger than previously estimated in DIII-D.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
DOE OSTI2022

Instability seeding mechanisms due to internal defects in inertial confinement fusion targets

Performance degradation in laser-driven inertial confinement fusion (ICF) implosions is caused by several effects, one of which is Rayleigh–Taylor instability growth. Defects in ICF targets, such as internal voids and surface roughness, create instability seeds in the shell as shocks propagate through the target. A comprehensive understanding of seeding mechanisms is essential to characterize the impact of target defects on inflight shell integrity and mass injection into the central, lower-density vapor region. An analysis of early-time behavior of both single-mode shell mass modulations and isolated voids is performed by examining the evolution of the acoustic waves launched by these target imperfections. A systematic study of localized perturbation growth as a function of defect placement and size is presented. Furthermore, the use of low-density ablator materials (such as foams) is suggested as a potential mitigation strategy to improve target robustness against the impact of defect-initiated growth.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
DOE OSTI2023

Enhanced electron acceleration by high-intensity lasers in extended (confined) preplasma in cone targets

Here we report on experimental results from a high-intensity laser interaction with cone targets that increase the number (×3) and temperature (×3) of the measured hot electrons over a traditional planar target. This increase is caused by a substantial increase in the plasma density within the cone target geometry, which was induced by 17 ± 9 mJ prepulse that arrived 1.5 ns prior to the main high intensity (>10 19 W/cm 2 ). Three-dimensional hydrodynamic simulations are conducted using hydra which show that the cone targets create substantially longer and denser plasma than planar targets due to the geometric confinement of the expanding plasma. The density within the cone is a several hundred-micron plasma “shelf” with a density of approximately 10 20 n e /cc. The HYDRA simulated plasma densities are used as the initial conditions for two-dimensional particle-in-cell simulations using EPOCH. These simulations show that the main acceleration mechanism is direct-laser-acceleration, with close agreement between experimentally measured and simulated electron temperatures. Further analysis is conducted to investigate the acceleration of the electrons within the long plasma generated within a compound parabolic concentrator by the prepulse.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗