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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 253 records · Page 14
All sourcesNASA NTRSDOE OSTI
DOE OSTI2023

A Novel Platform for Evaluating Dose Rate Effects on Oxidative Damage to Peptides: Toward a High-Throughput Method to Characterize the Mechanisms Underlying the FLASH Effect

High dose rate radiation has gained considerable interest recently as a possible avenue for increasing the therapeutic window in cancer radiation treatment. The sparing of healthy tissue at high dose rates relative to conventional dose rates, while maintaining tumor control, has been termed the FLASH effect. Although the effect has been validated in animal models using multiple radiation sources, it is not yet well understood. Here, in this work, we demonstrate a new experimental platform for quantifying oxidative damage to protein sidechains in solution as a function of radiation dose rate and oxygen availability using liquid chromatography mass spectrometry. Using this reductionist approach, we show that for both X-ray and electron sources, isolated peptides in solution are oxidatively modified to different extents as a function of both dose rate and oxygen availability. Our method provides an experimental platform for exploring the parameter space of the dose rate effect on oxidative changes to proteins in solution.

61 RADIATION PROTECTION AND DOSIMETRY↗
DOE OSTI2020

Radiobiological Studies Using Cs-137 Gamma or 320 kV X Rays

There are numerous self-shielded research irradiators used in various facilities throughout the United States. The irradiators employ radioactive sources containing either 137 Cs or 60 Co and the irradiators are used for a variety of radiobiological investigations involving cellular and/or animal models. A report from the National Academy of Sciences described security issues associated with particular radiation sources and the desire for their replacement with suitable X-ray irradiators. One possible replacement would be a 320 kV X-ray irradiator. The participants in this research successfully performed in vivo radiobiological studies involving mice exposed to filtered (HVL ≈ 4 mm Cu) 320 kV X rays. Two publications (one published and one submitted at the publishing of this report) documenting key findings are provided in Appendices A and B of this report. The 320 kV X rays were found suitable for in vivo (in mice) cell survival studies and are expected to be suitable for bone marrow transplantation studies using mice but this needs to be experimentally validated.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2022

225 Ac-MACROPATATE: A Novel α-Particle Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors

Neuroendocrine tumors (NETs) express somatostatin receptors (SSTRs) 2 and 5. Modified variants of somatostatin, the cognate ligand for SSTR2 and SSTR5, are used in treatment for metastatic and locoregional disease. Peptide receptor radionuclide therapy with 177 Lu-DOTATATE (DOTA-octreotate), a β-particle–emitting somatostatin derivative, has demonstrated survival benefit in patients with SSTR-positive NETs. Despite excellent results, a subset of patients has tumors that are resistant to treatment, and alternative agents are needed. Targeted α-particle therapy has been shown to kill tumors that are resistant to targeted β-particle therapy, suggesting that targeted α-particle therapy may offer a promising treatment option for patients with 177 Lu-DOTATATE–resistant disease. Although DOTATATE can chelate the clinically relevant α-particle–emitting radionuclide 225 Ac, the labeling reaction requires high temperatures, and the resulting radioconjugate has suboptimal stability. Methods: We designed and synthesized MACROPATATE (MACROPA-octreotate), a novel radioconjugate capable of chelating 225 Ac at room temperature, and assessed its in vitro and in vivo performance. Results: MACROPATATE demonstrated comparable affinity to DOTATATE (dissociation constant, 21 nM) in U2-OS-SSTR2, a SSTR2-positive transfected cell line. 225 Ac-MACROPATATE demonstrated superior serum stability at 37°C over time compared with 225 Ac-DOTATATE. Biodistribution studies demonstrated higher tumor uptake of 225 Ac-MACROPATATE than of 225 Ac-DOTATATE in mice engrafted with subcutaneous H69 NETs. Therapy studies showed that 225 Ac-MACROPATATE exhibits significant antitumor and survival benefit compared with saline control in mice engrafted with SSTR-positive tumors. However, the increased accumulation of 225 Ac-MACROPATATE in liver and kidneys and subsequent toxicity to these organs decreased its therapeutic index compared with 225 Ac-DOTATATE. Conclusion: 225 Ac-MACROPATATE and 225 Ac-DOTATATE exhibit favorable therapeutic efficacy in animal models. Because of elevated liver and kidney accumulation and lower administered activity for dose-limiting toxicity of 225 Ac-MACROPATATE, 225 Ac-DOTATATE was deemed the superior agent for targeted α-particle peptide receptor radionuclide therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2022

A Double-Pronged Sword: XJB-5-131 Is a Suppressor of Somatic Instability and Toxicity in Huntington’s Disease

Due to large increases in the elderly populations across the world, age-related diseases are expected to expand dramatically in the coming years. Among these, neurodegenerative diseases will be among the most devastating in terms of their emotional and economic impact on patients, their families, and associated subsidized health costs. There is no currently available cure or rescue for dying brain cells. Viable therapeutics for any of these disorders would be a breakthrough and provide relief for the large number of affected patients and their families. Neurodegeneration is accompanied by elevated oxidative damage and inflammation. While natural antioxidants have largely failed in clinical trials, preclinical phenotyping of the unnatural, mitochondrial targeted nitroxide, XJB-5-131, bodes well for further translational development in advanced animal models or in humans. Here we consider the usefulness of synthetic antioxidants for the treatment of Huntington’s disease. The mitochondrial targeting properties of XJB-5-131 have great promise. It is both an electron scavenger and an antioxidant, reducing both somatic expansion and toxicity simultaneously through the same redox mechanism. By quenching reactive oxygen species, XJB-5-131 breaks the cycle between the rise in oxidative damage during disease progression and the somatic growth of the CAG repeat which depends on oxidation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Application of Multi-Criteria Decision Analysis Techniques for Informing Select Agent Designation and Decision Making

The Centers for Disease Control and Prevention (CDC) Select Agent Program establishes a list of biological agents and toxins that potentially threaten public health and safety, the procedures governing the possession, utilization, and transfer of those agents, and training requirements for entities working with them. Every 2 years the Program reviews the select agent list, utilizing subject matter expert (SME) assessments to rank the agents. In this study, we explore the applicability of multi-criteria decision analysis (MCDA) techniques and logic tree analysis to support the CDC Select Agent Program biennial review process, applying the approach broadly to include non-select agents to evaluate its generality. We conducted a literature search for over 70 pathogens against 15 criteria for assessing public health and bioterrorism risk and documented the findings for archiving. The most prominent data gaps were found for aerosol stability and human infectious dose by inhalation and ingestion routes. Technical review of published data and associated scoring recommendations by pathogen-specific SMEs was found to be critical for accuracy, particularly for pathogens with very few known cases, or where proxy data (e.g., from animal models or similar organisms) were used to address data gaps. Analysis of results obtained from a two-dimensional plot of weighted scores for difficulty of attack (i.e., exposure and production criteria) vs. consequences of an attack (i.e., consequence and mitigation criteria) provided greater fidelity for understanding agent placement compared to a 1-to-n ranking and was used to define a region in the upper right-hand quadrant for identifying pathogens for consideration as select agents. A sensitivity analysis varied the numerical weights attributed to various properties of the pathogens to identify potential quantitative (x and y) thresholds for classifying select agents. The results indicate while there is some clustering of agent scores to suggest thresholds, there are still pathogens that score close to any threshold, suggesting that thresholding “by eye” may not be sufficient. The sensitivity analysis indicates quantitative thresholds are plausible, and there is good agreement of the analytical results with select agent designations. A second analytical approach that applied the data using a logic tree format to rule out pathogens for consideration as select agents arrived at similar conclusions.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Neutralizing epitopes on Clostridioides difficile toxin A revealed by the structures of two camelid VHH antibodies

Toxin A (TcdA) and toxin B (TcdB) are two key virulence factors secreted by Clostridioides difficile, which is listed as an urgent threat by the CDC. These two large homologous exotoxins are mainly responsible for diseases associated with C. difficile infection (CDI) with symptoms ranging from diarrhea to life threatening pseudomembranous colitis. Single-domain camelid antibodies (VHHs) AH3 and AA6 are two potent antitoxins against TcdA, which when combined with two TcdB-targeting VHHs showed effective protection against both primary and recurrent CDI in animal models. Here, we report the co-crystal structures of AH3 and AA6 when they form complexes with the glucosyltransferase domain (GTD) and a fragment of the delivery and receptor-binding domain (DRBD) of TcdA, respectively. Based on these structures, we find that AH3 binding enhances the overall stability of the GTD and interferes with its unfolding at acidic pH, and AA6 may inhibit the pH-dependent conformational changes in the DRBD that is necessary for pore formation of TcdA. These studies reveal two functionally critical epitopes on TcdA and shed new insights into neutralizing mechanisms and potential development of epitope-focused vaccines against TcdA.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Developmental Ethanol Exposure Impacts Purkinje Cells but Not Microglia in the Young Adult Cerebellum

Fetal alcohol spectrum disorders (FASD) caused by developmental ethanol exposure lead to cerebellar impairments, including motor problems, decreased cerebellar weight, and cell death. Alterations in the sole output of the cerebellar cortex, Purkinje cells, and central nervous system immune cells, microglia, have been reported in animal models of FASD. To determine how developmental ethanol exposure affects adult cerebellar microglia and Purkinje cells, we used a human third-trimester binge exposure model in which mice received ethanol or saline from postnatal (P) days 4–9. In adolescence, cerebellar cranial windows were implanted and mice were aged to young adulthood for examination of microglia and Purkinje cells in vivo with two-photon imaging or in fixed tissue. Ethanol had no effect on microglia density, morphology, dynamics, or injury response. However, Purkinje cell linear frequency was reduced by ethanol. Microglia–Purkinje cell interactions in the Purkinje Cell Layer were altered in females compared to males. Overall, developmental ethanol exposure had few effects on cerebellar microglia in young adulthood and Purkinje cells appeared to be more susceptible to its effects.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Revising the Role of Cortical Cytoskeleton during Secretion: Actin and Myosin XI Function in Vesicle Tethering

In plants, secretion of cell wall components and membrane proteins plays a fundamental role in growth and development as well as survival in diverse environments. Exocytosis, as the last step of the secretory trafficking pathway, is a highly ordered and precisely controlled process involving tethering, docking, and fusion of vesicles at the plasma membrane (PM) for cargo delivery. Although the exocytic process and machinery are well characterized in yeast and animal models, the molecular players and specific molecular events that underpin late stages of exocytosis in plant cells remain largely unknown. Here, by using the delivery of functional, fluorescent-tagged cellulose synthase (CESA) complexes (CSCs) to the PM as a model system for secretion, as well as single-particle tracking in living cells, we describe a quantitative approach for measuring the frequency of vesicle tethering events. Genetic and pharmacological inhibition of cytoskeletal function, reveal that the initial vesicle tethering step of exocytosis is dependent on actin and myosin XI. In contrast, treatments with the microtubule inhibitor, oryzalin, did not significantly affect vesicle tethering or fusion during CSC exocytosis but caused a minor increase in transient or aborted tethering events. With data from this new quantitative approach and improved spatiotemporal resolution of single particle events during secretion, we generate a revised model for the role of the cortical cytoskeleton in CSC trafficking.

Zhang, Weiwei↗
DOE OSTI2023

Acute Ozone-Induced Transcriptional Changes in Markers of Oxidative Stress and Glucocorticoid Signaling in the Rat Hippocampus and Hypothalamus Are Sex-Specific

Exposure to a prototypic air pollutant ozone (O 3 ) has been associated with the activation of neuroendocrine stress response along with neural changes in oxidative stress (OS), inflammation, and Alzheimer’s disease-like pathologies in susceptible animal models. We hypothesized that neural oxidative and transcriptional changes induced by O 3 in stress responsive regions are sex-dependent. Male and female adult Long–Evans rats were exposed to filtered air or O 3 for two consecutive days (0.8 ppm, 4 h/day) and brain regions were flash-frozen. Activities of cerebellar OS parameters and mitochondrial complex I, II, and IV enzymes were assessed to confirm prior findings. We assessed transcriptional changes in hypothalamus (HYP) and hippocampus (HIP) for markers of OS, microglial activity and glucocorticoid signaling using qPCR. Although there were no O 3 or sex-related differences in the cerebellar activities of OS and mitochondrial enzymes, the levels of protein carbonyls and complex II activities were higher in females regardless of O 3 . There were no statistical differences in baseline expression of genes related to OS (Cat, Dhcr24, Foxm1, Gpx1, Gss, Nfe2l2, Sod1) except for lower HYP Sod1 expression in air-exposed females than males, and higher HIP Gss expression in O 3 -exposed females relative to matched males. Microglial marker Aif1 expression was higher in O 3 -exposed females relative to males; O 3 inhibited Itgam only in males. The expression of Bdnf in HIP and HYP was inhibited by O 3 in both sexes. Genes related to glucocorticoid signaling (Fkbp4, Fkbp5, Hsp90aa1, Hspa4, nr3c1, nr3c2) showed sex-specific effects due to O 3 exposure. Baseline expression of HIP Fkbp4 was higher in females relative to males. O 3 inhibited Nr3c1 in female HIP and male HYP, but Nr3c2 was inhibited in male HYP. Fkbp4 expression was higher in O 3 -exposed females when compared to matched males, whereas Fkbp5 was expressed at higher levels in both brain regions of males and females. These results indicate that sex-specific brain region responses to O 3 might, in part, be caused by OS and regulation of glucocorticoid signaling.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Imprinting and Reproductive Health: A Toxicological Perspective

This overview discusses the role of imprinting in the development of an organism, and how exposure to environmental chemicals during fetal development leads to the physiological and biochemical changes that can have adverse lifelong effects on the health of the offspring. There has been a recent upsurge in the use of chemical products in everyday life. These chemicals include industrial byproducts, pesticides, dietary supplements, and pharmaceutical products. They mimic the natural estrogens and bind to estradiol receptors. Consequently, they reduce the number of receptors available for ligand binding. This leads to a faulty signaling in the neuroendocrine system during the critical developmental process of ‘imprinting’. Imprinting causes structural and organizational differentiation in male and female reproductive organs, sexual behavior, bone mineral density, and the metabolism of exogenous and endogenous chemical substances. Several studies conducted on animal models and epidemiological studies provide profound evidence that altered imprinting causes various developmental and reproductive abnormalities and other diseases in humans. Altered metabolism can be measured by various endpoints such as the profile of cytochrome P-450 enzymes (CYP450’s), xenobiotic metabolite levels, and DNA adducts. The importance of imprinting in the potentiation or attenuation of toxic chemicals is discussed.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Molecular Pathogenesis and Immune Evasion of Vesicular Stomatitis New Jersey Virus Inferred from Genes Expression Changes in Infected Porcine Macrophages

The molecular mechanisms associated with the pathogenesis of vesicular stomatitis virus (VSV) in livestock remain poorly understood. Several studies have highlighted the relevant role of macrophages in controlling the systemic dissemination of VSV during infection in different animal models, including mice, cattle, and pigs. To gain more insight into the molecular mechanisms used by VSV to impair the immune response in macrophages, we used microarrays to determine the transcriptomic changes produced by VSV infection in primary cultures of porcine macrophages. The results indicated that VSV infection induced the massive expression of multiple anorexic, pyrogenic, proinflammatory, and immunosuppressive genes. Overall, the interferon (IFN) response appeared to be suppressed, leading to the absence of stimulation of interferon-stimulated genes (ISG). Interestingly, VSV infection promoted the expression of several genes known to downregulate the expression of IFNβ. This represents an alternate mechanism for VSV control of the IFN response, beyond the recognized mechanisms mediated by the matrix protein. Although there was no significant differential gene expression in macrophages infected with a highly virulent epidemic strain compared to a less virulent endemic strain, the endemic strain consistently induced higher expression of all upregulated cytokines and chemokines. Collectively, this study provides novel insights into VSV molecular pathogenesis and immune evasion that warrant further investigation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Cell-free Scaled Production and Adjuvant Addition to a Recombinant Major Outer Membrane Protein from Chlamydia muridarum for Vaccine Development

Subunit vaccines offer advantages over more traditional inactivated or attenuated whole-cell-derived vaccines in safety, stability, and standard manufacturing. To achieve an effective protein-based subunit vaccine, the protein antigen often needs to adopt a native-like conformation. This is particularly important for pathogensurface antigens that are membrane-bound proteins. Cell-free methods have been successfully used to produce correctly folded functional membrane protein through the co-translation of nanolipoprotein particles (NLPs), commonly known as nanodiscs. This strategy can be used to produce subunit vaccines consisting of membrane proteins in a lipid-bound environment. However, cell-free protein production is often limited to small scale (<1 mL). The amount of protein produced in small-scale production runs is usually sufficient for biochemical and biophysical studies. However, the cell-free process needs to be scaled up, optimized, and carefully tested to obtain enough protein for vaccine studies in animal models. Other processes involved in vaccine production, such as purification, adjuvant addition, and lyophilization, need to be optimized in parallel. This paper reports the development of a scaled-up protocol to express, purify, and formulate a membrane-bound protein subunit vaccine

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1977

The chimpanzee as a flight candidate

Some of the characteristics that make the chimpanzee an attractive animal model (anatomy, size, intelligence, and durability) also create some very unique problems. The universally recognized problems of availability and expensive maintenance, combined with the often underestimated problems associated with routine housing, husbandry, restraint, and medical management, severely limit the availabe avenues of approach. Problems involved in using implantable, multichannel radiotelemetry systems to monitor cardiodynamics in chimpanzees are discussed.

Source record↗
NASA NTRS1982

Changes in blood volume and response to vaso-active drugs in horizontally casted primates

Experiments were performed on horizontally casted primates (male rhesus monkeys) in order to note changes in blood volume caused by horizontal restraint, to compare orthostatic tolerance before and after casting using the responses to upright tilting, to begin to uncover the cardiovascular and neural mechanisms involved in deconditioning, and to compare the data with that obtained from bed-rested human subjects and from humans exposed to weightlessness. Bolus injections of norepinephrine of 2.0 microgram/kg, phenylephrine of 4.0 microgram/kg, and nitroprusside of 2.0 microgram/kg were administered; and aortic pressure and heart rate were recorded during the injections. The results indicate that the horizontally casted primate is a valid animal model for studying the effects of simulated zero-G on the human cardiovascular system.

Dickey, D. T.↗
NASA NTRS1983

A study of stress-free living bone and its application to space flight

Observations of animals and human subjects in weightless space flight (Skylab and COSMOS) document altered bone metabolism. Bone metabolism is affected by a number of local and systemic factors. The calcification and growth of transplanted bone is independent of local muscle, nervous, and mechanical forces; therefore, transplanted bone would provide data on the role of local vs. systematic factors. Bone metabolism in living transplanted bone, devoid of stress, was investigated as a possible tool for the investigation of countermeasures against disuse bone loss. An animal model using Sprague-Dawley rats was developed for transplantation of femur bone tissue on a nutrient vascular pedicel. The long term course of these implants was assessed through the measure of regional and total bone mineral, blood flow, and methylene diphosphonate (MDP) uptake. Clomid, an estrogen agonist/antagonist, was shown to protect bone from disuse loss of minerals by retarding trabecular and cortical resorption.

Leblanc, A.↗
NASA NTRS1983

Spacelab mission 4 - The first dedicated life sciences mission

Plans for the first Spacelab-4 mission dedicated entirely to the life sciences, are reviewed. The thrust of the scientific mission scheduled for late 1985 will be to study the acute effects of weightlessness on living systems, particularly humans. The payload of the Spacelab compartment will contain 24 experiments of which approximately half will involve humans. Among the major areas of interest are cardiovascular and pulmonary function, vestibular function, renal and endocrine physiology, hematology, nitrogen balance, immunological function, the gravitational biology of plants, inflight fertilization of frogs' eggs and the effects of zero gravity on monkeys and rats. In selecting the array of experiments an effort was made to combine investigations with complementary scientific objectives to develop animal models of human biological problems.

Perry, T. W.↗
NASA NTRS1984

Alterations in bone forming cells due to reduced weight bearing

A reduction in new bone formation occurred as a result of space flight (Cosmos 1129) and in the suspended animal model of Morey-Holton (1979, 1980). The results indicate that alkaline phosphatase activity of the bone-forming cells is also reduced under these conditions, and the cells in the diaphysis are more affected than those in the metaphyseal region. In addition, these cells show (1) reduced proline incorporation into bone matrix, and (2) increased intracellular lysosomal activity. A change in the cytoskeleton could be the common factor in explaining these results. This suggestion is futher supported by the previous observations that colchicine injections result in decreased osteoblastic function.

Doty, S. B.↗
NASA NTRS1990

Experiment K-6-08. Biochemical and histochemical observations of vastus medialis

Muscles of the hindlimb in the rat have been used to demonstrate the effects of unloading in weightlessness and in animal models used to mimic weightlessness. The vastus medialis (VM) is discussed here. Samples were obtained from rats exposed to weightlessness for 12 days in Cosmos 1887 (Experiment K-6-08, coordinated by Dr. V.S. Oganov). The principal objective of this study was to ascertain if the vastus medialis responded to 12 days of microgravity exposure. The loss in muscle mass is greatest, -43 percent, when comparing F vs B, and least, -13 percent, when comparing F vs. V. Taken at face value these differences may be misleading. Due to the variability of the muscle weight in the basal group, these muscle mass losses may be exaggerated. In terms of percent water, there were no differences between the flight and the control groups. In spite of the limited sample, researchers conclude that muscle mass changes in the VM are not significant. Although some of the morphological parameters suggest a small degree of atrophy in the vastus medialis, the biochemical analyses (protein, RNA and DNA) suggest that these may be minimal and functionally nonsignificant. The relatively similar CS and LDH activities of VM from F and various control groups, as well as the lack of difference in LPL activity between F and S rats, suggests that there is little or no effect on the oxidative or glycolytic function of this muscle. Since the VM is chiefly a mixed fast twitch muscle, these metabolic indices of energy production are relatively unchanged. The results of VM studies are in agreement with previous observations of another type II fast twitch muscle, the EDL, from SL-3 rats which did not respond markedly to weightlessness and whole body suspension.

Musacchia, X. J.↗