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At least 343 records · Page 19

All sources NASA NTRS DOE OSTI

NASA NTRS2012

Loading, Release, Biodegradation, and Biocompatibility of a Nanovector Delivery System

A nanovector multistage system has been created to overcome or bypass sequential barriers within the human body, in order to deliver a therapeutic or imaging agent to a specific location. This innovation consists of a composition that includes two or more stages of particles, such that smaller, later-stage particles are contained in the larger, early-stage particles. An active agent, such as a therapeutic agent or imaging agent, is preferentially delivered and/or localized to a particular target site in the body of a subject. The multistage composition overcomes multiple biological barriers in the body. The multistage composition also allows for simultaneous delivery and localization at the same or different target sites of multiple active agents.

Ferrai, Mauro↗

NASA NTRS2021

Predicting the Functional State of Protein Kinases Using Interpretable Graph Neural Networks

Kinases are a family of proteins that function as molecular switches, regulating several essential cellular activities such as cell proliferation. Dysfunctional kinases are implicated in several types of cancers and hence they are actively pursued as drug targets. Given the vast number of complex kinase structures that are available in the protein data bank (PDB), there is a necessity to develop methodologies that can identify structurally important moieties of the kinases in an automated fashion, for such techniques can be instrumental in identifying novel drug targets. In this work, we develop a graph neural network (GNN) based deep learning framework for classifying the functionally active and inactive states of a large set of eukaryotic protein kinases, making use of their 3D structure from the PDB. We show that GNN based machine learning models can classify protein states with an accuracy greater than 97%. We further use the GNN models to automatically identify regions of the kinases that are important for its function. For this purpose, Gradient-weighted Class Activation Mapping (Grad-CAM) was implemented on the protein graphs. Remarkably, Grad-CAM consistently identifies the highly conserved DFG motif as the most important part of the protein across the entire kinome, without any prior input. Other regions of the hydrophobic core such as the HRD motif were also identified by the interpretable GNN framework, consistent with the literature. We discuss the significance of each of these regions in detail.

Ashwin Ravichandran↗

DOE OSTI2023

Synergistic effect of polyaniline on stabilizing Pt nanoparticles in PEMFCs†

The stability of Pt nanoparticles on a carbon support is crucial for the lifespan of polymer electrolyte membrane fuel cells as well as other electrocatalysis systems such as electrolyzers. Here we took the approach of utilizing the covalently grafted polyaniline on carbon to stabilize Pt nanoparticles by simultaneously alleviating the particle migration and mitigating the Ostwald ripening, which are two major mechanisms for loss of the catalyst stability. A comprehensive investigation of the stability and performance of Pt catalyst nanoparticles on these supports reveals that the polyaniline can shift the Pt L edge binding energy and the Pt 4f peak energy, leading to the increased redox potential of the Pt nanoparticles and making them more resistant to oxidation. Interestingly, the highest polyaniline density (50 wt%) does not show the best catalyst stability, rather, the second (33 wt%) demonstrates the best catalyst stability among these catalysts. Combining the XPS, XAS and fuel cell stability studies, we concluded that the locations of the Pt nanoparticles over the polyaniline layer on the carbon surface depend on the surface density of the polyaniline over the carbon surface. The Pt nanoparticles in the 50 wt% polyaniline catalyst are wrapped by the polyaniline polymer but do not sit directly on the carbon surface, while Pt nanoparticles in the 33 wt% polyaniline catalyst sit on the carbon surface and are densely surrounded by the polyaniline polymer. The results show that the mass activity loss is 12.5% while the ECSA (electrochemically active surface area) loss is 37.1% after 30k cycles of accelerating stress test for the 33 wt% polyaniline catalyst, far exceeding the DOE 2020 target for MEA (i.e., mass activity loss < 50%, and ECSA loss < 40%). Overall, the polyaniline has a synergistic effect on mitigating the surface migration and slowing down the Ostwald ripening to stabilize the Pt nanoparticles in fuel cells. The novel strategy to stabilize Pt nanoparticles using polyaniline opens a new pathway in the development of highly stable catalysts: relying on the functionalization group on the carbon support, instead of just focusing on the catalyst itself.

Li, Chenzhao↗

DOE OSTI2023

The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity

Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity. However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8 + T cell function by enhancing JAK–STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2023

Structures, activity and mechanism of the Type IIS restriction endonuclease PaqCI

Abstract Type IIS restriction endonucleases contain separate DNA recognition and catalytic domains and cleave their substrates at well-defined distances outside their target sequences. They are employed in biotechnology for a variety of purposes, including the creation of gene-targeting zinc finger and TAL effector nucleases and DNA synthesis applications such as Golden Gate assembly. The most thoroughly studied Type IIS enzyme, FokI, has been shown to require multimerization and engagement with multiple DNA targets for optimal cleavage activity; however, details of how it or similar enzymes forms a DNA-bound reaction complex have not been described at atomic resolution. Here we describe biochemical analyses of DNA cleavage by the Type IIS PaqCI restriction endonuclease and a series of molecular structures in the presence and absence of multiple bound DNA targets. The enzyme displays a similar tetrameric organization of target recognition domains in the absence or presence of bound substrate, with a significant repositioning of endonuclease domains in a trapped DNA-bound complex that is poised to deliver the first of a series of double-strand breaks. PaqCI and FokI share similar structural mechanisms of DNA cleavage, but considerable differences in their domain organization and quaternary architecture, facilitating comparisons between distinct Type IIS enzymes.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Irradiation damage concurrent challenges with RAFM and ODS steels for fusion reactor first-wall/blanket: a review

Reduced activation ferritic martensitic (RAFM) and oxide dispersion strengthened (ODS) steels are the most promising candidates for fusion first-wall/blanket (FW/B) structures. The performance of these steels will deteriorate during service due to neutron damage and transmutation-induced gases, such as helium/hydrogen, at elevated operating temperatures. Here, after highlighting the operating conditions of fusion reactor concepts and a brief overview, the main irradiation-induced degradation challenges associated with RAFM/ODS steels are discussed. Their long-term degradation scenarios such as (a) low-temperature hardening embrittlement (LTHE)—including dose-temperature dependent yield stress, tensile elongations, necking ductility, test temperature effect on hardening, Charpy impact ductile-to-brittle transition temperature and fracture toughness, (b) intermediate temperature cavity swelling, (c) the effect of helium on LTHE and cavity swelling, (d) irradiation creep and (e) tritium management issues are reviewed. The potential causes of LTHE are discussed, which highlights the need for advanced characterisation techniques. The mechanical properties, including the tensile/Charpy impact of RAFM and ODS steels, are compared to show that the current generation of ODS steels also suffers from LTHE, and shows irradiation hardening up to high temperatures of ~400 °C–500 °C. To minimise this, future ODS steel development for FW/B-specific application should target materials with a lower Cr concentration (to minimise α'), and minimise other elements that could form embrittling phases under irradiation. RAFM steel-designing activities targeting improvements in creep and LTHE are reviewed. The need to better understand the synergistic effects of helium on the thermo-mechanical properties in the entire temperature range of FW/B is highlighted. Because fusion operating conditions will be complex, including stresses due to the magnetic field, primary loads like coolant pressure, secondary loads from thermal gradients, and due to spatial variation in damage levels and gas production rates, an experimentally validated multiscale modelling approach is suggested as a pathway to future reactor component designing such as for the fusion neutron science facility.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

DOE OSTI2022

Generation of Beamline Sources – Preliminary Design (Second Target Station (STS) Project)

This report provides a short summary of how four neutron beamline sources at the US Department of Energy’s Oak Ridge National Laboratory were generated for use in shielding and activation analysis along Second Target Station (STS) neutron beamlines, inside and outside the bunker, and inside instrument caves. Analysis of these sources shows that an angular acceptance of ±2° from the axis of the neutron beamline is all that is needed to accurately model dose rates for these applications. Further analysis shows that the surface area of the tallies used to calculate these sources, and therefore the number of particles in the sources (normalization), should be scaled up to ~19 × 19 cm to provide conservative estimates of dose rate outside the bunker. The spectrum of neutrons entering beamline 11 (ST11), which has the hardest spectrum at high energies and the most neutrons below 100 eV, produces the largest prompt dose rates inside and outside the bunker and the largest number of activation products inside the bunker, therefore, producing the largest residual dose rates.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

DOE OSTI2021

MINOS Infrasound Analysis Synopsis

This report was written as a guide to working with infrasound data collected as part of the Multi-Informatics for Nuclear Operations Scenarios (MINOS)project, an NA-22 funded venture. The main purpose of overall MINOS project is the combination of multiple, disparate data modalities to characterize the operations at a nuclear facility, specifically instrumenting and studying the High-Flux Isotope Reactor (HFIR) and Radiochemical Engineering Development Center (REDC) locate at Oak Ridge National Laboratory in Oak Ridge, TN. HFIR is an 85 MW research reactor and is used primarily for production of medical radioisotopes, material irradiation experiments, neutron activation, and neutron scattering. Targets for the reactor are constructed, processed, and dissolved at REDC. REDC also hosts other glove-box and hot-cell type activities.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

DOE OSTI2021

Selective and noncovalent targeting of RAS mutants for inhibition and degradation

Activating mutants of RAS are commonly found in human cancers, but to date selective targeting of RAS in the clinic has been limited to KRAS(G12C) through covalent inhibitors. Here, we report a monobody, termed 12VC1, that recognizes the active state of both KRAS(G12V) and KRAS(G12C) up to 400-times more tightly than wild-type KRAS. The crystal structures reveal that 12VC1 recognizes the mutations through a shallow pocket, and 12VC1 competes against RAS-effector interaction. When expressed intracellularly, 12VC1 potently inhibits ERK activation and the proliferation of RAS-driven cancer cell lines in vitro and in mouse xenograft models. 12VC1 fused to VHL selectively degrades the KRAS mutants and provides more extended suppression of mutant RAS activity than inhibition by 12VC1 alone. These results demonstrate the feasibility of selective targeting and degradation of KRAS mutants in the active state with noncovalent reagents and provide a starting point for designing noncovalent therapeutics against oncogenic RAS mutants.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2022

High power targets: Challenges of next-generation high-intensity neutrino beams

High power target systems are crucial elements in enabling future neutrino and other rare particle beams. These systems transform intense source of protons into secondary particles of interest to enable new scientific discoveries. As primary beam intensities increase in next-generation multi-megawatt accelerator facilities, high power target systems face key challenges. Thermal shock and radiation damage effects in beam-intercepting devices were identified as the leading cross-cutting challenges of high-power target facilities. Target materials R&D to address these challenges are therefore essential to enable and ensure reliable operation of future accelerator target facilities. This paper provides an overview of the R&D activities underway to help support high power target systems development for next-generation multi-MW facilities.

43 PARTICLE ACCELERATORS↗

DOE OSTI2020

Applying Two Active Acoustic Technologies to Document Presence of Large Marine Animal Targets at a Marine Renewable Energy Site

Coastal regions are highly used by humans. The growing marine renewable energy (MRE) industry will add to existing anthropogenic pressures in these regions. Regulatory bodies require animal risk assessment before new industrial activities can progress, and MRE is no exception. Preliminary data of marine mammal use of an MRE device deployment location could be informative to permitting. A combination of downlooking hydroacoustics using an echosounder and acoustic camera (imaging sonar) was used to provide a number of large targets (proxy for large fish and marine mammals) in an area of interest for MRE tidal turbine deployment in Western Passage, Maine, USA. Data were collected in May, June, August, and September of 2010 and 2011. Of the nine large targets confirmed to be animals, eight were porpoises and one was a shark. Few large targets were observed in May and June, with the majority (90%) being present in August and September of both years. The most large targets were observed when tidal current speed was less than 1 m·s−1. These data provide a preliminary assessment of large targets in a single location over sixteen 24-h surveys. The aforementioned methodology could be used for future pre- and post-installation assessments at MRE device deployment locations. Their use in concert with visual and passive acoustic monitoring can provide water depth usage by marine mammals, which is a metric that is difficult to assess with passive acoustic and visual techniques.

Staines, Garrett↗

DOE OSTI2024

Comparative study of decay heat calculations with FLUKA and MCNP/CINDER2008

In designing a high-power tungsten target, decay heat driven temperature rise in the spallation volume is a safety concern during maintenance and in loss of coolant accidents. As tungsten hydrates and becomes volatile in steam at above 800 ◦C, it is important to keep the target temperature below this threshold when active cooling is unavailable. Decay heat in a target is calculated with particle transport simulation codes combined with transmutation codes. The calculated decay heat usually differs depending on the nuclear cross sections and the decay particle transport models built in the code architecture. In this paper, we calculated decay heat of a water-cooled tungsten target using popular particle transport codes, FLUKA and MCNP6® paired with CINDER2008 and compared the results. The target-moderator-reflector (TMR) system is modeled with a water-cooled solid tungsten target, water premoderators, liquid hydrogen cold moderators and beryllium reflectors. Water-cooled stainless-steel shielding is modeled around the TMR system. The tungsten volume is clad with a thin layer of erosion/corrosion resistant material. This study provides information about the uncertainty range in decay heat prediction of high-power spallation targets for hazard analysis.

Lee, Yong Joong↗

DOE OSTI2020

Building Interfaces with Echo Using R

The following report details the functionality that was developed to directly query the MongoDB and read in echo records from within R, and the ability to create a cinema database directly from echo records. Both of these efforts used the data collected under the MINOS project for development. The nuclear facility under consideration is the High-Flux Isotope Reactor (HFIR) and co-located Radiochemical Engineering Development Center (REDC) at Oak Ridge National Laboratory in Oak Ridge, TN. HFIR is an 85 MW research reactor and is used primarily for production of a medical radioisotopes, material irradiation experiments, neutron activation, and neutron scattering. Targets for the reactor are fabricated and processed and dissolved at REDC, in addition to other glove-box and hot-cell type activities. An overhead view of the facility is provided. The rest of the report is organized as follows: Section 2 describes how to query the MongoDB and load in echo records from within R, with background information on the database type, MongoDB, and the file format of echo records, hdf5, as well as lessons learned during the development phase. Section 3 details the functionality and usage of creating a cinema database directly from echo records within R. A series of appendixes display all the R code (Section 5), some example scripts where the code is used (Section 6), and useful links for further exploration (Section 7).

21 SPECIFIC NUCLEAR REACTORS AND ASSOCIATED PLANTS↗

NASA NTRS1977

Inexpensive mass flowmeter

Device measures drag of body with known drag coefficient to determine flow rate. Drag on target is transferred by cantilevered arm to fully active strain-gage bridge. Given target will be useful with many types of fluids and flow rates.

Harman, H. S.↗

NASA NTRS1991

Relay Sequence Generation Software

Due to thermal and electromagnetic interactivity between the UHF (ultrahigh frequency) radio onboard the Mars Reconnaissance Orbiter (MRO), which performs relay sessions with the Martian landers, and the remainder of the MRO payloads, it is required to integrate and de-conflict relay sessions with the MRO science plan. The MRO relay SASF/PTF (spacecraft activity sequence file/ payload target file) generation software facilitates this process by generating a PTF that is needed to integrate the periods of time during which MRO supports relay activities with the rest of the MRO science plans. The software also generates the needed command products that initiate the relay sessions, some features of which are provided by the lander team, some are managed by MRO internally, and some being derived.

Gladden, Roy E.↗

DOE OSTI2024

Catalyst design for small molecule activation of energy consequence

This project targets the conversion of ubiquitous small molecules (e.g. NO, CO, H 2 O) into viable precursors to synthetic fuels. Current state of the art catalyst design has not directly targeted transition metal complexes capable of mediating the multi-electron redox processes necessary to reduce the overpotential (energy loss) required achieve efficient activation of small molecule substrates. In this vein, a new strategy has been developed for the assembly of polynuclear architectures; allowing for the construction of tunable polymetallic centers that assemble easily within a pre-organized template (conferring stability, selectivity and tunability) that can effect multi-electron redox processes for reactions. Catalyst development has commenced with the following target design elements: (1) catalysts featuring multiple transition metal ions in the same reaction space to greatly expand accessible molecular redox capabilities; (2) catalysts are assembled in a polynucleating ligand framework that permits control over the cluster morphology as well as the local steric and electronic environment of the transition metal ions within the cluster. The high-tunability of the catalyst composition (metal content) and geometric flexibility has permitted a rigorous assessment of electronic-structure-to-function relationship to be developed, further guiding synthetic efforts to realize more potent catalysts. The numerous permutations possible showcase the high degree of generality to this approach with many synthetic handles to tune redox and reaction chemistry. Trinuclear complexes have been synthesized featuring homo- and hetero-trinuclear cores featuring a variety of first row transition metal ions (Cr→Ni). The molecular clusters have been shown to successfully mediate multi-electron redox processes in a cooperative fashion without requiring strong chemical reductants or oxidants. The reactive molecular complexes are being utilized to activate and breakdown the robust bonds within typical waste stream small molecules (e.g., greenhouse gases) and convert them into value-added commodity chemicals. Ultimately, the catalysts developed by this approach will be required to convert energy acquired via renewable resources (e.g., solar or wind) into synthetic fuels as an energy storage mechanism.

10 SYNTHETIC FUELS↗

NASA NTRS2006

Mars Odyssey: Off-nadir Imaging

Science Objectives for off-nadir imaging: a) Daily observations of high activity and high interest targets in the Polar Regions; b) Daily imaging of regions of gas jetting through vents and the formation of dark spots and fans; c) Increases likelihood of observing these processes in an active phase; d) Stereo imaging for geographical analysis and landing site characterization; and e) Fill in existing gaps and gores.

off nadir imaging↗