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At least 361 records · Page 20

Fundamental space radiobiology

The unique feature of the space radiation environment is the dominance of high-energy charged particles (HZE or high LET radiation) emitted by the Sun and galactic sources, or trapped in the Van Allen radiation belts. These charged particles present a significant hazard to space flight crews, and accelerator-based experiments are underway to quantify the health risks due to unavoidable radiation exposure. There are three principal properties of charged particles that distinguish them from conventional radiation, i.e. gamma rays and x-rays. First, they have a defined range in matter rather than an exponential absorption profile. Second, they undergo nuclear reactions to produce secondary particles. Third, and most important, they deposit their energy along well-defined linear paths or tracks rather than diffuse fields. The structured energy deposition pattern interacts on multiple scales with the biological structures of DNA, cells and tissues to produce correlated patterns of damage that evade repair systems. Traditional concepts of dose and its associated normalization parameter, RBE (relative biological effectiveness), break down under experimental scrutiny, and probabilistic models of risk based on the number of particle traversals per cell may be more appropriate. Unique patterns of DNA damage, gene expression, mobilization of repair proteins, activation of cytokines and remodeling of cellular microenvironment are observed following exposure to high LET radiation. At low levels of exposure the communication of bioactive substances from irradiated to unirradiated "bystander" cells can amplify the damage and cause a significant deviation from linearity in dose vs. response relations. Under some circumstances, there is even a multigenerational delay in the expression of radiation-induced genetic damage (genomic instability) which is not strictly dose dependent. These issues and the experimental evidence derived from ground based experiments at particle accelerators are presented along with speculation about how modified inertial conditions might perturb homeostatic responses to radiation to further complicate risk assessment for space flight.

NASA Discipline Radiation Health↗

Understanding How Astronauts Adapt to Space and to Earth: Anatomical Studies of Central Vestibular Adaptation

Significant changes take place in the nervous systems of astronauts during and following exposure to microgravity. These changes, particularly in the part of the brain that controls balance, the vestibular system, can cause sensations of rotation, dizziness, and vertigo, as well as space adaptation syndrome. Adaptation to the microgravity environment usually occurs within one week, and a subsequent re-adaptation period of several days is often required upon return to Earth. In order to realize long-term spaceflight, effective countermeasures for these symptoms must be developed. The structural changes that take place in one of the vestibular regions of the brain (the cerebellar cortex) during the process of adaptation to Earth's gravity remain unclear and are the subject of an experiment being conducted on STS-107 by Dr. Gay Holstein of the Mount Sinai School of Medicine in New York. Using the rat as a model, Dr. Holstein and her team will seek to identify the cellular changes underlying the vestibular changes experienced by astronauts.

Holstein, Gay↗

How cells (might) sense microgravity

This article is a summary of a lecture presented at an ESA/NASA Workshop on Cell and Molecular Biology Research in Space that convened in Leuven, Belgium, in June 1998. Recent studies are reviewed which suggest that cells may sense mechanical stresses, including those due to gravity, through changes in the balance of forces that are transmitted across transmembrane adhesion receptors that link the cytoskeleton to the extracellular matrix and to other cells (e.g., integrins, cadherins, selectins). The mechanism by which these mechanical signals are transduced and converted into a biochemical response appears to be based, in part, on the finding that living cells use a tension-dependent form of architecture, known as tensegrity, to organize and stabilize their cytoskeleton. Because of tensegrity, the cellular response to stress differs depending on the level of pre-stress (pre-existing tension) in the cytoskeleton and it involves all three cytoskeletal filament systems as well as nuclear scaffolds. Recent studies confirm that alterations in the cellular force balance can influence intracellular biochemistry within focal adhesion complexes that form at the site of integrin binding as well as gene expression in the nucleus. These results suggest that gravity sensation may not result from direct activation of any single gravioreceptor molecule. Instead, gravitational forces may be experienced by individual cells in the living organism as a result of stress-dependent changes in cell, tissue, or organ structure that, in turn, alter extracellular matrix mechanics, cell shape, cytoskeletal organization, or internal pre-stress in the cell-tissue matrix.--Ingber, D. How cells (might) sense microgravity.

NASA Discipline Cell Biology↗

Use of microgravity bioreactors for development of an in vitro rat salivary gland cell culture model

During development, salivary gland (SG) cells both secrete factors which modulate cellular behavior and express specific hormone receptors. Whether SG cell growth is modulated by an autocrine epidermal growth factor (EGF) receptor-mediated signal transduction pathway is not clearly understood. SG tissue is the synthesis site for functionally distinct products including growth factors, digestive enzymes, and homeostasis maintaining factors. Historically, SG cells have proven difficult to grow and may be only maintained as limited three-dimensional ductal-type structures in collagen gels or on reconstituted basement membrane gels. A novel approach to establishing primary rat SG cultures is use of microgravity bioreactors originally designed by NASA as low-shear culture systems for predicting cell growth and differentiation in the microgravity environment of space. These completely fluid-filled bioreactors, which are oriented horizontally and rotate, have proven advantageous for Earth-based culture of three-dimensional cell assemblies, tissue-like aggregates, and glandular structures. Use of microgravity bioreactors for establishing in vitro models to investigate steroid-mediated secretion of EGF by normal SG cells may also prove useful for the investigation of cancer and other salivary gland disorders. These microgravity bioreactors promise challenging opportunities for future applications in basic and applied cell research.

NASA Program Space Biology↗

Late Effects of Heavy Ion Irradiation on Ex Vivo Osteoblastogenesis and Cancellous Bone Microarchitecture

Prolonged spaceflight causes degeneration of skeletal tissue with incomplete recovery even after return to Earth. We hypothesize that heavy ion irradiation, a component of Galactic Cosmic Radiation, damages osteoblast progenitors and may contribute to bone loss during long duration space travel beyond the protection of the Earth's magnetosphere. Male, 16 week old C57BL6/J mice were exposed to high LET (56 Fe, 600MeV) radiation using either low (5 or 10cGy) or high (50 or 200cGy) doses at the NASA Space Radiation Lab and were euthanized 3 - 4, 7, or 35 days later. Bone structure was quantified by microcomputed tomography (6.8 micron pixel size) and marrow cell redox assessed using membrane permeable, free radical sensitive fluorogenic dyes. To assess osteoblastogenesis, adherent marrow cells were cultured ex vivo, then mineralized nodule formation quantified by imaging and gene expression analyzed by RT PCR. Interestingly, 3 - 4 days post exposure, fluorogenic dyes that reflect cytoplasmic generation of reactive nitrogen/oxygen species (DAF FM Diacetate or CM H2DCFDA) revealed irradiation (50cGy) reduced free radical generation (20-45%) compared to sham irradiated controls. Alternatively, use of a dye showing relative specificity for mitochondrial superoxide generation (MitoSOX) revealed an 88% increase compared to controls. One week after exposure, reactive oxygen/nitrogen levels remained lower(24%) relative to sham irradiated controls. After one month, high dose irradiation (200 cGy) caused an 86% decrement in ex vivo nodule formation and a 16-31% decrement in bone volume to total volume and trabecular number (50, 200cGy) compared to controls. High dose irradiation (200cGy) up regulated expression of a late osteoblast marker (BGLAP) and select genes related to oxidative metabolism (Catalase) and DNA damage repair (Gadd45). In contrast, lower doses (5, 10cGy) did not affect bone structure or ex vivo nodule formation, but did down regulate iNOS by 0.54 - 0.58 fold. Thus, both low and high doses of heavy ion irradiation cause time dependent, adaptive changes in redox state within marrow cells but only high doses (50, 200cGy) inhibit osteoblastogenesis and cause cancellous bone loss. We conclude space radiation has the potential to cause persistent damage to bone marrow derived stem and progenitor cells for osteoblasts despite adaptive changes in cellular redox state.

Tran, Luan Hoang↗

Human physiology in space

The universality of gravity (1 g) in our daily lives makes it difficult to appreciate its importance in morphology and physiology. Bone and muscle support systems were created, cellular pumps developed, neurons organised and receptors and transducers of gravitational force to biologically relevant signals evolved under 1g gravity. Spaceflight provides the only microgravity environment where systematic experimentation can expand our basic understanding of gravitational physiology and perhaps provide new insights into normal physiology and disease processes. These include the surprising extent of our body's dependence on perceptual information, and understanding the effect and importance of forces generated within the body's weightbearing structures such as muscle and bones. Beyond this exciting prospect is the importance of this work towards opening the solar system for human exploration. Although both appear promising, we are only just beginning to taste what lies ahead.

NASA Center HQS↗

Ultrastructural and cellular mechanisms in myocardial deconditioning in weightlessness

The cardiovascular deconditioning that has been shown to result from immobilization on earth and in the microgravity environment during spaceflight is considered. The major interests to future long-term spaceflight are the determination of the specific factors causing myocardial deconditioning, the irreversibility/reversibility of the changes, and preventative/treatment methods for this deconditioning process. The results of earlier animal studies designed to determine the effects of immobilization on myocardial function demonstrate that both ultrastructural and functional changes occur during test periods ranging from 14 days to 6 months. Based on such results and the need for a more precise understanding of the structural and biochemical mechanisms leading to these effects, an experiment was designed for use in future studies. The results of the Cosmos 1887 and 2044 flights as well as their comparison and analysis indicate that significant differences exist between simulated and actual spaceflight subjects. Spaceflight subjects demonstrate greater changes than tail-suspended subjects. More spaceflight studies will be necessary to gain a greater understanding of the basic mechanism behind myocardial deconditioning resulting from spaceflight and the most effective methods to be utilized in its prevention and treatment.

Philpott, Delbert E.↗

The Cytoskeleton and Force Response Mechanisms

The long term aim of this project was to define the mechanisms by which cells sense and respond to the physical forces experienced at 1g and missing in microgravity. Identification and characterization of the elements of the cells force response mechanism could provide pathways and molecules to serve as targets for pharmacological intervention to mitigate the pathologic effects of microgravity. Mechanical forces experienced by the organism can be transmitted to cells through molecules that allow cells to bind to the extracellular matrix and through other types of molecules which bind cells to each other. These molecules are coupled in large complexes of proteins to structural elements such as the actin cytoskeleton that give the cell the ability to sense, resist and respond to force. Application of small forces to tissue culture cells causes local elevation of intracellular calcium through stretch activated ion channels, increased tyrosine phosphorylation and a restructuring of the actin cytoskeleton. Using collagen coated iron oxide beads and strong magnets, we can apply different levels of force to cells in culture. We have found that force application causes the cells to polymerize actin at the site of mechanical deformation and unexpectedly, to depolymerize actin across the rest of the cell. Observations of GFP- actin expressing cells demonstrate that actin accumulates at the site of deformation within the first five minutes of force application and is maintained for many tens of minutes after force is removed. Consistent with the reinforcement of the cytoskeletal structures underlying the integrin-bead interaction, force also alters the motion of bound magnetic beads. This effect is seen following the removal of the magnetic field, and is only partially ablated by actin disruption with cytochalsin B. While actin is polymerizing locally at the site of force application, force also stimulates a global reduction in actin filament content within the cells. We have examined the roles of several actin filament disassembly factors in the global reduction of cellular actin filaments. The calcium regulated actin filament severing protein gelsolin is not necessary for the increased actin turnover, as cells derived from gelsolin null and wildtype mice still show a reduction in total actin filament content. Instead, our work suggests that the actin binding protein cofilin may be important for these changes in actin dynamics. Cofilin binds to and enhances the disassembly of actin filaments. Using immunological methods, we observe transient changes in the phosphorylation state of cofilin upon force application that suggests that cofilin may mediate actin filament turnover. Early after force application, cofilin is transiently dephosphorylated, activating its actin disassembly activity. Subsequently, we find a hyper-phosphorylation of cofilin, rendering it inactive. This reduction in cofilin activity may explain the stability of the force induced actin structuttes. In testing this hypothesis, we aimed to generate cells that express the constituitively active kinase (LIM-kinase) that phosphorylates cofilin. lnidial attempts in the cell lines used for the our previous studies proved unsuccessful. While we prepare this work for pubication, we are continuing to study other cell lines and tissue sources to determine whether they show a reduction in F-actin content after force application.

Allen, Philip Goodwin↗

On the Current State of Sheaf Theoretic Networking

Advancing the Delay Tolerant Networking (DTN) effort has proven to be a unique and difficult challenge. In the journey to implementing space networking, NASA has considered several strategies. From direct translations of Internet Protocol (IP) to satellite networks to pre-planned routing structures in Contact Graph Routing (CGR), each potential solution for DTN has come with its fair share of setbacks and challenges. Frequently, these challenges can be traced back to specific assumptions made in the development of each protocol that do not carry over from ground networks to space networks. To address these fundamental assumptions, a more general and foundational networking theory is required. In this paper, we survey a novel mathematical foundation for networking using the theory of cellular sheaves. Sheaves form a mathematical tool for modeling local phenomenon that leads to global effects. Sheaves have been introduced a number of times, and our goal here is to summarize the applications and point towards important future work that must be done to build a stronger, cohesive theory for networking.

Sheaves↗

The endomembrane sheath: a key structure for understanding the plant cell?

Recent evidence suggests that integrin is abundant in endomembranes of plant cells, and the endomembranes are clad by a sheath of cytoskeleton including F-actin. A role for endomembrane integrin and the endomembrane sheath is proposed: this system might orchestrate metabolic regulation by providing and modulating loci for channelling, and might accelerate channeling as needed by dragging the endoplasmic reticulum (ER) and organelles through the cytoplasm. To accomplish this "streaming", F-actin might lever against the rest of the endomembrane sheath and the ER might also lever against adhesion sites (i.e., plasmodesmata and plasmalemmal control centers). As an important agent in the control of cellular activities, according to this model, the endomembrane sheath would play a major part in responses to diverse signals and stresses, and under extreme stress cell survival would depend on the ability of the system to maintain enough integrity to direct critical syntheses and degradations.

NASA Discipline Plant Biology↗

Late Effects of Heavy-Ion Irradiation on Ex Vivo Osteoblastogenesis and Cancellous Bone Microarchitecture

Prolonged spaceflight causes degeneration of skeletal tissue with incomplete recovery even after return to Earth. We hypothesize that heavy-ion irradiation, a component of Galactic Cosmic Radiation, damages osteoblast progenitors and may contribute to bone loss during long duration space travel beyond the protection of the Earth's magnetosphere. Male, 16 week-old C57BL6/J mice were exposed to high-LET (56-Fe, 600MeV) radiation using either low (5 or 10cGy) or high (50 or 200cGy) doses at the NASA Space Radiation Lab and were euthanized 3-4, 7, or 35 days later. Bone structure was quantified by microcomputed tomography (6.8 μm pixel size) and marrow cell redox assessed using membrane permeable, free radical-sensitive fluorogenic dyes. To assess osteoblastogenesis, adherent marrow cells were cultured ex vivo, then mineralized nodule formation quantified by imaging and gene expression analyzed by RT-PCR. Interestingly, 3-4 days post-exposure, fluorogenic dyes that reflect cytoplasmic generation of reactive nitrogen/oxygen species (DAF-FM Diacetate or CM-H2DCFDA) revealed irradiation (50cGy) reduced free radical generation (20-45%) compared to sham-irradiated controls. Alternatively, use of a dye showing relative specificity for mitochondrial superoxide generation (MitoSOX) revealed an 88% increase compared to controls. One week after exposure, reactive oxygen/nitrogen levels remained lower (24%) relative to sham-irradiated controls. After one month, high dose irradiation (200 cGy) caused an 86% decrement in ex vivo nodule formation and a 16-31% decrement in bone volume to total volume and trabecular number (50, 200cGy) compared to controls. High dose irradiation (200cGy) up-regulated expression of a late osteoblast marker (BGLAP) and select genes related to oxidative metabolism (Catalase) and DNA damage repair (Gadd45). In contrast, lower doses (5, 10cGy) did not affect bone structure or ex vivo nodule formation, but did down-regulate iNOS by 0.54-0.58 fold. Thus, both low- and high-doses of heavy-ion irradiation cause time-dependent, adaptive changes in redox state within marrow cells but only high doses (50, 200cGy) inhibit osteoblastogenesis and cause cancellous bone loss. We conclude space radiation has the potential to cause persistent damage to bone marrow-derived stem and progenitor cells for osteoblasts despite adaptive changes in cellular redox state.

LATE EFFECTS OF HEAVY-ION IRRADIATION↗

Membrane-Based Functions in the Origin of Cellular Life

If peptides consist of nonpolar residues only, they become inserted into the nonpolar phase. As demonstrated by the example of the leucine undecamer, such peptides fold into an a-helix as they partition into the nonpolar medium. The folding proceeds through an intermediate, called the 310-helix, which remains in equilibrium with the a-helix. This process represents a simple, protobiologically relevant example of environmentally-mediated self-organization of biological molecules. Once in the nonpolar environment, the peptides can readily change their orientation with respect to the interface from parallel to perpendicular, especially in response to local electric fields. The ability of nonpolar peptides to modify both the structure and orientation with changing external conditions may have provided a simple mechanism of transmitting signals from the environment to the interior of a protocell.

Wilson, Michael↗

Quasigeostrophic vertical motions diagnosed from along- and cross-isentrope components of the Q vector

In a recent paper on the kinematics of frontogenesis, Keyser et al. (1988) conjectured that partitioning the Q vector into along- and cross-isentrope components yields vertical-motion patterns that are respectively cellular and banded: the former on the scale of the baroclinic disturbance, and the latter on the scale of the embedded frontal zones. This conjecture is examined diagnostically through solution of the quasi-geostrophic omega equation, using the output from a nearly adiabatic and frictionless f-plane primitive equation channel model of the evolution of a baroclinic disturbance to finite amplitude. The results of the present study support the proposed conjecture, suggesting the following interpretation of the characteristic comma structure of the vertical-motion field in midlatitude baroclinic disturbances: the dipole is associated with the along-isentrope component of the Q vector, reflecting the wavelike pattern in the potential temperature field within the baroclinic disturbance; the asymmetries are associated with the cross-isentrope component of the Q vector, reflecting the presence of frontal zones within the baroclinic disturbance.

Keyser, Daniel↗

High order hybrid numerical simulations of two dimensional detonation waves

In order to study multi-dimensional unstable detonation waves, a high order numerical scheme suitable for calculating the detailed transverse wave structures of multidimensional detonation waves was developed. The numerical algorithm uses a multi-domain approach so different numerical techniques can be applied for different components of detonation waves. The detonation waves are assumed to undergo an irreversible, unimolecular reaction A yields B. Several cases of unstable two dimensional detonation waves are simulated and detailed transverse wave interactions are documented. The numerical results show the importance of resolving the detonation front without excessive numerical viscosity in order to obtain the correct cellular patterns.

Cai, Wei↗

Radio structure of the remnant of Tycho's supernova (SN 1572)

The radio emission from the remnant of Tycho's supernova of 1572 arises in a nearly circular, clumpy shell. A very distinct, thin bright rim just outside the main shell can be seen around most of the periphery of the remnant. The outer edge of radio emission, usually defined by this bright rim, coincides perfectly with the outer X-ray boundary. Most of the emission is polarized by a modest amount, with the outer rim particularly prominent. Observations at several wavelengths are used to map out the rotation measure at high angular resolution, and determine the intrinsic magnetic field direction. The magnetic field shows a somewhat cellular pattern but with a net radial orientation and a generally fairly low degree of polarization.

Dickel, J. R.↗

The origin of cellular life

This essay presents a scenario of the origin of life that is based on analysis of biological architecture and mechanical design at the microstructural level. My thesis is that the same architectural and energetic constraints that shape cells today also guided the evolution of the first cells and that the molecular scaffolds that support solid-phase biochemistry in modern cells represent living microfossils of past life forms. This concept emerged from the discovery that cells mechanically stabilize themselves using tensegrity architecture and that these same building rules guide hierarchical self-assembly at all size scales (Sci. Amer 278:48-57;1998). When combined with other fundamental design principles (e.g., energy minimization, topological constraints, structural hierarchies, autocatalytic sets, solid-state biochemistry), tensegrity provides a physical basis to explain how atomic and molecular elements progressively self-assembled to create hierarchical structures with increasingly complex functions, including living cells that can self-reproduce.

Review, Academic↗

Neurovascular Responses to Simulated Deep Space Radiation in a Human Organ-on-a-Chip Model

A major health risk for human deep space exploration is central nervous system (CNS) damage by galactic cosmic ray radiation. Simulated galactic cosmic rays or their components, especially the high-linear energy transfer (LET) particles such as 56Fe ions, have been shown to cause CNS damage, neuroinflammation and cognitive dysfunction in rodent models, but their effects on human CNS remain to be investigated. CNS damage from any insult, including ionizing radiation, is partially mediated by the blood-brain barrier (BBB), which regulates interactions between CNS and the rest of the body. The main cellular regulators of BBB permeability are astrocytes, which also modulate neuroinflammation. However, there have been few studies on BBB and astrocyte functions in regulating CNS responses, especially in human tissue analogs. Therefore, we utilized a high-throughput 3D organ-on-a-chip system, seeded with human induced pluripotent stem cell-derived astrocytes and brain endothelial cells, or brain endothelial cells alone, to study human neurovascular responses to simulated deep space radiation. We investigated the permeability and morphology of vascular structures formed by endothelial cells, as well as oxidative stress and secreted cytokines and chemokine levels over 1-7 days after irradiation with 0.25 – 0.5 Gy 5-ion simplified simulated galactic cosmic rays or 0.3 – 0.8 Gy high-LET 600 MeV/n 56Fe particles, and compared the outcomes to low-LET X-ray irradiation. We observed that simulated deep space radiation caused delayed astrocyte activation in a pattern resembling CNS responses to brain injury, caused oxidative stress and the production of inflammatory cytokines, and compromised BBB integrity by damaging tight junctions, thus increasing vascular permeability. Furthermore, our results indicate that astrocytes have a dual role in regulating radiation responses: they exacerbate blood-brain barrier permeability early after irradiation, followed by switching to a more protective scar-like phenotype by reducing oxidative stress and pro-inflammatory cytokine and chemokine secretion. In a follow-up study using the same platform, we investigated the dose-rate effects of ionizing radiation, by exposing our model to chronic, low dose-rate, gamma radiation. Our model was significantly improved by adding additional cell types composing the BBB, modelling immune cell infiltration into the brain, and studying the effect of an antioxidant, to measure more complex outcomes and model more closely the effect of deep space radiation on the human BBB. In summary, our results present a human neurovascular model for space radiation studies and potential future automated payload adaptation, and suggest astrocyte regulatory mechanisms as targets for countermeasures to mitigate human neurovascular impairments during deep space exploration.

Ionizing radiation↗

High School Citizen Scientists Use AI/ML to Predict Intra-Ocular Pressure From Gene Expression Data for Spaceflown Mice

Artificial Intelligence (AI) and Machine Learning (ML) have increasingly become pivotal in biological and biomedical research, largely due to the culture of open data sharing and its associated benefits. The methodologies inherent in AI/ML are particularly adept at identifying and forecasting biological phenotypes from the vast amounts of data generated by next-generation sequencing technologies. These techniques offer substantial promise for advancing research in space biosciences and for the development of automated systems for monitoring space health. Nevertheless, there are crucial aspects to consider when training, validating, and testing machine learning models in both biological research and clinical contexts. It is essential that Open Science principles, including data sharing and the availability of open-source code, are complemented by high-quality, publicly accessible training resources. These resources should focus on best practices and include modules based on real-world scientific cases and data to ensure that future AI/ML practitioners gain practical experience with genuine problems. Addressing this knowledge gap, we have designed, developed, and delivered both interactive and self-paced training programs for citizen scientists worldwide, enabling them to utilize AI/ML for space biology research. This initiative was made possible through generous funding from a Transformation to Open Science Training grant. The interactive training sessions, conducted this summer, utilized AI/ML techniques to analyze data from the Open Science Data Repository, specifically targeting the effects of spaceflight on ocular structure and function. The dataset OSD-583, from the Rodent Research 9 mission, provides experimental data detailing the ocular responses of mice subjected to a 35-day spaceflight, compared with ground control counterparts. Using OSD-583 as observational data, our summer training participants applied AI/ML methods to predict intraocular pressure from RNA-seq data and identify the genes most predictive of the observed responses. Further analysis through pathway enrichment and gene set enrichment revealed that these genes are involved in molecular and cellular processes contributing to retinal degeneration.

James Casaletto↗