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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 1,531 records · Page 85
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Harmonizing model organism data in the Alliance of Genome Resources

The Alliance of Genome Resources (the Alliance) is a combined effort of 7 knowledgebase projects: Saccharomyces Genome Database, WormBase, FlyBase, Mouse Genome Database, the Zebrafish Information Network, Rat Genome Database, and the Gene Ontology Resource. The Alliance seeks to provide several benefits: better service to the various communities served by these projects; a harmonized view of data for all biomedical researchers, bioinformaticians, clinicians, and students; and a more sustainable infrastructure. The Alliance has harmonized cross-organism data to provide useful comparative views of gene function, gene expression, and human disease relevance. The basis of the comparative views is shared calls of orthology relationships and the use of common ontologies. The key types of data are alleles and variants, gene function based on gene ontology annotations, phenotypes, association to human disease, gene expression, protein–protein and genetic interactions, and participation in pathways. The information is presented on uniform gene pages that allow facile summarization of information about each gene in each of the 7 organisms covered (budding yeast, roundworm Caenorhabditis elegans, fruit fly, house mouse, zebrafish, brown rat, and human). The harmonized knowledge is freely available on the alliancegenome.org portal, as downloadable files, and by APIs. We expect other existing and emerging knowledge bases to join in the effort to provide the union of useful data and features that each knowledge base currently provides.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

The Efficacy and Safety of an Intra-articular Dual-Acting Antibacterial Agent (TNP-2092) for Implant Infection–Associated Methicillin-Resistant Staphylococcus aureus

Abstract Owing to the presence of microbial biofilm on the implant, the eradication of biofilm-associated infections poses a challenge for antibiotic therapies. The study aimed to investigate the efficacy and safety of the novel antibiotic agent TNP-2092 in the context of implant infections. In vivo, rats with periprosthetic joint infection (PJI) treated with antibiotics showed an increase in body weight and decrease in swelling, temperature, and width of knee, compared with the control group. Meanwhile, inflammatory markers in synovium and serum were decreased in the TNP-2092 group, consistent with the pathological results. Moreover, TNP-2092 was effective in eliminating bacteria and disruption biofilm formation, and further alleviated the abnormal bone absorption and reactive bone changes around the prosthesis. In conclusion, intra-articular injection of TNP-2092 is safe and effective in treating knee PJI in a rat model. The study provides a foundation for the future utilization of TNP-2092 in the management of implant-related infections.

Dai, Tianyu↗
DOE OSTI2021

Assessment of Clonal Expansion Using CarcSeq Measurement of Lung Cancer Driver Mutations and Correlation With Mouse Strain- and Sex-Related Incidence of Spontaneous Lung Neoplasia

Quantification of variation in levels of spontaneously occurring cancer driver mutations (CDMs) was developed to assess clonal expansion and predict future risk of neoplasm development. Specifically, an error-corrected next-generation sequencing method, CarcSeq, and a mouse CarcSeq panel (analogous to human and rat panels) were developed and used to quantify low-frequency mutations in a panel of amplicons enriched in hotspot CDMs. Mutations in a subset of panel amplicons, Braf, Egfr, Kras, Stk11, and Tp53, were related to incidence of lung neoplasms at 2 years. This was achieved by correlating median absolute deviation (MAD) from the overall median mutant fraction (MF) measured in the lung DNA of 16-week-old male and female, B6C3F1 and CD-1 mice (10 mice/sex/strain) with percentages of spontaneous alveolar/bronchioloalveolar adenomas and carcinomas reported in bioassay control groups. A total of 1586 mouse lung mutants with MFs > x 10-4 were recovered. The ratio of nonsynonymous to synonymous mutations was used to assess the proportion of recovered mutations conferring a positive selective advantage. The greatest ratio was observed in what is considered the most lung tumor-sensitive model examined, male B6C3F1 mice. Of the recurrent, nonsynonymous mouse mutations recovered, 55.5% have been reported in human tumors, with many located in or around the mouse equivalent of human cancer hotspot codons. MAD for the same subset of amplicons measured in normal human lung DNA samples showed a correlation of moderate strength and borderline significance with age (a cancer risk factor), as well as age-related cumulative lung cancer risk, suggesting MAD may inform species extrapolation.

Toxicology↗
DOE OSTI2020

HIV influences microtubule associated protein-2: potential marker of HIV-associated neurocognitive disorders

Postmortem brains of patients diagnosed with HIV-1-associated neurocognitive disorders (HAND) exhibit loss of dendrites. However, the mechanisms by which synapses are damaged are not fully understood. Dendrite length and remodeling occurs via microtubules, the dynamics of which are regulated by microtubule-binding proteins, including microtubule-associated protein 2 (MAP2). The HIV protein gp120 is neurotoxic and interferes with neuronal microtubules. We measured MAP2 concentrations in human cerebrospinal fluid (CSF) and MAP2 immunoreactivity in rat cortical neurons exposed to HIV and gp120. First, we examined whether HIV affects MAP2 levels by analyzing the CSF of 27 persons living with HIV (PLH) whose neurocognitive performance had been characterized. We then used rat cortical neurons to study the mechanisms of HIV-mediated dendritic loss. PLH who had HAND had greater MAP2 concentrations within the CSF than cognitive normal PLH. In cortical neurons, the deleterious effect of HIV on MAP2-positive dendrites occurred through a gp120-mediated mechanism. The neurotoxic effect of HIV was blocked by a CCR5 antagonist and prevented by Helix-A, a peptide that displaces gp120 from binding to microtubules, conjugated to a nanolipoprotein particle delivery platform. Our findings support that HIV at least partially effects its neurotoxicity via neuronal cytoskeleton modifications and provide evidence of a new therapeutic compound that could be used to prevent the HIV-associated neuropathology.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Paternal preconception alcohol consumption increased Angiotensin II‐mediated vasoconstriction in male offspring cerebral arteries via oxidative stress‐AT1R pathway

Abstract Alcohol consumption is popular worldwidely and closely associated with cardiovascular diseases. Influences of paternal preconception alcohol consumption on offspring cerebral arteries are largely unknown. Male rats were randomly given alcohol or water before being mated with alcohol‐naive females to produce alcohol‐ and control‐sired offspring. Middle cerebral artery (MCA) was tested with a Danish Myo Technology wire myograph, patch‐clamp, IONOPTIX, immunofluorescence and quantitative PCR. Alcohol consumption enhanced angiotensin II (AngII)‐mediated constriction in male offspring MCA mainly via AT1R. PD123,319 only augmented AngII‐induced constriction in control offspring. AngII and Bay K8644 induced stronger intracellular calcium transient in vascular smooth muscle cells (VSMCs) from MCA of alcohol offspring. L‐type voltage‐dependent calcium channel (L‐Ca 2+ ) current at baseline and after AngII‐stimulation was higher in VSMCs. Influence of large‐conductance calcium‐activated potassium channel (BK C a ) was lower. Caffeine induced stronger constriction and intracellular calcium release in alcohol offspring. Superoxide anion was higher in alcohol MCA than control. Tempol and thenoyltrifluoroacetone alleviated AngII‐mediated contractions, while inhibition was significantly higher in alcohol group. The mitochondria were swollen in alcohol MCA. Despite lower Kcnma1 and Prkce expression, many genes expressions were higher in alcohol group. Hypoxia induced reactive oxygen species production and increased AT1R expression in control MCA and rat aorta smooth muscle cell line. In conclusion, this study firstly demonstrated paternal preconception alcohol potentiated AngII‐mediated vasoconstriction in offspring MCA via ROS‐AT1R. Alcohol consumption increased intracellular calcium via L‐Ca 2+ channel and endoplasmic reticulum and decreased BK Ca function. The present study provided new information for male reproductive health and developmental origin of cerebrovascular diseases.

Zhang, Ze↗
DOE OSTI2022

Thick filament activation is different in fast- and slow-twitch skeletal muscle

The contractile properties of fast-twitch and slow-twitch skeletal muscles are primarily determined by the myosin isoform content and modulated by a variety of sarcomere proteins. X-ray diffraction studies of regulatory mechanisms in muscle contraction have focused predominately on fast- or mixed-fibre muscle with slow muscle being much less studied. Here, we used time-resolved X-ray diffraction to investigate the dynamic behaviour of the myofilament proteins in relatively pure slow-twitch-fibre rat soleus (SOL) and pure fast-twitch-fibre rat extensor digitorum longus (EDL) muscle during twitch and tetanic contractions at optimal length. During twitch contractions the diffraction signatures indicating a transition in the myosin heads from ordered OFF states, where heads are held close to the thick filament backbone, to disordered ON states, where heads are free to bind to thin filaments, were found in EDL and not in SOL muscle. During tetanic contraction, changes in the disposition of myosin heads as active tension develops is a quasi-stepwise process in EDL muscle whereas in SOL muscle this relationship appears to be linear. The observed reduced extensibility of the thick filaments in SOL muscle as compared to EDL muscles indicates a molecular basis for this behaviour. These data indicate that for the EDL, thick filament activation is a cooperative strain-induced mechano-sensing mechanism, whereas for the SOL, thick filament activation has a more graded response. Further, these different approaches to thick filament regulation in fast- and slow-twitch muscles may be adaptations for short-duration, strong contractions versus sustained, finely controlled contractions, respectively.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Predicting Volume of Distribution in Humans: Performance of In Silico Methods for a Large Set of Structurally Diverse Clinical Compounds

Volume of distribution at steady state (V D,ss ) is one of the key pharmacokinetic parameters estimated during the drug discovery process. Despite considerable efforts to predict V D,ss , accuracy and choice of prediction methods remain a challenge, with evaluations constrained to a small set (<150) of compounds. To address these issues, a series of in silico methods for predicting human V D,ss directly from structure were evaluated using a large set of clinical compounds. Machine learning (ML) models were built to predict V D,ss directly and to predict input parameters required for mechanistic and empirical V D,ss predictions. In addition, log D, fraction unbound in plasma (fup), and blood-to-plasma partition ratio (BPR) were measured on 254 compounds to estimate the impact of measured data on predictive performance of mechanistic models. Furthermore, the impact of novel methodologies such as measuring partition (Kp) in adipocytes and myocytes (n = 189) on V D,ss predictions was also investigated. In predicting V D,ss directly from chemical structures, both mechanistic and empirical scaling using a combination of predicted rat and dog V D,ss demonstrated comparable performance (62%–71% within 3-fold). The direct ML model outperformed other in silico methods (75% within 3-fold, r 2 = 0.5, AAFE = 2.2) when built from a larger data set. Scaling to human from predicted V D,ss of either rat or dog yielded poor results (<47% within 3-fold). Measured fup and BPR improved performance of mechanistic V D,ss predictions significantly (81% within 3-fold, r 2 = 0.6, AAFE = 2.0). Adipocyte intracellular Kp showed good correlation to the V D,ss but was limited in estimating the compounds with low V D,ss .

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Bioadhesive polymer semiconductors and transistors for intimate biointerfaces

The use of bioelectronic devices relies on direct contact with soft biotissues. For transistor-type bioelectronic devices, the semiconductors that need to have direct interfacing with biotissues for effective signal transduction do not adhere well with wet tissues, thereby limiting the stability and conformability at the interface. Here we report a bioadhesive polymer semiconductor through a double-network structure formed by a bioadhesive brush polymer and a redox-active semiconducting polymer. The resulting semiconducting film can form rapid and strong adhesion with wet tissue surfaces together with high charge-carrier mobility of ~1 square centimeter per volt per second, high stretchability, and good biocompatibility. Further fabrication of a fully bioadhesive transistor sensor enabled us to produce high-quality and stable electrophysiological recordings on an isolated rat heart and in vivo rat muscles.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2021

Species Extrapolation of Propyl Acetate Dose Metrics

We demonstrate the ability of the propyl PBPK model to predict dose metrics of propyl acetate, propanol, and propionic acid from a standard 90-day subchronic inhalation study of propyl acetate in male and female rats. The model was used to predict the same dose metrics in “reference” male and female humans using the same exposure conditions. Finally, we used reverse dosimetry with the model to predict what exposure conditions would lead to the same dose metrics measured in rats. These extrapolations of internal dose metrics based on known species differences in physiology and measured differences in metabolism offer a more scientific species extrapolation than conventional uncertainty approaches, potentially of interest for risk assessment.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗
DOE OSTI2023

Developmental exposure to corn grown on Lake Erie dredged material: a preliminary analysis

While corn is considered to be a healthy food option, common agricultural practices, such as the application of soil amendments, might be introducing contaminants of concern (COC) into corn plants. The use of dredged material, which contain contaminants such as heavy metals, polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs), as a soil amendment is increasing. Contaminants from these amendments can accumulate in corn kernels harvested from plants grown on these sediments and potentially biomagnify in organisms that consume them. The extent to which secondary exposure to such contaminants in corn affect the mammalian central nervous system has been virtually unexplored. In this preliminary study, we examine the effects of exposure to corn grown in dredge amended soil or a commercially available feed corn on behavior and hippocampal volume in male and female rats. Perinatal exposure to dredge-amended corn altered behavior in the open-field and object recognition tasks in adulthood. Additionally, dredge-amended corn led to a reduction in hippocampal volume in male but not female adult rats. These results suggest the need for future studies examining how dredge-amended crops and/or commercially available feed corn may be exposing animals to COC that can alter neurodevelopment in a sex-specific manner. This future work will provide insight into the potential long-term consequences of soil amendment practices on the brain and behavior.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Preliminary Evaluations of [ 11 C]Verubulin: Implications for Microtubule Imaging With PET

[ 11 C]Verubulin (a.k.a.[ 11 C]MCP-6827), [ 11 C]HD-800 and [ 11 C]colchicine have been developed for imaging microtubules (MTs) with positron emission tomography (PET). The objective of this work was to conduct an in vivo comparison of [ 11 C]verubulin for MT imaging in mouse and rat brain, as well as an in vitro study with this radiotracer in rodent and human Alzheimer’s Disease tissue. Our preliminary PET imaging studies of [ 11 C]verubulin in rodents revealed contradictory results between mouse and rat brain uptake under pretreatment conditions. In vitro autoradiography with [ 11 C]verubulin showed an unexpected higher uptake in AD patient tissue compared with healthy controls. We also conducted the first comparative in vivo PET imaging study with [ 11 C]verubulin, [ 11 C]HD-800 and [ 11 C]colchicine in a non-human primate. [ 11 C]Verubulin and [ 11 C]HD-800 require pharmacokinetic modeling and quantification studies to understand the role of how these radiotracers bind to MTs before translation to human use.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Simulated Microgravity Alters Gene Regulation Linked to Immunity and Cardiovascular Disease

Microgravity exposure induces a cephalad fluid shift and an overall reduction in physical activity levels which can lead to cardiovascular deconditioning in the absence of countermeasures. Future spaceflight missions will expose crew to extended periods of microgravity among other stressors, the effects of which on cardiovascular health are not fully known. In this study, we determined cardiac responses to extended microgravity exposure using the rat hindlimb unloading (HU) model. We hypothesized that exposure to prolonged simulated microgravity and subsequent recovery would lead to increased oxidative damage and altered expression of genes involved in the oxidative response. To test this hypothesis, we examined hearts of male (three and nine months of age) and female (3 months of age) Long–Evans rats that underwent HU for various durations up to 90 days and reambulated up to 90 days post-HU. Results indicate sex-dependent changes in oxidative damage marker 8-hydroxydeoxyguanosine (8-OHdG) and antioxidant gene expression in left ventricular tissue. Three-month-old females displayed elevated 8-OHdG levels after 14 days of HU while age-matched males did not. In nine-month-old males, there were no differences in 8-OHdG levels between HU and normally loaded control males at any of the timepoints tested following HU. RNAseq analysis of left ventricular tissue from nine-month-old males after 14 days of HU revealed upregulation of pathways involved in pro-inflammatory signaling, immune cell activation and differential expression of genes associated with cardiovascular disease progression. Taken together, these findings provide a rationale for targeting antioxidant and immune pathways and that sex differences should be taken into account in the development of countermeasures to maintain cardiovascular health in space.

Genetics & Heredity↗
DOE OSTI2021

Altered microRNA expression in animal models of Huntington’s disease and potential therapeutic strategies

A review of recent animal models of Huntington’s disease showed many microRNAs had altered expression levels in the striatum and cerebral cortex, and which were mostly downregulated. Among the altered microRNAs were miR-9/9*, miR-29b, miR-124a, miR-132, miR-128, miR-139, miR-122, miR-138, miR-23b, miR-135b, miR-181 (all downregulated) and miR-448 (upregulated), and similar changes had been previously found in Huntington’s disease patients. In the animal cell studies, the altered microRNAs included miR-9, miR-9*, miR-135b, miR-222 (all downregulated) and miR-214 (upregulated). In the animal models, overexpression of miR-155 and miR-196a caused a decrease in mutant huntingtin mRNA and protein level, lowered the mutant huntingtin aggregates in striatum and cortex, and improved performance in behavioral tests. Improved performance in behavioral tests also occurred with overexpression of miR-132 and miR-124. In the animal cell models, overexpression of miR-22 increased the viability of rat primary cortical and striatal neurons infected with mutant huntingtin and decreased huntingtin -enriched foci of ≥ 2 µm. Also, overexpression of miR-22 enhanced the survival of rat primary striatal neurons treated with 3-nitropropionic acid. Exogenous expression of miR-214, miR-146a, miR-150, and miR-125b decreased endogenous expression of huntingtin mRNA and protein in Hdh Q111 /Hdh Q111 cells. Further studies with animal models of Huntington’s disease are warranted to validate these findings and identify specific microRNAs whose overexpression inhibits the production of mutant huntingtin protein and other harmful processes and may provide a more effective means of treating Huntington’s disease in patients and slowing its progression.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1971

Metabolic effects of artificial environments

The mechanisms by which inert gases influence metabolism were investigated from several viewpoints. Groups of rats were exposed at the thermal neutral temperature of the respective mixtures, to normoxic (P sub A 02 = 100 mm Hq) environments with argon, helium or nitrogen as the diluent at a total pressure of one atmosphere. The possible influence of diluent gases on oxygen transport to the cell was examined with hypoxic (P sub A O2 = 70 mm Hg) mixtures of the same diluent gases. Metabolic measurements included food, water, and oxygen consumption, CO2 production, hematocrit and the rate C-14O2 of expiration subsequent to intraperitoneal injection of acetate-1-C-14 or glucose UL-C-14. Argon-exposed animals showed a consistently decreased metabolic rate while, on the other hand, helium-exposed rats did not significantly alter metabolic rate relative to nitrogen. Certain indices, including acetate and glucose utilization, suggested that helium attenuated the imposed hypoxia at the cellular level while argon facilitated it as compared with nitrogen. These results suggest that metabolic influence of helium is largely thermal in nature while argon has a significant direct metabolic effect and that diluent gases may selectively influence oxygen availability to the interior of the cell.

Jordan, J. P.↗
NASA NTRS1971

Brain serotonin content - Increase following ingestion of carbohydrate diet.

In the rat, the injection of insulin or the consumption of carbohydrate causes sequential increases in the concentrations of tryptophan in the plasma and the brain and of serotonin in the brain. Serotonin-containing neurons may thus participate in systems whereby the rat brain integrates information about the metabolic state in its relation to control of homeostasis and behavior.

Fernstrom, J. D.↗
NASA NTRS1973

Some aversive characteristics of centrifugally generated gravity.

The effective weight of rats was manipulated by centrifugation. Two effective weight levels were obtained. In three escape avoidance conditions a lever press produced a change from a base level of 2.1 g to a response level of 1.1 g. In a punishment condition a response produced a change from a 1.1 g level to a 2.1 g level and in an extinction condition responses had no effect on the 2.1 g effective weight level present. All changes took 30 sec and were maintained for an additional 10 sec before a return to base level was initiated. When responses occurred closer together than the 40 sec, they delayed the return to base level by 40 sec. This 40 sec interval is referred to as response-contingent-time. The response rate and amount of response-contingent-time served as the data. The results confirmed previous data that centrifugation is aversive. The results are interpreted as indicating that the aversiveness is attributable to the increase in effective weight, and that rats can discriminate the different angular velocity-radius of rotation combinations used.

Altman, F.↗
NASA NTRS1970

Subcellular localization of pituitary enzymes

A cytochemical procedure is reported for identifying subcellular sites of enzymes hydrolyzing beta-naphthylamine substrates, and to study the sites of reaction product localization in cells of various tissues. Investigations using the substrate Leu 4-methoxy-8-naphthylamine, a capture with hexonium pararosaniline, and the final chelation of osmium have identified the hydrolyzing enzyme of rat liver cells; this enzyme localized on cell membranes with intense deposition in the areas of the parcanaliculi. The study of cells in the anterior pituitary of the rat showed the deposition of reaction product on cell membrane; and on the membranes of secretion granules contained within the cell. The deposition of reaction product on the cell membrane however showed no increase or decrease with changes in the physiological state of the gland and release of secretion granules from specific cells.

Smith, R. E.↗
NASA NTRS1974

Research on inert gas narcosis and air velocity effects on metabolic performance

The effects of air velocity on metabolic performance are studied by using high forced airflow in a closed environment as a mechanism to control the concentration of volatile animal wastes. Air velocities between 100 and 200 ft/min are without significant effects on the metabolism of rats. At velocities of 200 ft/min and above, oxygen consumption and CO2 production as well as food consumption increase. In most instances, the changes are on the order of 5-10%. At the same time, the RQ for the animals increases slightly and generally correlates well with oxygen consumption and CO2 production. Experiments on the nature of inert gas narcosis show that halothane and methoxyflurane are rather potent inhibitors of the NADH:O2 oxidoreductase system in rats. These experiments suggest that the mechanism of inert gas narcosis is not mandatorily related to a membrane surface phenomenon.

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