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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 1,495 records · Page 83
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

Progressive effects of silver nanoparticles on hormonal regulation of reproduction in male rats

The growing use of silver nanoparticles (AgNPs) in various applications, including consumer, agriculture and medicine products, has raised many concerns about the potential risks of nanoparticles (NPs) to human health and the environment. An increasing body of evidence suggests that AgNPs may have adverse effects of humans, thus the aim of this study was to investigate the effects of AgNPs on the male reproductive system. Silver particles (20 nm AgNPs (groups Ag I and Ag II) and 200 nm Ag sub-micron particles (SPs) (group Ag III)) were administered intravenously to male Wistar rats at a dose of 5 (groups Ag I and Ag III) or 10 (group Ag II) mg/kg of body weight. The biological material was sampled 24 h, 7 days and 28 days after injection. The obtained results revealed that the AgNPs had altered the luteinising hormone concentration in the plasma and the sex hormone concentration in the plasma and testes. Plasma and intratesticular levels of testosterone and dihydrotestosterone were significantly decreased both 7 and 28 days after treatment. No change in the prolactin and sex hormone-binding globulin concentration was observed. Exposure of the animals to AgNPs resulted in a considerable decrease in 5α-reductase type 1 and the aromatase protein level in the testis. Additionally, expression analysis of genes involved in steroidogenesis and the steroids metabolism revealed significant down-regulation of Star, Cyp11a1, Hsd3b1, Hsd17b3 and Srd5a1 mRNAs in AgNPs/AgSPs-exposed animals. The present study demonstrates the potential adverse effect on the hormonal regulation of the male reproductive function following AgNP/AgSP administration, in particular alterations of the sex steroid balance and expression of genes involved in steroidogenesis and the steroids metabolism. - Highlights: • Assessment of the toxic effects of AgNPs/AgSPs on the regulation of male reproductive function • AgNP −/AgSP-induced alterations of sex steroid status in male Wistar rats. • Regulation of male reproductive function is differently modulated by AgNPs and AgSPs. • Endocrine-mediated toxicity of AgNPs/AgSPs increased over time. • AgNPs/AgSPs alter male reproductive function regulation at the transcriptional level.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Acute lung injury and persistent small airway disease in a rabbit model of chlorine inhalation

Chlorine is a pulmonary toxicant to which humans can be exposed through accidents or intentional releases. Acute effects of chlorine inhalation in humans and animal models have been well characterized, but less is known about persistent effects of acute, high-level chlorine exposures. In particular, animal models that reproduce the long-term effects suggested to occur in humans are lacking. Here, we report the development of a rabbit model in which both acute and persistent effects of chlorine inhalation can be assessed. Male New Zealand White rabbits were exposed to chlorine while the lungs were mechanically ventilated. After chlorine exposure, the rabbits were extubated and were allowed to survive for up to 24 h after exposure to 800 ppm chlorine for 4 min to study acute effects or up to 7 days after exposure to 400 ppm for 8 min to study longer term effects. Acute effects observed 6 or 24 h after inhalation of 800 ppm chlorine for 4 min included hypoxemia, pulmonary edema, airway epithelial injury, inflammation, altered baseline lung mechanics, and airway hyperreactivity to inhaled methacholine. Seven days after recovery from inhalation of 400 ppm chlorine for 8 min, rabbits exhibited mild hypoxemia, increased area of pressure–volume loops, and airway hyperreactivity. Lung histology 7 days after chlorine exposure revealed abnormalities in the small airways, including inflammation and sporadic bronchiolitis obliterans lesions. Immunostaining showed a paucity of club and ciliated cells in the epithelium at these sites. These results suggest that small airway disease may be an important component of persistent respiratory abnormalities that occur following acute chlorine exposure. This non-rodent chlorine exposure model should prove useful for studying persistent effects of acute chlorine exposure and for assessing efficacy of countermeasures for chlorine-induced lung injury. - Highlights: • A novel rabbit model of chlorine-induced lung disease was developed. • Acute effects of chlorine were pulmonary edema, hypoxemia and impaired lung function. • Persistent small airway disease developed following recovery from acute injury. • Small airway disease included inflammation and bronchiolitis obliterans lesions. • The model should be useful for studying chlorine lung injury and testing treatments.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Distribution, lipid-bilayer affinity and kinetics of the metabolic effects of dinoseb in the liver

Dinoseb is a highly toxic pesticide of the dinitrophenol group. Its use has been restricted, but it can still be found in soils and waters in addition to being a component of related pesticides that, after ingestion by humans or animals, can originate the compound by enzymatic hydrolysis. As most dinitrophenols, dinoseb uncouples oxidative phosphorylation. In this study, distribution, lipid bilayer affinity and kinetics of the metabolic effects of dinoseb were investigated, using mainly the isolated perfused rat liver, but also isolated mitochondria and molecular dynamics simulations. Dinoseb presented high affinity for the hydrophobic region of the lipid bilayers, with a partition coefficient of 3.75 × 10{sup 4} between the hydrophobic and hydrophilic phases. Due to this high affinity for the cellular membranes dinoseb underwent flow-limited distribution in the liver. Transformation was slow but uptake into the liver space was very pronounced. For an extracellular concentration of 10 μM, the equilibrium intracellular concentration was equal to 438.7 μM. In general dinoseb stimulated catabolism and inhibited anabolism. Half-maximal stimulation of oxygen uptake in the whole liver occurred at concentrations (2.8–5.8 μM) at least ten times above those in isolated mitochondria (0.28 μM). Gluconeogenesis and ureagenesis were half-maximally inhibited at concentrations between 3.04 and 5.97 μM. The ATP levels were diminished, but differently in livers from fed and fasted rats. Dinoseb disrupts metabolism in a complex way at concentrations well above its uncoupling action in isolated mitochondria, but still at concentrations that are low enough to be dangerous to animals and humans even at sub-lethal doses. - Highlights: • Dinoseb presents high affinity for the hydrophobic region of the lipid bilayers. • Its cellular concentration may exceed the extracellular one by a factor of 43.9. • One order of magnitude separates the active concentrations in mitochondria and liver. • Hepatic metabolism is disrupted in the concentration range up to 10 μM.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Molecular evidence of offspring liver dysfunction after maternal exposure to zinc oxide nanoparticles

Recently, reproductive, embryonic and developmental toxicity have been considered as one important sector of nanoparticle (NP) toxicology, with some studies already suggesting varying levels of toxicity and possible transgenerational toxic effects. Even though many studies have investigated the toxic effects of zinc oxide nanoparticles (ZnO NPs), little is known of their impact on overall reproductive outcome and transgenerational effects. Previously we found ZnO NPs caused liver dysfunction in lipid synthesis. This investigation, for the first time, explored the liver dysfunction at the molecular level of gene and protein expression in offspring after maternal exposure to ZnO NPs. Three pathways were investigated: lipid synthesis, growth related factors and cell toxic biomarkers/apoptosis at 5 different time points from embryonic day-18 to postnatal day-20. It was found that the expression of 15, 16, and 16 genes in lipid synthesis, growth related factors and cell toxic biomarkers/apoptosis signalling pathway respectively in F1 animal liver were altered by ZnO NPs compared to ZnSO{sub 4}. The proteins in these signalling pathways (five in each pathways analyzed) in F1 animal liver were also changed by ZnO NPs compared to ZnSO{sub 4}. The results suggest that ZnO NPs caused maternal liver defects can also be detected in offspring that might result in problems on offspring liver development, mainly on lipid synthesis, growth, and lesions or apoptosis. Along with others, this study suggests that ZnO NPs may pose reproductive, embryonic and developmental toxicity; therefore, precautions should be taken with regard to human exposure during daily life. - Highlights: • Oral ZnO NPs exposure caused abnormal gene and protein expression in offspring liver. • Oral ZnO NPs exposure could induce inheritance impacts on liver development. • Oral ZnO NPs exposure could be considered as developmental hazardous material.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Microbiome breeding: conceptual and practical issues

Microbiome breeding is a new artificial selection technique that seeks to change the genetic composition of microbiomes in order to benefit plant or animal hosts. Recent experimental and theoretical analyses have shown that microbiome breeding is possible whenever microbiome-encoded genetic factors affect host traits (e.g., health) and microbiomes are transmissible between hosts with sufficient fidelity, such as during natural microbiome transmission between individuals of social animals, or during experimental microbiome transplanting between plants. Further, to address misunderstandings that stymie microbiome-breeding programs, we (i) clarify and visualize the corresponding elements of microbiome selection and standard selection; (ii) elucidate the eco-evolutionary processes underlying microbiome selection within a quantitative genetic framework to summarize practical guidelines that optimize microbiome breeding; and (iii) characterize the kinds of host species most amenable to microbiome breeding.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

In vitro metabolism of benzo[a]pyrene-7,8-dihydrodiol and dibenzo[def,p]chrysene-11,12 diol in rodent and human hepatic microsomes

Polycyclic aromatic hydrocarbons (PAHs) are contaminants that are ubiquitously found in the environment, produced through combustion of organic matter or petrochemicals, and many of which are procarcinogens. The prototypic PAH, benzo[a]pyrene (B[a]P) and the highly carcinogenic dibenzo[def,p]chrysene (DBC) are metabolically activated by isoforms of the P450 enzyme superfamily producing benzo[a]pyrene-7,8-dihydrodiol (B[a]P diol), dibenzo[def,p]chrysene-11,12 diol (DBC diol). Each of these diols can be further metabolized by cytochrome P450 enzymes to highly reactive diol-epoxide metabolites that readily react with DNA or by phase II conjugation facilitating excretion. To complement prior in vitro metabolism studies with parent B[a]P and DBC, both phase I metabolism and phase II glucuronidation of B[a]P diol and DBC diol were measured in hepatic microsomes from female B6129SF1/J mice, male Sprague-Dawley rats, and female humans. Metabolic parameters, including intrinsic clearance and Michaelis-Menten kinetics were calculated from substrate depletion data. Mice and rats demonstrated similar B[a]P diol phase I metabolic rates. Compared to rodents, human phase I metabolism of B[a]P diol demonstrated lower overall metabolic capacity, lower intrinsic clearance at higher substrate concentrations (>0.14 µM), and higher intrinsic clearance at lower substrate concentrations (<0.07 µM). Rates of DBC diol metabolism did not saturate in mice or humans and were highest overall in mice. Higher affinity constants and lower capacities were observed for DBC diol glucuronidation compared to B[a]P diol glucuronidation; however, intrinsic clearance values for these compounds were consistent within each species. Kinetic parameters reported here will be used to extend physiologically based pharmacokinetic (PBPK) models to include the disposition of B[a]P and DBC metabolites in animal models and humans to support future human health risk assessments.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Driving in the dark: Deciphering nighttime driver detection of free-ranging roadside wildlife

Wildlife-vehicle collisions are dangerous for motorists; however, few studies have addressed driver detection of roadside animals, and none have evaluated detection of free-ranging wildlife. Here, we used 24 volunteer drivers, infrared videography, a 75-km route, and free-ranging wildlife to quantify factors influencing (1) probability of wildlife detection, (2) detection distance, and (3) probability of dangerous encounters (i.e., detection distance < distance required for braking) for multiple species at night in South Carolina, USA. Detection probability of white-tailed deer (Odocoileus virginianus) was impacted by multiple driver, animal, and roadside factors. Deer detection distances increased by 20.99 m when drivers used high-beam headlights and 23.36 m when deer were moving but decreased by 0.71 m for every minute into a drive. Every encounter with wild pigs (Sus scrofa) and most encounters with small mammals were considered dangerous. Our findings suggest most drivers cannot safely detect deer, wild pigs, and small mammals at night.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2015

Small particle aerosol inoculation of cowpox Brighton Red in rhesus monkeys results in a severe respiratory disease

Cowpox virus (CPXV) inoculation of nonhuman primates (NHPs) has been suggested as an alternate model for smallpox (Kramski et al., 2010, PLoS One, 5, e10412). Previously, we have demonstrated that intrabronchial inoculation of CPXV-Brighton Red (CPXV-BR) into cynomolgus monkeys resulted in a disease that shared many similarities to smallpox; however, severe respiratory tract disease was observed (Smith et al., 2011, J. Gen. Virol.). Here we describe the course of disease after small particle aerosol exposure of rhesus monkeys using computed tomography (CT) to monitor respiratory disease progression. Subjects developed a severe respiratory disease that was uniformly lethal at 5.7 log{sub 10} PFU of CPXV-BR. CT indicated changes in lung architecture that correlated with changes in peripheral blood monocytes and peripheral oxygen saturation. While the small particle aerosol inoculation route does not accurately mimic human smallpox, the data suggest that CT can be used as a tool to monitor real-time disease progression for evaluation of animal models for human diseases. - Highlights: • Small particle aerosol exposure of rhesus results in a severe respiratory disease. • CT findings correlated with peripheral oxygen saturation and monocyte increases. • Virus dissemination was limited and mainly confined to the respiratory tract. • CT provides insight into pathogenesis to aid development of animal models of disease.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

An historical note on the cell theory

The development of the microscope was a precondition for the discovery of cells. This instrument magnifies objects too small to be seen by the naked eye. In 1673, the Dutch botanist, Anton van Leeuwenhoek, made a more advanced microscope and reported seeing a myriad of microscopic “animalcules” in water. He also made further studies of red blood cells and sperm cells. Most studies that followed were done on the easily studied plant tissues. Plant cells, rigidly encased in their cell walls, were ideal to study in situ. The cell theory proposes that nucleated cells are the basic structure of plants and animals. This concept was observed and published separately, first by the botanist, Matthias Schleiden, in 1838, and then by the zoologist, Theodor Schwann, in 1839. Their work demonstrated that cells form the basic unit of life of plants and animals. Rudolf Virchow concluded that all living organisms are the sum of single cellular units and that cells multiply.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Egr-1 mediated cardiac miR-99 family expression diverges physiological hypertrophy from pathological hypertrophy

The physiological cardiac hypertrophy is an adaptive condition without myocyte cell death, while pathological hypertrophy is a maladaptive condition associated with myocyte cell death. This study explores the miRNome of α-2M-induced physiologically hypertrophied cardiomyocytes and the role of miRNA-99 family during cardiac hypertrophy. Physiological and pathological cardiac hypertrophy was induced in H9c2 cardiomyoblast cell lines using α-2M and isoproterenol respectively. Total RNA isolation and small RNA sequencing were executed for physiological hypertrophy model. The differentially expressed miRNAs and its target mRNAs were validated in animal models. Transcription factor binding sites were predicted in the promoter of specific miRNAs and validated by ChIP-PCR. Subsequently, the selected miRNA was functionally characterized by overexpression and silencing. The effects of silencing of upstream regulator and downstream target gene were studied. Analysis of small RNA reads revealed the differential expression of a large set of miRNAs during hypertrophy, of which miR-99 family was highly downregulated upon α-2M treatment. However, this miR-99 family expression was upregulated during pathological hypertrophy and confirmed in animal models. ChIP-PCR confirms the binding of Egr-1 transcription factor to the miR-99 promoter. Further, silencing of Egr-1 decreased the expression of miR-99. The overexpression or silencing of miR-99 diverges the physiological hypertrophy to pathological hypertrophy and vice versa by regulating Akt-1 pathway. Silencing of Akt-1 replicates the effect of overexpression of miR-99.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Absorption and Phase Contrast X-Ray Imaging in Paleontology Using Laboratory and Synchrotron Sources

X-ray micro-computed tomography (CT) is commonly used for imaging of samples in biomedical or materials science research. Owing to the ability to visualize a sample in a nondestructive way, X-ray CT is perfectly suited to inspect fossilized specimens, which are mostly unique or rare. In certain regions of the world where important sedimentation events occurred in the Precambrian geological time, several fossilized animals are studied to understand questions related to their origin, environment, and life evolution. This article demonstrates the advantages of applying absorption and phase-contrast CT on the enigmatic fossil Corumbella werneri, one of the oldest known animals capable of building hard parts, originally discovered in Corumba (Brazil). Different tomographic setups were tested to visualize the fossilized inner structures: a commercial laboratory-based CT device, two synchrotron-based imaging setups using conventional absorption and propagation-based phase contrast, and a commercial X-ray microscope with a lens-coupled detector system, dedicated for radiography and tomography. Based on our results we discuss the strengths and weaknesses of the different imaging setups for paleontological studies.

Corumbella werneri↗
DOE OSTI2017

Bacillus anthracis Prolyl 4-Hydroxylase Interacts with and Modifies Elongation Factor Tu

Prolyl hydroxylation is a very common post-translational modification and plays many roles in eukaryotes such as collagen stabilization, hypoxia sensing, and controlling protein transcription and translation. There is a growing body of evidence that suggests that prokaryotes contain prolyl 4-hydroxylases (P4Hs) homologous to the hypoxia-inducible factor (HIF) prolyl hydroxylase domain (PHD) enzymes that act on elongation factor Tu (EFTu) and are likely involved in the regulation of bacterial translation. Recent biochemical and structural studies with a PHD from Pseudomonas putida (PPHD) determined that it forms a complex with EFTu and hydroxylates a prolyl residue of EFTu. Moreover, while animal, plant, and viral P4Hs act on peptidyl proline, most prokaryotic P4Hs have been known to target free l-proline; the exceptions include PPHD and a P4H from Bacillus anthracis (BaP4H) that modifies collagen-like proline-rich peptides. Here we use biophysical and mass spectrometric methods to demonstrate that BaP4H recognizes full-length BaEFTu and a BaEFTu 9-mer peptide for site-specific proline hydroxylation. Using size-exclusion chromatography coupled small-angle X-ray scattering (SEC–SAXS) and binding studies, we determined that BaP4H forms a 1:1 heterodimeric complex with BaEFTu. The SEC–SAXS studies reveal dissociation of BaP4H dimeric subunits upon interaction with BaEFTu. While BaP4H is unusual within bacteria in that it is structurally and functionally similar to the animal PHDs and collagen P4Hs, respectively, this work provides further evidence of its promiscuous substrate recognition. Lastly, it is possible that the enzyme might have evolved to hydroxylate a universally conserved protein in prokaryotes, similar to the PHDs, and implies a functional role in B. anthracis.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2016

Human Microdosing with Carcinogenic Polycyclic Aromatic Hydrocarbons: In Vivo Pharmacokinetics of Dibenzo[ def,p ]chrysene and Metabolites by UPLC Accelerator Mass Spectrometry

Metabolism is a key health risk factor following exposures to pro-carcinogenic polycyclic aromatic hydrocarbons (PAHs) such as dibenzo[def,p]chrysene (DBC), an IARC classified 2A probable human carcinogen. Human exposure to PAHs occurs primarily from the diet in non-smokers. However, little data is available on the metabolism and pharmacokinetics in humans of high molecular weight PAHs (≥4 aromatic rings), including DBC. We previously determined the pharmacokinetics of DBC in human volunteers orally administered a micro-dose (29 ng; 5 nCi) of [14C]-DBC by accelerator mass spectrometry (AMS) analysis of total [14C] in plasma and urine. In the current study, we utilized a novel “moving wire” interface between ultra-performance liquid chromatography (UPLC) and AMS to detect and quantify parent DBC and its major metabolites. The major [14C] product identified in plasma was unmetabolized [14C]-DBC itself, (Cmax= 18.5 ± 15.9 fg/mL, Tmax= 2.1 ± 1.0 h), whereas the major metabolite was identified as [14C]-(+/-)-DBC-11,12-diol (Cmax= 2.5 ± 1.3 fg/mL, Tmax= 1.8 h). Several minor species of [14C]-DBC metabolites were also detected for which no reference standards were available. Free and conjugated metabolites were detected in urine with [14C]-(+/-)-DBC-11,12,13,14-tetraol isomers identified as the major metabolites, 56.3% of which were conjugated (Cmax= 35.8 ± 23.0 pg/pool, Tmax= 6-12 h pool). [14C]-DBC-11,12-diol, of which 97.5% was conjugated, was also identified in urine (Cmax= 29.4 ± 11.6 pg/pool, Tmax= 6-12 h pool). Parent [14C]-DBC was not detected in urine. This is the first dataset to assess metabolite profiles and associated pharmacokinetics of a carcinogenic PAH in human volunteers at an environmentally relevant dose, providing the data necessary for translation of high dose animal models to humans for translation of environmental health risk assessment.

Madeen, Erin P.↗
DOE OSTI2025

Introduction: Neuromorphic Materials

The explosive growth in data collection and the need to process it efficiently, as well as the desire to automate increasingly complex tasks in transportation, medical care, manufacturing, security and many other fields have motivated a growing interest in neuromorphic computing. Unlike the binary, transistorbased ON/OFF logic gates and separate logic and memory functionalities employed in digital computing, neuromorphic computing is inspired by animal brains that use interconnected synapses and neurons to perform processing, storage and transmission of information at the same location, while only consuming ~20 W or less of power. Motivated by the brain’s efficiency, adaptability, self-learning and resiliency qualities, neuromorphic computing can be broadly defined as an approach to processing and storing information using hardware and algorithms inspired by models of biological neural systems. Present research in neuromorphic computing encompasses approaches that vary significantly in their degree of neuro-inspiration, from systems that only incorporate features such as asynchronous, event-driven operation or use crossbar arrays of non-volatile memory (NVM) elements to accelerate deep neural networks (DNNs), to designs that embrace the extreme parallelism, sparsity, reconfigurability, adaptability, complexity and stochasticity observed in nervous systems. The term ‘neuromorphic’ computing is often credited to Carver Mead, who in the 1980s investigated Si-based analog electronics to replicate functions of the animal retina. Earlier important advances in this field include the work of Frank Rosenblatt, who proposed the concept of the perceptron, Bernard Widrow, who used this concept to build one of the first analog neural networks, the Adaline and many other researchers (see ref. 6 for an historical perspective on neuromorphic computing). With the recent increase in the use of artificial intelligence and large language models, and rising concerns over the associated energy costs, interest in neuromorphic hardware has expanded rapidly. According to some estimates, driven largely by the drastic growth in the training use of artificial intelligence (AI) models using the current computing architectures, the energy cost of computing is projected to reach the energy supply worldwide by 2045. Furthermore, while this is not a realistic outcome, it means that, if more efficient computing technologies are not developed -- soon -- the world will soon become one where demand for energy and market constraints limit the continued increase of societal access to AI and cloud services from data centers. Data centers used for training and use of these models consume hundreds of terawatt hours of electricity, already past 4% of the US electricity demand.

Circuits↗
DOE OSTI2026

Investigating the Theranostic Potential of Elementally Matched [ 43 Sc]Sc-PSMA-617 and [ 47 Sc]Sc-PSMA-617

The theranostic approach, which employs diagnostic radiopharmaceuticals to select patients who would benefit from targeted radiotherapy agents, has become an invaluable strategy for effective medical care. Scandium radionuclides offer the advantage of forming elementally matched and chemically identical diagnostic and therapeutic compounds, making them ideal candidates for this strategy. PSMA-617 is an established prostate-specific membrane antigen targeting agent and can be used as a proof of concept to investigate 43 Sc, the diagnostic nuclide, and 47 Sc, the therapeutic nuclide, as a theranostic pair. Methods: Cellular uptake, competitive binding assays, and internalization studies were carried out using LNCaP or PC-3 cell lines. [ 43 Sc]Sc-PSMA-617 was used in PET imaging studies in LNCaP or PC-3 tumor models, with time points ranging from 1–9 h. LNCaP tumor-bearing mice injected with [ 47 Sc]Sc-PSMA-617 were imaged using SPECT up to 48 h. A longitudinal study was carried out using LNCaP tumor-bearing mice imaged with [ 43 Sc]Sc-PSMA-617 prior to receiving a therapeutic dose of [ 47 Sc]Sc-PSMA-617. Results: 43 Sc and 47 Sc were incorporated into PSMA-617 at radiochemical yields of >99%. Cellular uptake studies demonstrated high uptake and specificity to PSMA receptors for [ 47 Sc]Sc-PSMA-617. In vivo PET studies showed specificity of [ 43 Sc]Sc-PSMA-617 while SPECT studies demonstrated tumor retention of [ 47 Sc]Sc-PSMA-617 up to 48 h. [ 47 Sc]Sc-PSMA-617 demonstrated therapeutic efficacy by delaying tumor growth and increasing survival rates from a single administered dose in xenograft models. More importantly, the PET results from [ 43 Sc]Sc-PSMA-617 PET were highly correlated with the therapeutic response from [ 47 Sc]Sc-PSMA-617, showing that 43 Sc PET data can predict therapeutic outcomes in individual animals from 47 Sc agents, even in animals sharing a genetic background and implanted with tumors from the same cell line. Conclusions: Two chemically identical, PSMA-targeting radioscandium pharmaceuticals demonstrated in vivo stability, specificity and retention in PSMA+ tumor models. A theranostic study showed that a higher 43 Sc PET SUVmean was strongly correlated to therapeutic response from the 47 Sc agent, demonstrating that 43 Sc and 47 Sc can be used as an elementally matched theranostic pair.

Biodistribution↗
DOE OSTI2023

Evaluation of Copper Chelation Therapy in a Transgenic Rat Model of Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of the amyloid β (Aβ) protein in blood vessels and leads to hemorrhages, strokes, and dementia in elderly individuals. Recent reports have shown elevated copper levels colocalized with vascular amyloid in human CAA and Alzheimer’s disease patients, which have been suggested to contribute to cytotoxicity through the formation of reactive oxygen species. Here, we treated a transgenic rat model of CAA (rTg-DI) with the copper-specific chelator, tetrathiomolybdate (TTM), via intraperitoneal (IP) administration for 6 months to determine if it could lower copper content in vascular amyloid deposits and modify CAA pathology. In this work, results showed that TTM treatment led to elevated Aβ load in the hippocampus of the rTg-DI rats and increased microbleeds in the wild type (WT) animals. X-ray fluorescence microscopy was performed to image the distribution of copper and revealed a surprising increase in copper colocalized with Aβ aggregates in TTM-treated rTg-DI rats. Unexpectedly, we also found an increase in the copper content in unaffected vessels of both rTg-DI and WT animals. These results show that IP administration of TTM was ineffective in removing copper from vascular Aβ aggregates in vivo and increased the development of disease pathology in CAA.

36 MATERIALS SCIENCE↗
DOE OSTI2025

Subventricular Accumulation of Cu in the Aging Mouse Brain Does Not Associate with Anticipated Increases in Markers of Oxidative Stress

Natural aging is associated with mild memory loss and cognitive decline, and age is the greatest risk factor for neurodegenerative diseases, such as Alzheimer’s disease. There is substantial evidence that oxidative stress is a major contributor to both natural aging and neurodegenerative disease, and coincidently, levels of redox active metals such as Fe and Cu are known to be elevated later in life. Recently, a pronounced age-related increase in Cu content has been reported to occur in mice and rats around a vital regulatory brain region, the subventricular zone of lateral ventricles. In our study herein, we have characterized lateral ventricle Cu content in a unique murine model of accelerated aging, senescence accelerated mouse-prone 8 (SAMP8) mice. Our results confirm an age-related increase in ventricle Cu content, consistent with the studies by others in wild-type mice and rats. Specifically, we observed Cu content to increase over the time frame 1 to 5 months and 5 to 9 months, but interestingly, no significant increase occurred between 9 and 12 months (although brain Cu content at 12 months was significantly elevated relative to 1 and 5 month-old animals). Despite the magnitude of Cu increase observed within the cells that comprise the subventricular zone of lateral ventricles (average 3 mM Cu, with isolated subcellular concentrations of 17 mM), we did not detect spectroscopic markers of thiol oxidation, protein aggregation, or lipid oxidation. The lack of evidence for oxidative stress in ex vivo animal tissue is in contrast to in vitro studies demonstrating that thiol, protein, and lipid oxidation is pronounced at these Cu concentrations. We suggest that our findings most likely indicate that the Cu ions in this brain region are sequestered in an unreactive form, possibly extended chains of Cu-thiolate complexes, which do not readily redox cycle in the aqueous cytosol. In conclusion, these results also appear to partially challenge the long-held view that age-related increases in brain metal content drive oxidative stress as we did not observe a concomitant association between age-related Cu increase and markers of oxidative stress, nor did we observe a net increase in Cu content between mice aged 9 and 12 months.

X-ray fluorescence↗
DOE OSTI2020

Nutrient Capture from Aqueous Waste and Photocontrolled Fertilizer Delivery to Tomato Plants Using Fe(III)–Polysaccharide Hydrogels

Inexpensive and sustainable methods are needed to reclaim nutrients from agricultural waste solutions for use as a fertilizer while decreasing nutrient runoff. Fe(III)–polysaccharide hydrogels are able to flocculate solids and absorb nutrients in liquid animal waste from Confined Animal Feeding Operations (CAFOs). Fe(III)–alginate beads absorbed 0.05 mg g –1 NH 4 + and NO 3 - from 100 ppm solutions at pH = 7, with > 80% phosphate uptake and ~30% uptake of ammonium and nitrate. Ammonium uptake from a raw manure solution (1420 ppm NH 4 + ) showed a significant 0.7 mg g –1 uptake. Tomato plant trials carried out with Fe(III)–alginate hydrogel beads in greenhouse conditions showed controlled nutrient delivery for the plants compared to fertilizer solution with the same nutrient content. Plants showed an uptake of Fe from the gel beads, and Fe(III)–alginate hydrogel beads promoted root growth of the plants. The plants treated with nutrient-loaded Fe(III)–alginate hydrogels yielded comparable tomato harvest to plants treated with the conventional fertilizer solution.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗