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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 811 records · Page 45
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

WE-H-BRA-03: Development of a Model to Include the Evolution of Resistant Tumor Subpopulations Into the Treatment Optimization Process for Schedules Involving Targeted Agents in Chemoradiation Therapy

Purpose: To develop a model that includes the process of resistance development into the treatment optimization process for schedules that include targeted therapies. Further, to validate the approach using clinical data and to apply the model to assess the optimal induction period with targeted agents before curative treatment with chemo-radiation in stage III lung cancer. Methods: Growth of the tumor and its subpopulations is modeled by Gompertzian growth dynamics, resistance induction as a stochastic process. Chemotherapy induced cell kill is modeled by log-cell kill dynamics, targeted agents similarly but restricted to the sensitive population. Radiation induced cell kill is assumed to follow the linear-quadratic model. The validation patient data consist of a cohort of lung cancer patients treated with tyrosine kinase inhibitors that had longitudinal imaging data available. Results: The resistance induction model was successfully validated using clinical trial data from 49 patients treated with targeted agents. The observed recurrence kinetics, with tumors progressing from 1.4–63 months, result in tumor growth equaling a median volume doubling time of 92 days [34–248] and a median fraction of pre-existing resistance of 0.035 [0–0.22], in agreement with previous clinical studies. The model revealed widely varying optimal time points for the use of curative therapy, reaching from ∼1m to >6m depending on the patient’s growth rate and amount of pre-existing resistance. This demonstrates the importance of patient-specific treatment schedules when targeted agents are incorporated into the treatment. Conclusion: We developed a model including evolutionary dynamics of resistant sub-populations with traditional chemotherapy and radiation cell kill models. Fitting to clinical data yielded patient specific growth rates and resistant fraction in agreement with previous studies. Further application of the model demonstrated how proper timing of chemo-radiation could minimize the probability of resistance, increasing tumor control significantly.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Poster - 36: Effect of Planning Target Volume Coverage on the Dose Delivered in Lung Radiotherapy

Purpose: In lung radiotherapy, breathing motion may be encompassed by contouring the internal target volume (ITV). Remaining uncertainties are included in a geometrical expansion to the planning target volume (PTV). In IMRT, the treatment is then optimized until a desired PTV fraction is covered by the appropriate dose. The resulting beams often carry high fluence in the PTV margin to overcome low lung density and to generate steep dose gradients. During treatment, the high density tumour can enter the PTV margin, potentially increasing target dose. Thus, planning lung IMRT with a reduced PTV dose may still achieve the desired ITV dose during treatment. Methods: A retrospective analysis was carried out with 25 IMRT plans prescribed to 63 Gy in 30 fractions. The plans were re-normalized to cover various fractions of the PTV by different isodose lines. For each case, the isocentre was moved using 125 shifts derived from all 3D combinations of 0 mm, (PTV margin - 1 mm), and PTV margin. After each shift, the dose was recomputed to approximate the delivered dose. Results and Conclusion: Our plans typically cover 95% of the PTV by 95% of the dose. Reducing the PTV covered to 94% did not significantly reduce the delivered ITV doses for (PTV margin - 1 mm) shifts. Target doses were reduced significantly for all other shifts and planning goals studied. Thus, a reduced planning goal will likely deliver the desired target dose as long as the ITV rarely enters the last mm of the PTV margin.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen

Induction of broadly neutralizing antibodies (bnAbs) is a major HIV vaccine goal. Germline-targeting immunogens aim to initiate bnAb induction by activating bnAb germline precursor B cells. Critical unmet challenges are to determine whether bnAb precursor naïve B cells bind germline-targeting immunogens and occur at sufficient frequency in humans for reliable vaccine responses. We employed deep mutational scanning and multi-target optimization to develop a germline-targeting immunogen (eOD-GT8) for diverse VRC01-class bnAbs. We then used the immunogen to isolate VRC01-class precursor naïve B cells from HIV-uninfected donors. Frequencies of true VRC01-class precursors, their structures, and their eOD-GT8 affinities support this immunogen as a candidate human vaccine prime. Lastly, these methods could be applied to germline targeting for other classes of HIV bnAbs and for Abs to other pathogens.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

Identification of Ebola Virus Inhibitors Targeting GP2 Using Principles of Molecular Mimicry

A key step in the Ebola virus (EBOV) replication cycle involves conformational changes in viral glycoprotein 2 (GP2) which facilitate host-viral membrane fusion and subsequent release of the viral genome. Ebola GP2 plays a critical role in virus entry and has similarities in mechanism and structure to the HIV gp41 protein for which inhibitors have been successfully developed. In this work, a putative binding pocket for the C-terminal heptad repeat in the N-terminal heptad repeat trimer was targeted for identification of small molecules that arrest EBOV-host membrane fusion. Two computational structure-based virtual screens of ~1.7 M compounds were performed (DOCK program) against a GP2 five-helix bundle, resulting in 165 commercially available compounds purchased for experimental testing. Based on assessment of inhibitory activity, cytotoxicity, and target specificity, four promising candidates emerged with 50% inhibitory concentration values in the 3 to 26 μM range. Molecular dynamics simulations of the two most potent candidates in their DOCK-predicted binding poses indicate that the majority of favorable interactions involve seven highly conserved residues that can be used to guide further inhibitor development and refinement targeting EBOV. The most recent Ebola virus disease outbreak, from 2014 to 2016, resulted in approximately 28,000 individuals becoming infected, which led to over 12,000 causalities worldwide. The particularly high pathogenicity of the virus makes paramount the identification and development of promising lead compounds to serve as inhibitors of Ebola infection. To limit viral load, the virus-host membrane fusion event can be targeted through the inhibition of the class I fusion glycoprotein of. In the current work, several promising small-molecule inhibitors that target the glycoprotein GP2 were identified through systematic application of structure-based computational and experimental drug design procedures.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Single-Cell Discovery and Multiomic Characterization of Therapeutic Targets in Multiple Myeloma

Multiple myeloma (MM) is a highly refractory hematologic cancer. Targeted immunotherapy has shown promise in MM but remains hindered by the challenge of identifying specific yet broadly representative tumor markers. We analyzed 53 bone marrow (BM) aspirates from 41 MM patients using an unbiased, high-throughput pipeline for therapeutic target discovery via single-cell transcriptomic profiling, yielding 38 MM marker genes encoding cell-surface proteins and 15 encoding intracellular proteins. Of these, 20 candidate genes were highlighted that are not yet under clinical study, 11 of which were previously uncharacterized as therapeutic targets. The findings were cross-validated using bulk RNA sequencing, flow cytometry, and proteomic mass spectrometry of MM cell lines and patient BM, demonstrating high overall concordance across data types. Independent discovery using bulk RNA sequencing reiterated top candidates, further affirming the ability of single-cell transcriptomics to accurately capture marker expression despite limitations in sample size or sequencing depth. Target dynamics and heterogeneity were further examined using both transcriptomic and immuno-imaging methods. In summary, this study presents a robust and broadly applicable strategy for identifying tumor markers to better inform the development of targeted cancer therapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Targeted Analysis of Whole Genome Sequence Data to Diagnose Genetic Cardiomyopathy

Background—Cardiomyopathy is highly heritable but genetically diverse. At present, genetic testing for cardiomyopathy uses targeted sequencing to simultaneously assess the coding regions of more than 50 genes. New genes are routinely added to panels to improve the diagnostic yield. With the anticipated $1000 genome, it is expected that genetic testing will shift towards comprehensive genome sequencing accompanied by targeted gene analysis. Therefore, we assessed the reliability of whole genome sequencing and targeted analysis to identify cardiomyopathy variants in 11 subjects with cardiomyopathy. Methods and Results—Whole genome sequencing with an average of 37× coverage was combined with targeted analysis focused on 204 genes linked to cardiomyopathy. Genetic variants were scored using multiple prediction algorithms combined with frequency data from public databases. This pipeline yielded 1-14 potentially pathogenic variants per individual. Variants were further analyzed using clinical criteria and/or segregation analysis. Three of three previously identified primary mutations were detected by this analysis. In six subjects for whom the primary mutation was previously unknown, we identified mutations that segregated with disease, had clinical correlates, and/or had additional pathological correlation to provide evidence for causality. For two subjects with previously known primary mutations, we identified additional variants that may act as modifiers of disease severity. In total, we identified the likely pathological mutation in 9 of 11 (82%) subjects. We conclude that these pilot data demonstrate that ~30-40× coverage whole genome sequencing combined with targeted analysis is feasible and sensitive to identify rare variants in cardiomyopathy-associated genes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Data for "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.

AI/ML↗
DOE OSTI2022

A refined assessment of nuclear data target accuracy requirements for ALFRED

The interest in target accuracy assessment has been recently renewed within the OECD/NEA Working Party on International Nuclear Data Evaluation Cooperation with an update exercise, thanks to the invaluable initiative of Massimo Salvatores. This work, moving from evaluations on the main core integral parameters of the Advanced Lead-cooled Fast Reactor European Demonstrator (ALFRED), and the identification of the associated target accuracies needed for improving its design, approaches the retrieval of target accuracy requirements for nuclear data, as the inverse problem of uncertainty quantification. The preliminary results obtained in a previous work are here refined by explicitly taking into account the total contribution due to correlations among variables in the optimization constraint, while its various components are evaluated individually. Moreover, three different sets of cost parameters are considered to introduce a bias in the solution in order to take in due account the relative difficulties in the execution of new differential experiments as needed for achieving the proposed target accuracies. By this, the obtained results are deemed usefully informative, and proposed for the update of a High Priority List which identifies the isotopes-reaction couples of most interest for future refinement experiments, especially when integrated with further analogous information collected on other advanced nuclear systems. Among the cross-sections whose refinement contributes the most to the reduction of the multiplication factor, the fission of Pu{sup 239} was found, which needs to be fixed below 1% in the range of interest for ALFRED (2 keV-4 MeV). Another contribution for the amelioration of the multiplication factor calculation accuracy, is due to the capture channel of Pu{sup 239}, for which the initial high uncertainty (around 15%) can be significantly reduced resorting to easily practicable experiments. The same occurs for the inelastic of Pb{sup 207}, for which the initial uncertainty value of around 50% can be drastically reduced up to target values between 4% and 7%.

21 SPECIFIC NUCLEAR REACTORS AND ASSOCIATED PLANTS↗
DOE OSTI2020

Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens

The development of chemotherapies against eukaryotic pathogens is especially challenging because of both the evolutionary conservation of drug targets between host and parasite, and the evolution of strain-dependent drug resistance. There is a strong need for new nontoxic drugs with broad-spectrum activity against trypanosome parasites such as Leishmania and Trypanosoma. A relatively untested approach is to target macromolecular interactions in parasites rather than small molecular interactions, under the hypothesis that the features specifying macromolecular interactions diverge more rapidly through coevolution. We computed tRNA Class-Informative Features in humans and independently in eight distinct clades of trypanosomes, identifying parasite-specific informative features, including base pairs and base mis-pairs, that are broadly conserved over approximately 250 million years of trypanosome evolution. Validating these observations, we demonstrated biochemically that tRNA:aminoacyl-tRNA synthetase (aaRS) interactions are a promising target for anti-trypanosomal drug discovery. From a marine natural products extract library, we identified several fractions with inhibitory activity toward Leishmania major alanyl-tRNA synthetase (AlaRS) but no activity against the human homolog. These marine natural products extracts showed cross-reactivity towards Trypanosoma cruzi AlaRS indicating the broad-spectrum potential of our network predictions. We also identified Leishmania major threonyl-tRNA synthetase (ThrRS) inhibitors from the same library. We discuss why chemotherapies targeting multiple aaRSs should be less prone to the evolution of resistance than monotherapeutic or synergistic combination chemotherapies targeting only one aaRS.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2017

RNA and DNA Targeting by a Reconstituted Thermus thermophilus Type III-A CRISPR-Cas System

CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated) systems are RNA-guided adaptive immunity pathways used by bacteria and archaea to defend against phages and plasmids. Type III-A systems use a multi-subunit interference complex called Csm, containing Cas proteins and a CRISPR RNA (crRNA) to target cognate nucleic acids. The Csm complex is intriguing in that it mediates RNA-guided targeting of both RNA and transcriptionally active DNA, but the mechanism is not well understood. Here, we overexpressed the five components of the Thermus thermophilus (T. thermophilus) Type III-A Csm complex (TthCsm) with a defined crRNA sequence, and purified intact TthCsm complexes from E. coli cells. The complexes were thermophilic, targeting complementary ssRNA more efficiently at 65°C than at 37°C. Sequence-independent, endonucleolytic cleavage of single-stranded DNA (ssDNA) by TthCsm was triggered by recognition of a complementary ssRNA, and required a lack of complementarity between the first 8 nucleotides (50 tag) of the crRNA and the 30 flanking region of the ssRNA. Mutation of the histidine-aspartate (HD) nuclease domain of the TthCsm subunit, Cas10/Csm1, abolished DNA cleavage. Activation of DNA cleavage was dependent on RNA binding but not cleavage. This leads to a model in which binding of an ssRNA target to the Csm complex would stimulate cleavage of exposed ssDNA in the cell, such as could occur when the RNA polymerase unwinds double-stranded DNA (dsDNA) during transcription. Our findings establish an amenable, thermostable system for more in-depth investigation of the targeting mechanism using structural biology methods, such as cryoelectron microscopy and x-ray crystallography.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Multiphysics Simulations of Thermal Shock Testing of Nanofibrous High Power Targets

Increase of primary beam power for neutrino beam-lines leads to a reduced lifespan for production targets. New concepts for robust targets are emerging from the field of High Power Targetry (HPT); one idea being investigated by the HPT R&D Group at Fermilab is an electrospun nanofiber target. As part of their evaluation, samples with different densities were sent to the HiRadMat facility at CERN for thermal shock tests. The samples with the higher density, irradiated under a high intensity beam pulse, exhibit major damage at the impact site whereas those with the lower density show no apparent damage. The exact cause of this failure was unclear at the time. In this paper, we present the results of multiphysics simulations of the thermal shock experienced by the nanofiber targets that suggest the failure originates from the reduced permeability of the high density sample to air flow. The air present in the porous target expands due to heating from the beam, but is unable to flow freely in the high density sample, resulting in a larger back pressure that blows apart the nanofiber mat. We close with a discussion on how to further validate this hypothesis.

43 PARTICLE ACCELERATORS↗
DOE OSTI2024

Bayesian optimization scheme for the design of a nanofibrous high power target

High Power Targetry (HPT) R&D is critical in the context of increasing beam intensity and energy for next generation accelerators. Many target concepts and novel materials are being developed and tested for their ability to withstand extreme beam environments; the HPT R&D Group at Fermilab is developing an electrospun nanofiber material for this purpose. The performance of these nanofiber targets is sensitive to their construction parameters, such as the packing density of the fibers. Lowering the density improves the survival of the target, but reduces the secondary particle yield. Optimizing the lifetime and production efficiency of the target poses an interesting design problem, and in this paper we study the applicability of Bayesian optimization to its solution. We first describe how to encode the nanofiber target design problem as the optimization of an objective function, and how to evaluate that function with computer simulations. We then explain the optimization loop setup. Thereafter, we present the optimal design parameters suggested by the algorithm, and close with discussions of limitations and future refinements.

43 PARTICLE ACCELERATORS↗
DOE OSTI2022

Multiphysics Simulation of the Thermal Response of a Nanofibrous Target in a High-Intensity Beam

Nanofibrous structures are of high interest to the fields of engineering and materials science, and investigation of their properties as well as discovery of novel applications for them both constitute lively areas of research. A very promising application of nanofiber mats lies in the field of accelerator technology: beam targets made from nanofiber mats offer a solution to the problem of advancing the "intensity frontier"–-the limit on the beam intensities that can be realized in fixed target experiments and neutrino production facilities. However, testing has shown that the survivability of these nanofiber targets depends strongly on their manufacturing parameters, such as the packing density of fibers. In this work, we will use multiphysics simulations to perform a thermal study on how nanofiber targets react to high intensity beams, so that the dependency of the targets’ lifetime on their construction parameters can be better understood.

43 PARTICLE ACCELERATORS↗
DOE OSTI2015

Modeling to Support the Development of Habitat Targets for Piping Plovers on the Missouri River

This report describes analyses done in support of the establishment of quantitative targets for piping plovers on the Missouri River using predictive numerical models for emergent sandbar habitat and piping plovers developed for the Missouri River Effects Analysis. Several approaches were considered and modeled: current operations of the reservoirs to serve as a reference (Existing Conditions), an unregulated hydrograph to simulate historical conditions (Unregulated), a scenario where dams were present but not operated (No-Operations), and a scenario where the amount of habitat necessary to provide a desired level of population viability (5% risk of extinction in 50 years) was constructed (Calibrated Target). These scenarios were compared in terms of the distribution of standardized habitat produced, the proportion of time available habitat exceeded a given acreage, and the risk of quasi-extinction for plover populations. Sensitivity analyses were also conducted to demonstrate the effects of initial population size and target habitat acreage on extinction risk and the effects of viability criteria on habitat targets. Limitations and uncertainties in the modeling, including caveats on the use of these models to estimate historical conditions and the availability of information to build a metapopulation model are discussed. The challenges inherent in setting population targets and a possible alternative approach to assessing management alternatives in terms of population effects are also included.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2015

Multi-Channel Correlation Detectors: Accounting for and Reducing Non-target Detections [Slides]

Overwhelming non-target detections require more representative hypothesis test to target real events. Implicit signal model with convex-cone geometry includes both target waveforms and non-targets. New detector screens target waveforms from convex cone members that correlation detectors return. Proto-type detector returns analyst-equivalent detections, requires minimal modification from correlation detector, and has quantifiable detection performance, and satisfies all solution requirements to reduce false detections for GNDD.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2015

Production Target Design Report

The Northstar 99 Mo production target, a cylindrical length of 100 Mo rod, has evolved considerably since its first conception. The cylinder was very early sliced into disks to increase the heat transfer area, first to 1 mm thick disks then to the current 0.5 mm thick. The coolant was changed early in the target development from water to helium to eliminate corrosion and dissolution. The diameter has increased from initially 6 mm to 12 mm, the current diameter of the test target now at ANL, to nominally 28 mm (26-30.6 mm, depending upon optimal beam spot size and shape). The length has also changed to improve the production to cost ratio, so now the target is nominally 41 mm long (excluding coolant gaps between disks), and irradiated on both ends. This report summarizes the current status of the plant target design.

Accelerator Design, Technology, and Operations↗
DOE OSTI2016

Thermal Test on Target with Pressed Disks

A thorough test of the thermal performance of a target for Mo 99 production using solid Mo 100 target to produce the Mo 99 via a gamma-n reaction has previously been conducted at Argonne National Laboratory (ANL). The results are reported in “Zero Degree Line Mo Target Thermal Test Results and Analysis,” LANL report Number LA-UR-15-23134 dated 3/27/15. This target was comprised of 25 disks 1 mm thick and 12 mm in diameter, separated by helium coolant gaps 0.5 mm wide. The test reported in the above referenced report was conducted with natural Mo disks all cut from commercial rod. The production plant will have Mo 100 disks pressed and sintered using a process being developed at Oak Ridge National Laboratory (ORNL). The structural integrity of press-and-sinter disks is of some concern. The test reported herein included 4 disks made by the ORNL process and placed in the high heat, and therefore high thermal stress, region of the target. The electron beam energy was 23 MeV for these tests. Beam spot size was 3.5 mm horizontal and 3 mm vertical, FWHM. The thermal stress test of pressed-and-sintered disks resulted in no mechanical failures. The induced thermal stresses were below yield stress for natural Mo, indicating that up to that stress state no inherent deficiencies in the mechanical properties of the fabricated disks were evident.

07 ISOTOPE AND RADIATION SOURCES↗
DOE OSTI2016

Preliminary Mark-18A (Mk-18A) Target Material Recovery Program Product Acceptance Criteria

The Mk-18A Target Material Recovery Program (MTMRP) was established in 2015 to preserve the unique materials, e.g. 244 Pu, in 65 previously irradiated Mk-18A targets for future use. This program utilizes existing capabilities at SRS and Savannah River National Laboratory (SRNL) to process targets, recover materials from them, and to package the recovered materials for shipping to ORNL. It also utilizes existing capabilities at ORNL to receive and store the recovered materials, and to provide any additional processing of the recovered materials or residuals required to prepare them for future beneficial use. The MTMRP is presently preparing for the processing of these valuable targets which is expected to begin in ~2019. As part of the preparations for operations, this report documents the preliminary acceptance criteria for the plutonium and heavy curium materials to be recovered from the Mk-18A targets at SRNL for transport and storage at ORNL. These acceptance criteria were developed based on preliminary concepts developed for processing, transporting, and storing the recovered Mk-18A materials. They will need to be refined as these concepts are developed in more detail.

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS↗