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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 109 records · Page 6
All sourcesNASA NTRSDOE OSTI
DOE OSTI2020

Handheld Biosensor for COVID-19 Screening

We have made significant progress toward the development of an integrated nucleic acid amplification system for Autonomous Medical Devices Incorporated (AMDIs) Optikus handheld diagnostic device. In this effort, we developed a set of loop-mediated isothermal amplification (LAMP) primers for SARS-CoV-2 and then demonstrate amplification directly on a surface acoustic wave (SAW) sensor. We built associated hardware and developed a C-code to control the amplification process. The goal of this project was to develop a nucleic amplification assay that is compatible with SAW sensors to enable both nucleic and serological testing in a single handheld diagnostic device. Toward this goal, AMDI is collaborating Sandia National Laboratories to develop a rapid, portable diagnostic screening device that utilizes Sandias unique surface acoustic wave biosensor (SAW) for COVID-19 detection. Previously, the SANDIA- AMDI SAW sensor has successfully detected multiple high-profile bacteria viruses, including Ebola, HIV, Sin Nombre, and Anthrax. Over the last two years, AMDI and SANDIA have significantly improved the sensitivity and detection capability of the SAW biosensor and have also developed a modular hand-held, portable platform called the Optikus, which uses CD microfluidics and handheld instrumentation to automate all sample preparation, reagent introduction, sample delivery, and measurement for a number of different assay targets. We propose to use this platform for the development of a rapid (%3C30 minutes), point-of-care diagnostic test for detection of COVID-19 from nasal swab samples.

47 OTHER INSTRUMENTATION↗
DOE OSTI2020

Air Evacuation Bridge

Researchers at Los Alamos National Laboratory are researching and designing technology intended to help reduce the exposure of patients and medical staff to pathogens, such as SARS-CoV-2 while providing medical staff the dexterity and flexible work conditions necessary to conduct routine and complex patient care on infected patients. This investigative technology would potentially enable hospitals to adapt, utilize, and re-purpose existing and otherwise infrequently used equipment in the fight against COVID-19, thereby saving hospitals significant money, reducing exposure to staff and patients, and increasing the supply of critically needed devices at a time when supplies are scarce in the market place. A provisional patent has been filed on the technology and we are seeking a commercialization partner to license and further develop the product for commercial purposes, including processing the device through the FDA authorization or clearance process. Once FDA has cleared the product, at least one hospital system has expressed interest in the experimental test components for use in their hospitals.

42 ENGINEERING↗
DOE OSTI2024

Associations between SARS-CoV-2 Infection or COVID-19 Vaccination and Human Milk Composition: A Multi-Omics Approach

Background: The risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via human milk-feeding is virtually nonexistent. Adverse effects of coronavirus disease 2019 (COVID-19) vaccination for lactating individuals are not different from the general population, and no evidence has been found that their infants exhibit adverse effects. Yet, there remains substantial hesitation among this population globally regarding the safety of these vaccines. Objectives: Herein, we aimed to determine if compositional changes in milk occur following SARS-CoV-2 infection or COVID-19 vaccination, including any evidence of vaccine components. Methods: An extensive multiomics approach was taken using a subset of milk samples obtained as part of our broad studies examining the effects on milk of SARS-CoV-2 infection and COVID-19 vaccination. Results: We found that compared with unvaccinated individuals, SARS-CoV-2 infection was associated with significant compositional differences in 67 proteins, 385 lipids, and 13 metabolites. In contrast, COVID-19 vaccination was not associated with any changes in lipids or metabolites, although it was associated with changes in 13 or fewer proteins. Compositional changes in milk differed by vaccine. Changes following vaccination were greatest after 1–6 h for the mRNA-based Moderna vaccine (8 changed proteins), 3 d for the mRNA-based Pfizer (4 changed proteins), and adenovirus-based Johnson and Johnson (13 changed proteins) vaccines. Proteins that changed after both natural infection and Johnson and Johnson vaccine were associated mainly with systemic inflammatory responses. In addition, no vaccine components were detected in any milk sample. Conclusions: Together, our data provide evidence of only minimal changes in milk composition because of COVID-19 vaccination, with much greater changes after natural SARS-CoV-2 infection.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

A split luciferase system for studying coronavirus Mpro dimerization in vitro and in living cells

The main protease enzyme (Mpro) of coronaviruses cleaves the viral polyprotein into functional units essential for virus replication. Prior work has demonstrated that Mpro functions as a homodimer. However, studies on the mechanism of dimerization have been challenging because the purified protease is mostly dimeric, dimerization-defective mutants lack proteolytic activity, and robust cell-based assays have yet to be reported. To enable work on Mpro dimerization, we have developed a quantitative luciferase-based SARS-CoV-2 (SARS2) Mpro biosensor that accurately reports protein dimerization in living cells and, upon purification, also in vitro. Co-transfection of cells with a construct expressing Mpro fused to the 18 kDa LargeBiT of luciferase (LgBiT) and a second construct with Mpro fused to the 1 kDa SmallBiT of luciferase (SmBiT) results in a reconstitution of luciferase activity in a dose-dependent manner that requires conserved residues within the dimerization interface. Proteolytic activity is dispensable for dimerization and, uniquely, a C145A catalytically inactive mutant exhibits enhanced dimerization signal likely due to lower cytotoxicity. Mpro enzymes from multiple different coronaviruses also dimerize in this system, indicating mechanistic conservation. Interestingly, this dimerization biosensor also provides a quantitative read-out of inhibitor-facilitated dimerization. Covalent SARS2 Mpro inhibitors such as nirmatrelvir cause a 3- to 5-fold increase in luciferase activity. Together with corroborating structural, biophysical, and molecular dynamics experiments, our studies support a model in which covalent Mpro inhibitors such as nirmatrelvir simultaneously block catalytic activity and induce allosteric stabilization of the dimeric complex.

SARS-CoV-2 main protease (Mpro/3CLpro)↗
DOE OSTI2020

Filter Adapters for BI-PAP and CPAP Equipment

Researchers at Los Alamos National Laboratory are researching and designing technology intended to help reduce the exposure of patients and medical staff to pathogens, such as SARS-CoV-2, while providing medical staff the dexterity and flexible work conditions necessary to conduct routine and complex patient care on infected patients. This investigative technology would potentially enable hospitals to adapt, utilize, and repurpose existing Bilevel Positive Airway Pressure (BiPAP) or Continuous Positive Airway Pressure (C-PAP) equipment in the fight against COVID-19, which would potentially save hospitals significant money, reduce exposure to staff and patients, and increase the supply of critically needed devices at a time when supplies are scarce in the market place. A provisional patent has been filed on the technology and we are seeking a commercialization partner to license and further develop the product for commercial purposes, including processing the device through the FDA emergency use authorization or clearance process. One hospital system has indicated that upon FDA authorization or clearance, it would have interest in the product.

42 ENGINEERING↗
DOE OSTI2021

Leveraging Structured Biological Knowledge for Counterfactual Inference: A Case Study of Viral Pathogenesis

Counterfactual inference is a useful tool for comparing outcomes of interventions on complex systems. It requires us to represent the system in form of a structural causal model, complete with a causal diagram, probabilistic assumptions on exogenous variables, and functional assignments. Specifying such models can be extremely difficult in practice. The process requires substantial domain expertise, and does not scale easily to large systems, multiple systems, or novel system modifications. At the same time, many application domains, such as molecular biology, are rich in structured causal knowledge that is qualitative in nature. This manuscript proposes a general approach for querying a causal knowledge graph with a causal question and converting the qualitative result into a quantitative structural causal model that can learn from data to answer the question. Here, we demonstrate the feasibility, accuracy and versatility of this approach using two case studies in systems biology. The first demonstrates the appropriateness of the underlying assumptions and the accuracy of the results. The second demonstrates the versatility of the approach by querying a knowledge base for the molecular determinants of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced cytokine storm and performing counterfactual inference to predict the causal effect of medical countermeasures for severely ill COVID-19 patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Pooled PPIseq: Screening the SARS-CoV-2 and human interface with a scalable multiplexed protein-protein interaction assay platform

Protein-Protein Interactions (PPIs) are a key interface between virus and host, and these interactions are important to both viral reprogramming of the host and to host restriction of viral infection. In particular, viral-host PPI networks can be used to further our understanding of the molecular mechanisms of tissue specificity, host range, and virulence. At higher scales, viral-host PPI screening could also be used to screen for small-molecule antivirals that interfere with essential viral-host interactions, or to explore how the PPI networks between interacting viral and host genomes co-evolve. Current high-throughput PPI assays have screened entire viral-host PPI networks. However, these studies are time consuming, often require specialized equipment, and are difficult to further scale. Here, we develop methods that make larger-scale viral-host PPI screening more accessible. This approach combines the mDHFR split-tag reporter with the iSeq2 interaction-barcoding system to permit massively-multiplexed PPI quantification by simple pooled engineering of barcoded constructs, integration of these constructs into budding yeast, and fitness measurements by pooled cell competitions and barcode-sequencing. We applied this method to screen for PPIs between SARS-CoV-2 proteins and human proteins, screening in triplicate >180,000 ORF-ORF combinations represented by >1,000,000 barcoded lineages. Our results complement previous screens by identifying 74 putative PPIs, including interactions between ORF7A with the taste receptors TAS2R41 and TAS2R7, and between NSP4 with the transmembrane KDELR2 and KDELR3. We show that this PPI screening method is highly scalable, enabling larger studies aimed at generating a broad understanding of how viral effector proteins converge on cellular targets to effect replication.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Notes on Synthetic Aperture Radar Image Quality

Synthetic Aperture Radar (SAR) creates an image of a target scene by coherently processing radar echo returns collected along a flightpath. The quality of the SAR image is inextricably linked to the utility of the image for exploitation supporting the task at hand. Aspects of quality include the fidelity with which it can render the scene being imaged, to include the system’s Impulse Response (IPR) and underlying noise levels/characteristics. Other factors also impact utility.

47 OTHER INSTRUMENTATION↗
DOE OSTI2021

Dose Rate Analysis of the WCS Consolidated Interim Storage Facility

This report describes a confirmatory calculation for a proposed consolidated interim storage facility (CISF) to support the US Nuclear Regulatory Commission’s review of the license application submitted by the Interim Storage Partners. The scope of this report is limited to an assessment of the annual dose from direct radiation associated with Phase 1 of the Waste Control Specialists (WCS) CISF and the determination of the minimum controlled area boundary based on the 10 CFR 72.104 limit of 25 mrem annual dose to the whole body. The confirmatory dose rate calculations used the source term and shielding calculation capabilities of the SCALE 6.2.3 computer code system. The calculation method employed in the confirmatory calculations uses a detailed Monte Carlo radiation transport simulation from source to dose rate. This method differs from the two-step method used in the safety analysis report (SAR), which requires determination of the photon and neutron energy and angular distributions on the cask external surface and then the use of this surface source in a new radiation transport calculation to determine dose rate as a function of distance from the storage facility. A simulation was made using the complete site geometry (all casks present) but with only one cask containing source, and a total of 467 independent calculations were performed to obtain the dose rate maps produced by each storage cask. Basic input data and assumptions used in the SAR (e.g., cask design parameters and design basis assembly characteristics) were used in this confirmatory calculation for consistency with the SAR. Local atmospheric conditions for skyshine calculations were simulated using US standard atmosphere data, which describe average air temperature, pressure, and density as a function of altitude. The determined minimum required distances from the WCS Phase 1 CISF to a contour defined by the 25 mrem annual dose limit were approximately 623 m (0.387 miles) in the N-NE direction, 594 m (0.369 miles) in the SSW direction, and 533 m (0.331 miles) in the E-SE direction and the W-NW direction. The annual dose results of the confirmatory calculation are in relatively good agreement with the annual dose values presented in the WCS SAR. The annual dose produced by the Phase 1 CISF at the nearest site boundary, 0.75 miles away from the CISF, was estimated by this study to be approximately 6.02E-02 ± 2.0E-04 mrem, which is significantly smaller than the 25 mrem annual dose limit provided in 10 CFR 72.104. The SAR annual dose rate value for the nearest site boundary was 7.52E-2 mrem, which included 7.73E-03 mrem due to postulated leakage of the FO-, FC-, and FF-canisters. A comparison with the dose rate values reported in the SAR for 16 detector locations, D1 through D16, on the protected area boundary is also included in this report. This comparison shows that the SAR determined higher annual dose values for detectors D1 through D14 by 12% to 45% and lower annual dose values for detectors D15 and D16 by 18% and 8%, respectively, as compared with this ORNL confirmatory calculation. Sensitivity studies have been performed to support a comprehensive review of the application. In these studies, the effects on dose rate of the modeled air volume, density, and humidity were analyzed. The sensitivity calculations showed that the air volume used in the Monte Carlo simulations was adequate and that a larger air volume would not further increase the dose rate due to skyshine contributions. The sensitivity analysis showed that simulation of local atmospheric conditions is important for the accuracy of dose rate estimates at large distances from the facility. Air humidity was demonstrated to have negligible effects on dose rate values for the simulated local atmospheric conditions.

61 RADIATION PROTECTION AND DOSIMETRY↗
DOE OSTI2023

Notes on Minimum Area for Radar Antenna

Perhaps no single radar component has a more profound effect on Synthetic Aperture Radar (SAR) performance than the antenna. Especially for spaceborne SAR, one particular common design constraint for the antenna is the minimum antenna area constraint. While useful, it relies on a number of assumptions and approximations that may not always be valid or applicable. Indeed, useful operational systems have been built and flown that do not strictly adhere to this constraint. A closer examination of this constraint yields insights into what the real limitations are, or might be.

42 ENGINEERING↗
DOE OSTI2022

High-throughput native mass spectrometry as experimental validation for in silico drug design

In this project, we developed automated workflows for both experimental validation and computational prediction of protein-ligand interactions. The ultimate goal is to establish an integrated pipeline for high throughput design of inhibitors to enzymes relevant to all areas of biological research. Our experimental approach is based on native mass spectrometry (native MS), which measures accurate masses and quantify the relative abundance of protein-ligand complexes to define binding affinity. We set up an in-house built autosampler with highly flexible configurations to minimize the manual steps for high throughput native MS. In parallel, we also performed manual native MS to characterize the binding of substrates and inhibitors of SARS-Cov-2 nonstructural protein nsp10/16 in order to optimize the experimental parameters for future automation. On the computational side, we streamlined the pipeline to achieve minimal manual intervention for predicting enzyme inhibitors via simulation, using the same nsp10/16 system as an example. Using the native MS method we examined 8 top-ranked designed compounds, 2 of which showed weak binding of ~50 µM. The information from native MS experiment provided critical insights and the foundation for a fully integrated workflow for enzyme inhibitor design.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

A secure measurement unit for an inspection system used in nuclear arms-control verification

Verification of arms control treaties may require information barriers to protect sensitive data acquired during the verification process. These information barriers are commonly implemented in software, but must store and operate on data that are vulnerable to attack and tampering. Here, we present a new Secure Measurement Unit based on a modified pipeline SAR ADC architecture. The idea is to move the information barrier back into the digitization process so that prohibited data is never created. A prototype 65nm CMOS Secure Measurement Unit (SMU) was tested using U-235, U-238, Co-60, Cs-137 and Am-241 sources. Here, the prototype accurately digitized allowable signals while being immune to side-channel attacks on signals within preset forbidden regions.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗
DOE OSTI2022

COVID ‐19 outcomes in patients with cancer: Findings from the University of California health system database

Abstract Background The interaction between cancer diagnoses and COVID‐19 infection and outcomes is unclear. We leveraged a state‐wide, multi‐institutional database to assess cancer‐related risk factors for poor COVID‐19 outcomes. Methods We conducted a retrospective cohort study using the University of California Health COVID Research Dataset, which includes electronic health data of patients tested for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) at 17 California medical centers. We identified adults tested for SARS‐CoV‐2 from 2/1/2020–12/31/2020 and selected a cohort of patients with cancer. We obtained demographic, clinical, cancer type, and antineoplastic therapy data. The primary outcome was hospitalization within 30d after the first positive SARS‐CoV‐2 test. Secondary outcomes were SARS‐CoV‐2 positivity and severe COVID‐19 (intensive care, mechanical ventilation, or death within 30d after the first positive test). We used multivariable logistic regression to identify cancer‐related factors associated with outcomes. Results We identified 409,462 patients undergoing SARS‐CoV‐2 testing. Of 49,918 patients with cancer, 1781 (3.6%) tested positive. Patients with cancer were less likely to test positive (RR 0.70, 95% CI: 0.67–0.74, p < 0.001). Among the 1781 SARS‐CoV‐2‐positive patients with cancer, BCR/ABL‐negative myeloproliferative neoplasms (RR 2.15, 95% CI: 1.25–3.41, p = 0.007), venetoclax (RR 2.96, 95% CI: 1.14–5.66, p = 0.028), and methotrexate (RR 2.72, 95% CI: 1.10–5.19, p = 0.032) were associated with greater hospitalization risk. Cancer and therapy types were not associated with severe COVID‐19. Conclusions In this large, diverse cohort, cancer was associated with a decreased risk of SARS‐CoV‐2 positivity. Patients with BCR/ABL‐negative myeloproliferative neoplasm or receiving methotrexate or venetoclax may be at increased risk of hospitalization following SARS‐CoV‐2 infection. Mechanistic and comparative studies are needed to validate findings.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2026

In Situ Soil Moisture and Thaw Depth Measurements Coincident with Airborne SAR Data Collections, Seward Peninsula, Alaska, 2022

The in-situ soil moisture and thaw depth measurements provided in this dataset were collected coincident with airborne overflights of L-band synthetic aperture radar (SAR) instruments at the Teller, Kougarok, and Council study sites on the Seward Peninsula, Alaska. Overflights occurred on August 19, 2022. Soil moisture data at Teller and Kougarok was collected on August 19, and at Council on August 20. Thaw depth, soil pits, and any additional measurements were recorded on August 20 and 21. Field measurements and flights were conducted during the summer of 2022 as a collaboration between the National Aeronautics and Space Administration (NASA) Arctic-Boreal Vulnerability Experiment (ABoVE) Project’s Airborne SAR Campaign and the Next-Generation Ecosystem Experiments (NGEE) Arctic Project. This dataset includes a data file (*.csv), a data dictionary (*_dd.csv) and a file-level metadata (*_flmd.csv). The Next-Generation Ecosystem Experiments: Arctic (NGEE Arctic), a research effort to reduce uncertainty in Earth System Models by developing a predictive understanding of carbon-rich Arctic ecosystems and feedbacks to climate. NGEE Arctic was supported by the Department of Energy’s Office of Biological and Environmental Research. The NGEE Arctic project had two field research sites: 1) located within the Arctic polygonal tundra coastal region on the Barrow Environmental Observatory (BEO) and the North Slope near Utqiagvik (Barrow), Alaska and 2) multiple areas on the discontinuous permafrost region of the Seward Peninsula north of Nome, Alaska. Through observations, experiments, and synthesis with existing datasets, NGEE Arctic provided an enhanced knowledge base for multi-scale modeling and contributed to improved process representation at global pan-Arctic scales within the Department of Energy’s Earth system Model (the Energy Exascale Earth System Model, or E3SM), and specifically within the E3SM Land Model component (ELM).

EARTH SCIENCE > LAND SURFACE > FROZEN GROUND↗
DOE OSTI2020

Multi-omics Characterization of the Host Response to COVID-19

This project is a multi-disciplinary collaboration between investigators at PNNL with expertise in mass spectrometry (MS)-based omics technology development, omics measurement methods development and application, statistics, machine learning and integration of disparate datasets for a systems-level understanding, and expertise in pathogenic coronaviruses, and investigators at the University of Wisconsin-Madison (UW-Madison) with expertise in pathogenic respiratory viruses (e.g. influenza). The goal of this project is to obtain a comprehensive picture of the human host factors critical for the outcome of SARS-CoV-2 infection. We will generate broad untargeted multi-omics profiles using both state-of-the-art and novel instrumentation and approaches to enable the identification of the molecular mechanisms and host response pathways that impact human COVID-19 outcomes. We anticipate these results will lead to the generation of biomarker panels that are predictive of disease outcomes and mechanistic hypotheses that can be further interrogated in future studies and will provide the basis for vaccine or therapeutic development. To do so, we are obtaining and analyzing blood samples from COVID-19 patients with a range of disease outcomes that were treated at the Center Hospital of the National Center for Global Health and Medicine in Tokyo, Japan and other collaborating hospitals in our network. Specifically, this project will fund proteomics and metabolomics analyses of clinical COVID samples, machine learning-based integration of the data, and pathway-based interpretation of the data. This project was funded in June 2020. In the time span of June to September 2020, the project team developed an analytically and statistically robust analysis plan and made various preparations to facilitate sample receipt from our UW-Madison collaborators. This included blocking and randomization of sample prep orders, ordering of reagents and reference materials, and shipping of materials needed for preparation of the samples under BSL3 conditions to our collaborators at UW-Madison. As of FY21, this project has been picked up via a sponsor, the Naval Medical Research Center, which will cover the remainder of the proposed scope of work.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Cross-reactive sarbecovirus antibodies induced by mosaic RBD nanoparticles

Broad immune responses are needed to mitigate viral evolution and escape. To induce antibodies against conserved receptor-binding domain (RBD) regions of SARS-like betacoronavirus (sarbecovirus) spike proteins that recognize SARS-CoV-2 variants of concern and zoonotic sarbecoviruses, we developed mosaic-8b RBD nanoparticles presenting eight sarbecovirus RBDs arranged randomly on a 60-mer nanoparticle. Mosaic-8b immunizations protected animals from challenges from viruses whose RBDs were matched or mismatched to those on nanoparticles. Here, we describe neutralizing mAbs isolated from mosaic-8b-immunized rabbits, some on par with Pemgarda, the only currently FDA-approved therapeutic mAb. Deep mutational scanning, in vitro selection of spike resistance mutations, and single-particle cryo-electron microscopy structures of spike–antibody complexes demonstrated targeting of conserved RBD epitopes. Rabbit mAbs included critical D-gene segment RBD-recognizing features in common with human anti-RBD mAbs, despite rabbit genomes lacking an equivalent human D-gene segment, thus demonstrating that the immune systems of humans and other mammals can utilize different antibody gene segments to arrive at similar modes of antigen recognition. These results suggest that animal models can be used to elicit anti-RBD mAbs with similar properties to those raised in humans, which can then be humanized for therapeutic use, and that mosaic RBD nanoparticle immunization coupled with multiplexed screening represents an efficient way to generate and select broadly cross-reactive therapeutic pan-sarbecovirus and pan-SARS-CoV-2 variant mAbs.

Science & Technology - Other Topics↗
DOE OSTI2020

Proposed guidance for preparing and reviewing a molten salt non-power production or utilization facility application

Development of non-power molten salt reactors (MSRs) are under consideration to further establish an MSR experience base, support the requirements of Title 10 of the Code of Federal Regulations (10 CFR) Section 50.43(e), and provide any additional analyses needed for development of a full-scale MSR. Guidance provided in this report is based on MSRs operating with liquid fuel (i.e., fuel dissolved within a molten salt). These reactors, unless owned by the DOE or DOD, will require licensing by the US Nuclear Regulatory Commission (NRC) staff. Standard review plan (SRP) guidance for large light water reactors (LWRs) is available in NUREG-0800, Standard Review Plan for the Review of Safety Analysis Reports for Nuclear Power Plants; Light Water Reactor (LWR) Edition. However, NRC staff observed that NUREG-0800 is very cumbersome to apply to non-power reactors “because of the great differences in complexity and hazards between non-power reactors and nuclear power plants.” Therefore, a program to develop performance-based guidance applicable to non-power reactors was initiated. In 1996, NUREG-1537, Parts 1 and 2, Guidelines for Preparing and Reviewing Applications for the Licensing of Non-Power Reactors, was published. Part 1, the format and content guide, suggests a uniform format for presenting information in non-power reactor applications that is acceptable to the NRC staff, but conformance with the format and content is not required. Part 2, the SRP, ensures the quality and uniformity of the staff review of an application. Unfortunately, the application guidelines and SRP do not provide adequate guidance for all advanced non-LWR technologies and applications. This discrepancy eventually led to the 2012 development of interim staff guidance (ISG) for NUREG-1537, which includes criteria for describing and reviewing aqueous homogeneous reactors (AHRs). Specifically, NUREG-1537 ISG, 2012 expanded the original document to address three areas: 1. updated criteria for heterogeneous non-power reactors, 2. criteria for licensing AHRs, and 3. criteria for licensing a Part 50-licensed isotope production facility. In 2015, the US Department of Energy (DOE) opted to build on the AHR NUREG-1537 ISG experience by performing a gap analysis of the guidance that would be used to license a non-power MSR. MSRs represent one of the advanced non-LWR technologies selected by DOE for development through a multiyear cost share award with Southern Company Services. Under this Advanced Reactor Concepts 2015 (DOE Advanced Reactor Concepts [ARC] 15) award program, the DOE tasked Oak Ridge National Laboratory (ORNL) to evaluate the guidance changes that the NRC may need to consider when licensing an MSR non-power reactor. ORNL staff, with support from Boston Government Services, LLC, focused on five system-related chapters in NUREG-1537 that were considered most relevant to inform the effort that would be required for a non-power MSR applicant. ORNL documented this review in a technical report, ORNL/TM-2018/834, Proposed Guidance for Preparing and Reviewing Molten Salt Non-Power Reactor License Applications (NUREG-1537). The report was subsequently shared with industry and the NRC. The 2018 review was limited in scope, focusing on key system chapters based on the expected significance of each chapter relative to expected differences in addressing advanced non-LWR technologies, specifically non-power MSRs, compared with heterogeneously fueled non-power reactors. In the ORNL report, proposed generic adaptations were suggested for the following NUREG-1537 chapters: Chapter 4, “Reactor Description”; Chapter 5, “Reactor Coolant Systems”; Chapter 6, “Engineered Safety Features”; Chapter 9, “Auxiliary Systems”; Chapter 11, “Radiation Protection Program and Waste Management” The inclusion of Chapter 11 in the previous review effort was intended to provide guidance for categorizing the waste-handling process for an MSR operating with homogenous fuel. The introductions from Parts 1 and 2 of the 2012 NUREG-1537 ISG provide guidance for the application and review of production facilities. After a period of operation, non-power MSRs with homogenous fuel will include gaseous and soluble fission products. The gaseous fission products will be collected and held for decay in an off-gas system. There might also be an initiative to polish or filter the soluble fission products in the fuel salt by some mechanical or chemical means. The treatment and handling of fission products in the non-power MSR fuel salt and the description of this process in the safety analysis report (SAR) must be very precise to avoid the waste treatment facility being construed as a co-located special nuclear material (SNM) fuel cycle facility (see Section 2.3 of this report). Subsequent to the release of ORNL/TM-2018/834, NRC staff expressed a desire to continue the regulatory gap analysis that was begun in that report. This would provide additional clarity and information addressed in certain sections of the original report, while also providing new guidance on certain topics not addressed in the original report. This revision would benefit the NRC staff reviewing applications involving non-power MSR designs and would help developers understand how the NRC staff might approach the review of such applications. The focus of this report is to provide infrastructure support to the NRC staff for the regulatory review of non-power MSRs.

22 GENERAL STUDIES OF NUCLEAR REACTORS↗
DOE OSTI2023

Optimization of Spirulina for biomanufacturing and the delivery of protein therapeutics

Lumen Bioscience has developed a novel cyanobacterial platform that enormously decreases the cost of pharmaceuticals used to prevent and treat illnesses. Arthrospira platensis (spirulina), is a photosynthetic microorganism that has been consumed as a dietary supplement for centuries in part because of its high protein content. Commercial cultivation operations have matured over the last 50 years to allow large-scale cultivation in outdoor ponds. Lumen recently discovered methods that transform this commercially important cyanobacterium into a genetically tractable platform for bioengineering. The high protein accumulation in spirulina makes it an ideal chassis for heterologous protein expression, and centuries of safe human consumption suggest its utility as an administration vehicle for biologic drugs. Lumen can express a broad range of recombinant proteins in spirulina and has developed manufacturing processes and strains to mucosally deliver bioactive proteins to treat and/or prevent disease. For example, Lumen has produced an oral cocktail of dried whole-cell spirulina biomass, containing 3 toxin-neutralizing antibodies and 1 endolysin, that is efficacious in a preclinical in vivo models of C. difficile infection. Lumen has also demonstrated that intranasal administration of a spirulina-manufactured neutralizing antibody can prevent disease by a respiratory pathogen, SARS-CoV-2, in a hamster model. Lumen’s current pipeline includes therapeutics to treat or prevent C. difficile infection, COVID-19, inflammatory bowel disease, cardiometabolic disease, and traveler’s diarrhea. Lumen deploys strategies to maximize the expression of these therapeutics for optimal dose sizing, a key limiting factor with past food crop-based expression systems. Spirulina can express exogenous proteins at unusually high levels (>15% of dry weight) but reaching this maximum value requires optimization of multiple interacting factors. We describe our current statistics design of experiments approach that optimizes these factors with minimal replicates. This maximizes exogenous protein expression allowing Lumen to generate spirulina-based therapeutics for a rapidly expanding range of medical uses.

Heinnickel, Mark↗