Beyond Low-Earth Orbit: Characterizing Immune and microRNA Differentials following Simulated Deep Spaceflight Conditions in Mice

Spaceflight missions can cause immune system dysfunction in astronauts with little understanding of immune outcomes in deep space. This study assessed immune responses in mice following ground-based, simulated deep spaceflight conditions, compared with data from astronauts on International Space Station missions. For ground studies, we simulated microgravity using the hindlimb unloaded mouse model alone or in combination with acute simulated galactic cosmic rays or solar particle events irradiation. Immune profiling results revealed unique immune diversity following each experimental condition, suggesting each stressor results in distinct circulating immune responses, with clear consequences for deep spaceflight. Circulating plasma microRNA sequence analysis revealed involvement in immune system dysregulation. Furthermore, a large astronaut cohort showed elevated inflammation during low-Earth orbit missions, thereby supporting our simulated ground experiments in mice. Herein, circulating immune biomarkers are defined by distinct deep space irradiation types coupled to simulated microgravity and could be targets for future space health initiatives

Correctness and response time distributions in the MemTrax continuous recognition task: Analysis of strategies and a reverse-exponential model

A critical issue in addressing medical conditions is measurement. Memory measurement is difficult, especially episodic memory, which is disrupted by many conditions. On-line computer testing can precisely measure and assess several memory functions. This study analyzed memory performances from a large group of anonymous, on-line participants using a continuous recognition task (CRT) implemented at https://memtrax.com. These analyses estimated ranges of acceptable performance and average response time (RT). For 344,165 presumed unique individuals completing the CRT a total of 602,272 times, data were stored on a server, including each correct response (HIT), Correct Rejection, and RT to the thousandth of a second. Responses were analyzed, distributions and relationships of these parameters were ascertained, and mean RTs were determined for each participant across the population. From 322,996 valid first tests, analysis of correctness showed that 63% of these tests achieved at least 45 correct (90%), 92% scored at or above 40 correct (80%), and 3% scored 35 correct (70%) or less. The distribution of RTs was skewed with 1% faster than 0.62 s, a median at 0.890 s, and 1% slower than 1.57 s. The RT distribution was best explained by a novel model, the reverse-exponential (RevEx) function. Increased RT speed was most closely associated with increased HIT accuracy. The MemTrax on-line memory test readily provides valid and reliable metrics for assessing individual episodic memory function that could have practical clinical utility for precise assessment of memory dysfunction in many conditions, including improvement or deterioration over time

Neutrophil-to-Lymphocyte Ratio: A Biomarker to Monitor the Immune Status of Astronauts

A comprehensive understanding of spaceflight factors involved in immune dysfunction and the evaluation of biomarkers to assess in-flight astronaut health are essential goals for NASA. An elevated neutrophil-to-lymphocyte ratio (NLR) is a potential biomarker candidate, as leukocyte differentials are altered during spaceflight. In the reduced gravity environment of space, rodents and astronauts displayed elevated NLR and granulocyte-to-lymphocyte ratios (GLR), respectively. To simulate microgravity using two well-established ground-based models, we cultured human whole blood-leukocytes in high-aspect rotating wall vessels (HARV-RWV) and used hindlimb unloaded (HU) mice. Both HARV-RWV simulation of leukocytes and HU-exposed mice showed elevated NLR profiles comparable to spaceflight exposed samples. To assess mechanisms involved, we found the simulated microgravity HARV-RWV model resulted in an imbalance of redox processes and activation of myeloperoxidase-producing inflammatory neutrophils, while antioxidant treatment reversed these effects. In the simulated microgravity HU model, mitochondrial catalase-transgenic mice that have reduced oxidative stress responses showed reduced neutrophil counts, NLR, and a dampened release of selective inflammatory cytokines compared to wildtype HU mice, suggesting simulated microgravity induced oxidative stress responses that triggered inflammation. In brief, both spaceflight and simulated microgravity models caused elevated NLR, indicating this as a potential biomarker for future in-flight immune health monitoring

Artificial gravity partially protects space-induced neurological deficits in Drosophila melanogaster

Spaceflight poses risks to the central nervous system (CNS), and understanding neurological responses is important for future missions. We report CNS changes in Drosophila aboard the International Space Station in response to spaceflight microgravity (SFμg) and artificially simulated Earth gravity (SF1g) via inflight centrifugation as a countermeasure. While inflight behavioral analyses of SFμg exhibit increased activity, postflight analysis displays significant climbing defects, highlighting the sensitivity of behavior to altered gravity. Multi-omics analysis shows alterations in metabolic, oxidative stress and synaptic transmission pathways in both SFμg and SF1g; however, neurological changes immediately postflight, including neuronal loss, glial cell count alterations, oxidative damage, and apoptosis, are seen only in SFμg. Additionally, progressive neuronal loss and a glial phenotype in SF1g and SFμg brains, with pronounced phenotypes in SFμg, are seen upon acclimation to Earth conditions. Overall, our results indicate that artificial gravity partially protects the CNS from the adverse effects of spaceflight

Immunological and hematological outcomes following protracted low dose/low dose rate ionizing radiation and simulated microgravity

Using a ground-based model to simulate spaceflight [21-days of single-housed, hindlimb unloading (HLU) combined with continuous low-dose gamma irradiation (LDR, total dose of 0.04 Gy)], an in-depth survey of the immune and hematological systems of mice at 7-days post-exposure was performed. Collected blood was profiled with a hematology analyzer and spleens were analyzed by whole transcriptome shotgun sequencing (RNA-sequencing). The results revealed negligible differences in immune differentials. However, hematological system analyses of whole blood indicated large disparities in red blood cell differentials and morphology, suggestive of anemia. Murine Reactome networks indicated majority of spleen cells displayed differentially expressed genes (DEG) involved in signal transduction, metabolism, cell cycle, chromatin organization, and DNA repair. Although immune differentials were not changed, DEG analysis of the spleen revealed expression profiles associated with inflammation and dysregulated immune function persist to 1-week post-simulated spaceflight. Additionally, specific regulation pathways associated with human blood disease gene orthologs, such as blood pressure regulation, transforming growth factor-β receptor signaling, and B cell differentiation were noted. Collectively, this study revealed differential immune and hematological outcomes 1-week post-simulated spaceflight conditions, suggesting recovery from spaceflight is an unremitting process