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All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Tetranuclear Polypyridylruthenium(II) Complexes as Selective Nucleic Acid Stains for Flow Cytometric Analysis of Monocytic and Epithelial Lung Carcinoma Large Extracellular Vesicles

Selective staining of extracellular vesicles (EVs) is a major challenge for diagnostic and therapeutic applications. Herein, the EV labeling properties of a new class of tetranuclear polypyridylruthenium(II) complexes, Rubb7-TNL and Rubb7-TL, as phosphorescent stains are described. These new stains have many advantages over standard stains to detect and characterize EVs, including: high specificity for EV staining versus cell staining; high phosphorescence yields; photostability; and a lack of leaching from EVs until incorporation with target cells. As an example of their utility, large EVs released from control (basal) or lipopolysaccharide (LPS)-stimulated THP-1 monocytic leukemia cells were studied as a model of immune system EVs released during bacterial infection. Key findings from EV staining combined with flow cytometry were as follows: (i) LPS-stimulated THP-1 cells generated significantly larger and more numerous large EVs, as compared with those from unstimulated cells; (ii) EVs retained native EV physical properties after staining; and (iii) the new stains selectively differentiated intact large EVs from artificial liposomes, which are models of cell membrane fragments or other lipid-containing debris, as well as distinguished two distinct subpopulations of monocytic EVs within the same experiment, as a result of biochemical differences between unstimulated and LPS-stimulated monocytes. Comparatively, the staining patterns of A549 epithelial lung carcinoma-derived EVs closely resembled those of THP-1 cell line-derived EVs, which highlighted similarities in their selective staining despite their distinct cellular origins. This is consistent with the hypothesis that these new phosphorescent stains target RNA within the EVs.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
NASA NTRS2022

International Standard Measures During the AGBRESA Bed Rest Study

The Artificial Gravity Bed Rest with European Space Agency (AGBRESA) study involved 2 campaigns of 60-day bed rest at 6° head down tilt in the:envihab facility in Cologne, Germany, in 2019. The objective was to determine whether centrifugation of supine subjects mitigates physiological changes that occur due to the exposure to the spaceflight analog of 6° head down tilt. A set of international standard measures was used to evaluate bone, muscle, nutritional status, ocular changes, and psychological state and to assess cardiovascular, sensorimotor, and immune systems functions. After 60 days of bed rest, the subjects who were not exposed to centrifugation had significant decreases in mineral density at the hip and lumbar spine, decreased muscle strength of the knee and ankle, reduced maximal aerobic capacity, orthostatic intolerance, and impaired balance and locomotion, as well as significant biochemical, immunological, and psychological alterations. A daily 30-min exposure to 1 Gz supine centrifugation at the center of mass (0.3 Gz at the head, 2 Gz at the feet) mitigated mineral density loss in the femur neck and lumbar spine; and lessened the effects of bed rest on aerobic capacity, biochemistry, and immunology. However, low statistical power could contribute to the non-significant effects that are reported.

Bed rest↗
NASA NTRS2007

Recommendations for Refinement and Validation of Intermittent Artificial Gravity

The IMAG Pilot Study, recently completed at the University of Texas Medical Branch, filled in the second major gap in knowledge standing in the way of development of a practical Short Radius Centrifuge (SRC) and the use of Artificial Gravity (AG) as a multi-system countermeasure to combat the deconditioning associated with extended weightlessness. (The first challenge, to adapt rapidly rotating subjects to permit unlimited head movements without excessive motion sickness, was achieved in a series of studies at MIT involving incremental increases in head and centrifuge velocity.) It remained to be demonstrated that intermittent exposure to AG, at only one hour per day for 21 days, would have any positive effect on slowing or eliminating of deconditioning. Bed-rested normal subjects were used as a ground analog for astronauts in weightlessness. The results are clearly positive for the key physiological systems of interest: cardiovascular, muscle, and bone. No functionally relevant changes were observed in immune, cognitive, or sensory-motor function. Furthermore, we found that our initial concerns about the inability of deconditioned subjects to withstand daily centrifugation without syncope were misplaced. These encouraging initial results clearly support the further development of AG protocols. We recommend, as the next steps, the integration of a controlled exercise device on the SRC to determine the synergy between AG and exercise. Coupled with appropriate exercise device(s) the AG protocol will be tuned to-ward an optimal prescription for minimum exposure duration and frequency, maximum AG level and SRC speed.. Performance of these next steps will require extensive use of bed-rest/centrifuge facilities and eventually validation using an SRC in space. A space SRC could be placed in the ISS or on a planetary surface.

Young, Lauren R.↗
NASA NTRSDate not supplied

Creating Benchmark Data for Artificial Intelligence and Machine Learning Space Biology Research

To identify an appropriate AI/ML approach for a specific problem, the best practice is to measure algorithm performance through the benchmarking process. A scientific benchmark consists of an AI-ready dataset and a reference implementation on a specific scientific question. The NASA Science Mission Directorate (SMD) has started the “Benchmark Initiative for AI/ML to create scientific benchmark datasets in three applications: 1) scientific benchmarking, which finds the best algorithm for a specific problem; 2) application benchmarking, which measures algorithm performance against a set of parameters; and 3) system benchmarking, which evaluates performance of hardware and software architecture. Currently, there are no standardized datasets available to benchmark AI/ML algorithms in the domain of space biology. In this work, we constructed two AI/ML-ready biological datasets from experiments in space-flown mice: cellular imaging and RNA-seq. First, radiation-exposed immune cells harbor DNA damage foci that can be fluorescently marked to visualize the amount of damage following exposure to ionizing radiation. However, such large datasets are difficult to analyze visually, due to imaging inconsistencies and human bias, and classical image processing approaches can fail on imaging artifacts. AI/ML are therefore exciting alternative, providing the speed of machines and the accuracy of humans. We have made this dataset available at https://registry.opendata.aws/bps_microscopy/. Second, high-throughput nucleic acid sequencing (DNA-seq, RNA-seq) has become widespread in biomedical research due to the growing availability and affordability of these assays. However, most sequencing datasets suffer from high dimensionality and low sample count. In this work, we used a generative adversarial network to synthesize a standardized, AI-ready, publicly available benchmark dataset for space biology RNA-seq data with sufficient space-flown and ground control mouse liver samples from NASA GeneLab. This dataset is available at https://registry.opendata.aws/bps_rnaseq/. These datasets are now fully open the Space Biology community to test their favorite AI/ML approaches.

James Casaletto↗
NASA NTRS2007

Multi-System Effects of Daily Artificial Gravity Exposures in Humans Deconditioned by Bed Rest

We have begun to explore the utility of intermittent artificial gravity (AG) as a multi-system countermeasure to the untoward health and performance effects of adaptation to decreased gravity during prolonged space flight. The first study in this exploration was jointly designed by an international, multi-disciplinary team of scientists interested in standardizing an approach so that comparable data could be obtained from follow-on studies performed in multiple international locations. Fifteen rigorously screened male volunteers participated in the study after providing written informed consent. All were subjected to 21 days of 6deg head-down-tilt (HDT) bed rest. Eight were treated with daily 1hr AG exposures (2.5g at the feet decreasing to 1.0g at the heart) aboard a short radius (3m) centrifuge, while the other seven served as controls. Multiple observations were made of dependent measures in the bone, muscle, cardiovascular, sensory-motor, immune, and behavioral systems during a 10 day acclimatization period prior to HDT bed rest and again during an 8 day recovery period after the bed rest period. Comparisons between the treatment and control subjects demonstrated salutary effects of the AG exposure on aspects of the muscle and cardiovascular systems, with no untoward effects on the vestibular system, the immune system, or cognitive function. Bone deconditioning was similar between the treatment and control groups, suggesting that the loading provided by this specific AG paradigm was insufficient to protect that system from deconditioning. Future work will be devoted to varying the loading duty cycle and/or coupling the AG loading with exercise to provide maximum physiological protection across all systems. Testing will also be extended to female subjects. The results of this study suggest that intermittent AG could be an effective multi-system countermeasure.

Paloski, William H.↗
NASA NTRS2015

Physiological Health Challenges for Human Missions to Mars

During the next decades, manned space missions are expected to be aiming at the Lagrange points, near Earth asteroids, and Mars flyby and/or landing. The question is therefore: Are we ready to go? To answer this with a yes, we are currently using the International Space Station to develop an integrated human physiological countermeasure suite. The integrated countermeasure suite will most likely encounter: 1) Exercise devices for aerobic, dynamic and resistive exercise training; 2) sensory‐motor computer training programs and anti‐motion sickness medication for preparing EVAs and G‐transitions; 3) lower limb bracelets for preventing and/or treating the VIIP (vision impairment and intracranial pressure) syndrome; 4) nutritional components for maintenance of bone, muscle, the cardiovascular system and preventing oxidative stress and damage and immune deficiencies (e. g. omega‐3 fatty acids, PRO/K, anti‐oxidants and less salt and iron); 5) bisphosphonates for preventing bone degradation.; 6) lower body compression garment and oral salt and fluid loading for landing on a planetary surface to combat orthostatic intolerance; 7) laboratory analysis equipment for individualized monitoring of biomarkers in blood, urine and saliva for estimation of health status in; 8) advanced ultrasound techniques for monitoring bone and cardiovascular health; and 9) computer modeling programs for individual health status assessments of efficiency and subsequent adjustments of countermeasures. In particular for future missions into deep space, we are concerned with the synergistic effects of weightlessness, radiation, operational constraints and other spaceflight environmental factors. Therefore, increased collaboration between physiological, behavioral, radiation and space vehicle design disciplines are strongly warranted. Another venue we are exploring in NASA's Human Research Program is the usefulness of artificial gravity for mitigating the health risks of long duration weightlessness.

Norsk, Peter↗
NASA NTRSDate not supplied

Developing Open-Source Training Materials for AI/ML and Space Biological Sciences Using NASA Cloud-Based Data

Artificial Intelligence (AI) and Machine Learning (ML) has gained significant traction in the biological and biomedical research fields, in part due to a culture of open data sharing and reuse. AI/ML methodology is well-suited to recognize and predict biological patterns from high-dimensional next-generation sequencing data (e.g. whole genome sequencing, transcriptomic sequencing), as well as from biological or medical imaging data (e.g. microscopy, computed tomography, ultrasound, magnetic resonance imaging, radiography). These methodologies hold particular promise for space biosciences research and automated space health monitoring systems. However, there are key considerations for properly training, validating, and testing a machine learning model in biological research or clinical application. Inexperienced researchers can produce models that perform poorly outside of the training dataset. Open Science principles such as data sharing and open-source code must go hand-in-hand with publicly available, high-quality training curricula in best practices, with modules centered on real-life scientific use cases and data so future AI/ML practitioners gain experience on real problems. Here we present the development of open-source training materials for AI/ML and space biosciences, as part of the NASA Transform to Open Science Training (TOPST) initiative. We develop 4 independent training programs, focused on the following topics: 1) Fundamentals of Machine Learning and Space Biosciences Domain, 2) Open Science, Artificial Intelligence, and Ethical Best Practices for Data Sharing and Analysis, 3) Using AI/ML Classification to Identify Gene Networks Affected By Space Exposure in Mouse Liver, and 4) Using Neural Networks to Find DNA Damage Patterns in Immune Cells after Radiation. All programs leverage cloud-based NASA biological datasets. The curriculum we present will enable worldwide access to training in AI/ML and scientific analysis.

James Casaletto↗
NASA NTRSDate not supplied

Developing Open-Source Training Materials for AI/ML and Space Biological Sciences Using NASA Cloud-Based Data

Artificial Intelligence (AI) and Machine Learning (ML) has gained significant traction in the biological and biomedical research fields in the last two decades, in part thanks to an increasing culture of open data sharing and reuse. Due to its capability for identifying complex relationships and patterns, AI/ML methodology is particularly well suited to recognize and predict biological patterns from high-dimensional next-generation sequencing data (e.g. whole genome sequencing, transcriptomic sequencing), as well as from biological or medical imaging data (e.g. microscopy, computed tomography, ultrasound, magnetic resonance imaging, radiography). These methodologies hold particular promise for space biosciences research and automated space health monitoring systems. However, there are many key considerations for properly training, validating, and testing a machine learning model in biological research or clinical application. Even with the positive culture of Open Science and data sharing, inexperienced researchers working quickly without proper checks can produce models that perform poorly outside of the immediate training dataset. Lessons learned from biological AI/ML research indicate that Open Science principles such as data sharing and open-source code must go hand-in-hand with publicly available, high-quality training curricula in best practices, with modules centered on real-life scientific use cases and data so future AI/ML practitioners gain experience on real problems. Here we present the development of open-source training materials for AI/ML and space biosciences, as part of the NASA Transform to Open Science Training (TOPST) initiative. We develop 4 independent training programs, focused on the following topics: 1) Fundamentals of Machine Learning and Space Biosciences Domain, 2) Open Science, Artificial Intelligence, and Ethical Best Practices for Data Sharing and Analysis, 3) Using AI/ML Classification to Identify Gene Networks Affected By Space Exposure in Mouse Liver, and 4) Using Neural Networks to Find DNA Damage Patterns in Immune Cells after Radiation. All programs leverage cloud-based NASA biological datasets. The curriculum we present will enable worldwide access to training in AI/ML and scientific analysis.

James Andrew Casaletto↗
NASA NTRS2013

Benefits, Consequences, and Uncertainties of Conventional (Exercise) Countermeasure Approaches

This presentation will review the pros, cons, and uncertainties of using exercise countermeasures in hypothetical long duration exploration missions. The use of artificial gravity and exercise will be briefly discussed. One benefit to continued use of exercise is related to our extensive experience with spaceflight exercise hardware and programming. Exercise has been a part of each space mission dating back to the 1960's when simple isometric and bungee exercises were performed in the Gemini capsule. Over the next 50 years, exercise hardware improved cumulating in today's ISS suite of exercise equipment: Cycle Ergometer with Vibration Isolation and Stabilization System (CEVIS), Treadmill (T2) and Advanced Resistive Exercise Device (ARED). Today's exercise equipment is the most robust ever to be flown in space and allows the variety and intensity of exercise that might reasonably be expected to maintain muscle mass and function, bone density and cardiovascular fitness. A second benefit is related to the large body of research literature on exercise training. There is a considerable body of supporting research literature including >40,000 peer reviewed research articles on exercise training in humans. A third benefit of exercise is its effectiveness. With the addition of T2 and ARED to our ISS exercise suite, crew member outcomes on standard medical tests have improved. Additionally exercise has other positive side effects such as stress relief, possible improvement of immune function, improved sleep, etc. Exercise is not without its consequences. The major cons to performance of in‐flight exercise are the time and equipment required. Currently crew are scheduled 2.5 hrs/day for exercise and there is considerable cost to develop, fly and maintain exercise hardware. While no major injuries have been reported on ISS, there is always some risk of injury with any form of exercise There are several uncertainties going forward; these relate mostly to the development of small compact robust effective exercise devices for the next generation of space vehicles. It is becoming increasingly apparent that high intensity exercise is required for maintenance of fitness and functional capability and so future hardware will need to be developed, tested and implemented that allow for a wide variety of exercise, at high intensity while likely involving low mass, volume and power. There are many unanswered issues related to the minimum number and type of exercise devices required for exploration, optimizing exercise prescriptions for these devices, whether a treadmill is absolutely required, and even whether any single countermeasure can adequately protect muscle, bone, cardiovascular and sensorimotor function.

Ploutz-Snyder, Lori↗
NASA NTRS2010

Growing B Lymphocytes in a Three-Dimensional Culture System

A three-dimensional (3D) culture system for growing long-lived B lymphocytes has been invented. The capabilities afforded by the system can be expected to expand the range of options for immunological research and related activities, including testing of immunogenicity of vaccine candidates in vitro, generation of human monoclonal antibodies, and immunotherapy. Mature lymphocytes, which are the effectors of adaptive immune responses in vertebrates, are extremely susceptible to apoptotic death, and depend on continuous reception of survival-inducing stimulation (in the forms of cytokines, cell-to-cell contacts, and antigen receptor signaling) from the microenvironment. For this reason, efforts to develop systems for long-term culture of functional, non-transformed and non-activated mature lymphocytes have been unsuccessful until now. The bone-marrow microenvironment supports the growth and differentiation of many hematopoietic lineages, in addition to B-lymphocytes. Primary bone-marrow cell cultures designed to promote the development of specific cell types in vitro are highly desirable experimental systems, amenable to manipulation under controlled conditions. However, the dynamic and complex network of stromal cells and insoluble matrix proteins is disrupted in prior plate- and flask-based culture systems, wherein the microenvironments have a predominantly two-dimensional (2D) character. In 2D bone-marrow cultures, normal B-lymphoid cells become progressively skewed toward precursor B-cell populations that do not retain a normal immunophenotype, and such mature B-lymphocytes as those harvested from the spleen or lymph nodes do not survive beyond several days ex vivo in the absence of mitogenic stimulation. The present 3D culture system is a bioreactor that contains highly porous artificial scaffolding that supports the long-term culture of bone marrow, spleen, and lymph-node samples. In this system, unlike in 2D culture systems, B-cell subpopulations developing within 3D cultures that have been modified to foster lymphopoiesis retain an immunophenotype that closely recapitulates cells in fresh bone marrow harvests. The 3D culture system has been found to be capable of supporting long-lived (8 weeks) populations of B and T lymphocytes from peripheral lymphoid organs, in the absence of activation signals, to an extent not achievable by conventional culture techniques. Interestingly, it has been found that 3D-culture B cells display a phenotype that has characteristics of both B1a and B2 cells. These promising preliminary observations suggest that the 3D culture system could be used with success in the study of peripheral-B-lymphocyte biology and in the development of biotechnological techniques and processes.

Wu, J. H. David↗
NASA NTRS2007

Artificial Gravity as a Multi-System Countermeasure to Bed Rest Deconditioning: Pilot Study Overview

Efficient, effective, multi-system countermeasures will likely be required to protect the health, safety, and performance of crews aboard planned exploration-class space flight missions to Mars and beyond. To that end, NASA, DLR, and IMBP initiated a multi-center international project to begin systematically exploring the utility of artificial gravity (AG) as a multi-system countermeasure in ground based venues using test subjects deconditioned by bed rest. The goal of this project is to explore the efficacy of short-radius, intermittent AG as a countermeasure to bone, muscle, cardiovascular, and sensory-motor adaptations to hypogravity. This session reports the results from a pilot study commissioned to validate a standardized protocol to be used by all centers involved in the project. Subject selection criteria, medical monitoring requirements, medical care procedures, experiment control procedures, and standardized dependent measures were established jointly. Testing was performed on 15 rigorously screened male volunteers subjected to 21 days of 6deg HDT bed rest. (All provided written consent to volunteer after the nature of the study and its hazards were clearly explained to them.) Eight were treated with daily 1hr AG exposures (2.5g at the feet decreasing to 1.0g at the heart) aboard a short radius (3m) centrifuge, while the other seven served as controls. Multiple tests of multiple dependent measures were made in each of the primary physiological systems of interest during a 10 day acclimatization period prior to HDT bed rest and again during an 8 day recovery period after the bed rest period was complete. Analyses of these data (presented in other papers in this session) suggest the AG prescription had salutary effects on aspects of the bone, muscle, and cardiovascular systems, with no untoward effects on the vestibular system, the immune system, or cognitive function. Furthermore, treatment subjects were able to tolerate 153/160 centrifuge sessions over the 21 day deconditioning protocol, suggesting that tolerance was unaffected by deconditioning. These positive results set the stage for full implementation of the planned multi-center international AG project. Future work will be devoted to developing optimization techniques for AG prescriptions (likely supplemented by exercise) to provide maximum physiological protection across all systems subject to space flight deconditioning in both men and women with minimum time and/or side effects. While a continuous AG solution (rotating vehicle) would likely be more efficient, this study suggests that intermittent AG could be an effective multi-system countermeasure.

Paloski, William H.↗