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DOE OSTI2020

Role of immune cells in the removal of deleterious senescent cells

Cellular senescence is an essentially irreversible arrest of cell proliferation coupled to a complex senescence-associated secretory phenotype (SASP). The senescence arrest prevents the development of cancer, and the SASP can promote tissue repair. Recent data suggest that the prolonged presence of senescent cells, and especially the SASP, could be deleterious, and their beneficial effects early in life can become maladaptive such that they drive aging phenotypes and pathologies late in life. It is therefore important to develop strategies to eliminate senescent cells. There are currently under development or approved several immune cell-based therapies for cancer, which could be redesigned to target senescent cells. This review focuses on this possible use of immune cells and discusses how current cell-based therapies could be used for senescent cell removal.

59 BASIC BIOLOGICAL SCIENCES↗

NASA NTRS2004

Calibration Experiments Conducted for Noninvasive Blood Glucose Sensing Through the Eye

There are more than 16 million diabetics in the United States and more than 100 million worldwide. Diabetes can lead to severe complications over time such as blindness, renal and cardiovascular diseases, and peripheral neuropathy in the limbs. Poor blood circulation in diabetics can lead to gangrene and the subsequent amputation of extremities. In addition, this pathology is the fourth leading cause of death in the United States. The most effective way to manage diabetes is frequent blood glucose monitoring performed by the patients themselves. However, because of pain, inconvenience, and the fear of developing infections from finger-prick blood tests or implants, many patients monitor their blood glucose levels less frequently than is recommended by their physicians. Therefore, a noninvasive, painless, and convenient method to monitor blood glucose would greatly benefit diabetics. Likewise, detecting, preventing, and treating the untoward effects of prolonged space travel (e.g., a human mission to Mars) in real-time requires the development of noninvasive diagnostic technologies that are compact and powerful. As a "window to the body," the eye offers the opportunity to use light in various forms to detect ocular and systemic abnormalities long before clinical symptoms appear and to help develop preventative and therapeutic countermeasures early. The noninvasive feature of these technologies permits frequent repetition of tests, enabling an evaluation of the response to therapy.

Ansari, Rafat R.↗

NASA NTRS1973

The pathology of innactivation in monkeys.

Progress report on a long-term experiment using rhesus monkeys and designed to study the effects of isolation up to one year, as well as the effects of bed rest simulated by immobilization in a plaster cast for six months. The investigation includes histopathological and histochemical studies of these effects on various internal organs and tissues, and some of the preliminary results of these studies are presented and discussed.

Bourne, G. H.↗

NASA NTRS1992

Effect of antiorthostatic BedRest (BR) on GastroIntestinal Motility (GIM) of normal subjects

The combined effects of postural changes, fluid shifts and diuresis associated with the absence of the gravity vector may decrease gastrointestinal motility (GIM) during space flight. GIM can be estimated from the mouth to cecum transit time (MCTT) of orally administered lactulose (LAC); this test is used to assess changes in GIM in normal subjects and in patients with GI pathology and related disease conditions. Since bedrest (BR) mimics some of the physiological changes that occur during space flight, the effect of ten days of BR on GIM was evaluated from the MCTT of LAC. Methods: Subjects were 12 nonsmoking males between the ages of 35 and 50. After an 8-10 hour fast, subjects ingested Cephulac (registered) (20 g solution) with a low-fiber breakfast on four different days (45, 30, 25, and 20) before BR and on three separate days (4, 7, and 10) during BR. Breath-H2 concentrations were measured before and at 10 minute intervals for 4 hours after breakfast using a Quintron breathalyzer and MCTT was determined from these data. Results: MCTT ranged between 10 and 122 minutes during ambulation and 80 to 120 minutes during BR with means of 79 minutes and 122 minutes respectively. Conclusion: Mean MCTT during BR was 54 percent longer than during ambulation, suggesting that absorption and availability of orally administered medications and nutrients may be delayed or impaired as a result of decreased GIM during bedrest.

Putcha, L.↗

NASA NTRS1980

Functional-morphological parallels of the hypothalamo-pituitary-adrenal system response reaction to long-term hypokinesia

The effect of 2 and 4 week hypokinesia regimens on the hypothalamo-pituitary-adrenal system (HPAS) was investigated in 110 inbred mice. Progressive exhaustion and pathological reorganization of the HPAS morphofunctional structures was revealed. On the basis of established facts of interlineary and interspecies differences in the HPAS response, it is suggested that the animal body response reaction to the long term effects of hypokinesia depends largely on its HPAS resistance and the values of this system's defensive adaptation potential.

Tsvetov, Y. P.↗

NASA NTRS2015

An Overview of NASA's Risk of Cardiovascular Disease from Radiation Exposure

The association between high doses of radiation exposure and cardiovascular damage is well established. Patients that have undergone radiotherapy for primary cancers of the head and neck and mediastinal regions have shown increased risk of heart and vascular damage and long-term development of radiation-induced heart disease [1]. In addition, recent meta-analyses of epidemiological data from atomic bomb survivors and nuclear industry workers has also shown that acute and chronic radiation exposures is strongly correlated with an increased risk of circulatory disease at doses above 0.5 Sv [2]. However, these analyses are confounded for lower doses by lifestyle factors, such as drinking, smoking, and obesity. The types of radiation found in the space environment are significantly more damaging than those found on Earth and include galactic cosmic radiation (GCR), solar particle events (SPEs), and trapped protons and electrons. In addition to the low-LET data, only a few studies have examined the effects of heavy ion radiation on atherosclerosis, and at lower, space-relevant doses, the association between exposure and cardiovascular pathology is more varied and unclear. Understanding the qualitative differences in biological responses produced by GCR compared to Earth-based radiation is a major focus of space radiation research and is imperative for accurate risk assessment for long duration space missions. Other knowledge gaps for the risk of radiation-induced cardiovascular disease include the existence of a dose threshold, low dose rate effects, and potential synergies with other spaceflight stressors. The Space Radiation Program Element within NASA's Human Research Program (HRP) is managing the research and risk mitigation strategies for these knowledge gaps. In this presentation, we will review the evidence and present an overview of the HRP Risk of Cardiovascular Disease and Other Degenerative Tissue Effects from Radiation Exposure.

Patel, Zarana S.↗

NASA NTRS1997

Efficacy of Code Optimization on Cache-based Processors

The current common wisdom in the U.S. is that the powerful, cost-effective supercomputers of tomorrow will be based on commodity (RISC) micro-processors with cache memories. Already, most distributed systems in the world use such hardware as building blocks. This shift away from vector supercomputers and towards cache-based systems has brought about a change in programming paradigm, even when ignoring issues of parallelism. Vector machines require inner-loop independence and regular, non-pathological memory strides (usually this means: non-power-of-two strides) to allow efficient vectorization of array operations. Cache-based systems require spatial and temporal locality of data, so that data once read from main memory and stored in high-speed cache memory is used optimally before being written back to main memory. This means that the most cache-friendly array operations are those that feature zero or unit stride, so that each unit of data read from main memory (a cache line) contains information for the next iteration in the loop. Moreover, loops ought to be 'fat', meaning that as many operations as possible are performed on cache data-provided instruction caches do not overflow and enough registers are available. If unit stride is not possible, for example because of some data dependency, then care must be taken to avoid pathological strides, just ads on vector computers. For cache-based systems the issues are more complex, due to the effects of associativity and of non-unit block (cache line) size. But there is more to the story. Most modern micro-processors are superscalar, which means that they can issue several (arithmetic) instructions per clock cycle, provided that there are enough independent instructions in the loop body. This is another argument for providing fat loop bodies. With these restrictions, it appears fairly straightforward to produce code that will run efficiently on any cache-based system. It can be argued that although some of the important computational algorithms employed at NASA Ames require different programming styles on vector machines and cache-based machines, respectively, neither architecture class appeared to be favored by particular algorithms in principle. Practice tells us that the situation is more complicated. This report presents observations and some analysis of performance tuning for cache-based systems. We point out several counterintuitive results that serve as a cautionary reminder that memory accesses are not the only factors that determine performance, and that within the class of cache-based systems, significant differences exist.

VanderWijngaart, Rob F.↗

DOE OSTI2022

Metacognition, cortical thickness, and tauopathy in aging

We investigated self-rating of cognitive task performance (self-appraisal) and the difference between self-rating and actual task performance (appraisal discrepancy) in cognitively healthy older adults and their relationship with cortical thickness and Alzheimer's disease (AD) biomarkers, amyloid and tau. All participants (N = 151) underwent neuropsychological testing and 1.5T structural magnetic resonance imaging. A subset (N = 66) received amyloid-PET with [11C] PiB and tau-PET with [18F] Flortaucipir. We found that worse performers had lower self-appraisal ratings, but still overestimated their performance, consistent with the Dunning-Kruger effect. Self-appraisal rating and appraisal discrepancy revealed distinct relationships with cortical thickness and AD pathology. Greater appraisal discrepancy, indicating overestimation, was related to thinning of inferior-lateral temporal, fusiform, and rostral anterior cingulate cortices. Lower self-appraisal was associated with higher entorhinal and inferior temporal tau. These results suggest that overestimation could implicate structural atrophy beyond AD pathology, while lower self-appraisal could indicate early behavioral alteration due to AD pathology, supporting the notion of subjective cognitive decline prior to objective deficits.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2025

Feed status and skin injury modulate immunopathology, global gene expression, and survival in channel catfish during virulent Aeromonas hydrophila infection

Introduction VirulentAeromonas hydrophilais a major pathogen in channel catfish (Ictalurus punctatus), that causes motileAeromonassepticemia and significant economic losses. We investigated the effect of feeding status and skin integrity on the host immune response, disease survival, and gastrointestinal pathology following a vAh challenge. Methods Using a bath immersion model, channel catfish were divided into four treatment groups: fin clipped and fed (FCF), fin clipped but not fed (FCN), not fin clipped but fed (NCF), and not fin clipped nor fed (NCN) alongside non-challenged control groups The FCF and NCF groups were fed 2 h prior to the challenge, but the FCN and NCN groups were not. Survival analysis, histopathological assessment, and RNA sequencing were conducted across groups at different time intervals throughout the vAh challenge. Results Survival rates were lowest in the FCF and FCN groups (30% and 23% survival, respectively), suggesting that both feeding and skin damage contributed to disease severity. Histopathological analyses revealed more severe intestinal and gastric lesions in fed groups, characterized by epithelial necrosis, hemorrhage, and edema. Transcriptomic analysis among the groups identified significant differentially expressed genes associated with inflammation, apoptosis, and metabolic stress, with notable upregulation of interleukin 1-beta (il-1β), and complement C3 (c3). Gene ontology enrichment highlighted distinct immune activation patterns between fed and unfed groups, with enhanced pathogen recognition and pro-inflammatory responses in unfed fish. Discussion These findings suggest feeding prior to infection may exacerbate disease pathology, potentially by creating a physiological state conducive to facilitate pathogen proliferation and dampened early immune responses, whereas short-term fasting appears to promote early immune activation. This study provides novel insights into the complex interplay between feed status, physical injury, and immune response to vAh infection.

Immunology↗

NASA NTRS1974

A study of the biological effect of continuous inhalation exposure of 1, 1, 1-trichloroethene (methyl chloroform) on animals

The effects of continuous exposure to 1,1,1-trichloroethane on hepatic morphology and function are evaluated and compared with those produced by methylene chloride (dichloromethane) to determine environmental concentrations of each compound that would produce a similar biological response, i.e., a comparable increase in liver triglycerides over control levels. Experimental findings on mice, rats, dogs, and monkeys indicate that the pathological alternations observed with 1,1,1-trichloroethane are similar to those observed with dichloromethane except for different time courses of the effects and different degrees of recovery. A ten fold greater atmospheric concentration of 1,1,1-trichloroethane is required to produce the minimal liver changes found at 100 ppm dichloromethane.

Macewen, J. D.↗

NASA NTRS1978

Cosmic ray effects on the eyes of rats flown on Cosmos no. 782, Experiment K-007

A study was undertaken to determine if, and to what extent, pathological damage results from high-energy particles (HZE) transversing the eye. Light flashes experienced by space travellers indicate that HZE do indeed pass through and activate the retina, but whether actual biological damage occurs has not been investigated thoroughly. Thus, autopsies were performed on the eyes of rats which has been flown in Cosmos 782 satellite for 19.5 days. Comparisons with a control sample subjected to 1000 rads of Ar and Ne radiation show that pathological damage, when it occurs, affects the nucleus of the retina; simple light flashes are not thought to indicate a pathology, and result from activation of (but not damage to) the retina's outer segments.

Philpott, D. E.↗

NASA NTRS1964

Conference on Nutrition in Space and Related Waste Problems

As part of a continuing process man constantly seeks new habitats. In the late 1950's, he ventured into a vast and challenging new habitat, extraterrestrial space. Extending the realm of human life has always been a challenge to man, and inherent to all successful extensions of man into new domains is his ability to provide the essentials for life itself, his nutrition and controlled use of metabolic products. The provision of these essential requirements has always been a challenge and a motivating force in maintaining and extending human life on Earth. This challenge has now been extended beyond the Earth. As illustrated in this volume, many men and women of vision who continually devote their energies to feeding man on Earth have accepted the additional challenge of nutrition in space. They have already made inroads into the new problem of nutrition and waste handling in space and have already collected much physiological, psychological, toxicological, and pathological data related to space nutrition, feeding and elimination. They have elucidated man-machine interactions and the effects of these interactions on alimentation and elimination requirements in space. Thus light has been shed on specific research and development programs needed to establish requirements for nutrition and handling of metabolic wastes during manned space missions of 20 days' to 3 years' duration. These initial accomplishments have entailed the considerable efforts of many people and the knowledge and experience in nutrition and feeding gained by the Space Science Board of the National Academy of Sciences. This volume clearly represents the ability of scientists, engineers, and administrators to attack a problem as it arises; it clearly demonstrates the capability of the scientific and engineering communities to combine efforts, mobilize quickly, and devote their talents to a national need

Space environment↗

NASA NTRS2005

RTO Technical Publications: A Quarterly Listing

This is a listing of recent unclassified RTO technical publications processed by the NASA Center for AeroSpace Information covering the period from July 1, 2005 to September 30, 2005; and available in the NASA Aeronautics and Space Database. Contents include: Aeroelastic Deformation: Adaptation of Wind Tunnel Measurement Concepts to Full-Scale Vehicle Flight Testing; Actively Controlling Buffet-Induced Excitations; Modelling and Simulation to Address NATO's New and Existing Military Requirements; Latency in Visionic Systems: Test Methods and Requirements; Personal Hearing Protection including Active Noise Reduction; Virtual Laboratory Enabling Collaborative Research in Applied Vehicle Technologies; A Method to Analyze Tail Buffet Loads of Aircraft; Particle Image Velocimetry Measurements to Evaluate the Effectiveness of Deck-Edge Columnar Vortex Generators on Aircraft Carriers; Introduction to Flight Test Engineering, Volume 14; Pathological Aspects and Associated Biodynamics in Aircraft Accident Investigation;

Source record↗

DOE OSTI2021

Construction of extracellular matrix-based 3D hydrogel and its effects on cardiomyocytes

Highlights: • SOD and Triton X-100 could efficiently decellularize cells to get cardiac ECM. • Main proteins of cECM were fibronectin, collagen, elastin, fibrillin, laminin, etc. • 75% cECM-containing 3D hydrogel promoted cell proliferation and anti-apoptosis. • cECM3DH facilitated the differentiation of ESCs into CMs. • APcECM3DH was more conducive to NCM and ESC-derived CM maturation. Some discoveries resulted from 2-dimensional (2D) cultured cardiac cells have been disqualified in animal testing and later clinical trials. Extracellular matrix (ECM) plays a vital role in cardiac homeostasis, cardiac ECM (cECM)-based 3D cell cultures can mimics the physiological and pathological conditions in vivo closely, it is hopeful of addressing this challenge. Construction of cECM-based 3-dimensional (3D) hydrogel (cECM3DH) and its effects on cell behaviors were studied here. The results indicated that cellular compartments could be efficiently removed from heart tissue via sodium dodecyl sulfonate (SDS)- and Triton X-100-mediated decellularization, remaining the natural fibrous network structure and major proteins. 3D hydrogel consisted of 1 × 10{sup 7} cells/mL cells and 75% cECM could promote the proliferation and anti-apoptosis ability of human embryonic kidney (HEK)-293T cells. 0.25% trypsin or 0.20% collagenase was suitable to retrieve these cells from 3D hydrogel for further researches. Compared with 2D culture system, cECM3DH could significantly increase the proportion of GATA 4{sup +} cardiomyocytes (CMs) derived from heart tissue of neonatal mouse or induced differentiation of embryonic stem cells (ESCs) (P < 0.05) The expression levels of mature genes including cTnT, JCN, CaV1.2, MYL2, CASQ2, NCX1, and Cx43 of these CMs in adult pig cECM-based 3D hydrogel (APcECM3DH) were significantly higher than that in 2D culture system and in newborn piglet cECM-based 3D hydrogel (NPcECM3DH), respectively (P < 0.05). Therefore, cECM3DH supports the generation of primary CMs and ESC-derived CMs, APcECM3DH was more conducive to promoting CM maturation, which contributes to building 3D model for pathogenesis exploration, drug screening, and regenerative medicine of heart diseases.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2024

Development of message passing-based graph convolutional networks for classifying cancer pathology reports

Abstract Background Applying graph convolutional networks (GCN) to the classification of free-form natural language texts leveraged by graph-of-words features (TextGCN) was studied and confirmed to be an effective means of describing complex natural language texts. However, the text classification models based on the TextGCN possess weaknesses in terms of memory consumption and model dissemination and distribution. In this paper, we present a fast message passing network (FastMPN), implementing a GCN with message passing architecture that provides versatility and flexibility by allowing trainable node embedding and edge weights, helping the GCN model find the better solution. We applied the FastMPN model to the task of clinical information extraction from cancer pathology reports, extracting the following six properties: main site, subsite, laterality, histology, behavior, and grade. Results We evaluated the clinical task performance of the FastMPN models in terms of micro- and macro-averaged F1 scores. A comparison was performed with the multi-task convolutional neural network (MT-CNN) model. Results show that the FastMPN model is equivalent to or better than the MT-CNN. Conclusions Our implementation revealed that our FastMPN model, which is based on the PyTorch platform, can train a large corpus (667,290 training samples) with 202,373 unique words in less than 3 minutes per epoch using one NVIDIA V100 hardware accelerator. Our experiments demonstrated that using this implementation, the clinical task performance scores of information extraction related to tumors from cancer pathology reports were highly competitive.

59 BASIC BIOLOGICAL SCIENCES↗

NASA NTRS2012

Effects of High Dietary HEME Iron and Radiation on Cardiovascular Function

The radiation related health risks to astronauts is of particular concern to NASA. Data support that exposure to radiation is associated with a number of disorders including a heightened risk for cardiovascular diseases. Independent of radiation, altered nutrient status (e.g. high dietary iron) also increases ones risk for cardiovascular disease. However, it is unknown whether exposure to radiation in combination with high dietary iron further increases ones cardiovascular risk. The intent of our proposal is to generate compulsory data examining the combined effect of radiation exposure and iron overload on sensitivity to radiation injury to address HRP risks: 1) Risk Factor of Inadequate Nutrition; 2) Risk of Cardiac Rhythm Problems; and 3) Risk of Degenerative Tissue or other Health Effects from Space Radiation. Towards our goal we propose two distinct pilot studies using the following specific aims: Vascular Aim 1: To determine the short-term consequences of the independent and combined effects of exposure to gamma radiation and elevated body iron stores on measures of endothelial function and cell viability and integrity. We hypothesize that animals that have high body iron stores and are exposed to gamma radiation will show a greater reduction in endothelial dependent nitric oxid production and larger pathological changes in endothelial integrity than animals that have only 1 of those treatments (either high iron stores or exposure to gamma radiation). Vascular Aim 2: Identify and compare the effects of gamma radiation and elevated body iron stores on the genetic and epigenetic regulation of proteins associated with endothelial cell function. We hypothesize that modifications of epigenetic control and posttranslational expression of proteins associated with endothelial cell function will be differentially altered in rats with high body iron stores and exposed to gamma radiation compared to rats with only 1 type of treatment. Cardiac Aim 1: To determine the short-term consequences of the independent and combined effects of gamma radiation and elevated body iron stores on measures of cardiac structure. We hypothesize that modifications to cardiac structure and function will be greater in rats with high body iron stores and exposed to gamma radiation than in rats that have only 1 of those treatments. Cardiac Aim 2: Identify and compare the effects of gamma radiation and elevated body iron stores on the genetic and epigenetic regulation of proteins associated with cardiac structure and function. We hypothesize that modifications of epigenetic control and posttranslational expression of proteins associated with cardiac contractile function will be differentially altered in rats with high body iron stores and exposed to gamma radiation compared to rats with only 1 type of treatment.

Westby, Christian M.↗

DOE OSTI2021

Bayesian sparse learning with preconditioned stochastic gradient MCMC and its applications

Deep neural networks have been successfully employed in an extensive variety of research areas, including solving partial differential equations. Despite its significant success, there are some challenges in effectively training DNN, such as avoiding overfitting in over-parameterized DNNs and accelerating the optimization in DNNs with pathological curvature. Here, we propose a Bayesian type sparse deep learning algorithm. The algorithm utilizes a set of spike-and-slab priors for the parameters in the deep neural network. The hierarchical Bayesian mixture will be trained using an adaptive empirical method. That is, one will alternatively sample from the posterior using preconditioned stochastic gradient Langevin Dynamics (PSGLD), and optimize the latent variables via stochastic approximation. The sparsity of the network is achieved while optimizing the hyperparameters with adaptive searching and penalizing. A popular SG-MCMC approach is Stochastic gradient Langevin dynamics (SGLD). However, considering the complex geometry in the model parameter space in nonconvex learning, updating parameters using a universal step size in each component as in SGLD may cause slow mixing. To address this issue, we apply a computationally manageable preconditioner in the updating rule, which provides a step-size parameter to adapt to local geometric properties. Moreover, by smoothly optimizing the hyperparameter in the preconditioning matrix, our proposed algorithm ensures a decreasing bias, which is introduced by ignoring the correction term in the preconditioned SGLD. According to the existing theoretical framework, we show that the proposed algorithm can asymptotically converge to the correct distribution with a controllable bias under mild conditions. Numerical tests are performed on both synthetic regression problems and learning solutions of elliptic PDE, which demonstrate the accuracy and efficiency of the present work.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗

DOE OSTI2020

Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity

The accumulation of senescent cells (SnCs) is a causal factor of various age-related diseases as well as some of the side effects of chemotherapy. Pharmacological elimination of SnCs (senolysis) has the potential to be developed into novel therapeutic strategies to treat these diseases and pathological conditions. Here we show that ubiquitin-specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of USP7 by RNA interference induces apoptosis selectively in SnCs. The senolytic activity of USP7 inhibitors is likely attributable in part to the promotion of the human homolog of mouse double minute 2 (MDM2) ubiquitination and degradation by the ubiquitin–proteasome system. This degradation increases the levels of p53, which in turn induces the pro-apoptotic proteins PUMA, NOXA, and FAS and inhibits the interaction of BCL-XL and BAK to selectively induce apoptosis in SnCs. Further, we show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the senescence-associated secretory phenotype (SASP) induced by doxorubicin in mice. These findings suggest that small molecule USP7 inhibitors are novel senolytics that can be exploited to reduce chemotherapy-induced toxicities and treat age-related diseases.

59 BASIC BIOLOGICAL SCIENCES↗