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Special Issue "Adaptation of Living Organisms in Space: From Mammals to Plants"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 March 2019).

Special Issue Editors

Guest Editor
Dr. Honglu Wu Website E-Mail
NASA Johnson Space Center, Houston, TX, United States
Interests: microgravity; space radiation; gene expression; DNA damage response
Guest Editor
Dr. Ye Zhang Website E-Mail
NASA Kennedy Space Center, Cape Canaveral, FL, United States
Interests: microgravity; space radiation
Guest Editor
Dr. Maria Moreno-Villanueva Website E-Mail
Molecular Toxicology Group, Department of Biology, University of Konstanz, Universitaetsstrasse 10, 78457 Konstanz, Germany
Interests: molecular toxicology; DNA damage; DNA repair; aging

Special Issue Information

Dear Colleagues,

When living organisms travel from the surface of the Earth to space, they will experience, not only a gravity change from 1 to 0 g, but also other environmental stresses, such as cosmic radiation. To adapt to the new environment, organisms inevitably undergo changes at all levels from molecular to physiological. Within a cell, microgravity has already been shown to alter RNA and protein expression. In humans, such an adaptation would result in immune dysfunction, and bone and muscle loss, with underlying changes of transcriptomic, metabolomic and proteomic profiles. Impacts of the space environment can also be found in insects, plants and microorganisms. This Special Issue is dedicated to understanding the effects of the space environment on a wide range of organisms from mammals to microbes and plants, with a focus on the molecular mechanisms by which these organisms adapt to the new environment.

Dr. Honglu Wu
Dr. Ye Zhang
Guest Editors

Manuscript Submission Information

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Keywords

  • Microgravity
  • Space radiation
  • Gene expression
  • Protein induction
  • DNA damage
  • Mammalian cells
  • Animal studies
  • Plants

Published Papers (23 papers)

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Open AccessCommunication
Proteome Profiling of the Exhaled Breath Condensate after Long-Term Spaceflights
Int. J. Mol. Sci. 2019, 20(18), 4518; https://doi.org/10.3390/ijms20184518 - 12 Sep 2019
Abstract
Comprehensive studies of the effects of prolonged exposure to space conditions and the overload experienced during landing on physiological and biochemical changes in the human body are extremely important in the context of planning long-distance space flights, which can be associated with constant [...] Read more.
Comprehensive studies of the effects of prolonged exposure to space conditions and the overload experienced during landing on physiological and biochemical changes in the human body are extremely important in the context of planning long-distance space flights, which can be associated with constant overloads and various risk factors for significant physiological changes. Exhaled breath condensate (EBC) can be considered as a valuable subject for monitoring physiological changes and is more suitable for long-term storage than traditional monitoring subjects such as blood and urine. Herein, the EBC proteome changes due to the effects of spaceflight factors are analyzed. Thirteen EBC samples were collected from five Russian cosmonauts (i) one month before flight (background), (ii) immediately upon landing modules in the field (R0) after 169–199 days spaceflights, and (iii) on the seventh day after landing (R+7). Semi-quantitative label-free EBC proteomic analysis resulted in 164 proteins, the highest number of which was detected in EBC after landing (R0). Pathways enrichment analysis using the GO database reveals a large group of proteins which take part in keratinization processes (CASP14, DSG1, DSP, JUP, and so on). Nine proteins (including KRT2, KRT9, KRT1, KRT10, KRT14, DCD, KRT6C, KRT6A, and KRT5) were detected in all three groups. A two-sample Welch’s t-test identified a significant change in KRT2 and KRT9 levels after landing. Enrichment analysis using the KEGG database revealed the significant participation of detected proteins in pathogenic E. coli infection (ACTG1, TUBA1C, TUBA4A, TUBB, TUBB8, and YWHAZ), which may indicate microbiota changes associated with being in space. This assumption is confirmed by microbial composition analysis. In general, the results suggest that EBC can be used for noninvasive monitoring of health status and respiratory tract pathologies during spaceflights, and that the obtained data are important for the development of medicine for use in extreme situations. Data are available from ProteomeXchange using the identifier PXD014191. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessArticle
Nitric Oxide Is Involved in Heavy Ion-Induced Non-Targeted Effects in Human Fibroblasts
Int. J. Mol. Sci. 2019, 20(18), 4327; https://doi.org/10.3390/ijms20184327 - 04 Sep 2019
Abstract
Previously, we investigated the dose response for chromosomal aberration (CA) for exposures corresponding to less than one particle traversal per cell nucleus by high energy and charge (HZE) particles, and showed that the dose responses for simple exchanges for human fibroblast irradiated under [...] Read more.
Previously, we investigated the dose response for chromosomal aberration (CA) for exposures corresponding to less than one particle traversal per cell nucleus by high energy and charge (HZE) particles, and showed that the dose responses for simple exchanges for human fibroblast irradiated under confluent culture conditions were best fit by non-linear models motivated by a non-targeted effect (NTE). Our results suggested that the simple exchanges in normal human fibroblasts have an important NTE contribution at low particle fluence. Nitric oxide (NO) has been reported as a candidate for intercellular signaling for NTE in many studies. In order to estimate the contribution of NTE components in induced CA, we measured CA with and without an NO scavenger in normal skin fibroblasts cells after exposure to 600 MeV/u and 1 GeV/u 56Fe ions, less than one direct particle traversal per cell nucleus. Yields of CA were significantly lower in fibroblasts exposed to the NO scavenger compared to controls, suggesting involvement of NO in cell signaling for induction of CA. Media transferred from irradiated cells induced CA in non-irradiated cells, and this effect was abrogated with NO scavengers. Our results strongly support the importance of NTE contributions in the formation of CA at low-particle fluence in fibroblasts. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessArticle
The Effects of Spaceflight Factors on the Human Plasma Proteome, Including Both Real Space Missions and Ground-Based Experiments
Int. J. Mol. Sci. 2019, 20(13), 3194; https://doi.org/10.3390/ijms20133194 - 29 Jun 2019
Cited by 1
Abstract
The aim of the study was to compare proteomic data on the effects of spaceflight factors on the human body, including both real space missions and ground-based experiments. LC–MS/MS-based proteomic analysis of blood plasma samples obtained from 13 cosmonauts before and after long-duration [...] Read more.
The aim of the study was to compare proteomic data on the effects of spaceflight factors on the human body, including both real space missions and ground-based experiments. LC–MS/MS-based proteomic analysis of blood plasma samples obtained from 13 cosmonauts before and after long-duration (169–199 days) missions on the International Space Station (ISS) and for five healthy men included in 21-day-long head-down bed rest (HDBR) and dry immersion experiments were performed. The semi-quantitative label-free analysis revealed significantly changed proteins: 19 proteins were significantly different on the first (+1) day after landing with respect to background levels; 44 proteins significantly changed during HDBR and 31 changed in the dry immersion experiment. Comparative analysis revealed nine common proteins (A1BG, A2M, SERPINA1, SERPINA3, SERPING1, SERPINC1, HP, CFB, TF), which changed their levels after landing, as well as in both ground-based experiments. Common processes, such as platelet degranulation, hemostasis, post-translational protein phosphorylation and processes of protein metabolism, indicate common pathogenesis in ground experiments and during spaceflight. Dissimilarity in the lists of significantly changed proteins could be explained by the differences in the dynamics of effective development in the ground-based experiments. Data are available via ProteomeXchange using the identifier PXD013305. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessCommunication
Influence of Acute Exercise on DNA Repair and PARP Activity before and after Irradiation in Lymphocytes from Trained and Untrained Individuals
Int. J. Mol. Sci. 2019, 20(12), 2999; https://doi.org/10.3390/ijms20122999 - 19 Jun 2019
Abstract
Several studies indicate that acute exercise induces DNA damage, whereas regular exercise increases DNA repair kinetics. Although the molecular mechanisms are not completely understood, the induction of endogenous reactive oxygen species (ROS) during acute exhaustive exercise due to metabolic processes might be responsible [...] Read more.
Several studies indicate that acute exercise induces DNA damage, whereas regular exercise increases DNA repair kinetics. Although the molecular mechanisms are not completely understood, the induction of endogenous reactive oxygen species (ROS) during acute exhaustive exercise due to metabolic processes might be responsible for the observed DNA damage, while an adaptive increase in antioxidant capacity due to regular physical activity seems to play an important protective role. However, the protective effect of physical activity on exogenously induced DNA damage in human immune cells has been poorly investigated. We asked the question whether individuals with a high aerobic capacity would have an enhanced response to radiation-induced DNA damage. Immune cells are highly sensitive to radiation and exercise affects lymphocyte dynamics and immune function. Therefore, we measured endogenous and radiation-induced DNA strand breaks and poly (ADP-ribose) polymerase-1 (PARP1) activity in peripheral blood mononuclear cells (PBMCs) from endurance-trained (maximum rate of oxygen consumption measured during incremental exercise V’O2max > 55 mL/min/kg) and untrained (V’O2max < 45 mL/min/kg) young healthy male volunteers before and after exhaustive exercise. Our results indicate that: (i) acute exercise induces DNA strand breaks in lymphocytes only in untrained individuals, (ii) following acute exercise, trained individuals repaired radiation-induced DNA strand breaks faster than untrained individuals, and (iii) trained subjects retained a higher level of radiation-induced PARP1 activity after acute exercise. The results of the present study indicate that increased aerobic fitness can protect immune cells against radiation-induced DNA strand breaks. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessArticle
Effects of Spaceflight and Simulated Microgravity on YAP1 Expression in Cardiovascular Progenitors: Implications for Cell-Based Repair
Int. J. Mol. Sci. 2019, 20(11), 2742; https://doi.org/10.3390/ijms20112742 - 04 Jun 2019
Abstract
Spaceflight alters many processes of the human body including cardiac function and cardiac progenitor cell behavior. The mechanism behind these changes remains largely unknown; however, simulated microgravity devices are making it easier for researchers to study the effects of microgravity. To study the [...] Read more.
Spaceflight alters many processes of the human body including cardiac function and cardiac progenitor cell behavior. The mechanism behind these changes remains largely unknown; however, simulated microgravity devices are making it easier for researchers to study the effects of microgravity. To study the changes that take place in cardiac progenitor cells in microgravity environments, adult cardiac progenitor cells were cultured aboard the International Space Station (ISS) as well as on a clinostat and examined for changes in Hippo signaling, a pathway known to regulate cardiac development. Cells cultured under microgravity conditions, spaceflight-induced or simulated, displayed upregulation of downstream genes involved in the Hippo pathway such as YAP1 and SOD2. YAP1 is known to play a role in cardiac regeneration which led us to investigate YAP1 expression in a sheep model of cardiovascular repair. Additionally, to mimic the effects of microgravity, drug treatment was used to induce Hippo related genes as well as a regulator of the Hippo pathway, miRNA-302a. These studies provide insight into the changes that occur in space and how the effects of these changes relate to cardiac regeneration studies. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessArticle
Rapid Morphological and Cytoskeletal Response to Microgravity in Human Primary Macrophages
Int. J. Mol. Sci. 2019, 20(10), 2402; https://doi.org/10.3390/ijms20102402 - 15 May 2019
Abstract
The FLUMIAS (Fluorescence-Microscopic Analyses System for Life-Cell-Imaging in Space) confocal laser spinning disk fluorescence microscope represents a new imaging capability for live cell imaging experiments on suborbital ballistic rocket missions. During the second pioneer mission of this microscope system on the TEXUS-54 suborbital [...] Read more.
The FLUMIAS (Fluorescence-Microscopic Analyses System for Life-Cell-Imaging in Space) confocal laser spinning disk fluorescence microscope represents a new imaging capability for live cell imaging experiments on suborbital ballistic rocket missions. During the second pioneer mission of this microscope system on the TEXUS-54 suborbital rocket flight, we developed and performed a live imaging experiment with primary human macrophages. We simultaneously imaged four different cellular structures (nucleus, cytoplasm, lysosomes, actin cytoskeleton) by using four different live cell dyes (Nuclear Violet, Calcein, LysoBrite, SiR-actin) and laser wavelengths (405, 488, 561, and 642 nm), and investigated the cellular morphology in microgravity (10−4 to 10−5 g) over a period of about six minutes compared to 1 g controls. For live imaging of the cytoskeleton during spaceflight, we combined confocal laser microscopy with the SiR-actin probe, a fluorogenic silicon-rhodamine (SiR) conjugated jasplakinolide probe that binds to F-actin and displays minimal toxicity. We determined changes in 3D cell volume and surface, nuclear volume and in the actin cytoskeleton, which responded rapidly to the microgravity environment with a significant reduction of SiR-actin fluorescence after 4–19 s microgravity, and adapted subsequently until 126–151 s microgravity. We conclude that microgravity induces geometric cellular changes and rapid response and adaptation of the potential gravity-transducing cytoskeleton in primary human macrophages. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessArticle
Single-Cell RNA-Sequencing Identifies Activation of TP53 and STAT1 Pathways in Human T Lymphocyte Subpopulations in Response to Ex Vivo Radiation Exposure
Int. J. Mol. Sci. 2019, 20(9), 2316; https://doi.org/10.3390/ijms20092316 - 10 May 2019
Abstract
Detrimental health consequences from exposure to space radiation are a major concern for long-duration human exploration missions to the Moon or Mars. Cellular responses to radiation are expected to be heterogeneous for space radiation exposure, where only high-energy protons and other particles traverse [...] Read more.
Detrimental health consequences from exposure to space radiation are a major concern for long-duration human exploration missions to the Moon or Mars. Cellular responses to radiation are expected to be heterogeneous for space radiation exposure, where only high-energy protons and other particles traverse a fraction of the cells. Therefore, assessing DNA damage and DNA damage response in individual cells is crucial in understanding the mechanisms by which cells respond to different particle types and energies in space. In this project, we identified a cell-specific signature for radiation response by using single-cell transcriptomics of human lymphocyte subpopulations. We investigated gene expression in individual human T lymphocytes 3 h after ex vivo exposure to 2-Gy gamma rays while using the single-cell sequencing technique (10X Genomics). In the process, RNA was isolated from ~700 irradiated and ~700 non-irradiated control cells, and then sequenced with ~50 k reads/cell. RNA in each of the cells was distinctively barcoded prior to extraction to allow for quantification for individual cells. Principal component and clustering analysis of the unique molecular identifier (UMI) counts classified the cells into three groups or sub-types, which correspond to CD4+, naïve, and CD8+/NK cells. Gene expression changes after radiation exposure were evaluated using negative binomial regression. On average, BBC3, PCNA, and other TP53 related genes that are known to respond to radiation in human T cells showed increased activation. While most of the TP53 responsive genes were upregulated in all groups of cells, the expressions of IRF1, STAT1, and BATF were only upregulated in the CD4+ and naïve groups, but were unchanged in the CD8+/NK group, which suggests that the interferon-gamma pathway does not respond to radiation in CD8+/NK cells. Thus, single-cell RNA sequencing technique was useful for simultaneously identifying the expression of a set of genes in individual cells and T lymphocyte subpopulation after gamma radiation exposure. The degree of dependence of UMI counts between pairs of upregulated genes was also evaluated to construct a similarity matrix for cluster analysis. The cluster analysis identified a group of TP53-responsive genes and a group of genes that are involved in the interferon gamma pathway, which demonstrate the potential of this method for identifying previously unknown groups of genes with similar expression patterns. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessArticle
Real-Time 3D High-Resolution Microscopy of Human Cells on the International Space Station
Int. J. Mol. Sci. 2019, 20(8), 2033; https://doi.org/10.3390/ijms20082033 - 25 Apr 2019
Cited by 1
Abstract
Here we report the successful first operation of FLUMIAS-DEA, a miniaturized high-resolution 3D fluorescence microscope on the International Space Station (ISS) by imaging two scientific samples in a temperature-constant system, one sample with fixed cells and one sample with living human cells. The [...] Read more.
Here we report the successful first operation of FLUMIAS-DEA, a miniaturized high-resolution 3D fluorescence microscope on the International Space Station (ISS) by imaging two scientific samples in a temperature-constant system, one sample with fixed cells and one sample with living human cells. The FLUMIAS-DEA microscope combines features of a high-resolution 3D fluorescence microscope based on structured illumination microscope (SIM) technology with hardware designs to meet the requirements of a space instrument. We successfully demonstrated that the FLUMIAS technology was able to acquire, transmit, and store high-resolution 3D fluorescence images from fixed and living cells, allowing quantitative and dynamic analysis of subcellular structures, e.g., the cytoskeleton. The capability of real-time analysis methods on ISS will dramatically extend our knowledge about the dynamics of cellular reactions and adaptations to the space environment, which is not only an option, but a requirement of evidence-based medical risk assessment, monitoring and countermeasure development for exploration class missions. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessArticle
Physiological Responses of Jurkat Lymphocytes to Simulated Microgravity Conditions
Int. J. Mol. Sci. 2019, 20(8), 1892; https://doi.org/10.3390/ijms20081892 - 17 Apr 2019
Abstract
The presence of microgravity conditions deeply affects the human body functions at the systemic, organ and cellular levels. This study aimed to investigate the effects induced by simulated-microgravity on non-stimulated Jurkat lymphocytes, an immune cell phenotype considered as a biosensor of the body [...] Read more.
The presence of microgravity conditions deeply affects the human body functions at the systemic, organ and cellular levels. This study aimed to investigate the effects induced by simulated-microgravity on non-stimulated Jurkat lymphocytes, an immune cell phenotype considered as a biosensor of the body responses, in order to depict at the cellular level the effects of such a peculiar condition. Jurkat cells were grown at 1 g or on random positioning machine simulating microgravity. On these cells we performed: morphological, cell cycle and proliferation analyses using cytofluorimetric and staining protocols—intracellular Ca2+, reactive oxygen species (ROS), mitochondria membrane potential and O2 measurements using fluorescent probes—aconitase and mitochondria activity, glucose and lactate content using colorimetric assays. After the first exposure days, the cells showed a more homogeneous roundish shape, an increased proliferation rate, metabolic and detoxifying activity resulted in decreased intracellular Ca2+ and ROS. In the late exposure time, the cells adapted to the new environmental condition. Our non-activated proliferating Jurkat cells, even if responsive to altered external forces, adapted to the new environmental condition showing a healthy status. In order to define the cellular mechanism(s) triggered by microgravity, developing standardized experimental approaches and controlled cell culture and simulator conditions is strongly recommended. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessArticle
Altered Promoter and G-Box Binding Factor for 1-Deoxy-d-Xylulose-5-Phosphate Synthase Gene Grown from Poa pratensis Seeds after Spaceflight
Int. J. Mol. Sci. 2019, 20(6), 1398; https://doi.org/10.3390/ijms20061398 - 21 Mar 2019
Abstract
In plant cells, the nucleus DNA is considered the primary site of injury by the space environment, which could generate genetic alteration. As the part of genomic mutation, genetic variation in the promoter region could regulate gene expression. In the study, it is [...] Read more.
In plant cells, the nucleus DNA is considered the primary site of injury by the space environment, which could generate genetic alteration. As the part of genomic mutation, genetic variation in the promoter region could regulate gene expression. In the study, it is observed that there is a deletion in the upstream regulatory region of the 1-deoxy-d-xylulose-5-phosphate synthase 1 gene (PpDXS1) of Poa pratensis dwarf mutant and the PpDXS1 transcript abundance is lower in the dwarf mutant. It is indicated that the deletion in the promoter region between wild type and dwarf mutant could be responsible for the regulation of PpDXS1 gene expression. The PpDXS1 promoter of dwarf mutant shows a lower activity as determined by dual luciferase assay in Poa pratensis protoplast, as well as the GUS activity is lower in transgenic Poa pratensis plant. To further investigate the effect of the deletion in the promoter region on PpDXS1 transcript accumulation, the transient assay and yeast one-hybrid experiment demonstrate that the deletion comprises a motif which is a target of G-box binding factor (GBF1), and the motif correlates with an increase in transactivation by GBF1 protein. Taken together, these results indicate that the deletion in the promoter of PpDXS1 isolated from dwarf mutant is sufficient to account for the decrease in PpDXS1 transcript level and GBF1 can regulate the PpDXS1 gene expression, and subsequently affect accumulation of various isoprenoids throughout the plant. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessArticle
Changes in Human Foetal Osteoblasts Exposed to the Random Positioning Machine and Bone Construct Tissue Engineering
Int. J. Mol. Sci. 2019, 20(6), 1357; https://doi.org/10.3390/ijms20061357 - 18 Mar 2019
Cited by 5
Abstract
Human cells, when exposed to both real and simulated microgravity (s-µg), form 3D tissue constructs mirroring in vivo architectures (e.g., cartilage, intima constructs, cancer spheroids and others). In this study, we exposed human foetal osteoblast (hFOB 1.19) cells to a Random [...] Read more.
Human cells, when exposed to both real and simulated microgravity (s-µg), form 3D tissue constructs mirroring in vivo architectures (e.g., cartilage, intima constructs, cancer spheroids and others). In this study, we exposed human foetal osteoblast (hFOB 1.19) cells to a Random Positioning Machine (RPM) for 7 days and 14 days, with the purpose of investigating the effects of s-µg on biological processes and to engineer 3D bone constructs. RPM exposure of the hFOB 1.19 cells induces alterations in the cytoskeleton, cell adhesion, extra cellular matrix (ECM) and the 3D multicellular spheroid (MCS) formation. In addition, after 7 days, it influences the morphological appearance of these cells, as it forces adherent cells to detach from the surface and assemble into 3D structures. The RPM-exposed hFOB 1.19 cells exhibited a differential gene expression of the following genes: transforming growth factor beta 1 (TGFB1, bone morphogenic protein 2 (BMP2), SRY-Box 9 (SOX9), actin beta (ACTB), beta tubulin (TUBB), vimentin (VIM), laminin subunit alpha 1 (LAMA1), collagen type 1 alpha 1 (COL1A1), phosphoprotein 1 (SPP1) and fibronectin 1 (FN1). RPM exposure also induced a significantly altered release of the cytokines and bone biomarkers sclerostin (SOST), osteocalcin (OC), osteoprotegerin (OPG), osteopontin (OPN), interleukin 1 beta (IL-1β) and tumour necrosis factor 1 alpha (TNF-1α). After the two-week RPM exposure, the spheroids presented a bone-specific morphology. In conclusion, culturing cells in s-µg under gravitational unloading represents a novel technology for tissue-engineering of bone constructs and it can be used for investigating the mechanisms behind spaceflight-related bone loss as well as bone diseases such as osteonecrosis or bone injuries. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessArticle
GeneLab Database Analyses Suggest Long-Term Impact of Space Radiation on the Cardiovascular System by the Activation of FYN Through Reactive Oxygen Species
Int. J. Mol. Sci. 2019, 20(3), 661; https://doi.org/10.3390/ijms20030661 - 03 Feb 2019
Abstract
Space radiation has recently been considered a risk factor for astronauts’ cardiac health. As an example, for the case of how to query and identify datasets within NASA’s GeneLab database and demonstrate the database utility, we used an unbiased systems biology method for [...] Read more.
Space radiation has recently been considered a risk factor for astronauts’ cardiac health. As an example, for the case of how to query and identify datasets within NASA’s GeneLab database and demonstrate the database utility, we used an unbiased systems biology method for identifying key genes/drivers for the contribution of space radiation on the cardiovascular system. This knowledge can contribute to designing appropriate experiments targeting these specific pathways. Microarray data from cardiomyocytes of male C57BL/6 mice followed-up for 28 days after exposure to 900 mGy of 1 GeV proton or 150 mGy of 1 GeV/n 56Fe were compared to human endothelial cells (HUVECs) cultured for 7 days on the International Space Station (ISS). We observed common molecular pathways between simulated space radiation and HUVECs flown on the ISS. The analysis suggests FYN is the central driver/hub for the cardiovascular response to space radiation: the known oxidative stress induced immediately following radiation would only be transient and would upregulate FYN, which in turn would reduce reactive oxygen species (ROS) levels, protecting the cardiovascular system. The transcriptomic signature of exposure to protons was also much closer to the spaceflight signature than 56Fe’s signature. To our knowledge, this is the first time GeneLab datasets were utilized to provide potential biological indications that the majority of ions on the ISS are protons, clearly illustrating the power of omics analysis. More generally, this work also demonstrates how to combine animal radiation studies done on the ground and spaceflight studies to evaluate human risk in space. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessArticle
Expression of Hypoxia-Inducible Factor 1α (HIF-1α) and Genes of Related Pathways in Altered Gravity
Int. J. Mol. Sci. 2019, 20(2), 436; https://doi.org/10.3390/ijms20020436 - 20 Jan 2019
Cited by 1
Abstract
Immune system deterioration in space represents a major risk, which has to be mitigated for exploration-class missions into the solar system. Altered gravitational forces have been shown to regulate adaptation processes in cells of the immune system, which are important for appropriate risk [...] Read more.
Immune system deterioration in space represents a major risk, which has to be mitigated for exploration-class missions into the solar system. Altered gravitational forces have been shown to regulate adaptation processes in cells of the immune system, which are important for appropriate risk management, monitoring and development of countermeasures. T lymphocytes and cells of the monocyte-macrophage system are highly migratory cell types that frequently encounter a wide range of oxygen tensions in human tissues and in hypoxic areas, even under homeostatic conditions. Hypoxia-inducible factor 1 and 2 (HIF’s) might have an important role in activation of T cells and cells of the monocyte-macrophages system. Thus, we investigated the regulation of HIF-dependent and, therefore, hypoxia-signaling systems in both cell types in altered gravity and performed transcript and protein analysis from parabolic flight and suborbital ballistic rocket experiments. We found that HIF-1α and HIF-1-dependent transcripts were differently regulated in altered gravity, whereas HIF-1α-dependent gene expression adapted after 5 min microgravity. Inter-platform comparisons identified PDK1 as highly responsive to gravitational changes in human U937 myelomonocytic cells and in Jurkat T cells. We suggest HIF-1 as a potential pharmacological target for counteracting immune system deterioration during space flight. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessArticle
HSFA2 Functions in the Physiological Adaptation of Undifferentiated Plant Cells to Spaceflight
Int. J. Mol. Sci. 2019, 20(2), 390; https://doi.org/10.3390/ijms20020390 - 17 Jan 2019
Abstract
Heat Shock Factor A2 (HsfA2) is part of the Heat Shock Factor (HSF) network, and plays an essential role beyond heat shock in environmental stress responses and cellular homeostatic control. Arabidopsis thaliana cell cultures derived from wild type (WT) ecotype Col-0 and a [...] Read more.
Heat Shock Factor A2 (HsfA2) is part of the Heat Shock Factor (HSF) network, and plays an essential role beyond heat shock in environmental stress responses and cellular homeostatic control. Arabidopsis thaliana cell cultures derived from wild type (WT) ecotype Col-0 and a knockout line deficient in the gene encoding HSFA2 (HSFA2 KO) were grown aboard the International Space Station (ISS) to ascertain whether the HSF network functions in the adaptation to the novel environment of spaceflight. Microarray gene expression data were analyzed using a two-part comparative approach. First, genes differentially expressed between the two environments (spaceflight to ground) were identified within the same genotype, which represented physiological adaptation to spaceflight. Second, gene expression profiles were compared between the two genotypes (HSFA2 KO to WT) within the same environment, which defined genes uniquely required by each genotype on the ground and in spaceflight-adapted states. Results showed that the endoplasmic reticulum (ER) stress and unfolded protein response (UPR) define the HSFA2 KO cells’ physiological state irrespective of the environment, and likely resulted from a deficiency in the chaperone-mediated protein folding machinery in the mutant. Results further suggested that additional to its universal stress response role, HsfA2 also has specific roles in the physiological adaptation to spaceflight through cell wall remodeling, signal perception and transduction, and starch biosynthesis. Disabling HsfA2 altered the physiological state of the cells, and impacted the mechanisms induced to adapt to spaceflight, and identified HsfA2-dependent genes that are important to the adaption of wild type cells to spaceflight. Collectively these data indicate a non-thermal role for the HSF network in spaceflight adaptation. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessArticle
Hibernation and Radioprotection: Gene Expression in the Liver and Testicle of Rats Irradiated under Synthetic Torpor
Int. J. Mol. Sci. 2019, 20(2), 352; https://doi.org/10.3390/ijms20020352 - 16 Jan 2019
Abstract
Hibernation has been proposed as a tool for human space travel. In recent years, a procedure to induce a metabolic state known as “synthetic torpor” in non-hibernating mammals was successfully developed. Synthetic torpor may not only be an efficient method to spare resources [...] Read more.
Hibernation has been proposed as a tool for human space travel. In recent years, a procedure to induce a metabolic state known as “synthetic torpor” in non-hibernating mammals was successfully developed. Synthetic torpor may not only be an efficient method to spare resources and reduce psychological problems in long-term exploratory-class missions, but may also represent a countermeasure against cosmic rays. Here we show the preliminary results from an experiment in rats exposed to ionizing radiation in normothermic conditions or synthetic torpor. Animals were irradiated with 3 Gy X-rays and organs were collected 4 h after exposure. Histological analysis of liver and testicle showed a reduced toxicity in animals irradiated in torpor compared to controls irradiated at normal temperature and metabolic activity. The expression of ataxia telangiectasia mutated (ATM) in the liver was significantly downregulated in the group of animal in synthetic torpor. In the testicle, more genes involved in the DNA damage signaling were downregulated during synthetic torpor. These data show for the first time that synthetic torpor is a radioprotector in non-hibernators, similarly to natural torpor in hibernating animals. Synthetic torpor can be an effective strategy to protect humans during long term space exploration of the solar system. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessArticle
Short and Long-Term Changes in Social Odor Recognition and Plasma Cytokine Levels Following Oxygen (16O) Ion Radiation Exposure
Int. J. Mol. Sci. 2019, 20(2), 339; https://doi.org/10.3390/ijms20020339 - 15 Jan 2019
Cited by 2
Abstract
Future long-duration space missions will involve travel outside of the Earth’s magnetosphere protection and will result in astronauts being exposed to high energy and charge (HZE) ions and protons. Exposure to this type of radiation can result in damage to the central nervous [...] Read more.
Future long-duration space missions will involve travel outside of the Earth’s magnetosphere protection and will result in astronauts being exposed to high energy and charge (HZE) ions and protons. Exposure to this type of radiation can result in damage to the central nervous system and deficits in numerous cognitive domains that can jeopardize mission success. Social processing is a cognitive domain that is important for people living and working in groups, such as astronauts, but it has received little attention in terms of HZE ion exposure. In the current study, we assessed the effects of whole-body oxygen ion (16O; 1000 MeV/n) exposure (1 or 10 cGy) on social odor recognition memory in male Long-Evans rats at one and six months following exposure. Radiation exposure did not affect rats’ preferences for a novel social odor experienced during Habituation at either time point. However, rats exposed to 10 cGy displayed short and long-term deficits in 24-h social recognition. In contrast, rats exposed to 1 cGy only displayed long-term deficits in 24-h social recognition. While an age-related decrease in Ki67+ staining (a marker of cell proliferation) was found in the subventricular zone, it was unaffected by radiation exposure. At one month following exposure, plasma KC/GRO (CXCL1) levels were elevated in the 1 cGy rats, but not in the 10 cGy rats, suggesting that peripheral levels of this cytokine could be associated with intact social recognition at earlier time points following radiation exposure. These results have important implications for long-duration missions and demonstrate that behaviors related to social processing could be negatively affected by HZE ion exposure. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessArticle
Increased Chromosome Aberrations in Cells Exposed Simultaneously to Simulated Microgravity and Radiation
Int. J. Mol. Sci. 2019, 20(1), 43; https://doi.org/10.3390/ijms20010043 - 22 Dec 2018
Abstract
Space radiation and microgravity (μG) are two major environmental stressors for humans in space travel. One of the fundamental questions in space biology research is whether the combined effects of μG and exposure to cosmic radiation are interactive. While studies [...] Read more.
Space radiation and microgravity (μG) are two major environmental stressors for humans in space travel. One of the fundamental questions in space biology research is whether the combined effects of μG and exposure to cosmic radiation are interactive. While studies addressing this question have been carried out for half a century in space or using simulated μG on the ground, the reported results are ambiguous. For the assessment and management of human health risks in future Moon and Mars missions, it is necessary to obtain more basic data on the molecular and cellular responses to the combined effects of radiation and µG. Recently we incorporated a μG–irradiation system consisting of a 3D clinostat synchronized to a carbon-ion or X-ray irradiation system. Our new experimental setup allows us to avoid stopping clinostat rotation during irradiation, which was required in all other previous experiments. Using this system, human fibroblasts were exposed to X-rays or carbon ions under the simulated μG condition, and chromosomes were collected with the premature chromosome condensation method in the first mitosis. Chromosome aberrations (CA) were quantified by the 3-color fluorescent in situ hybridization (FISH) method. Cells exposed to irradiation under the simulated μG condition showed a higher frequency of both simple and complex types of CA compared to cells irradiated under the static condition by either X-rays or carbon ions. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessArticle
Effects of Space Flight on Mouse Liver versus Kidney: Gene Pathway Analyses
Int. J. Mol. Sci. 2018, 19(12), 4106; https://doi.org/10.3390/ijms19124106 - 18 Dec 2018
Cited by 3
Abstract
Understanding genome wide, tissue-specific, and spaceflight-induced changes in gene expression is critical to develop effective countermeasures. Transcriptome analysis has been performed on diverse tissues harvested from animals flown in space, but not the kidney. We determined the genome wide gene expression using a [...] Read more.
Understanding genome wide, tissue-specific, and spaceflight-induced changes in gene expression is critical to develop effective countermeasures. Transcriptome analysis has been performed on diverse tissues harvested from animals flown in space, but not the kidney. We determined the genome wide gene expression using a gene array analysis of kidney and liver tissue from mice flown in space for 12 days versus ground based control animals. By comparing the transcriptome of liver and kidney from animals flown in space versus ground control animals, we tested a unique hypothesis: Are there common gene expression pathways activated in multiple tissue types in response to spaceflight stimuli? Although there were tissue-specific changes, both liver and kidney overexpressed genes in the same four areas: (a) cellular responses to peptides, hormones, and nitrogen/organonitrogen compounds; (b) apoptosis and cell death; (c) fat cell differentiation and (d) negative regulation of protein kinase. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessArticle
Microgravity Affects Thyroid Cancer Cells during the TEXUS-53 Mission Stronger than Hypergravity
Int. J. Mol. Sci. 2018, 19(12), 4001; https://doi.org/10.3390/ijms19124001 - 12 Dec 2018
Cited by 5
Abstract
Thyroid cancer is the most abundant tumor of the endocrine organs. Poorly differentiated thyroid cancer is still difficult to treat. Human cells exposed to long-term real (r-) and simulated (s-) microgravity (µg) revealed morphological alterations and changes in the expression profile [...] Read more.
Thyroid cancer is the most abundant tumor of the endocrine organs. Poorly differentiated thyroid cancer is still difficult to treat. Human cells exposed to long-term real (r-) and simulated (s-) microgravity (µg) revealed morphological alterations and changes in the expression profile of genes involved in several biological processes. The objective of this study was to examine the effects of short-term µg on poorly differentiated follicular thyroid cancer cells (FTC-133 cell line) resulting from 6 min of exposure to µg on a sounding rocket flight. As sounding rocket flights consist of several flight phases with different acceleration forces, rigorous control experiments are mandatory. Hypergravity (hyper-g) experiments were performed at 18g on a centrifuge in simulation of the rocket launch and s-µg was simulated by a random positioning machine (RPM). qPCR analyses of selected genes revealed no remarkable expression changes in controls as well as in hyper-g samples taken at the end of the first minute of launch. Using a centrifuge initiating 18g for 1 min, however, presented moderate gene expression changes, which were significant for COL1A1, VCL, CFL1, PTK2, IL6, CXCL8 and MMP14. We also identified a network of mutual interactions of the investigated genes and proteins by employing in-silico analyses. Lastly, µg-samples indicated that microgravity is a stronger regulator of gene expression than hyper-g. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessCommunication
Temporary Loading Prevents Cancer Progression and Immune Organ Atrophy Induced by Hind-Limb Unloading in Mice
Int. J. Mol. Sci. 2018, 19(12), 3959; https://doi.org/10.3390/ijms19123959 - 09 Dec 2018
Abstract
Although the body’s immune system is altered during spaceflight, the effects of microgravity (μG) on tumor growth and carcinogenesis are, as yet, unknown. To assess tumor proliferation and its effects on the immune system, we used a hind-limb unloading (HU) murine [...] Read more.
Although the body’s immune system is altered during spaceflight, the effects of microgravity (μG) on tumor growth and carcinogenesis are, as yet, unknown. To assess tumor proliferation and its effects on the immune system, we used a hind-limb unloading (HU) murine model to simulate μG during spaceflight. HU mice demonstrated significantly increased tumor growth, metastasis to the lung, and greater splenic and thymic atrophy compared with mice in constant orthostatic suspension and standard housing controls. In addition, mice undergoing temporary loading during HU (2 h per day) demonstrated no difference in cancer progression and immune organ atrophy compared with controls. Our findings suggest that temporary loading can prevent cancer progression and immune organ atrophy induced by HU. Further space experiment studies are warranted to elucidate the precise effects of μG on systemic immunity and cancer progression. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessArticle
Synergistic Effects of Weightlessness, Isoproterenol, and Radiation on DNA Damage Response and Cytokine Production in Immune Cells
Int. J. Mol. Sci. 2018, 19(11), 3689; https://doi.org/10.3390/ijms19113689 - 21 Nov 2018
Cited by 1
Abstract
The implementation of rotating-wall vessels (RWVs) for studying the effect of lack of gravity has attracted attention, especially in the fields of stem cells, tissue regeneration, and cancer research. Immune cells incubated in RWVs exhibit several features of immunosuppression including impaired leukocyte proliferation, [...] Read more.
The implementation of rotating-wall vessels (RWVs) for studying the effect of lack of gravity has attracted attention, especially in the fields of stem cells, tissue regeneration, and cancer research. Immune cells incubated in RWVs exhibit several features of immunosuppression including impaired leukocyte proliferation, cytokine responses, and antibody production. Interestingly, stress hormones influence cellular immune pathways affected by microgravity, such as cell proliferation, apoptosis, DNA repair, and T cell activation. These pathways are crucial defense mechanisms that protect the cell from toxins, pathogens, and radiation. Despite the importance of the adrenergic receptor in regulating the immune system, the effect of microgravity on the adrenergic system has been poorly studied. Thus, we elected to investigate the synergistic effects of isoproterenol (a sympathomimetic drug), radiation, and microgravity in nonstimulated immune cells. Peripheral blood mononuclear cells were treated with the sympathomimetic drug isoproterenol, exposed to 0.8 or 2 Gy γ-radiation, and incubated in RWVs. Mixed model regression analyses showed significant synergistic effects on the expression of the β2-adrenergic receptor gene (ADRB2). Radiation alone increased ADRB2 expression, and cells incubated in microgravity had more DNA strand breaks than cells incubated in normal gravity. We observed radiation-induced cytokine production only in microgravity. Prior treatment with isoproterenol clearly prevents most of the microgravity-mediated effects. RWVs may be a useful tool to provide insight into novel regulatory pathways, providing benefit not only to astronauts but also to patients suffering from immune disorders or undergoing radiotherapy. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessArticle
Reactivation of Latent Epstein-Barr Virus: A Comparison after Exposure to Gamma, Proton, Carbon, and Iron Radiation
Int. J. Mol. Sci. 2018, 19(10), 2961; https://doi.org/10.3390/ijms19102961 - 28 Sep 2018
Cited by 1
Abstract
Among the many stressors astronauts are exposed to during spaceflight, cosmic radiation may lead to various serious health effects. Specifically, space radiation may contribute to decreased immunity, which has been documented in astronauts during short- and long-duration missions, as evidenced by several changes [...] Read more.
Among the many stressors astronauts are exposed to during spaceflight, cosmic radiation may lead to various serious health effects. Specifically, space radiation may contribute to decreased immunity, which has been documented in astronauts during short- and long-duration missions, as evidenced by several changes in cellular immunity and plasma cytokine levels. Reactivation of latent herpes viruses, either directly from radiation of latently infected cells and/or from perturbation of the immune system, may result in disease in astronauts. Epstein‒Barr virus (EBV) is one of the eight human herpes viruses known to infect more than 90% of human adults and persists for the life of the host without normally causing adverse effects. Reactivation of several latent viruses in astronauts is well documented, although the mechanism of reactivation is not well understood. We studied the effect of four different types of radiation, (1) 137Cs gamma rays, (2) 150-MeV protons, (3) 600 MeV/n carbon ions, and (4) 600 MeV/n iron ions on the activation of lytic gene transcription and of reactivation of EBV in a latently infected cell line (Akata) at doses of 0.1, 0.5, 1.0, and 2.0 Gy. The data showed that for all doses used in this study, lytic gene transcription was induced and median viral loads were significantly higher for all types of radiation than in corresponding control samples, with the increases detected as early as four days post-exposure and generally tapering off at later time points. The viability and size of EBV-infected Akata cells were highly variable and exhibited approximately the same trend in time for all radiation types at 0.1, 0.5, 1.0, and 2.0 Gy. This work shows that reactivation of viruses can occur due to the effect of different types of radiation on latently infected cells in the absence of changes or cytokines produced in the immune system. In general, gamma rays are more effective than protons, carbon ions, and iron ions in inducing latent virus reactivation, though these high-energy particles did induce more sustained and later reactivation of EBV lytic gene transcription. These findings also challenge the common relative biological effectiveness concept that is often used in radiobiology for other end points. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Review

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Open AccessReview
Reptiles in Space Missions: Results and Perspectives
Int. J. Mol. Sci. 2019, 20(12), 3019; https://doi.org/10.3390/ijms20123019 - 20 Jun 2019
Abstract
Reptiles are a rare model object for space research. However, some reptile species demonstrate effective adaptation to spaceflight conditions. The main scope of this review is a comparative analysis of reptile experimental exposure in weightlessness, demonstrating the advantages and shortcomings of this model. [...] Read more.
Reptiles are a rare model object for space research. However, some reptile species demonstrate effective adaptation to spaceflight conditions. The main scope of this review is a comparative analysis of reptile experimental exposure in weightlessness, demonstrating the advantages and shortcomings of this model. The description of the known reptile experiments using turtles and geckos in the space and parabolic flight experiments is provided. Behavior, skeletal bones (morphology, histology, and X-ray microtomography), internal organs, and the nervous system (morphology, histology, and immunohistochemistry) are studied in the spaceflight experiments to date, while molecular and physiological results are restricted. Therefore, the results are discussed in the scope of molecular data collected from mammalian (mainly rodents) specimens and cell cultures in the parabolic and orbital flights and simulated microgravity. The published data are compared with the results of the gecko model studies after the 12–44.5-day spaceflights with special reference to the unique peculiarities of the gecko model for the orbital experiments. The complex study of thick-toed geckos after three spaceflights, in which all geckos survived and demonstrated effective adaptation to spaceflight conditions, was performed. However, future investigations are needed to study molecular mechanisms of gecko adaptation in space. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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