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At least 955 records · Page 53

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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 OSTI2015

3D distribution of interstellar medium in the Galaxy: Preparation for analysis of Gaia observations

Accurate and detailed three-dimensional (3D) maps of Galactic interstellar medium (ISM) are still lacking. One way to obtain such 3D descriptions is to record a large set of individual absorption or reddening measurements toward target stars located at various known distances and directions. The inversion of these measurements using a tomographic method can produce spatial distribution of the ISM. Until recently absorption data were very limited and distances to the target stars are still uncertain, but the situation will greatly improve thanks to current and future massive stellar surveys from ground, and to Gaia mission. To prepare absorption data for inversion from a huge number of stellar spectra, automated tools are needed. We have developed various spectral analysis tools adapted to different type of spectra, early- or late- type star. We also have used diffuse interstellar bands (DIBs) to trace IS structures and kinematics. Although we do not know yet their carriers, they can be a promising tool to trace distant interstellar clouds or Galactic arms. We present some examples of the interstellar fitting and show the potentiality of DIBs in tracing the ISM. We will also briefly show and comment the latest 3D map of the local ISM which reveal nearby cloud complexes and cavities.

79 ASTRONOMY AND ASTROPHYSICS↗

DOE OSTI2017

A physics-based solver to optimize the illumination of cylindrical targets in spherically distributed high power laser systems

In recent years, our understanding of high energy density plasmas has played an important role in improving inertial fusion confinement and in emerging new fields of physics, such as laboratory astrophysics. Every new idea required developing innovative experimental platforms at high power laser facilities, such as OMEGA or NIF. These facilities, designed to focus all their beams onto spherical targets or hohlraum windows, are now required to shine them on more complex targets. While the pointing on planar geometries is relatively straightforward, it becomes problematic for cylindrical targets or target with more complex geometries. This publication describes how the distribution of laser beams on a cylindrical target can be done simply by using a set of physical laws as a pointing procedure. The advantage of the method is threefold. First, it is straightforward, requiring no mathematical enterprise besides solving ordinary differential equations. Second, it will converge if a local optimum exists. Finally, it is computationally inexpensive. Experimental results show that this approach produces a geometrical beam distribution that yields cylindrically symmetric implosions.

47 OTHER INSTRUMENTATION↗

DOE OSTI2025

High-compression implosions based on high density carbon ablator using modified drive and capsule dopant profiles

Laser-driven inertial fusion experiments have, for the first time, achieved a target gain greater than unity in a laboratory setting [Abu-Shawareb et al., Phys. Rev. Lett. 132, 065102 (2024)]. Despite this breakthrough, the burn-up fraction remains limited to about one-fourth of ideal estimates due to insufficient areal density, highlighting the potential for greater gains through enhanced compression. In our previous work, we demonstrated record-high compression of stagnated fuel in indirectly driven implosions using high-density carbon ablators. This was achieved by combining a continuous ramped pulse drive with a modified ablator dopant profile, which reduced mixing at the fuel–ablator interface and improved stability [Tommasini et al., Phys. Rev. Res. 5, L042034 (2023)]. Based on this foundation, the study presented here investigates the limits of compression achievable by combining the continuous ramped pulse drive with different dopant profiles to further minimize unstable interfaces and gradient discontinuities, thereby reducing fuel–ablator mixing. Our results demonstrate that the continuous ramped pulse consistently outperforms designs based on 3-shock drive pulses across all ablator profiles studied, with compression showing only a relatively modest dependence on dopant configurations that reduce the number of interfaces or eliminate discontinuities in the dopant gradient profile. Sub-scale experiments using the continuous ramped pulse achieved compression levels exceeding those of full-scale “HyE” implosions [Kritcher et al., Phys. Plasmas 28, 072706 (2021)] at similar adiabat, anticipating significant performance gains with increased scale, as supported by models and simulations. These findings underscore the critical role of the continuous ramped pulse in reducing mix and achieving improved compression. They also provide a foundation for future large-scale experiments to test the continuous ramped pulse design on deuterium–tritium fuel in the burn-wave propagation regime, leveraging the most effective combinations of continuous ramped pulse and dopant profiles identified in this study.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

DOE OSTI2021

VPF-Class: taxonomic assignment and host prediction of uncultivated viruses based on viral protein families

Abstract Motivation Two key steps in the analysis of uncultured viruses recovered from metagenomes are the taxonomic classification of the viral sequences and the identification of putative host(s). Both steps rely mainly on the assignment of viral proteins to orthologs in cultivated viruses. Viral Protein Families (VPFs) can be used for the robust identification of new viral sequences in large metagenomics datasets. Despite the importance of VPF information for viral discovery, VPFs have not yet been explored for determining viral taxonomy and host targets. Results In this work, we classified the set of VPFs from the IMG/VR database and developed VPF-Class. VPF-Class is a tool that automates the taxonomic classification and host prediction of viral contigs based on the assignment of their proteins to a set of classified VPFs. Applying VPF-Class on 731K uncultivated virus contigs from the IMG/VR database, we were able to classify 363K contigs at the genus level and predict the host of over 461K contigs. In the RefSeq database, VPF-class reported an accuracy of nearly 100% to classify dsDNA, ssDNA and retroviruses, at the genus level, considering a membership ratio and a confidence score of 0.2. The accuracy in host prediction was 86.4%, also at the genus level, considering a membership ratio of 0.3 and a confidence score of 0.5. And, in the prophages dataset, the accuracy in host prediction was 86% considering a membership ratio of 0.6 and a confidence score of 0.8. Moreover, from the Global Ocean Virome dataset, over 817K viral contigs out of 1 million were classified. Availability and implementation The implementation of VPF-Class can be downloaded from https://github.com/biocom-uib/vpf-tools. Supplementary information Supplementary data are available at Bioinformatics online.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2014

Measurements Of Spin Observables In Pseudoscalar-Meson Photo-Production Using Polarized Neutrons In Solid HD

Psuedo-scalar meson photo production measurements have been carried out with longitudinally-polarized neutrons using the circularly and linearly polarized photon beams and the CLAS at Thomas Jefferson National Accelerator Facility (Jlab). The experiment aims to obtain a complete set of spin observables on an efficient neutron target. Preliminary E asymmetries for the exclusive reaction, gamma + n(p)--> pi- + p(p), selecting quasi free neutron kinematics are discussed.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

DOE OSTI2016

Surveillance for Western equine encephalitis St. Louis encephalitis and West Nile viruses using reverse transcription loop-mediated isothermal amplification

In this study, collection of mosquitoes and testing for vector-borne viruses is a key surveillance activity that directly influences the vector control efforts of public health agencies, including determining when and where to apply insecticides. Vector control districts in California routinely monitor for three human pathogenic viruses including West Nile virus (WNV), Western equine encephalitis virus (WEEV), and St. Louis encephalitis virus (SLEV). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) offers highly sensitive and specific detection of these three viruses in a single multiplex reaction, but this technique requires costly, specialized equipment that is generally only available in centralized public health laboratories. We report the use of reverse transcription loop-mediated isothermal amplification (RT-LAMP) to detect WNV, WEEV, and SLEV RNA extracted from pooled mosquito samples collected in California, including novel primer sets for specific detection of WEEV and SLEV, targeting the nonstructural protein 4 (nsP4) gene of WEEV and the 3’ untranslated region (3’-UTR) of SLEV. Our WEEV and SLEV RT-LAMP primers allowed detection of <0.1 PFU/reaction of their respective targets in <30 minutes, and exhibited high specificity without cross reactivity when tested against a panel of alphaviruses and flaviviruses. Furthermore, the SLEV primers do not cross-react with WNV, despite both viruses being closely related members of the Japanese encephalitis virus complex. The SLEV and WEEV primers can also be combined in a single RT-LAMP reaction, with discrimination between amplicons by melt curve analysis. Although RT-qPCR is approximately one order of magnitude more sensitive than RT-LAMP for all three targets, the RT-LAMP technique is less instrumentally intensive than RT-qPCR and provides a more cost-effective method of vector-borne virus surveillance.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2017

Structure and Recognition of a Novel HIV-1 gp120-gp41 Interface Antibody that Caused MPER Exposure through Viral Escape

A comprehensive understanding of the regions on HIV-1 envelope trimers targeted by broadly neutralizing antibodies may contribute to rational design of an HIV-1 vaccine. We previously identified a participant in the CAPRISA cohort, CAP248, who developed trimer-specific antibodies capable of neutralizing 60% of heterologous viruses at three years post-infection. Here, we report the isolation by B cell culture of monoclonal antibody CAP248-2B, which targets a novel membrane proximal epitope including elements of gp120 and gp41. Despite low maximum inhibition plateaus, often below 50% inhibitory concentrations, the breadth of CAP248-2B significantly correlated with donor plasma. Site-directed mutagenesis, X-ray crystallography, and negative-stain electron microscopy 3D reconstructions revealed how CAP248-2B recognizes a cleavage-dependent epitope that includes the gp120 C terminus. While this epitope is distinct, it overlapped in parts of gp41 with the epitopes of broadly neutralizing antibodies PGT151, VRC34, 35O22, 3BC315, and 10E8. CAP248-2B has a conformationally variable paratope with an unusually long 19 amino acid light chain third complementarity determining region. Two phenylalanines at the loop apex were predicted by docking and mutagenesis data to interact with the viral membrane. Neutralization by CAP248-2B is not dependent on any single glycan proximal to its epitope, and low neutralization plateaus could not be completely explained by N- or O-linked glycosylation pathway inhibitors, furin co-transfection, or pre-incubation with soluble CD4. Viral escape from CAP248-2B involved a cluster of rare mutations in the gp120-gp41 cleavage sites. Simultaneous introduction of these mutations into heterologous viruses abrogated neutralization by CAP248-2B, but enhanced neutralization sensitivity to 35O22, 4E10, and 10E8 by 10-100-fold. Altogether, this study expands the region of the HIV-1 gp120-gp41 quaternary interface that is a target for broadly neutralizing antibodies and identifies a set of mutations in the gp120 C terminus that exposes the membrane-proximal external region of gp41, with potential utility in HIV vaccine design.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

Broadly neutralizing humanized SARS-CoV-2 antibody binds to a conserved epitope on Spike and provides antiviral protection through inhalation-based delivery in non-human primates

The COVID-19 pandemic represents a global challenge that has impacted and is expected to continue to impact the lives and health of people across the world for the foreseeable future. The rollout of vaccines has provided highly anticipated relief, but effective therapeutics are required to further reduce the risk and severity of infections. Monoclonal antibodies have been shown to be effective as therapeutics for SARS-CoV-2, but as new variants of concern (VoC) continue to emerge, their utility and use have waned due to limited or no efficacy against these variants. Furthermore, cumbersome systemic administration limits easy and broad access to such drugs. As well, concentrations of systemically administered antibodies in the mucosal epithelium, a primary site of initial infection, are dependent on neonatal Fc receptor mediated transport and require high drug concentrations. To reduce the viral load more effectively in the lung, we developed an inhalable formulation of a SARS-CoV-2 neutralizing antibody binding to a conserved epitope on the Spike protein, ensuring pan-neutralizing properties. Administration of this antibody via a vibrating mesh nebulization device retained antibody integrity and resulted in effective distribution of the antibody in the upper and lower respiratory tract of non-human primates (NHP). In comparison with intravenous administration, significantly higher antibody concentrations can be obtained in the lung, resulting in highly effective reduction in viral load post SARS-CoV-2 challenge. This approach may reduce the barriers of access and uptake of antibody therapeutics in real-world clinical settings and provide a more effective blueprint for targeting existing and potentially emerging respiratory tract viruses.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2020

Maximizing the external radiative efficiency of hybrid perovskite solar cells

Despite rapid advancements in power conversion efficiency in the last decade, perovskite solar cells still perform below their thermodynamic efficiency limits. Non-radiative recombination, in particular, has limited the external radiative efficiency and open circuit voltage in the highest performing devices. We review the historical progress in enhancing perovskite external radiative efficiency and determine key strategies for reaching high optoelectronic quality. Specifically, we focus on non-radiative recombination within the perovskite layer and highlight novel approaches to reduce energy losses at interfaces and through parasitic absorption. By strategically targeting defects, it is likely that the next set of record-performing devices with ultra-low voltage losses will be achieved.

14 SOLAR ENERGY↗

DOE OSTI2014

Syntrophic interactions and mechanisms underpinning anaerobic methane oxidation: targeted metaproteogenomics, single-cell protein detection and quantitative isotope imaging of microbial consortia

Syntrophy and mutualism play a central role in carbon and nutrient cycling by microorganisms. Yet, our ability to effectively study symbionts in culture has been hindered by the inherent interdependence of syntrophic associations, their dynamic behavior, and their frequent existence at thermodynamic limits. Now solutions to these challenges are emerging in the form of new methodologies. Developing strategies that establish links between the identity of microorganisms and their metabolic potential, as well as techniques that can probe metabolic networks on a scale that captures individual molecule exchange and processing, is at the forefront of microbial ecology. Understanding the interactions between microorganisms on this level, at a resolution previously intractable, will lead to our greater understanding of carbon turnover and microbial community resilience to environmental perturbations. In this project, we studied an enigmatic syntrophic association between uncultured methane-oxidizing archaea and sulfate-reducing bacteria. This environmental archaeal-bacterial partnership represents a globally important sink for methane in anoxic environments. The specific goals of this project were organized into 3 major tasks designed to address questions relating to the ecophysiology of these syntrophic organisms under changing environmental conditions (e.g. different electron acceptors and nutrients), primarily through the development of microanalytical imaging methods which enable the visualization of the spatial distribution of the partners within aggregates, consumption and exchange of isotopically labeled substrates, and expression of targeted proteins identified via metaproteomics. The advanced tool set developed here to collect, correlate, and analyze these high resolution image and isotope-based datasets from methane-oxidizing consortia has the potential to be widely applicable for studying and modeling patterns of activity and interactions across a broad range of spatially structured microbial partnerships, including other syntrophic associations, microbial mats, biofilms, and plant-microbe or animal-microbe symbioses in nature.

03 NATURAL GAS↗

DOE OSTI2020

TMS XTRRA experiments on NIF

The study of x-ray induced rapid heating and the resulting material responses - (thermomechanical shock (TMS) and thermo-structural response (TSR)) - is important to our understanding of material behavior in extreme environments. A series of high conversion efficiency (XRCE) x-ray sources have been developed for the NIF laser facility ranging in fluence and spectral content. In conjunction with source development, we have developed a new XTRRA (X-ray Transport and Radiation Response Analysis) test cassette to hold a set of samples, each at equal distance from target chamber center (TCC) where the x-ray source is placed. Design and performance details of the x-ray sources is discussed elsewhere. Here, we describe the development and use of this TMS XTRRA test cassette. The XTRRA test cassette is a snout mounted on a NIF Diagnostic Instrument Manipulator (DIM) designed to position six samples equidistant from the x-ray source to assure uniform irradiation of all samples. Photon Displacement interferometry (PDI) is used to measure the displacement of the rear surface of each sample resulting from x-ray exposure on the front of the sample. This will help determine the x-ray generated impulse on the sample. The samples are retrieved from the snout after the shot for inspection and post-shot analysis including the measurement of sample ablated mass and engineering tests examining changes in the material structure. The data from experiments are compared to predictions from LLNL’s ASC codes and used to inform models implemented in these codes. Thus, XRCE x-ray sources with the XTRRA snout at the National Ignition Facility (NIF) laser at the Lawrence Livermore National Laboratory [1,2] provide the ability to expose a broad range of material samples directly to high x-ray fluence, measure shock transits, and recover the sample for further analysis post-shot.

36 MATERIALS SCIENCE↗

DOE OSTI2020

Thermo-Mechanical Shock, X-Ray Transport and Radiation Response Analysis Experiments on NIF

The study of x-ray induced rapid heating and the resulting material responses - (thermomechanical shock (TMS) and thermo-structural response (TSR)) - is important to our understanding of material behavior in extreme environments. A series of high conversion efficiency (XRCE) x-ray sources have been developed for the NIF laser facility ranging in fluence and spectral content. In conjunction with source development, we have developed a new XTRRA (X-ray Transport and Radiation Response Analysis) test cassette to hold a set of samples, each at equal distance from target chamber center (TCC) where the x-ray source is placed. Design and performance details of the x-ray sources is discussed elsewhere. Here, we describe the development and use of this TMS XTRRA test cassette. The XTRRA test cassette is a snout mounted on a NIF Diagnostic Instrument Manipulator (DIM) designed to position six samples equidistant from the x-ray source to assure uniform irradiation of all samples. Photon Displacement interferometry (PDI) is used to measure the displacement of the rear surface of each sample resulting from x-ray exposure on the front of the sample. This will help determine the x-ray generated impulse on the sample. The samples are retrieved from the snout after the shot for inspection and post-shot analysis including the measurement of sample ablated mass and engineering tests examining changes in the material structure. The data from experiments are compared to predictions from LLNL’s ASC codes and used to inform models implemented in these codes. Thus, XRCE x-ray sources with the XTRRA snout at the National Ignition Facility (NIF) laser at the Lawrence Livermore National Laboratory provide the ability to expose a broad range of material samples directly to high x-ray fluence, measure shock transits, and recover the sample for further analysis post-shot.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

DOE OSTI2024

IER-580 CED-3b: Experiment Execution Summary for the Pulsed-Neutron Die-Away Experiments (PNDA) with H 2 O

This report summarizes new experiments performed with H 2 O for IER-580, a testbed for pulsed-neutron die-away (PNDA) experiments at Lawrence Livermore National Laboratory (LLNL). The experiments will become high-quality benchmarksthat serve to optimize and validate thermal neutron scattering laws (TSLs) of H 2 O, which are high-priority nuclear data for the Department of Energy’s Nuclear Criticality Safety Program (NCSP). The report presents the details of the measurements conducted in October of 2023, including the experimental set-up (PNDA equipment and H 2 O targets) and all experimentally measured data. The report gives the fitted decay constants for the die-away curves of each target sample. It also provides the tabulated data for the die-away curves in the appendices.

42 ENGINEERING↗

DOE OSTI2022

$\nu_μ$ Disappearance in MicroBooNE using the Deep Learning 1$\mu$1$p$ Selection

We test a 3+1 model with the MicroBooNE data using a 1µ1p selection developed using Deep-Learning-based reconstruction. In order to test this model we apply a muon neutrino disappearance effect to the selection, and search across a grid of oscillation model parameters using a Feldman Cousins technique. We determine MicroBooNE’s sensitivity across this model parameter space, and perform several validation studies to test this study’s robustness. Finally, we examine the allowed and excluded regions per MicroBooNE’s data at 90% confidence, using a data set corresponding to 6.67 × 10 20 protons on target. The null model remains allowed, and several of the high-disappearance models are excluded.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

DOE OSTI2022

$\nu_μ$ Disappearance in MicroBooNE using the Deep Learning 1$\mu$1$p$ Selection

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

DOE OSTI2025

An Open-Source Framework for Rapid Validation of Scientific ASICs

Spacely is an open-source framework for the post-silicon validation of analog, digital, and mixed-signal ASICs (Application-Specific Integrated Circuits) which maximizes the reuse of hardware and software, reducing the time taken to achieve meaningful test results. Spacely specifically addresses the needs of small, flexible ASIC design teams commonly found in academia or research institutions which benefit most from sharing the overhead of test stand creation between many unique ASIC designs. Spacely is a set of software, firmware, and design practices. It targets two primary hardware platforms (NI-PXI and Caribou) as well as offering extensible support for bench instruments. Spacely provides a high-level Python interface to all test hardware for accessibility, while also giving more sophisticated teams the opportunity to integrate custom test firmware. The design principles of Spacely are presented in brief. Current documentation is available at https://github.com/SpacelyProject/spacely-docs.

Quinn, Adam [Fermilab]↗

DOE OSTI2025

Monitored Natural Attenuation (MNA) Assessment for the Chemicals, Metals, and Pesticides (CMP) Pits Operable Unit (OU) and the Pen Branch Wetland

In October 2024, Savannah River National Laboratory (SRNL) was tasked to conduct an independent review of groundwater data and assess the monitored natural attenuation (MNA) performance related to the Chemicals, Metals, and Pesticides (CMP) Pits Operable Unit (OU) located in the central portion of the Savannah River Site (SRS). The SRNL assessment of MNA entailed an independent analysis of groundwater concentration data, groundwater elevation data, available surface water concentration data, soil concentration data, and relevant historical geological characterization logs for the CMP Pits OU. Historical data tables and records were obtained from both the Savannah River Nuclear Solutions - Area Completion Projects (SRNSACP) team and South Carolina State University (SCSU) and condensed into new data sets by the SRNL project team for more targeted analysis of MNA performance characteristics. All data pertaining to groundwater concentration, surface water concentration, and groundwater elevation were restricted to collection dates after any known active remediation for the CMP OU.

54 ENVIRONMENTAL SCIENCES↗