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NASA NTRS2017

Mapping Bone Mineral Density Obtained by Quantitative Computed Tomography to Bone Volume Fraction

Methods for relating or mapping estimates of volumetric Bone Mineral Density (vBMD) obtained by Quantitative Computed Tomography to Bone Volume Fraction (BVF) are outlined mathematically. The methods are based on definitions of bone properties, cited experimental studies and regression relations derived from them for trabecular bone in the proximal femur. Using an experimental range of values in the intertrochanteric region obtained from male and female human subjects, age 18 to 49, the BVF values calculated from four different methods were compared to the experimental average and numerical range. The BVF values computed from the conversion method used data from two sources. One source provided pre bed rest vBMD values in the intertrochanteric region from 24 bed rest subject who participated in a 70 day study. Another source contained preflight vBMD values from 18 astronauts who spent 4 to 6 months on the ISS. To aid the use of a mapping from BMD to BVF, the discussion includes how to formulate them for purpose of computational modeling. An application of the conversions would be used to aid in modeling of time varying changes in vBMD as it relates to changes in BVF via bone remodeling and/or modeling.

Pennline, James A.↗

NASA NTRS2017

Computational Modeling of Space Physiology for Informing Spaceflight Countermeasure Design and Predictions of Efficacy

MOTIVATION: Spaceflight countermeasures mitigate the harmful effects of the space environment on astronaut health and performance. Exercise has historically been used as a countermeasure to physical deconditioning, and additional countermeasures including lower body negative pressure, blood flow occlusion and artificial gravity are being researched as countermeasures to spaceflight-induced fluid shifts. The NASA Digital Astronaut Project uses computational models of physiological systems to inform countermeasure design and to predict countermeasure efficacy.OVERVIEW: Computational modeling supports the development of the exercise devices that will be flown on NASAs new exploration crew vehicles. Biomechanical modeling is used to inform design requirements to ensure that exercises can be properly performed within the volume allocated for exercise and to determine whether the limited mass, volume and power requirements of the devices will affect biomechanical outcomes. Models of muscle atrophy and bone remodeling can predict device efficacy for protecting musculoskeletal health during long-duration missions. A lumped-parameter whole-body model of the fluids within the body, which includes the blood within the cardiovascular system, the cerebral spinal fluid, interstitial fluid and lymphatic system fluid, estimates compartmental changes in pressure and volume due to gravitational changes. These models simulate fluid shift countermeasure effects and predict the associated changes in tissue strain in areas of physiological interest to aid in predicting countermeasure effectiveness. SIGNIFICANCE: Development and testing of spaceflight countermeasure prototypes are resource-intensive efforts. Computational modeling can supplement this process by performing simulations that reduce the amount of necessary experimental testing. Outcomes of the simulations are often important for the definition of design requirements and the identification of factors essential in ensuring countermeasure efficacy.

biomedical data↗

NASA NTRS2017

Dose- and Ion-Dependent Effects in the Oxidative Stress Response to Space-Like Radiation Exposure in the Skeletal System

Exposure to space radiation may pose a risk to skeletal health during subsequent aging. Irradiation acutely stimulates bone remodeling in mice, although the long-term influence of space radiation on bone-forming potential (osteoblastogenesis) and possible adaptive mechanisms are not well understood. We hypothesized exposure to ionizing radiation impairs osteoblastogenesis in an ion-type specific manner, with low doses capable of modulating expression of redox-related genes. 16-week old, male, C57BL6/J mice were exposed to low linear-energy-transfer (LET) protons (150 mega electron volts per nucleon) or high-LET (sup 56) Fe ions (600 mega electron volts per nucleon) using either low (5 or 10 centigrays) or high (50 or 200 centigrays) doses at NASAs Space Radiation Lab at Brookhaven National Lab (NSRL/BNL). Tissues were harvested 5 weeks or 1 year after irradiation and bones were analyzed by microcomputed tomography for cancellous microarchitecture and cortical geometry. Marrow-derived, adherent cells were grown under osteoblastogenic culture conditions. Cell lysates were analyzed for select groups by RT-PCR (Reverse Transcription-Polymerase Chain Reaction) during the proliferative phase or the mineralizing phase, and differentiation was analyzed by imaging mineralized nodules (percentage surface area). Representative genes were selected for expression analyses, including cell proliferation (PCNA, Cdk2, p21, p53), differentiation (Runx2, Alpl, Bglap), oxidative metabolism (Catalase, GPX, MnSOD, CuZnSOD, iNos, Foxo1), DNA-damage repair (Gadd45), or apoptosis (Caspase 3). As expected, a high dose (200 centigrays), but not low doses, of either (sup 56) Fe or protons caused a loss of cancellous bone volume per total volume. Marrow cells produced mineralized nodules ex vivo regardless of radiation type or dose; (sup 56) Fe (200 centigrays) inhibited median nodule area by more than 90 percent at 5 weeks and 1 year post-irradiation, compared to controls. At 5 weeks post exposure, irradiation with protons or (sup 56) Fe caused few changes in gene expression levels during osteoblastogenesis, although a high dose of (sup 56) Fe (200 centigrays) increased levels of Catalase and Gadd45. In addition, supplementing cell culture media with SOD protected marrow-derived osteoprogenitors from the damaging effects of exposure to low-LET ((sup 137) Cs gamma) if irradiated in vitro, but had limited protective effects on high-LET (sup 56) Fe-exposed cells. In sum, exposure of mice to either protons or (sup 56) Fe at a relatively high dose (200 cGy) caused persistent bone loss, whereas only high-LET (sup 56) Fe increased expression of redox-related genes and inhibited osteoblastogenesis, albeit to a limited extent. We conclude that high-LET irradiation impaired osteoblastogenesis and regulated steady-state gene expression of select redox-related genes during osteoblastogenesis, which may contribute to persistent bone loss.

ionizing radiation↗

NASA NTRS2018

Differences in Pre and Post Vascular Patterning of Retinas from ISS Crew Members and HDT Subjects by VESGEN Analysis

Accelerated research by NASA [1] has investigated the significant risks for visual and ocular impairments Spaceflight Associated Neuro-Ocular Syndrome /Visual Impairment/Intracranial Pressure (SANS/VIIP) incurred by microgravity spaceflight, especially long-duration missions. Our study investigates the role of blood vessels in the incidence and etiology of SANS/VIIP within the retinas of Astronaut crewmembers pre-and post-flight to the International Space Station (ISS) by NASA's VESsel GENeration Analysis (VESGEN). The response of retinal vessels in crewmembers to microgravity was compared to that of retinal vessels to Head-Down Tilt (HDT) in subjects undergoing 70-Day Bed Rest. The study tests the proposed hypothesis that cephalad fluid shifts missions, resulting in ocular and visual impairments, are necessarily mediated in part by retinal blood vessels, and are therefore accompanied by significant remodeling of retinal vasculature.Vascular patterns in the retinas of crew members and HDTBR subjects extracted from 30° infrared (IR) Heidelberg Spectralis® images collected pre/postflight and pre/post HDTBR, respectively, were analyzed by VESGEN (patent pending). a mature, automated software developed as a research discovery tool for progressive vascular diseases in the retina and other tissues [2]. The weighted, multi-parametric VESGEN analysis generates maps of branching arterial and venous trees and quantification by parameters such as the fractal dimension (Df, a modern measure of vascular space-filling capacity), vessel diameters, and densities of vessel length and number classified into specific branching generations by vascular physiological branching rules [2,3]. The retrospective study approved by NASA’s Institutional Review Board included six HDT subjects (NASA Flight Analogs Research Unit [FARU] Campaign 11; for example, [4]) and eight ISS crewmembers monitored by routine occupational surveillance who provided their study consents to NASA’s Lifetime Surveillance of Astronaut Health (LSAH). For the initial blinded VESGEN phase, ophthalmic retinal images were masked as to subject identity and pre- and post-status. In the second unblinded phase, VESGEN results were analyzed according to the pre- and post-status of left and right retinas matched to each subject. To complete our study, vascular results will be subjected to NASA biostatistical analysis and correlated with other ophthalmic and medical findings. Preliminary results for changes in the pre- to post-status of vascular patterning in the retinas of crewmembers and HDT subjects are strikingly opposite. By Df and other vascular branching measures, the space-filling capacity of arterial and venous trees decreased in a substantial subset of crewmembers (11/16 retinas). In contrast, vascular densities increased in a substantial subset of HDT subjects by the same parameters (6/10 retinas, currently excluding one anomalous subject). To conclude the study, biostatistical and medical analyses will be of critical importance for investigating the validity of these vascular findings. Vascular densities appeared to decrease in the retinas of crewmembers following ISS Missions, and increase in subjects after HDT. The vascular increases and decreases most likely derive primarily from limits of resolution to the ophthalmic imaging that does not capture the smallest vessels, rather than from vessel growth or atrophy. Differences in arterial and venous response to cephalad fluid shifts induced by ISS and HDT may have resulted from a long-duration conditioning phenomenon (for example, 6-month ISS missions compared to 70-day HDT), or the presence of gravity in HDT compared to microgravity onboard the ISS. To conclude our study, the biostatistical and medical analyses will be of critical importance for investigating the validity and significance of the VESGEN findings.

Murray, M. C.↗

NASA NTRS2017

VESsel GENeration Analysis (VESGEN): Innovative Vascular Mappings for Astronaut Exploration Health Risks and Human Terrestrial Medicine

Currently, astronauts face significant health risks in future long-duration exploration missions such as colonizing the Moon and traveling to Mars. Numerous risks include greatly increased radiation exposures beyond the low earth orbit (LEO) of the ISS, and visual and ocular impairments in response to microgravity environments. The cardiovascular system is a key mediator in human physiological responses to radiation and microgravity. Moreover, blood vessels are necessarily involved in the progression and treatment of vascular-dependent terrestrial diseases such as cancer, coronary vessel disease, wound-healing, reproductive disorders, and diabetes. NASA developed an innovative, globally requested beta-level software, VESsel GENeration Analysis (VESGEN) to map and quantify vascular remodeling for application to astronaut and terrestrial health challenges. VESGEN mappings of branching vascular trees and networks are based on a weighted multi-parametric analysis derived from vascular physiological branching rules. Complex vascular branching patterns are determined by biological signaling mechanisms together with the fluid mechanics of multi-phase laminar blood flow.

astronaut↗

NASA NTRS2018

CDKN1a/p21 Plays a Critical Role in Suppressing Stem Cell Regenerative Potential During Aging

Unloading during spaceflight is known to adversely affect mammalian physiology. Mechanical stimulation is required for repair and regeneration by stem cell lineages to maintain tissue health and mass. CDKN1a/p21 functions as a potent cell cycle arrest molecule and we previously found that CDKN1a/p21 was overexpressed in mouse bone during 15-days of spaceflight on STS-131 and localized to osteoprecursor cells in the femur. Therefore, we hypothesized that altered expression of CDKN1a/p21 leads to an arrest of bone formation during spaceflight in response to altered load. To study CDKN1a/p21 and its role in stem cell-based tissue regeneration, we use a CDKN1a/p21 knockout (KO) mouse to investigate the impact on bone structure, osteoprogenitor proliferation, and mineralized nodule formation. We have shown that bone marrow stem cells isolated from juvenile (11-week-old) and skeletally mature (18-week-old) KO mice have an increased bone formation potential as evidenced by increased proliferation and mineralization rates. In addition, we have shown that juvenile KO mice display significantly increased bone volume fraction (BV/TV) relative to wildtype (WT) mice, but not in skeletally mature KO mice, indicating increased resorption and bone turnover in adult mice. To more closely examine age differences in the KO mouse, we will study a wider spectrum of mice ranging from 4 weeks to 12 months in age. To do this, we will analyze differences in bone morphometric parameters using MicroCT and osteoblastogenesis assays. The pelvis, femur, and tibia are key in distributing weight and we expect to see altered remodeling and stem cell potential with age. In combination with histomorphometry, these results will help elucidate the complex mechanisms underlying bone tissue maintenance and stem cell regeneration.

stem cells↗

NASA NTRS2016

Superoxide Dismutase Protects Osteoprogenitors from Irradiation with Low-LET but Not High-LET Species

Ionizing radiation-induced bone loss appears to be a two-stage process: first an early increase in pro-resorption cytokines and increased bone resorption by osteoclasts, followed by a decrease in bone formation by osteoblasts. This results in a net loss of mass in mineralized bone tissue. The molecular mechanisms underlying the imbalance in bone remodeling caused by exposure to radiation are not fully understood. We hypothesized that the radiation-induced rise in reactive oxygen species (ROS) damages osteoblast progenitors, leading to a decrease in number and activity of differentiated progeny. We have shown that a diet high in antioxidant capacity prevents radiation-induced bone loss in adult mice (Schreurs et al. 2016) by reducing the early increase in pro-resotption cytokines. Here, we investigated the damaging effects of radiation exposure on cells in the osteoblast lineage, testing if addition of the exogenous antioxidant enzyme, superoxide dismutase (SOD) can mitigate radiation damage. Osteoprogenitors were grown in vitro from the marrow of 16-week-old, male C57Bl6 mice. Cells were irradiated 3 days after plating (day 0) with either gamma (137Cs, 0.1-5Gy) or iron (56Fe, 600 MeVn, 0.5-2Gy), and then grown until day 10. SOD or vehicle was added 2 hours before irradiation (SOD at 200Uml), twice a day and up to day 5, for a total of 2 days treatment. Cell behavior was assessed by: (a) colony number (counted on day 7), (b) DNA content (surrogate for cell number) to assess cell growth (percent change between day 3 and day 10) and (c) alkaline phosphatase activity (osteoblast differentiation marker). Results show that SOD protected cells from the adverse effects of low-LET(Linear Energy Transfer) ionizing radiation, but not high-LET radiation. These novel results provide an interesting platform to explore further diverse effects and damages caused by low-LET and high-LET, pointing toward different mechanisms and possible intervention strategies for radiation-induced bone loss.

osteoblasts↗

NASA NTRS2017

The Effects of CDKN1a/p21 on Oxidative Stress and Mitochondrial Function During Long Duration Spaceflight

Spaceflight factors, such as microgravity and space radiation, are known to put astronauts at risk for negative effects to their tissue regeneration and degenerative conditions. On our previous spaceflight research, we found that long duration spaceflight produced increased oxidative stress and activation of the inflammatory response as a major contributor to physiological changes, including alterations to the cardiovascular and musculoskeletal systems, metabolism, and the liver. Proliferation, apoptosis, and ion-channel remodeling of vascular smooth muscle cells, as well as endothelial inflammation, and nitric oxide synthase-nitric oxide system regulation have been shown by spaceflight and simulated spaceflight projects. CDKN1ap21 is a regulatory gene for tissue regeneration and also plays an important role in upregulating oxidative stress caused by radiation. In further research, we have also determined CDKN1ap21 to be overexpressed during spaceflight. When knocked out in mice, however, it protects against unloading-induced changes to the morphology and physiology of carotid arteries. In this proposal, we seek to test a potential dietary countermeasure to down-regulate CDKN1ap21 in the mice and protect against oxidative stress in the rodents. Specifically, we will expose both Wildtype and CDKN1ap21-null mice to hydrogen peroxide to induce oxidative stress and observe the molecular mechanisms in which a dietary supplement protects vascular smooth muscle cells against the consequences of the apoptotic environment within Wildtype mice versus the, hypothetically, sound physiology of CDKN1ap21-null mice. The successful completion of this experiment will conclusively determine accuracy of a dietary supplement as a CDKN1ap21 suppressor. This will provide a new perspective on the problem of increased oxidative stress developing into cardiovascular disease as a result of long-term space flight. This research will address the Human Research Plan Roadmaps Risk of Cardiac Rhythm Problems including CV-8, the Risk of Cardiovascular Disease and Other Degenerative Tissue Effects from Radiation Exposure including Degen-6 and Degen-7, and the Risk of Adverse Health Event from Radiation Exposure including IM-8. Additionally, this research will address Space Biology Research Plans questions SBP CMB-1, SBP CMB-3, and SB AN-2.

Oxidative Stress↗

NASA NTRS2017

The Effects of CDKN1a/p21 on Oxidative Stress and Mitochondrial Function During Long Duration Spaceflight

Broad tissue degeneration and the failure of normal tissue regenerative processes in microgravity because of mechanical unloading are increasing concerns for sustaining life in space as the duration of future flight missions increases. Work in our laboratory has identified normal adult stem cell-based tissue regenerative processes, such as the formation of new bone, cartilage, and immune cells, as being particularly sensitive to the stresses of mechanical unloading in microgravity. Our studies have also identified the inhibition of differentiation of marrow mesenchymal stem cells and activation of CDKN1ap21-mediated cell cycle arrest in proliferative osteoprecursor cells on the bone surface as potential mechanisms for spaceflight-induced skeletal changes. This finding, in combination with the role of CDKN1ap21 as a suppressor of mammalian tissue regeneration, suggests that this gene could be responsible for suppressing stem cell-based tissue regeneration in response to disuse. In this work, we hypothesized that CDKN1ap21 regulates regenerative bone formation in response to alterations in mechanical load and tested this hypothesis by studying the skeletal phenotype and stem cell regenerative ability of juvenile (4-11 weeks old) and adult (18 weeks-12 months old) p21 (--) knockout (KO) mice. Additionally, we analyzed bone micro-architectural properties, bone formation rates and differentiation capacity of bone marrow stem cells (BMSCs) from male and female KO mice exposed to hindlimb unloading (HU) for 15-30 days. We found that juvenile KO mice exhibited increased femoral trabecular and cortical bone formation, whilst three-point bending of the tibias from KO mice showed decreased bone stiffness. Conversely, adult KO mice exhibited no significant differences in micro-architectural properties compared to WT (wild-type) but woven bone structure was indicative of rapid bone remodeling. Furthermore, cortical bone properties showed similar characteristics to aged bone, including increased cross-sectional area and perimeter, whilst three-point bending showed increased stiffness and toughness. Interestingly, in-vitro, KO mice exhibited increased differentiation and mineralized nodule formation in osteoblastogenesis assays compared to WT. Preliminary results from CDKN1ap21 KO mice subjected to HU suggest altered sensitivity to mechanical unloading resulting in decreased cortical thickness compared to WT mice. However, KO mice subjected to short and long-duration HU show increased in-vitro differentiation potential of BMSCs to from form mature, mineral-forming osteoblasts, indicating maintenance of regenerative potential. Analysis of bone formation rates, cell proliferation rates and key genes of interest are currently underway. These results indicate a novel role for CDKN1ap21 in load-dependent osteoprogenitor proliferation and differentiation and that deletion of CDKN1ap21 results in an age-dependent release of osteoblast proliferation inhibition and increased bone formation and turnover.

Stem Cells↗

NASA NTRS2016

Neural Mechanisms to the Space Environment

Highly conserved neural systems have evolved to sense the inertial forces due to head translation and head tilt relative to gravitational vertical. These structures consist of ciliated mechanosensitive receptor cells inserted into a neuroepithelium surmounted by biomineral grains of calcium carbonate (CaCO3) called oto- (vertebrates) or stato-conia (invertebrates). Detection of these forces by receptor cells relies on the CaCO3 mass being weighted in Earths 1G. A change in gravity or orientation with respect to gravity has a profound effect on how an organism interacts with its environment, and it is evident that the nervous system responds to the new gravity state. This response might involve the peripheral receptors, the CaCO3 mass, the brain or any combination of these mechanisms based on the intensity and duration of the gravity change. Here, we examine the arguments supporting the different mechanisms of adaptation to the space environment. First, a pre- or post-synaptic alteration in the strength of synaptic transmission between the receptor cell and nerve afferent can adjust the system output. The number of synaptic ribbons in certain type II hair cells in rodent is labile, increasing following exposure to microgravity. An increase in number of synaptic ribbons in toadfish otolith hair cells following exposure to microgravity could potentially explain the observed afferent hypersensitivity to acceleration postflight. The physiological findings in the isolated statocyst in snails are in line with the vertebrate data, and conform to the proposition that G exposure leads to changes in gravireceptor function. At the same time this similarity in neural response to G exposure between the vertebrates and invertebrates is intriguing: the increased neural sensitivity in the vertebrate was detected in the nerve afferents, one synapse away from the receptor cell, whereas the increased neural sensitivity observed in the snail was detected directly at the receptor level. Second, the CaCO3 mass provides mechanical loading of receptor cell cilia, and their density alters sensitivity. A widely considered mechanism by which the animal responds to a chronic change in amplitude of gravity is a change in weight-lending CaCO3 mass. In G, it is argued, the organism counters the loss of gravity by increasing CaCO3 production, thereby increasing its mass, as a means to increase system gain. In hypergravity, the converse is argued. Earlier evidence in mollusks and recent results in mice suggest a remodeling might occur, especially after long-term space exposure. Lastly, we have to distinguish at least two kinds of neural feedbacks. One is connected with local mechanisms of self-regulation and specific for initial period of organ development when the neural connections are still absent. And the other feedback is related to neural self-regulation and specific for later stages of the organ development, and includes an efferent vestibular feedback. Complexity of the problem is enhanced by incompleteness of experiments, and consequently the experimental results have not led to a clear interpretation despite the numerous studies.

Boyle, Richard D.↗

NASA NTRSDate not supplied

Retinal Image Quality Assessment for Spaceflight-Induced Visual Impairment Study

Medical reports have identified visual impairments as a risk associated with extended exposure to microgravity. Etiology of these ocular changes is currently unknown. Current hypotheses propose cephalad fluid shifts resulting from microgravity as the primary cause of ocular damage. One approach to studying ocular response to microgravity is by examining possible changes in retinal blood vessels using a NASA model of microgravity, the head-down tilt (HDT) of human subjects undergoing prolonged bed rest (BR). Retinal vessels in astronauts and BR subjects are monitored by Heidelberg Spectralis infrared (IR) imaging, in which retinal image quality is limited by insufficient resolution of small vessels. Yet small vessels respond and remodel most actively to physiological stress.For our NASA study of BR subjects, we identify retinal image quality as thecapability to capture vascular detail to acceptable resolution of small vessels. We therefore are analyzing Spectralis images acquired with fluorescein angiography(FA), where increased contrast significantly improves image resolution. The FA images are of normal subjects participating in a clinical study on diabeticretinopathy (US National Institutes of Health). We hypothesize that FA Spectralis images are of superior quality compared to non-FA Spectralis IR images.

Rodrigo Rene Rai Munoz Abujder↗

NASA NTRSDate not supplied

Abrstract - OnePlace Redesign Spring 2020 Internship

The project I worked on was the OnePlace Redesign. In that, I converted the OnePlace home page to the Service Portal to match NASA OnePlace’s current application design standards, I was able to allow users to easily find applications in OnePlace and I was able to allow users to easily find and request OnePlace services (new app development, new knowledge base, etc.). It was a major accomplishment to be able to remodel a website that soon the entire Langley center that uses OnePlace will use. The website was made through ServiceNow’s Service Portal, and I organized the applications like never before, allowed a clear styling to applications a user does not have access to and/or are new applications, browsing of applications with clear button divisions, and allowing for different options depending if app is accessible or not, with proper error checking in place and very-well documented code. It was amazing to incorporate all this logic into one widget so that whoever wants to utilize this feature has no trouble at all to do so. The 3 most important things I learned were being able to do this work within ServiceNow, as it is such an important enterprise platform for CRM and boosting the connected workforce of NASA, incorporate built-in APIs from ServiceNow Glide Records to connect Server Scripts to Client Scripts and HTML, and be able to use agile to get another experience of managing work capacity with stories, and having proper communication with the team if every feature is done correctly and steps for continuing forward. The part that I enjoyed the most was the training I did for ServiceNow and I freedom I had to experiment to see how to structure the Service Portal. I was not tied down, and I believe this allowed for a better outcome of the product. As part of the internship, I created a very in-depth design document with the help of my team to document the project goals before it was started and technical documentation (including the design document) summarizing the final result of the product in terms of the new features added and the explanation of the logic thoroughly so that anyone can understand the project easily. The technical documentation will be published as a Knowledge Article within OnePlace Knowledge Base documentation.

Ariel Wald↗

NASA NTRSDate not supplied

Printed Electrochemical Sensor for Quantifying Bone Density Loss in Microgravity

Printed electrochemical biosensors have been developed for astronaut point-of-care testing. Our fabrication approach is complimentary with in-space manufacturing for an on-demand and hands-free fabrication process. These sensors are developed using a combination of thin film materials printing and 3D printing and are comprised of carbon nanotube, gold nanoparticle, silver nanoparticle and dielectric inks to make traditional electrochemical sensor devices. Initial prototyped printed electrochemical sensors demonstrate good electrochemical performance while also displaying low batch to batch variability. Here we report the development of a printed sensor to monitor bone turnover. The absence of load bearing forces experienced in microgravity causes a reduction of overall bone mass and results in the development of space osteopenia/osteoporosis.(1,2) Our approach to identify space osteopenia/osteoporosis is to monitor the change in bone mass indirectly through an excreted biomarker of bone remodeling, amino-terminal collagen crosslinks (NTX). Antibodies specific to NTX are added to the sensor’s electrode ink and applied during the manufacturing process. NTX is measured from a urine sample by changes in voltammetry and electrochemical impedance as it binds to the antibody modified electrode surface. The measurement is rapid, quantitative and requires only small handheld electronics to perform the measurement. By this process, ground and flight physicians will receive frequent and real-time insight into the development of space osteopenia/osteoporosis to guide appropriate countermeasures. REFERENCES [1] Nabavi, N. et al (2011) Bone 49, 965-974. [2] Tamma, R. et al (2009) FASEB J 23, 2549-2554.

in-space manufacturing↗

NASA NTRS2021

Reducing Risk of InSight Surface Operations Through High-Fidelity Command Sequence Modeling

Simulating spacecraft behavior is crucial for the success of deep space missions, and failure to do so may result in damages to or the loss of the spacecraft. Many previous deep space missions have made use of ground-simulation of sequenced commanding, at speeds far greater than real time, to predict spacecraft state over time through the execution of onboard sequences. This type of modeling can be done at any fidelity, and most missions have opted to decrease fidelity to reduce cost and complexity. However, NASA’s Interior Exploration using Seismic Investigations, Geodesy and Heat Transport (InSight) mission expanded the scope of ground modeling considerably, which has led to numerous benefits over past implementations. This paper will discuss the process and products that InSight created, as well as the lessons learned from successfully operating the spacecraft on Mars. InSight is the first JPL mission to expand the scope of ground modeling to include the uplink of files from Earth to the spacecraft, rather than making the simplification that any command sequences already exist onboard the spacecraft. The advantages of modeling the uplink of files are numerous. First, it allows for accurate modeling of the onboard filesystem of the spacecraft at all points in time, meaning that all file loads and deletions throughout the mission are modeled at the exact moment they are predicted to actually happen. Second, operators can be more certain that dependencies between sequences are not broken due to the dynamic nature of the filesystem as files are deleted, copied, and uplinked. Lastly, spacecraft filesystem tracking allows for management of sequences prior to uplink, limiting the uplink to only new sequences. The onboard filesystem model became crucial to mission success, emphasizing the importance of investing in accurate models before the need for them arises. During daily tactical operations of a spacecraft on Mars, a model is only useful if the results can be interpreted quickly. In this fast-paced environment, it is essential that command products are modeled and reviewed, errors are found and diagnosed, and new command products are redelivered, remodeled, re-reviewed in a timely manner. It is impossible to review the entire model and therefore the results of the model must be condensed and presented in a fashion that is intuitive, easy-to-navigate, complete, and trustworthy. InSight developed a number of innovative sequence review products that are designed to provide operators with the information required to quickly assess the validity of command products and diagnose potential issues. Together, these products provide a complete, yet succinct picture of the command and sequence model to the operators and facilitate a quick assessment of all sequence command products. This paper will cover planning and sequencing innovations made during InSight surface operations, and will compare the tools, processes, and results to those on other missions. Additionally, the paper will cover the flexible, yet robust nature of the planning and sequencing system architecture and how that flexibility allowed for rapid development and response to the unpredictability of Mars.

Cloutier, Kyle↗

NASA NTRS2023

Regulatory response to a hybrid ancestral nitrogenase in Azotobacter vinelandii

Biological nitrogen fixation, the microbial reduction of atmospheric nitrogen to bioavailable ammonia, represents both a major limitation on biological productivity and a highly desirable engineering target for synthetic biology. However, the engineering of nitrogen fixation requires an integrated understanding of how the gene regulatory dynamics of host diazotrophs respond across sequence-function space of its central catalytic metalloenzyme, nitrogenase. Here, we interrogate this relationship by analyzing the transcriptome of Azotobacter vinelandii engineered with a phylogenetically inferred ancestral nitrogenase protein variant. The engineered strain exhibits reduced cellular nitrogenase activity but recovers wild-type growth rates following an extended lag period. We find that expression of genes within the immediate nitrogen fixation network is resilient to the introduced nitrogenase sequence-level perturbations. Rather the sustained physiological compatibility with the ancestral nitrogenase variant is accompanied by reduced expression of genes that support trace metal and electron resource allocation to nitrogenase. Our results spotlight gene expression changes in cellular processes adjacent to nitrogen fixation as productive engineering considerations to improve compatibility between remodeled nitrogenase proteins and engineered host diazotrophs.

nitrogen fixation↗

NASA NTRS2003

Contractile reserve and calcium regulation are depressed in myocytes from chronically unloaded hearts

BACKGROUND: Chronic cardiac unloading of the normal heart results in the reduction of left ventricular (LV) mass, but effects on myocyte contractile function are not known. METHODS AND RESULTS: Cardiac unloading and reduction in LV mass were induced by heterotopic heart transplantation to the abdominal aorta in isogenic rats. Contractility and [Ca(2+)](i) regulation in LV myocytes were studied at both 2 and 5 weeks after transplantation. Native in situ hearts from recipient animals were used as the controls for all experiments. Contractile function indices in myocytes from 2-week unloaded and native (control) hearts were similar under baseline conditions (0.5 Hz, 1.2 mmol/L [Ca(2+)](o), and 36 degrees C) and in response to stimulation with high [Ca(2+)](o) (range 2.5 to 4.0 mmol/L). In myocytes from 5-week unloaded hearts, there were no differences in fractional cell shortening and peak-systolic [Ca(2+)](i) at baseline; however, time to 50% relengthening and time to 50% decline in [Ca(2+)](i) were prolonged compared with controls. Severe defects in fractional cell shortening and peak-systolic [Ca(2+)](i) were elicited in myocytes from 5-week unloaded hearts in response to high [Ca(2+)](o). However, there were no differences in the contractile response to isoproterenol between myocytes from unloaded and native hearts. In 5-week unloaded hearts, but not in 2-week unloaded hearts, LV protein levels of phospholamban were increased (345% of native heart values). Protein levels of sarcoplasmic reticulum Ca(2+) ATPase and the Na(+)/Ca(2+) exchanger were not changed. CONCLUSIONS: Chronic unloading of the normal heart caused a time-dependent depression of myocyte contractile function, suggesting the potential for impaired performance in states associated with prolonged cardiac atrophy.

NASA Discipline Cardiopulmonary↗

NASA NTRS2001

Cellular and molecular mechanisms for the bone response to mechanical loading

To define the cellular and molecular mechanisms for the osteogenic response of bone to increased loading, several key steps must be defined: sensing of the mechanical signal by cells in bone, transduction of the mechanical signal to a biochemical one, and transmission of that biochemical signal to effector cells. Osteocytes are likely to serve as sensors of loading, probably via interstitial fluid flow produced during loading. Evidence is presented for the role of integrins, the cell's actin cytoskeleton, G proteins, and various intracellular signaling pathways in transducing that mechanical signal to a biochemical one. Nitric oxide, prostaglandins, and insulin-like growth factors all play important roles in these pathways. There is growing evidence for modulation of these mechanotransduction steps by endocrine factors, particularly parathyroid hormone and estrogen. The efficiency of this process is also impaired in the aged animal, yet what remains undefined is at what step mechanotransduction is affected.

Review↗

NASA NTRS2001

Biomaterials and bone mechanotransduction

Bone is an extremely complex tissue that provides many essential functions in the body. Bone tissue engineering holds great promise in providing strategies that will result in complete regeneration of bone and restoration of its function. Currently, such strategies include the transplantation of highly porous scaffolds seeded with cells. Prior to transplantation the seeded cells are cultured in vitro in order for the cells to proliferate, differentiate and generate extracellular matrix. Factors that can affect cellular function include the cell-biomaterial interaction, as well as the biochemical and the mechanical environment. To optimize culture conditions, good understanding of these parameters is necessary. The new developments in bone biology, bone cell mechanotransduction, and cell-surface interactions are reviewed here to demonstrate that bone mechanotransduction is strongly influenced by the biomaterial properties.

Review↗