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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 199 records · Page 11
All sourcesNASA NTRSDOE OSTI
NASA NTRS2019

Evaluating Effects of Altered Gravity on the Nervous System Using D. melanogaster

A comprehensive understanding of the effects of spaceflight and altered gravity on human physiology is necessary for continued human space exploration and long-term space habitation. The oxidative stress response has been identified in astronauts exposed to short- and long-term space missions that are exposed to the multitude of stress factors of spaceflight, including altered gravity and radiation exposure. Reactive oxygen species (ROS) are byproducts of homeostatic cellular metabolism, yet when overproduced the oxidative stress response ensues, rendering molecules destructive causing cell death and inflammation. Controlling aberrant ROS production is necessary to prevent pathological consequences, in particular within the nervous system, since neurons are extremely sensitive overexpressed ROS insults. We hypothesize that exposure to altered gravity triggers the oxidative stress response, leading to impairments in the nervous system. In this study, we used a well-established spaceflight model organism, Drosophila melanogaster, to assess altered gravity associated changes in the nervous system using a ground-based hypergravity model. Acute hypergravity resulted in an induction of oxidative stress-related genes with an increase in reactive oxygen species (ROS) in fly brains (p<0.001). Also, qPCR analysis shows that parkin gene expression is significantly reduced in these fly brains(p<0.05). Additionally, chronic hypergravity resulted in depressed locomotor phenotype in these flies (p<0.05) in conjunction to decreased dopaminergic neuron counts (p<0.0001) and increased apoptosis in these fly brains (p<0.0001). Further, assessment of neurological changes, including the neuronal architecture, synaptic integrity and genetic regulation caused by hypergravity conditions were noted. Overall, our results validate chronic hypergravity simulation as a behavioral model to study spaceflight effects, and oxidative stress pathway as a potential avenue for countermeasure development for astronauts undergoing short- and long-term missions and for neurodegenerative research on Earth.

Mhatre, Siddhita↗
DOE OSTI2024

Characterization of Humanized Mouse Model of Organophosphate Poisoning and Detection of Countermeasures via MALDI-MSI

Organophosphoate (OP) chemicals are known to inhibit the enzyme acetylcholinesterase (AChE). Studying OP poisoning is difficult because common small animal research models have serum carboxylesterase, which contributes to animals’ resistance to OP poisoning. Historically, guinea pigs have been used for this research; however, a novel genetically modified mouse strain (KIKO) was developed with nonfunctional serum carboxylase (Es1 KO) and an altered acetylcholinesterase (AChE) gene, which expresses the amino acid sequence of the human form of the same protein (AChE KI). KIKO mice were injected with 1xLD50 of an OP nerve agent or vehicle control with or without atropine. After one to three minutes, animals were injected with 35 mg/kg of the currently fielded Reactivator countermeasure for OP poisoning. Postmortem brains were imaged on a Bruker RapifleX ToF/ToF instrument. Data confirmed the presence of increased acetylcholine in OP-exposed animals, regardless of treatment or atropine status. More interestingly, we detected a small amount of Reactivator within the brain of both exposed and unexposed animals; it is currently debated if reactivators can cross the blood–brain barrier. Further, we were able to simultaneously image acetylcholine, the primary affected neurotransmitter, as well as determine the location of both Reactivator and acetylcholine in the brain. This study, which utilized sensitive MALDI-MSI methods, characterized KIKO mice as a functional model for OP countermeasure development.

2-PAM↗
NASA NTRSDate not supplied

Developing High-Throughput Organ-on-a-Chip Models to Investigate the Effects of Ionizing Radiation on the Central Nervous System

One of the main health risks in human space exploration is central nervous system (CNS) damage by ionizing radiation due to exposure to the galactic cosmic rays (GCRs). In animal models, irradiation with simulated GCRs or their components has been shown to cause neuronal damage and neuroinflammation associated with cognitive and behavioral dysfunction. In general, the extent of CNS damage is partially regulated by the blood-brain barrier (BBB), which enables immune cells to enter the CNS. The main cellular regulators of BBB permeability are astrocytes, which also modulate neuronal death, immune responses and oxidative stress, and thus could serve as a robust CNS-specific target for countermeasure development. However, studies on BBB permeability and astrocyte functions in regulating CNS responses to ionizing radiation have been limited, especially in human tissue/organ analogs. Therefore, we established a high-throughput 3D organ-on-a-chip system to study human CNS and BBB impairments in response to ionizing radiation, based on commercially available OrganoPlates (Mimetas, Inc.) seeded with primary or induced pluripotent stem cell-derived human cells. We investigated both immediate and delayed CNS responses to major GCR components: 0.15-0.5 Gy 250MeV/n 4-He, and 0.3-0.8 Gy 600 MeV/n 56-Fe; as well as to 0.5-1 Gy X-rays. We observed ionizing radiation-mediated increases in BBB permeability that was exacerbated by astrocyte presence and accompanied by morphological changes in endothelial cells and tight junctions, altered cytokine profile including TNFa upregulation, and increased oxidative stress. We also quantified irradiation-mediated changes in astrocyte activation and neuronal functions, revealing major astrocyte damage mediated by 600MeV/n 56-Fe particles. Thus, we demonstrate that deep space radiation may contribute to CNS damage by disrupting both astrocyte and endothelial cell components of the blood-brain barrier. Our next steps include mapping and validating the transcriptomic changes induced by simulated GCRs and their components in human CNS models. Ultimately, we aim to uncover potential novel targets for countermeasure developments to mitigate CNS damage in long duration spaceflight.

Radiation↗
DOE OSTI2020

Schizophrenia-related microdeletion causes defective ciliary motility and brain ventricle enlargement via microRNA-dependent mechanisms in mice

Progressive ventricular enlargement, a key feature of several neurologic and psychiatric diseases, is mediated by unknown mechanisms. Here, using murine models of 22q11-deletion syndrome (22q11DS), which is associated with schizophrenia in humans, we found progressive enlargement of lateral and third ventricles and deceleration of ciliary beating on ependymal cells lining the ventricular walls. The cilia-beating deficit observed in brain slices and in vivo is caused by elevated levels of dopamine receptors (Drd1), which are expressed in motile cilia. Haploinsufficiency of the microRNA-processing gene Dgcr8 results in Drd1 elevation, which is brought about by a reduction in Drd1-targeting microRNAs miR-382-3p and miR-674-3p. Replenishing either microRNA in 22q11DS mice normalizes ciliary beating and ventricular size. Knocking down the microRNAs or deleting their seed sites on Drd1 mimicked the cilia-beating and ventricular deficits. These results suggest that the Dgcr8–miR-382-3p/miR-674-3p–Drd1 mechanism contributes to deceleration of ciliary motility and age-dependent ventricular enlargement in 22q11DS.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1972

Miniature biotelemeter gives multichannel wideband biomedical data

A miniature biotelemeter was developed for sensing and transmitting multiple channels of biomedical data over a radio link. The design of this miniature, 10-channel, wideband (5 kHz/channel), pulse amplitude modulation/ frequency modulation biotelemeter takes advantage of modern device technology (e.g., integrated circuit operational amplifiers, complementary symmetry/metal oxide semiconductor logic, and solid state switches) and hybrid packaging techniques. The telemeter is being used to monitor 10 channels of neuron firings from specific regions of the brain in rats implanted with chronic electrodes. Design, fabrication, and testing of an engineering model biotelemeter are described.

Carraway, J. B.↗
DOE OSTI2022

Fine-tuning of mTOR signaling by the UBE4B-KLHL22 E3 ubiquitin ligase cascade in brain development

ABSTRACT Spatiotemporal regulation of the mechanistic target of rapamycin (mTOR) pathway is pivotal for establishment of brain architecture. Dysregulation of mTOR signaling is associated with a variety of neurodevelopmental disorders. Here, we demonstrate that the UBE4B-KLHL22 E3 ubiquitin ligase cascade regulates mTOR activity in neurodevelopment. In a mouse model with UBE4B conditionally deleted in the nervous system, animals display severe growth defects, spontaneous seizures and premature death. Loss of UBE4B in the brains of mutant mice results in depletion of neural precursor cells and impairment of neurogenesis. Mechanistically, UBE4B polyubiquitylates and degrades KLHL22, an E3 ligase previously shown to degrade the GATOR1 component DEPDC5. Deletion of UBE4B causes upregulation of KLHL22 and hyperactivation of mTOR, leading to defective proliferation and differentiation of neural precursor cells. Suppression of KLHL22 expression reverses the elevated activity of mTOR caused by acute local deletion of UBE4B. Prenatal treatment with the mTOR inhibitor rapamycin rescues neurogenesis defects in Ube4b mutant mice. Taken together, these findings demonstrate that UBE4B and KLHL22 are essential for maintenance and differentiation of the precursor pool through fine-tuning of mTOR activity.

Kong, Xiangxing↗
NASA NTRS2007

Scheduling Accessory Assists Patients with Cognitive Disorders

Recom Technologies Inc. received initial funding from NASA to research the commercial potential of an artificially intelligent planning reaction model to serve as a tool to help individuals suffering from various forms and levels of brain impairment. In 1993, the chief of the Artificial Intelligence Research Branch at Ames Research Center suggested collaborative research with Santa Clara Valley Medical Center. This partnership led to further development of the technology and funding to support clinical research from the U.S. Department of Education's National Institute on Disability and Rehabilitation Research. In 1996, Attention Control Systems Inc. was founded to market the finished device, called the Planning and Execution Assistant and Trainer (PEAT). PEAT is a pocket-sized PDA-like device with a graphical display, touchscreen controls, an electronic calendar, an address book, and a built-in phone, that cues users to start or stop scheduled activities, monitors their progress, and adjusts schedules as necessary in response to delays or calendar changes. It uses an automatic planning model developed for NASA to adjust daily plans when a situation changes. PEAT is sold as a complete system that includes software, hardware, documentation, and technical support. In addition to the flagship Pocket PEAT device, there is PEAT Phone, PC PEAT, and PEAT Link. Clinical studies of PEAT continue at Santa Clara Valley Medical Center

Source record↗
DOE OSTI2024

NANO.PTML model for read-across prediction of nanosystems in neurosciences. computational model and experimental case of study

Abstract Neurodegenerative diseases involve progressive neuronal death. Traditional treatments often struggle due to solubility, bioavailability, and crossing the Blood-Brain Barrier (BBB). Nanoparticles (NPs) in biomedical field are garnering growing attention as neurodegenerative disease drugs (NDDs) carrier to the central nervous system. Here, we introduced computational and experimental analysis. In the computational study, a specific IFPTML technique was used, which combined Information Fusion (IF) + Perturbation Theory (PT) + Machine Learning (ML) to select the most promising Nanoparticle Neuronal Disease Drug Delivery (N2D3) systems. For the application of IFPTML model in the nanoscience, NANO.PTML is used. IF-process was carried out between 4403 NDDs assays and 260 cytotoxicity NP assays conducting a dataset of 500,000 cases. The optimal IFPTML was the Decision Tree (DT) algorithm which shown satisfactory performance with specificity values of 96.4% and 96.2%, and sensitivity values of 79.3% and 75.7% in the training (375k/75%) and validation (125k/25%) set. Moreover, the DT model obtained Area Under Receiver Operating Characteristic (AUROC) scores of 0.97 and 0.96 in the training and validation series, highlighting its effectiveness in classification tasks. In the experimental part, two samples of NPs (Fe 3 O 4 _A and Fe 3 O 4 _B) were synthesized by thermal decomposition of an iron(III) oleate (FeOl) precursor and structurally characterized by different methods. Additionally, in order to make the as-synthesized hydrophobic NPs (Fe 3 O 4 _A and Fe 3 O 4 _B) soluble in water the amphiphilic CTAB (Cetyl Trimethyl Ammonium Bromide) molecule was employed. Therefore, to conduct a study with a wider range of NP system variants, an experimental illustrative simulation experiment was performed using the IFPTML-DT model. For this, a set of 500,000 prediction dataset was created. The outcome of this experiment highlighted certain NANO.PTML systems as promising candidates for further investigation. The NANO.PTML approach holds potential to accelerate experimental investigations and offer initial insights into various NP and NDDs compounds, serving as an efficient alternative to time-consuming trial-and-error procedures.

60 APPLIED LIFE SCIENCES↗
NASA NTRS2005

Activation of nuclear transcription factor-kappaB in mouse brain induced by a simulated microgravity environment

Microgravity induces inflammatory responses and modulates immune functions that may increase oxidative stress. Exposure to a microgravity environment induces adverse neurological effects; however, there is little research exploring the etiology of these effects resulting from exposure to such an environment. It is also known that spaceflight is associated with increase in oxidative stress; however, this phenomenon has not been reproduced in land-based simulated microgravity models. In this study, an attempt has been made to show the induction of reactive oxygen species (ROS) in mice brain, using ground-based microgravity simulator. Increased ROS was observed in brain stem and frontal cortex with concomitant decrease in glutathione, on exposing mice to simulated microgravity for 7 d. Oxidative stress-induced activation of nuclear factor-kappaB was observed in all the regions of the brain. Moreover, mitogen-activated protein kinase kinase was phosphorylated equally in all regions of the brain exposed to simulated microgravity. These results suggest that exposure of brain to simulated microgravity can induce expression of certain transcription factors, and these have been earlier argued to be oxidative stress dependent.

Non-NASA Center↗
DOE OSTI2024

Identifying Heterogeneous Micromechanical Properties of Biological Tissues via Physics–Informed Neural Networks

The heterogeneous micromechanical properties of biological tissues have profound implications across diverse medical and engineering domains. However, identifying full-field heterogeneous elastic properties of soft materials using traditional engineering approaches is fundamentally challenging due to difficulties in estimating local stress fields. Recently, there has been a growing interest in data-driven models for learning full-field mechanical responses, such as displacement and strain, from experimental or synthetic data. However, research studies on inferring full-field elastic properties of materials, a more challenging problem, are scarce, particularly for large deformation, hyperelastic materials. Here, a physics-informed machine learning approach is proposed to identify the elasticity map in nonlinear, large deformation hyperelastic materials. This study reports the prediction accuracies and computational efficiency of physics-informed neural networks (PINNs) in inferring the heterogeneous elasticity maps across materials with structural complexity that closely resemble real tissue microstructure, such as brain, tricuspid valve, and breast cancer tissues. Further, the improved architecture is applied to three hyperelastic constitutive models: Neo-Hookean, Mooney Rivlin, and Gent. Furthermore, the improved network architecture consistently produces accurate estimations of heterogeneous elasticity maps, even when there is up to 10% noise present in the training data.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2002

Paralysis recovery in humans and model systems

Considerable evidence now demonstrates that extensive functional and anatomical reorganization following spinal cord injury occurs in centers of the brain that have some input into spinal motor pools. This is very encouraging, given the accumulating evidence that new connections formed across spinal lesions may not be initially functionally useful. The second area of advancement in the field of paralysis recovery is in the development of effective interventions to counter axonal growth inhibition. A third area of significant progress is the development of robotic devices to quantify the performance level of motor tasks following spinal cord injury and to 'teach' the spinal cord to step and stand. Advances are being made with robotic devices for mice, rats and humans.

Review↗
DOE OSTI2021

A NIR fluorescent smart probe for imaging tumor hypoxia

Abstract Background Tumor hypoxia is a characteristic of paramount importance due to low oxygenation levels in tissue negatively correlating with resistance to traditional therapies. The ability to noninvasively identify such could provide for personalized treatment(s) and enhance survival rates. Accordingly, we recently developed an NIR fluorescent hypoxia‐sensitive smart probe ( NO 2 ‐Rosol ) for identifying hypoxia via selectively imaging nitroreductase (NTR) activity, which could correlate to oxygen deprivation levels in cells, thereby serving as a proxy. We demonstrated proof of concept by subjecting a glioblastoma (GBM) cell line to extreme stress by evaluating such under radiobiological hypoxic ( p O 2 ≤ ~0.5%) conditions, which is a far cry from representative levels for hypoxia for brain glioma ( p O 2 = ~1.7%) which fluctuate little from physiological hypoxic ( p O 2 = 1.0‐3.0%) conditions. Aim We aimed to evaluate the robustness, suitability, and feasibility of NO 2 ‐Rosol for imaging hypoxia in vitro and in vivo via assessing NTR activity in diverse GBM models under relevant oxygenation levels ( p O 2 = 2.0%) within physiological hypoxic conditions that mimic oxygenation levels in GBM tumor tissue in the brain. Methods We evaluated multiple GBM cell lines to determine their relative sensitivity to oxygenation levels via measuring carbonic anhydrase IX (CAIX) levels, which is a surrogate marker for indirectly identifying hypoxia by reporting on oxygen deprivation levels and upregulated NTR activity. We evaluated for hypoxia via measuring NTR activity when employing NO 2 ‐Rosol in in vitro and tumor hypoxia imaging studies in vivo. Results The GBM39 cell line demonstrated the highest CAIX expression under hypoxic conditions representing that of GBM in the brain. NO 2 ‐Rosol displayed an 8‐fold fluorescence enhancement when evaluated in GBM39 cells ( p O 2 = 2.0%), thereby establishing its robustness and suitability for imaging hypoxia under relevant physiological conditions. We demonstrated the feasibility of NO 2 ‐Rosol to afford tumor hypoxia imaging in vivo via it demonstrating a tumor‐to‐background of 5 upon (i) diffusion throughout, (ii) bioreductive activation by NTR activity in, and (iii) retention within, GBM39 tumor tissue. Conclusion We established the robustness, suitability, and feasibility of NO 2 ‐Rosol for imaging hypoxia under relevant oxygenation levels in vitro and in vivo via assessing NTR activity in GBM39 models.

Hettie, Kenneth S.↗
DOE OSTI2022

Data-driven Mapping of the Mouse Connectome: The utility of transfer learning to improve the performance of deep learning models performing axon segmentation on light-sheet microscopy images

Light sheet microscopy has made possible the high temporal and spatial 3D imaging of both fixed and live biological tissue, with samples as large as the entire mouse brain. However, segmentation and quantification of that data remains a time-consuming manual process. Machine learning methods promise the possibility of automating this process. This study seeks to advance the performance of prior models through the application of refinements such as transfer learning.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism

Abstract Background Previous research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution of protein-coding (coding) de novo variants (DNVs) within specific genes. The role of de novo noncoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2671 families with autism (discovery cohort of 516 families, replication cohort of 2155 families). We focused on DNVs in enhancers with characterized in vivo activity in the brain and identified an excess of DNVs in an enhancer named hs737. Results We adapted the fitDNM statistical model to work in noncoding regions and tested enhancers for excess of DNVs in families with autism. We found only one enhancer (hs737) with nominal significance in the discovery (p = 0.0172), replication (p = 2.5 × 10 −3 ), and combined dataset (p = 1.1 × 10 −4 ). Each individual with a DNV in hs737 had shared phenotypes including being male, intact cognitive function, and hypotonia or motor delay. Our in vitro assessment of the DNVs showed they all reduce enhancer activity in a neuronal cell line. By epigenomic analyses, we found that hs737 is brain-specific and targets the transcription factor gene EBF3 in human fetal brain. EBF3 is genome-wide significant for coding DNVs in NDDs (missense p = 8.12 × 10 −35 , loss-of-function p = 2.26 × 10 −13 ) and is widely expressed in the body. Through characterization of promoters bound by EBF3 in neuronal cells, we saw enrichment for binding to NDD genes (p = 7.43 × 10 −6 , OR = 1.87) involved in gene regulation. Individuals with coding DNVs have greater phenotypic severity (hypotonia, ataxia, and delayed development syndrome [HADDS]) in comparison to individuals with noncoding DNVs that have autism and hypotonia. Conclusions In this study, we identify DNVs in the hs737 enhancer in individuals with autism. Through multiple approaches, we find hs737 targets the gene EBF3 that is genome-wide significant in NDDs. By assessment of noncoding variation and the genes they affect, we are beginning to understand their impact on gene regulatory networks in NDDs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Nicotinamide-Loaded Peptoid Nanotubes for Energy Regeneration in Acute Brain Injury

Acute brain injuries such as perinatal asphyxia, stroke, and traumatic brain injury result in ischemia, oxidative stress, excitotoxicity, and inflammation, leading to a depletion of ATP. Nicotinamide adenine dinucleotide (NAD+) is crucial for ATP regeneration and DNA repair during postinjury recovery. However, the therapeutic benefits of NAD+ and its precursors, such as nicotinamide (NAM), are limited by challenges in achieving effective cell-specific intracellular delivery. In this study, we use a nanopeptoid delivery strategy to replenish the cellular redox state and increase energy production in the acutely injured brain. By self-assembling peptoids into tubular structures, we created biocompatible NAM-conjugated peptoid nanotubes (NAM-PNTs) that vary in tubular length. NAM-PNTs demonstrated significant therapeutic benefits by enhancing cell viability and replenishing intracellular ATP levels within 24 h of treatment in oxygen–glucose-deprived (OGD) BV-2 cells. In organotypic brain slices, NAM-PNT treatment promoted glial proliferation, reduced proinflammatory cytokines, and increased anti-inflammatory cytokines after OGD, an ex vivo model of hypoxia-ischemia. The effect of NAM-PNTs is associated with their uptake into microglia via fluid-phase phagocytosis and caveolae-mediated endocytosis. A single systemic dose of NAM-PNTs localized in microglia in the injured hemisphere and reduced brain tissue loss and improved neuropathology after hypoxia-ischemia in term-equivalent rats. These findings highlight the therapeutic potential of NAM-PNTs for cell-specific targeted delivery and energy restoration in the acutely injured neonatal brain. In the neonatal brain injury field, this work demonstrates the development of an innovative nanoparticle platform from first-principles design and synthesis to in vitro screening and then demonstration of efficacy in vivo .

ATP↗
DOE OSTI2022

Correlation of Injury Simulation with Clinical Assessment of Traumatic Brain Injury

This report contains a summary of our efforts to correlate head injury simulations predicting intracranial fluid cavitation with clinical assessments of brain injury from blunt impact to the head. Magnetic resonance imaging (MRI) data, collected on traumatic brain injury (TBI) subjects by researchers at the MIND Institute of New Mexico, was acquired for the current work. Specific blunt impact TBI case histories were selected from the TBI data for further study and possible correlation with simulation. Both group and single-subject case histories were examined. We found one single-subject case that was particularly suited for correlation with simulation. Diffusion tensor image (DTI) analysis of the TBI subject identified white matter regions within the brain displaying reductions in fractional anisotropy (FA), an indicator of local damage to the white matter axonal structures. Analysis of functional magnetic resonance image (fMRI) data collected on this individual identified localized regions of the brain displaying hypoactivity, another indicator of brain injury. We conducted high fidelity simulations of head impact experienced by the TBI subject using the Sandia head-neck-torso model and the shock physics computer code CTH. Intracranial fluid cavitation predictions were compared with maps of DTI fractional anisotropy and fMRI hypoactivity to assess whether a possible correlation exists. The ultimate goal of this work is to assess whether one can correlate simulation predictions of intracranial fluid cavitation with the brain injured sites identified by the fMRI and DTI analyses. The outcome of this effort is described in this report.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗