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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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Evaluation of Minimum Detectable Activities for Stack Sample Analyses

The Rad-NESHAP program takes samples at major point sources to track how much of select nuclides are being emitted out of the stack. Samples are taken at the site where the radiological operations are being performed. The samples are then sent to analytical laboratories for analysis to determine what nuclides exist in the sample. However, due to the sensitivity of the instruments, false positives are often reported. To reduce the number of false positives, the results reported from the analytical labs are compared to set detection limits. Anything below the set detection limit is considered part of the background while anything above the limit is considered a positive hit. Therefore, the detection limit must be set low enough that any false negatives do not result in a significant dose missed at the end of the year but high enough that there are not enough false positives to skew the annual dose being reported. All detection limits listed in this section for the analyses below were designed to meet the stated equivalent emissions rate and subsequent off-site doses. These minimum detectable activities (MDAs) were developed in the 1990s and documented in the memo cited for each analysis below. These limits and memos are all currently referenced in the Quality Assurance Project Plan (QAPP) for the Rad-NESHAP Compliance Task, which is being updated to a Project Implementation Plan (PIP) concurrently with this document. As part of this update process, the original MDAs defined in this section needed to be verified that they were still conservative and meet the off-site dose levels stated.

2019 MDA↗

Unraveling Vulnerabilities in Endocrine Therapy-Resistant HER2+/ER+ Breast Cancer

Abstract Breast tumors overexpressing human epidermal growth factor receptor (HER2) confer intrinsic resistance to endocrine therapy (ET), and patients with HER2/estrogen receptor–positive (HER2+/ER+) breast cancer (BCa) are less responsive to ET than HER2–/ER+. However, real-world evidence reveals that a large subset of patients with HER2+/ER+ receive ET as monotherapy, positioning this treatment pattern as a clinical challenge. In the present study, we developed and characterized 2 in vitro models of ET-resistant (ETR) HER2+/ER+ BCa to identify possible therapeutic vulnerabilities. To mimic ETR to aromatase inhibitors (AIs), we developed 2 long-term estrogen deprivation (LTED) cell lines from BT-474 (BT474) and MDA-MB-361 (MM361). Growth assays, PAM50 subtyping, and genomic and transcriptomic analyses, followed by validation and functional studies, were used to identify targetable differences between ET-responsive parental and ETR-LTED HER2+/ER+ cells. Compared to their parental cells, MM361 LTEDs grew faster, lost ER, and increased HER2 expression, whereas BT474 LTEDs grew slower and maintained ER and HER2 expression. Both LTED variants had reduced responsiveness to fulvestrant. Whole-genome sequencing of aggressive MM361 LTEDs identified mutations in genes encoding transcription factors and chromatin modifiers. Single-cell RNA sequencing demonstrated a shift towards non-luminal phenotypes, and revealed metabolic remodeling of MM361 LTEDs, with upregulated lipid metabolism and ferroptosis-associated antioxidant genes, including GPX4. Combining a GPX4 inhibitor with anti-HER2 agents induced significant cell death in both MM361 and BT474 LTEDs. The BT474 and MM361 AI-resistant models capture distinct phenotypes of HER2+/ER+ BCa and identify altered lipid metabolism and ferroptosis remodeling as vulnerabilities of this type of ETR BCa.

60 APPLIED LIFE SCIENCES↗

SEASAT SAR performance evaluation study

The performance of the SEASAT synthetic aperture radar (SAR) sensor was evaluated using data processed by the MDA digital processor. Two particular aspects are considered the location accuracy of image data, and the calibration of the measured backscatter amplitude of a set of corner reflectors. The image location accuracy was assessed by selecting identifiable targets in several scenes, converting their image location to UTM coordinates, and comparing the results to map sheets. The error standard deviation is measured to be approximately 30 meters. The amplitude was calibrated by measuring the responses of the Goldstone corner reflector array and comparing the results to theoretical values. A linear regression of the measured against theoretical values results in a slope of 0.954 with a correlation coefficient of 0.970.

Source record↗

Effects of Simulated Spaceflight on Mitochondrial Oxidative Stress in Bone Remodelling

Microgravity and ionizing radiation may contribute to cellular stress; resulting in increased generation of reactive oxygen species (ROS), DNA damage, cell cycle arrest, and cell death. We hypothesized that suppression of excess ROS in osteoblasts and osteoclasts will improve bone microarchitecture. To test our hypothesis, we used irradiated transgenic mCAT mice overexpressing human anti-oxidant catalase gene targeted to the mitochondria (main site for ROS production). mCAT mice expressed the transgene and displayed elevated catalase activity in bone and ex vivo osteoblast and osteoclast cultures. Treated bone from wildtype mice showed elevated levels of oxidative damage whereas mCAT mice did not. Also, increased catalase activity correlated with decreased MDA levels and that increased oxidative damage correlated with decreased % bone volume. Ex-vivo osteoblast colony growth positively correlated with osteoblast catalase activity. mCAT mice displayed reduced % bone volume. Treatment caused significant bone loss in wildtype mice. Treatment also caused slight deficits in microarchitecture of mCAT mice. In conclusion, ROS signaling in both osteoblast and osteoclast lineage cells contribute to skeletal development and remodeling and quenching oxidative damage could play a role in bone loss prevention.

bone loss↗

A Multi-Disciplinary Analysis Framework for the Design of Small Launch Vehicles

Between the years of 1995 and 2014 the number of small satellites (1-500 kg) went up from 20 to 180. [1] Out of the 180 launched in 2014 66% were Nano satellites (1-10 kg). [1] With this trend of smaller satellites, one would expect a rise in number of small launch vehicles (SLVs are defined by capability to carry 1-100 kg to orbit), but this has not happened: [3] only 8% of all small satellites are launched on SLVs and the others become secondary payloads on regular launch vehicles. [1] This results in small satellites being placed into either suboptimal orbits or waiting for launch schedules to align with bigger launches, resulting in long waiting times. Dedicated SLVs could improve the responsiveness of small satellite launches, but SLV design is complicated by the large architecture space needed to be explored in order to find efficient and affordable designs. The SLV architecture trade space contains many discrete options, e.g. solid vs. liquid fuels, air launch vs. ground launch, number of stages, etc. [2][3] Performing detailed analysis for all the options at once would be prohibitive. Thus, a sizing environment/framework that is capable of providing necessary information for conceptual-level trade studies and can rapidly explore the vast SLV architecture space is necessary. The framework, illustrated in Figure 1, consists of four disciplines central to the sizing and synthesis of launch vehicles: propulsion, aerodynamics, structures, and trajectory. For the aerodynamics and trajectory disciplines, Missile DATCOM and POST2 are used, respectively. The propulsion and structures disciplines are represented in the framework with tools developed at ASDL Georgia Tech. For propulsion, the Solid Motor Analysis Code (SMAC) is a physics-based conceptual design tool for solid rocket motors. SMAC is capable of geometric burn simulation, ballistic analysis, and prediction of thrust performance. [4] For structures, Launch Vehicle Structural Analysis (LVSA) tool is a physics-based tool that focuses on structural dynamic analysis with sizing capability. These tools are integrated into the framework illustrated in Figure 1 with the corresponding connections described in Table 1. The process flow is as follows: first, SMAC sizes insulation and calculates maximum operating pressures for each vehicle stage. The MEOP and insulation thickness values from SMAC are fed to LVSA which then utilizes this information to size the motor casing. This creates a feedback loop between LVSA and SMAC that converges on the radius available for fuel, casing, and insulation thickness. Once the stage sizing is converged on SMAC creates an engine deck that is passed to POST2. Next, the data from SMAC and LVSA goes into Missile DATCOM which generates an aerodynamics database for POST2. Finally, POST2 performs a targeting optimization while maximizing the payload mass to orbit. Within the framework, POST2 is automated in order to be robust to a wide variety of possible designs by performing a Monte Carlo simulation over the initialization vector of the POST2 optimization variables. To demonstrate the capability of this framework, a sample problem of exploring the design space of an SLV capable of placing satellites into a low Earth orbit (inclination=47 deg, 196.5 by 211.3 nm) is used. This sample problem is a ground-launched SLV consisting of four in-line SRM stages. The multidisciplinary design analysis (MDA) environment is utilized to explore a design space consisting of 22 continuous and 12 discrete variables, shown by Table 1 by blocks 1,2,3. Running a full factorial design of experiments (DOE) would have been prohibitively expensive even with this reduced design space, thus a space filling design with 3,502 and then additional expansion of 2,602 cases was used. The first DOE consisted of 3,502 cases, and all of the variables were varied. These input variables are listed in blocks 1, 2, and 3 in Table 1. Most of the variables are propulsion related with stage lengths determining the delta-V split of the SLV. The expansion consisted of 2,602 cases, and the continuous variables were set to be equal to the most promising designs from the sizing of first DOE. For each set of continuous variables, the discrete variables (grain type, star points, and propellant) were to varied. The results of the DOE can be seen in Figure 2; each of the points in this plot represents a closed launch vehicle that reaches the targeted orbit. For each of the cases, there is information on flown trajectory, structural, and propulsion properties of the SLV. For example, Figure 3 shows changes in altitude and velocity with time for a particular case. The right side of Figure 3 clearly shows the coasting (slow decrease) and burning phases (sharp increase) of the SLV mission. LV mass is positively correlated with the optimized payload mass to orbit because heavier LVs carry more fuel and thus have more stored chemical energy. Furthermore, for any given payload mass to orbit, the most efficient design would result in the smallest LV. The results as visualized in Figure 2 shows this tradeoff, and the Pareto frontier of the efficient designs can be seen along the dotted line. Figure 2 can be divided into regions with the lowest mass vehicles corresponding to the minimum bound on radius, and the highest mass vehicles corresponding to the maximum bound on radius. Within a mass region, the discrete variables, such as propellant type and propellant grain arrangement, have the most effect on payload mass. This paper presents an MDA framework that can perform an automated physics-based sizing of SLV designs and a corresponding methodology to utilize the MDA to explore the design space of SLVs. The proposed methodology was applied to a perform a design space exploration for a four stage SLV. The outputs show the expected pareto frontier forming and provide detailed information about the SLV performance and staging. Using the produced data, it will be possible to select a set of pareto optimal designs that can then be further explored in subsequent design cycles. This demonstration shows that automated design space exploration should be used in the early phase design of future SLV concepts.

Nikita S Birbasov↗

Materials dispersion and biodynamics project research

The Materials Dispersion and Biodynamics Project (MDBP) focuses on dispersion and mixing of various biological materials and the dynamics of cell-to-cell communication and intracellular molecular trafficking in microgravity. Research activities encompass biomedical applications, basic cell biology, biotechnology (products from cells), protein crystal development, ecological life support systems (involving algae and bacteria), drug delivery (microencapsulation), biofilm deposition by living organisms, and hardware development to support living cells on Space Station Freedom (SSF). Project goals are to expand the existing microgravity science database through experiments on sounding rockets, the Shuttle, and COMET program orbiters and to evolve,through current database acquisition and feasibility testing, to more mature and larger-scale commercial operations on SSF. Maximized utilization of SSF for these science applications will mean that service companies will have a role in providing equipment for use by a number of different customers. An example of a potential forerunner of such a service for SSF is the Materials Dispersion Apparatus (MDA) 'mini lab' of Instrumentation Technology Associates, Inc. (ITA) in use on the Shuttle for the Commercial MDAITA Experiments (CMIX) Project. The MDA wells provide the capability for a number of investigators to perform mixing and bioprocessing experiments in space. In the area of human adaptation to microgravity, a significant database has been obtained over the past three decades. Some low-g effects are similar to Earth-based disorders (anemia, osteoporosis, neuromuscular diseases, and immune system disorders). As new information targets potential profit-making processes, services and products from microgravity, commercial space ventures are expected to expand accordingly. Cooperative CCDS research in the above mentioned areas is essential for maturing SSF biotechnology and to ensure U.S. leadership in space technology. Currently, the MDBP conducts collaborative research with investigators at the Rockefeller University, National Cancer Institute, and the Universities of California, Arizona, and Alabama in Birmingham. The growing database from these collaborations provides fundamental information applicable to development of cell products, manipulation of immune cell response, bone cell growth and mineralization, and other processes altered by low-gravity. Contacts with biotechnology and biopharmaceutical companies are being increased to reach uninformed potential SSF users, provide access through the CMDS to interested users for feasibility studies, and to continue active involvement of current participants. We encourage and actively seek participation of private sector companies, and university and government researchers interested in biopharmaceuticals, hardware development and fundamental research in microgravity.

Lewis, Marian L.↗

Neutral rhenium( i ) tricarbonyl complexes with sulfur-donor ligands: anti-proliferative activity and cellular localization

Rhenium(I) tricarbonyl complexes are widely studied for their cell imaging properties and anti-cancer and anti-microbial activities, but the complexes with S-donor ligands remain relatively unexplored. A series of six fac-[Re(NN)(CO) 3 (SR)] complexes, where (NN) is 2,2'-bipyridyl (bipy) or 1,10-phenanthroline (phen), and RSH is a series of thiocarboxylic acid methyl esters, have been synthesized and characterized. Cellular uptake and anti-proliferative activities of these complexes in human breast cancer cell lines (MDA-MB-231 and MCF-7) were generally lower than those of the previously described fac-[Re(NN)(CO) 3 (OH 2 )]+ complexes; however, one of the complexes, fac-[Re(CO) 3 (phen)(SC(Ph)CH 2 C(O)OMe)] (3b), was active (IC 50 ~ 10 μM at 72 h treatment) in thiol-depleted MDA-MB-231 cells. Moreover, unlike fac-[Re(CO) 3 (phen)(OH 2 )]+, this complex did not lose activity in the presence of extracellular glutathione. Taken together these properties show promise for further development of 3b and its analogues as potential anti-cancer drugs for co-treatment with thiol-depleting agents. Conversely, the stable and non-toxic complex, fac-[Re(bipy)(CO) 3 (SC(Me)C(O)OMe)] (1a), predominantly localized in the lysosomes of MDA-MB-231 cells, as shown by live cell confocal microscopy (λ ex = 405 nm, λ em = 470–570 nm). It is strongly localized in a subset of lysosomes (25 μM Re, 4 h treatment), as shown by co-localization with a Lysotracker dye. Longer treatment times with 1a (25 μM Re for 48 h) resulted in partial migration of the probe into the mitochondria, as shown by co-localization with a Mitotracker dye. These properties make complex 1a an attractive target for further development as an organelle probe for multimodal imaging, including phosphorescence, carbonyl tag for vibrational spectroscopy, and Re tag for X-ray fluorescence microscopy.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Neutral rhenium(i) tricarbonyl complexes with sulfur-donor ligands: anti-proliferative activity and cellular localization

Rhenium(I) tricarbonyl complexes are widely studied for their cell imaging properties and anticancer and anti-microbial activities, but the complexes with S-donor ligands remain relatively unexplored. A series of six fac-[Re(NN)(CO) 3 (SR)] complexes, where (NN) is 2,2'-bipyridyl (bipy) or 1,10-phenanthroline (phen), and RSH is a series of thiocarboxylic acid methyl esters, have been synthesized and characterized. Cellular uptake and anti-proliferative activities of these complexes in human breast cancer cell lines (MDA-MB-231 and MCF-7) were generally lower than those of the previously described fac-[Re(NN)(CO) 3 (OH 2 )] + complexes; however, one of the complexes, fac-[Re(CO) 3 (phen)(SC(Ph)CH 2 C(O)OMe))] (3b), was active (IC 50 ~ 10 μM at 72 h treatment) in thiol-depleted MDA-MB-231 cells. Moreover, unlike fac- [Re(CO) 3 (phen)(OH 2 )] + , this complex did not lose activity in the presence of extracellular glutathione. Taken together these properties show promise for further development of 3b and its analogues as potential anti-cancer drugs for co-treatment with thiol-depleting agents. Conversely, the stable and non-toxic complex, fac-[Re(bipy)(CO) 3 (SC(Me)C(O)OMe)] (1a), predominantly localized in the lysosomes of MDA-MB-231 cells, as shown by live cell confocal microscopy (λ ex = 405 nm, λ em = 470-570 nm). It is strongly localized in a subset of lysosomes (25 μM Re, 4 h treatment), as shown by co-localization with a Lysotracker dye. Longer treatment times with 1a (25 μM Re for 48 h) resulted in partial migration of the probe into the mitochondria, as shown by co-localization with a Mitotracker dye. These properties make complex 1a an attractive target for further development as an organelle probe for multimodal imaging, including phosphorescence, carbonyl tag for vibrational spectroscopy, and Re tag for X-ray fluorescence microscopy.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Transgenic Mouse Model for Reducing Oxidative Damage in Bone

Bone loss can occur due to many challenges such age, radiation, microgravity, and Reactive Oxygen Species (ROS) play a critical role in bone resorption by osteoclasts (Bartell et al. 2014). We hypothesize that suppression of excess ROS in skeletal cells, both osteoblasts and osteoclasts, regulates skeletal growth and remodeling. To test our hypothesis, we used transgenic mCAT mice which overexpress the human anti-oxidant catalase gene targeted to the mitochondria, the main site for endogenous ROS production. mCAT mice have a longer life-span than wildtype controls and have been used to study various age-related disorders. To stimulate remodeling, 16 week old mCAT mice or wildtype mice were exposed to treatment (hindlimb-unloading and total body-irradiation) or sham treatment conditions (control). Tissues were harvested 2 weeks later for skeletal analysis (microcomputed tomography), biochemical analysis (gene expression and oxidative damage measurements), and ex vivo bone marrow derived cell culture (osteoblastogenesis and osteoclastogenesis). mCAT mice expressed the transgene and displayed elevated catalase activity in skeletal tissue and marrow-derived osteoblasts and osteoclasts grown ex vivo. In addition, when challenged with treatment, bone tissues from wildtype mice showed elevated levels of malondialdehyde (MDA), indicating oxidative damage) whereas mCAT mice did not. Correlation analysis revealed that increased catalase activity significantly correlated with decreased MDA levels and that increased oxidative damage correlated with decreased percent bone volume (BVTV). In addition, ex-vivo cultured osteoblast colony growth correlated with catalase activity in the osteoblasts. Thus, we showed that these transgenic mice can be used as a model to study the relationship between markers of oxidative damage and skeletal properties. mCAT mice displayed reduced BVTV and trabecular number relative to wildtype mice, as well as increased structural model index in the cancellous tibia. Treatment caused bone loss in wildtype mice, as expected. Treatment also caused deficits in microarchitecture of mCAT mice, although less severe than wildtype mice in some parameters (percent bone volume, structural model index and cortical area). In conclusion, our results indicate that endogenous ROS signaling in both osteoblast and osteoclast lineage cells contributes to skeletal growth and remodeling, and quenching oxidative damage could play a role in bone loss prevention.

transgenic mice↗

Role of Oxidative Damage in Radiation-Induced Bone Loss

During prolonged spaceflight, astronauts are exposed to both microgravity and space radiation, and are at risk for increased skeletal fragility due to bone loss. Evidence from rodent experiments demonstrates that both microgravity and ionizing radiation can cause bone loss due to increased bone-resorbing osteoclasts and decreased bone-forming osteoblasts, although the underlying molecular mechanisms for these changes are not fully understood. We hypothesized that excess reactive oxidative species (ROS), produced by conditions that simulate spaceflight, alter the tight balance between osteoclast and osteoblast activities, leading to accelerated skeletal remodeling and culminating in bone loss. To test this, we used the MCAT mouse model; these transgenic mice over-express the human catalase gene targeted to mitochondria, the major organelle contributing free radicals. Catalase is an anti-oxidant that converts reactive species, hydrogen peroxide into water and oxygen. This animal model was selected as it displays extended lifespan, reduced cardiovascular disease and reduced central nervous system radio-sensitivity, consistent with elevated anti-oxidant activity conferred by the transgene. We reasoned that mice overexpressing catalase in mitochondria of osteoblast and osteoclast lineage cells would be protected from the bone loss caused by simulated spaceflight. Over-expression of human catalase localized to mitochondria caused various skeletal phenotypic changes compared to WT mice; this includes greater bone length, decreased cortical bone area and moment of inertia, and indications of altered microarchitecture. These findings indicate mitochondrial ROS are important for normal bone-remodeling and skeletal integrity. Catalase over-expression did not fully protect skeletal tissue from structural decrements caused by simulated spaceflight; however there was significant protection in terms of cellular oxidative damage (MDA levels) to the skeletal tissue. Furthermore, we used an array of countermeasures (Antioxidant diets and injections) to prevent the radiation-induced bone loss, although these did not prevent bone loss, analysis is ongoing to determine if these countermeasure protected radiation-induced damage to other tissues.

oxidative damage↗

Development of 225Ac-doped biocompatible nanoparticles for targeted alpha therapy

Abstract Targeted alpha therapy (TAT) relies on chemical affinity or active targeting using radioimmunoconjugates as strategies to deliver α-emitting radionuclides to cancerous tissue. These strategies can be affected by transmetalation of the parent radionuclide by competing ions in vivo and the bond-breaking recoil energy of decay daughters. The retention of α-emitting radionuclides and the dose delivered to cancer cells are influenced by these processes. Encapsulating α-emitting radionuclides within nanoparticles can help overcome many of these challenges. Poly(lactic- co -glycolic acid) (PLGA) nanoparticles are a biodegradable and biocompatible delivery platform that has been used for drug delivery. In this study, PLGA nanoparticles are utilized for encapsulation and retention of actinium-225 ([ 225 Ac]Ac 3+ ). Encapsulation of [ 225 Ac]Ac 3+ within PLGA nanoparticles (Z ave = 155.3 nm) was achieved by adapting a double-emulsion solvent evaporation method. The encapsulation efficiency was affected by both the solvent conditions and the chelation of [ 225 Ac]Ac 3+ . Chelation of [ 225 Ac]Ac 3+ to a lipophilic 2,9-bis-lactam-1,10-phenanthroline ligand ([ 225 Ac]AcBLPhen) significantly decreased its release (< 2%) and that of its decay daughters (< 50%) from PLGA nanoparticles. PLGA nanoparticles encapsulating [ 225 Ac]AcBLPhen significantly increased the delivery of [ 225 Ac]Ac 3+ to murine (E0771) and human (MCF-7 and MDA-MB-231) breast cancer cells with a concomitant increase in cell death over free [ 225 Ac]Ac 3+ in solution. These results demonstrate that PLGA nanoparticles have potential as radionuclide delivery platforms for TAT to advance precision radiotherapy for cancer. In addition, this technology offers an alternative use for ligands with poor aqueous solubility, low stability, or low affinity, allowing them to be repurposed for TAT by encapsulation within PLGA nanoparticles. Graphical Abstract

60 APPLIED LIFE SCIENCES↗