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NASA NTRS2019

Impacts of In-Space Assembly as Applied to Human Exploration Architectures

Human missions to Mars present several major challenges that must be overcome, including delivering multiple large mass and volume elements, keeping the crew safe and productive, meeting cost constraints, and ensuring a sustainable campaign. Traditional methods for executing human Mars missions minimize or eliminate in-space assembly (iSA), which provides a narrow range of options for addressing these challenges and limits the types of missions that can be performed. This paper discusses recent work to evaluate how the inclusion of in-space assembly in space mission architectural concepts could provide novel solutions to address these challenges by increasing operational flexibility, robustness, risk reduction, crew health and safety, and sustainability. Several assembly focus areas identified through previous work were developed and evaluated to identify high-potential iSA applications that can have meaningful impacts on the challenges facing Mars missions. Architecture trade options were developed and assessed through sensitivity analyses, resulting in identification of six iSA-based architecture solutions that could be incorporated into Mars mission architectures with moderate levels of assembly. Assembly agent and infrastructure concepts were also developed that would be necessary to enable or facilitate the iSA operations. Several observations developed through the study are presented to inform future human mission architecture and campaign developments.

Jefferies, Sharon A.↗

DOE OSTI2020

Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface

The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells. The recognition mode is unprecedented in that the targeted domain of CEP250 is a coiled coil and is topologically featureless, embodying both a structural motif and surface topology previously considered on the extreme limits of “undruggability” for an intracellular target. Structural studies reveal extensive protein–WDB002 and protein–protein contacts, with the latter being distinct from those seen in FKBP12 ternary complexes formed by FK506 and rapamycin. Outward-facing structural changes in a bound small molecule can thus reprogram FKBP12 to engage diverse, otherwise “undruggable” targets. The flat-targeting modality demonstrated here has the potential to expand the druggable target range of small-molecule therapeutics. As CEP250 was recently found to be an interaction partner with the Nsp13 protein of the SARS-CoV-2 virus that causes COVID-19 disease, it is possible that WDB002 or an analog may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2024

Synthetic β-sheets mimicking fibrillar and oligomeric structures for evaluation of spectral X-ray scattering technique for biomarker quantification

Archetypical cross-β spines sharpen the boundary between functional and pathological proteins including β-amyloid, tau, α-synuclein and transthyretin are linked to many debilitating human neurodegenerative and non-neurodegenerative amyloidoses. An increased focus on development of pathogenic β-sheet specific fluid and imaging structural biomarkers and conformation-specific monoclonal antibodies in targeted therapies has been recently observed. Identification and quantification of pathogenic oligomers remain challenging for existing neuroimaging modalities. We propose two artificial β-sheets which can mimic the nanoscopic structural characteristics of pathogenic oligomers and fibrils for evaluating the performance of a label free, X-ray based biomarker detection and quantification technique. Highly similar structure with elliptical cross-section and parallel cross-β motif is observed among recombinant α-synuclein fibril, Aβ-42 fibril and artificial β-sheet fibrils. We then use these β-sheet models to assess the performance of spectral small angle X-ray scattering (sSAXS) technique for detecting β-sheet structures. sSAXS showed quantitatively accurate detection of antiparallel, cross-β artificial oligomers from a tissue mimicking environment and significant distinction between different oligomer packing densities such as diffuse and dense packings. The proposed synthetic β-sheet models mimicked the nanoscopic structural characteristics of β-sheets of fibrillar and oligomeric states of Aβ and α-synuclein based on the ATR-FTIR and SAXS data. The tunability of β-sheet proportions and shapes of structural motifs, and the low-cost of these β-sheet models can become useful test materials for evaluating β-sheet or amyloid specific biomarkers in a wide range of neurological diseases. By using the proposed synthetic β-sheet models, our study indicates that the sSAXS has potential to evaluate different stages of β-sheet-enriched structures including oligomers of pathogenic proteins.

59 BASIC BIOLOGICAL SCIENCES↗

NASA NTRSDate not supplied

TPSAS-NF1676L-18493-DND

The Air Traffic Operations Lab is a multi-fidelity, part-task, aircraft and air traffic operations simulation facility. Used to explore interactions between new airborne and ground-based tools in a NextGeneration ATC environment, including: - Concept-level flight operations research, looking at human decision making, situation awareness, transfer of authority/responsibility, etc. - Performance impact assessments of new operational concepts on the National Airspace System (NAS) - Rapid prototyping of new flight deck tools and automation - Concept-level safety assessments - Identification and evaluation of future communication, navigation, and surveillance (CNS) infrastructure requirements - Controller-pilot data link - Precision trajectory-based ops - Air-to-air data exchange

Michael T Palmer↗

NASA NTRSDate not supplied

COSPAR Workshop Series on Refining Planetary Protection Requirements for Human Missions to Mars

COSPAR and its space agency partners are supporting a multi-year stepwise process devel-oping needed approaches to address planetary protection requirements for human missions beyond Earth orbit. The objective is to support incremental development from the current qualitative COSPAR planetary protection “Principles and Guidelines for Human Missions to Mars” to quantitative implementable planetary protection requirements for such future mis-sions. The workshops and meetings in this series have involved participants from NASA, ESA, JAXA and other national space agencies, as well as the scientific/technical community, and commercial/private enterprise stakeholders, based around three main topic areas: Microbial and Human Health Monitoring; Spacecraft Technology and Operations, and; Natural Trans-port of Contamination at Mars. This presentation provides a status update on the findings of the COSPAR Meetings on this topic to date. First, the identification and prioritization of knowledge gaps will be summarized. Next, where a knowledge gap is to be addressed by new measurements, example descriptions of measurements needed to close the knowledge gaps (and instruments necessary to make those measurements) will be discussed. Where the knowledge gaps closure is based on Agency policy decisions, the scope of the decision-making parameters and process will be described. Lastly, the presentation will consider how the findings of the study series can be integrated into current and future space agency and COSPAR activities.

J. Andy Spry↗

NASA NTRS2004

Multimodality instrument for tissue characterization

A system with multimodality instrument for tissue identification includes a computer-controlled motor driven heuristic probe with a multisensory tip. For neurosurgical applications, the instrument is mounted on a stereotactic frame for the probe to penetrate the brain in a precisely controlled fashion. The resistance of the brain tissue being penetrated is continually monitored by a miniaturized strain gauge attached to the probe tip. Other modality sensors may be mounted near the probe tip to provide real-time tissue characterizations and the ability to detect the proximity of blood vessels, thus eliminating errors normally associated with registration of pre-operative scans, tissue swelling, elastic tissue deformation, human judgement, etc., and rendering surgical procedures safer, more accurate, and efficient. A neural network program adaptively learns the information on resistance and other characteristic features of normal brain tissue during the surgery and provides near real-time modeling. A fuzzy logic interface to the neural network program incorporates expert medical knowledge in the learning process. Identification of abnormal brain tissue is determined by the detection of change and comparison with previously learned models of abnormal brain tissues. The operation of the instrument is controlled through a user friendly graphical interface. Patient data is presented in a 3D stereographics display. Acoustic feedback of selected information may optionally be provided. Upon detection of the close proximity to blood vessels or abnormal brain tissue, the computer-controlled motor immediately stops probe penetration. The use of this system will make surgical procedures safer, more accurate, and more efficient. Other applications of this system include the detection, prognosis and treatment of breast cancer, prostate cancer, spinal diseases, and use in general exploratory surgery.

Mah, Robert W.↗

NASA NTRS2000

Multimodality Instrument for Tissue Characterization

A system with multimodality instrument for tissue identification includes a computer-controlled motor driven heuristic probe with a multisensory tip is discussed. For neurosurgical applications, the instrument is mounted on a stereotactic frame for the probe to penetrate the brain in a precisely controlled fashion. The resistance of the brain tissue being penetrated is continually monitored by a miniaturized strain gauge attached to the probe tip. Other modality sensors may be mounted near the probe tip to provide real-time tissue characterizations and the ability to detect the proximity of blood vessels, thus eliminating errors normally associated with registration of pre-operative scans, tissue swelling, elastic tissue deformation, human judgement, etc., and rendering surgical procedures safer, more accurate, and efficient. A neural network, program adaptively learns the information on resistance and other characteristic features of normal brain tissue during the surgery and provides near real-time modeling. A fuzzy logic interface to the neural network program incorporates expert medical knowledge in the learning process. Identification of abnormal brain tissue is determined by the detection of change and comparison with previously learned models of abnormal brain tissues. The operation of the instrument is controlled through a user friendly graphical interface. Patient data is presented in a 3D stereographics display. Acoustic feedback of selected information may optionally be provided. Upon detection of the close proximity to blood vessels or abnormal brain tissue, the computer-controlled motor immediately stops probe penetration.

Mah, Robert W.↗

DOE OSTI2020

Ultrasensitive single-cell proteomics workflow identifies >1000 protein groups per mammalian cell

Here, we report on the combination of nanodroplet sample preparation, ultra-low-flow nanoLC, high-field asymmetric ion mobility spectrometry (FAIMS), and the latest-generation Orbitrap Eclipse Tribrid mass spectrometer for greatly improved single-cell proteome profiling. FAIMS effectively filtered out singly charged ions for more effective MS analysis of multiply charged peptides, resulting in an average of 1056 protein groups identified from single HeLa cells without MS1-level feature matching. This is 2.3 times more identifications than without FAIMS and a far greater level of proteome coverage for single mammalian cells than has been previously reported for a label-free study. Differential analysis of single microdissected motor neurons and interneurons from human spinal tissue indicated a similar level of proteome coverage, and the two subpopulations of cells were readily differentiated based on single-cell label-free quantification.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

NASA NTRS1972

Speed in Information Processing with a Computer Driven Visual Display in a Real-time Digital Simulation

Information transfer between the operator and computer-generated display systems is an area where the human factors engineer discovers little useful design data relating human performance to system effectiveness. This study utilized a computer-driven, cathode-ray-tube graphic display to quantify human response speed in a sequential information processing task. The performance criteria was response time to sixteen cell elements of a square matrix display. A stimulus signal instruction specified selected cell locations by both row and column identification. An equal probable number code, from one to four, was assigned at random to the sixteen cells of the matrix and correspondingly required one of four, matched keyed-response alternatives. The display format corresponded to a sequence of diagnostic system maintenance events, that enable the operator to verify prime system status, engage backup redundancy for failed subsystem components, and exercise alternate decision-making judgements. The experimental task bypassed the skilled decision-making element and computer processing time, in order to determine a lower bound on the basic response speed for given stimulus/response hardware arrangement.

Kyle, R. G.↗

NASA NTRS1992

Chemical and microbiological experimentation for development of environmental control and life support systems

Microbiological techniques are under study with a view to the identification of viable microorganisms in liquid cultures, improve the identification of stressed organisms, and determine the biocidal activity of iodine and other chemicals on isolates from recycled water. A quality-assurance program has been implemented to validate data employed in making decisions concerning engineering and human health and safety. Analytical laboratory refinements will strongly aid the development of environmental control and life-support systems.

Whitman, G. A.↗

NASA NTRS1999

Visual- and Vestibular-Autonomic Influence on Short-Term Cardiovascular Regulatory Mechanisms

This synergy project was a one-year effort conducted cooperatively by members of the NSBRI Cardiovascular Alterations and Neurovestibular Adaptation Teams in collaboration with NASA Johnson Space Center (JSC) colleagues. The objective of this study was to evaluate visual autonomic interactions on short-term cardiovascular regulatory mechanisms. Based on established visual-vestibular and vestibular-autonomic shared neural pathways, we hypothesized that visually induced changes in orientation will trigger autonomic cardiovascular reflexes. A second objective was to compare baroreflex changes during postural changes as measured with the new Cardiovascular System Identification (CSI) technique with those measured using a neck barocuff. While the neck barocuff stimulates only the carotid baroreceptors, CSI provides a measure of overall baroreflex responsiveness. This study involved a repeated measures design with 16 healthy human subjects (8 M, 8 F) to examine cardiovascular regulatory responses during actual and virtual head-upright tilts. Baroreflex sensitivity was first evaluated with subjects in supine and upright positions during actual tilt-table testing using both neck barocuff and CSI methods. The responses to actual tilts during this first session were then compared to responses during visually induced tilt and/or rotation obtained during a second session.

Mullen, Thomas J.↗

NASA NTRS2010

Visual Impairment/Intracranial Pressure Risk Assessment

Since 2006 there have been 6 reported cases of altered visual acuity and intracranial pressure (ICP) in long duration astronauts. In order to document this risk and develop an integrated approach to its mitigation, the NASA Space Life Sciences Directorate (SLSD) and Human Research Program (HRP) have chosen to use the Human System Risk Board (HSRB) and the risk management analysis tool (RMAT). The HSRB is the venue in which the stakeholders and customers discuss and vet the evidence and the RMAT is the tool that facilitates documentation and comparison of the evidence across mission profiles as well as identification of risk factors, and documentation of mitigation strategies. This process allows for information to be brought forward and dispositioned so that it may be properly incorporated into the RMAT and contribute to the design of the research and mitigation plans. The evidence thus far has resulted in the identification of a visual impairment/intracranial pressure (VIIP) project team, updating of both short and long duration medical requirements designed to assess visual acuity, and a research plan to characterize this issue further. In order to understand this issue more completely, a plan to develop an Accelerated Research Collaboration (ARC) has been approved by the HSRB. The ARC is a novel research model pioneered by the Myelin Repair Foundation. It is a patient centered research model that brings together researchers and clinicians, under the guidance of a scientific advisory panel, to collaborate and produce results much quickly than accomplished through traditional research models. The data and evidence from the updated medical requirements and the VIIP ARC will be reviewed at the HSRB on a regular basis. Each review package presented to the HSRB will include an assessment and recommendation with respect to continuation of research, countermeasure development, occupational surveillance modalities, selection criteria, etc. This process will determine the course of the VIIP project and ultimately how SLSD and HRP mitigate this emerging human health and performance risk.

Fogarty, Jennifer A.↗

NASA NTRS2023

Identifying and Closing Medical Capability Gaps for Human Spaceflight Missions Beyond Low Earth Orbit

BACKGROUND: Features of human space missions beyond low Earth orbit such as increasing distance from Earth, lack of real-time communication, and limited or no evacuation or resupply capability are expected to drive an increase in medical risk and require crews to operate in an increasingly autonomous fashion. A diverse set of stakeholders at NASA are seeking to fund the development of concepts of operations, medical requirements, and medical capabilities for such missions. However, a systematic approach to identification of current medical capability gaps and a strategic framework to gap closure is needed. OVERVIEW: The Exploration Medical Integrated Product Team (XMIPT) has developed a list of nine high-level medical capability gaps and associated activities required for gap closure. The list was derived based on inputs from subject matter experts at NASA including flight surgeons, other clinical providers, as well as operational and research communities regarding medical capabilities required to support human missions to the Moon and the Mars surface. Responses were reviewed and distilled to identify common themes across capabilities. To ensure alignment with established human system risks, the gap list was further refined based on inputs from NASA’s Human System Risk Board. Relevant medical gap closure activities outside of those funded by the XMIPT were identified through solicitation of inputs from Elements of NASA’s Human Research Program (particularly Exploration Medical Capability), the broader medical operations community, and other stakeholders. This medical capability gap list is reviewed and updated regularly as new information becomes available or new stakeholders are identified. DISCUSSION: The medical capability gap list has matured to include a large group of NASA stakeholders and development activities. This has enabled articulation of priorities to funding entities and programmatic stakeholders, while serving as an accessible resource summarizing gap closure activities, relevant programmatic infusion points, and opportunities for collaboration between stakeholders. This presentation will provide an overview of the nine NASA medical capability gaps and their associated gap closure activities.

Moriah Thompson↗

NASA NTRS2023

Using Virtual Reality to Envision Deployment of Spacesuit-Compatible Augmented Reality Displays for Lunar Surface Operations

The National Aeronautics and Space Administration (NASA) will soon land crew on the lunar surface to establish a sustainable presence and develop operational concepts for future long-duration missions. New technologies will be necessary to extend planning and execution capabilities for lunar surface activities. The Joint Augmented Reality Visual Informatics System (Joint AR) at NASA Johnson Space Center (JSC) is one such technology. Joint AR is a suit-mounted augmented reality (AR) display and compute system which facilitates unprecedented information exchange and data visualization capabilities between mission support operators and suited crew. This paper describes challenges associated with developing an AR technology for an envisioned work domain by applying a sociotechnical lens to the iterative testing and development of novel AR technology through virtual reality (VR). A foundational VR testbed was established, providing a high-fidelity approximation of the lunar surface and enabling testing of envisioned AR system features in parallel with real world product development. Using this environment, a series of human-in-the-loop experiments were conducted using VR to deploy a notional AR system supporting use cases envisioned for lunar exploration extravehicular activity (xEVA). Our findings indicate VR is a powerful and immersive tool for testing capabilities which extend beyond the limitations of current AR technology. Our VR testbed enables early testing of proposed system features, advancing identification of high-value features and driving present-day development of Joint AR. Future work directions are discussed, including lessons learned and a roadmap for an iterative research and development approach applying VR (among other testbeds) to accelerate Joint AR system maturation.

Augmented reality↗

DOE OSTI2025

Identification and Clinical Evaluation of Potential Biomarkers for Breast Cancer Resistance Protein ( BCRP / ABCG2 )

Clinical inhibition and genetic variation of the Breast Cancer Resistance Protein (BCRP/ABCG2) efflux transporter can significantly influence drug exposure, highlighting the need for reliable BCRP functional biomarkers. This study aimed to identify and evaluate biomarkers predictive of BCRP function in humans. A comprehensive analysis of metabolomic genome‐wide association studies (mGWAS) was conducted to discover potential BCRP biomarkers, followed by evaluation inin vitrotransporter assays and a clinical drug–drug interaction (DDI) study. Across multiple mGWAS datasets, plasma concentrations of three herbicide derivatives—4‐hydroxychlorothalonil (4HC), 3‐bromo‐5‐chloro‐2,6‐dihydroxybenzoic acid (BCDBA), and 3,5‐dichloro‐2,6‐dihydroxybenzoic acid (DCDBA)—were significantly elevated (P < 5E‐8) in individuals carrying reduced functionABCG2polymorphisms. These compounds were confirmed as novel BCRP substrates via transporter uptake assays and selected for clinical evaluation alongside riboflavin, a known BCRP substrate and potential BCRP biomarker. In a DDI study with 11 healthy subjects, eltrombopag, a BCRP inhibitor, increased rosuvastatin concentrations by approximately twofold (P = 0.002). No significant changes in the plasma concentrations of organic anion transporting polypeptide 1B (OATP1B) biomarkers (CP‐I and CP‐III) or potential BCRP biomarkers (4HC, BCDBA, DCDBA, or riboflavin) were observed. Notably, two subjects were heterozygous carriers for theABCG2p.Q141K variant and exhibited significantly higher baseline concentrations of 4HC (P = 0.004) and BCDBA (P = 0.0003), consistent with reduced BCRP function. These findings suggest that 4HC and BCDBA are promising biomarkers for baseline BCRP function in specific populations, such as those harboring reduced function genetic polymorphisms, but do not appear suitable for detecting acute BCRP inhibition.

Pharmacology & Pharmacy↗

NASA NTRSDate not supplied

Strategies for Identifying Resilient Behavior In Aviation

When we imagine a situation where people fly aircraft and nothing scary happens, we assume it is the system that affords this phenomenon. That is, the overall design is the cause of the success. However, this is not always true. There are many examples of how the presence of a human in the system is the reason for a successful outcome, despite flaws in the system’s design. This resilient behavior is often overlooked and challenging to characterize. In an attempt to identify this phenomenon in a generalizable way, we named and investigated two strategies, as well as identification methods, that exemplify resilient performance: 1) controls; and 2) modifications. First, controls are resilient actions in situations known to be problematic. To capture this, instead of looking at the examples of how the problem became a reality, we look at the examples of how the problem was successfully avoided or controlled. For example, a country road may have a hairpin turn where a higher-than-normal rate of accidents occur. Given that there is a likely system flaw identified, we would look at how the successful drivers navigated the turn. This can be accomplished using current safety reporting systems. Second, modifications are augmentations or changes that people create to fill in the gap between work-as-imagined and work-as-done. This type of resilient performance is directly related to poor design. In aviation, work-as-imagined is often scripted explicitly, so it can be compared to work-as-done through the use of examining system-generated data as well as narrative reports written by the system operators. These two approaches aim to identify resilient human actions to better understand how current systems function, as well as how people contribute to successes that were otherwise unknown.

human factors↗

DOE OSTI2026

A Multiplexed Quantitative Analysis of Germline Single Amino Acid Variants by Targeted Proteomics in Nondepleted Human Plasma

Single amino acid variants (SAAVs) in protein sequences are often a direct result of single-nucleotide polymorphisms (SNPs). Certain germline SAAVs have shown biological relevance in different disease conditions but lack precise quantification in circulation, which could hinder functional investigations and progress in biomarker development. Here, we have developed a multiplexed liquid chromatography-selected reaction monitoring (LC-SRM) assay that monitors 5 wild-type and variant peptide pairs (Complement Factor B: CFB-R32Q/R32W, Clusterin: CLU-N317H, Fetuin B: FETUB-K360R, and Kininogen: KNG1-L212P) in nondepleted human plasma. The assay was optimized for imprecision, linearity, stability, and calibration assessments with CVs of under 20%. The wild-type and variant peptide pairs were characterized in a set of healthy individual plasma samples. These target identifications were also validated by SNP genotyping with more than 99% accuracy. For all protein targets, we observed significantly lower concentrations of WT species in the presence variant peptides. In CFB, the concentration of R32Q was significantly lower than its counterpart R32W variant and WT species. Furthermore, our results distinguished phenotypes of homozygosity and heterozygosity of the SAAV presence through direct concentration level characterization. These findings provide some insights into how SAAVs affect quantitative assessments of target peptides. The assay demonstrates a platform for proteogenomic analyses with potential applications in both research and clinical settings.

genetics↗

NASA NTRS2002

Uncertainties in Estimates of the Risks of Late Effects from Space Radiation

The health risks faced by astronauts from space radiation include cancer, cataracts, hereditary effects, and non-cancer morbidity and mortality risks related to the diseases of the old age. Methods used to project risks in low-Earth orbit are of questionable merit for exploration missions because of the limited radiobiology data and knowledge of galactic cosmic ray (GCR) heavy ions, which causes estimates of the risk of late effects to be highly uncertain. Risk projections involve a product of many biological and physical factors, each of which has a differential range of uncertainty due to lack of data and knowledge. Within the linear-additivity model, we use Monte-Carlo sampling from subjective uncertainty distributions in each factor to obtain a Maximum Likelihood estimate of the overall uncertainty in risk projections. The resulting methodology is applied to several human space exploration mission scenarios including ISS, lunar station, deep space outpost, and Mar's missions of duration of 360, 660, and 1000 days. The major results are the quantification of the uncertainties in current risk estimates, the identification of factors that dominate risk projection uncertainties, and the development of a method to quantify candidate approaches to reduce uncertainties or mitigate risks. The large uncertainties in GCR risk projections lead to probability distributions of risk that mask any potential risk reduction using the "optimization" of shielding materials or configurations. In contrast, the design of shielding optimization approaches for solar particle events and trapped protons can be made at this time, and promising technologies can be shown to have merit using our approach. The methods used also make it possible to express risk management objectives in terms of quantitative objective's, i.e., the number of days in space without exceeding a given risk level within well defined confidence limits.

Cucinotta, F. A.↗