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Gravity has profoundly influenced life on Earth, yet how organisms adapt to changes in gravity remains largely unknown. This study examines vestibular plasticity, specifically how the vestibular system responds to altered gravity. We subjected male C57BL/6J mice to hypergravity (2 G) followed by normal gravity (1 G) to analyze changes in vestibular function and gene expression. Mice showed significant vestibular dysfunction, assessed by righting reflex tests, which persisted for days but reversed at 1 G after exposure to 2 G. Gene expression analysis in the vestibular ganglion identified significant changes in 212 genes out of 49,585 due to gravitational changes. Specifically, 25 genes were upregulated under 2 G and recovered at 1 G after 2 G exposure, while one gene showed the opposite trend. Key neural function genes like Shisa3, Slc25a37, Ntn4, and Snca were involved. Our results reveal that hypergravity-induced vestibular dysfunction is reversible and highlight genes critical for adaptation., (© 2024. The Author(s).)

Purpose: The present study aimed to analyze the influence of muscle activation on lumbar injury under a specific +Gz load., Methods: A hybrid finite element human body model with detailed lumbar anatomy and lumbar muscle activation capabilities was developed. Using the specific +Gz loading acceleration as input, the kinematic and biomechanical responses of the occupant's lower back were studied for both activated and deactivated states of the lumbar muscles., Results: The results indicated that activating the major lumbar muscles enhanced the stability of the occupant's torso, which delayed the contact between the occupant's head and the headrest. Lumbar muscle activation led to higher strain and stress output in the lumbar spine under +Gz load, such as the maximum Von Mises stress of the vertebrae and intervertebral discs increased by 177.9% and 161.8%, respectively, and the damage response index increased by 84.5%., Conclusion: In both simulations, the occupant's risk of lumbar injury does not exceed 10% probability. Therefore, the activation of muscles could provide good protection for maintaining the lumbar spine and reduce the effect of acceleration in vehicle travel direction., (Copyright © 2024 Chinese Medical Association. Production and hosting by Elsevier B.V. All rights reserved.)

Introduction: High + Gz loads, the gravitational forces experienced by the body in hypergravity environments, can lead to bone loss in pilots and astronauts, posing significant health risks., Materials and Methods: To explore the effect of treadmill exercise on bone tissue recovery, a study was conducted on 72 male Wistar rats. These rats were subjected to four weeks of varying levels of periodic high + Gz loads (1G, 8G, 20G) experiments, and were subsequently divided into the treadmill group and the control group. The treadmill group underwent a continuous two-week treadmill experiment, while the control group rested during this period. The mechanical properties, microstructure, and molecular markers of their tibial bone tissue were measured using three-point bending, micro-CT, and PCR., Results: The results showed that treadmill exercise improved the elastic modulus, ultimate deflection, and ultimate load of rat bone tissue. It also increased the number, density, and volume fraction of bone trabeculae, and decreased their separation. Moreover, treadmill exercise enhanced osteogenesis and inhibited osteoclastogenesis., Conclusion: This study demonstrates that treadmill exercise can promote the recovery of bone tissue in rats subjected to high + Gz loads, providing a potential countermeasure for bone loss in pilots and astronauts., (© 2024. The Japanese Society Bone and Mineral Research.)

The fighter pilots exposed to high gravitational (G) acceleration must perform anti-G maneuvers similar to the Valsalva maneuver. However, the effects of high-G acceleration and anti-G maneuvers on cardiac function have rarely been studied. This study aimed to investigate the effects of high-G forces on cardiac function of fighter pilots. Fighter pilots who underwent regular health check-ups and echocardiography were included (n = 29; 100% men, 41 ± 10 years old; mean flight time, 1821 ± 1186 h). Trainees who had not experienced any flights were included in the control group (n = 16; 100% men, 36 ± 17 years old). Echocardiographic data included left ventricular chamber size, systolic and diastolic functions, right ventricular systolic pressure (RVSP), inferior vena cava (IVC) collapsibility, and tricuspid annular plane systolic excursion (TAPSE). No significant differences in left ventricular ejection fraction, RVSP, or IVC collapsibility were observed between two groups. In the multivariate linear regression analysis with total flight time as an independent continuous variable for fighter pilots, TAPSE was positively correlated with total flight time. The experience of fighter pilots who were exposed to high-G acceleration forces and anti-G maneuvers did not cause cardiac structural changes, but the exposure might be associated with right heart function changes., (© 2024. The Author(s).)

In the age of space exploration, the effect of hypergravity on human physiology is a relatively neglected topic. However, astronauts have several experiences of hypergravity during their missions. The main disturbance of altered gravity can be imputed to cell cytoskeleton alteration and physiologic homeostasis of the body. Testis has proved to be a particularly sensible organ, subject to environmental alteration and physiological disturbance. This makes testis an organ eligible for investigating the alteration following exposure to altered gravity. In our study, mice were exposed to hypergravity (3g for 14 days) in the Large Diameter Centrifuge machine (ESA, Netherland). We have observed a morphological alteration of the regular architecture of the seminiferous tubules of testis as well as an altered expression of factors involved in the junctional complexes of Sertoli cells, responsible for ensuring the morpho-functional integrity of the organ. The expression of key receptors in physiological performance, such as Androgen Receptors and Interstitial Cells Stimulating Hormone receptors, was found lower expressed. All these findings indicate the occurrence of altered physiological organ performance such as the reduction of the spermatozoa number and altered endocrine parameters following hypergravity exposure., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Bonetto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The effects of hypergravity and the associated increased pressure on the human body have not yet been studied in detail, but are of great importance for the safety of astronauts on space missions and could have a long-term impact on rehabilitation strategies for neurological patients. Considering the plans of international space agencies with the exploration of Mars and Moon, it is important to explore the effects of both extremes, weightlessness and hypergravity. During parabolic flights, a flight manoeuvre that artificially creates weightlessness and hypergravity, electrocortical activity as well as behavioural parameters (error rate and reaction time) and neuronal parameters (event-related potentials P300 and N200) were examined with an electroencephalogram. Thirteen participants solved a neurocognitive task (mental arithmetic task as a primary task and oddball paradigm as a secondary task) within normal as well as hypergravity condition in fifteen consecutive parabolas for 22 s each. No changes between the different gravity levels could be observed for the behavioural parameters and cortical current density. A significantly lower P300 amplitude was observed in 1 G, triggered by the primary task and the target sound of the oddball paradigm. The N200, provoked by the sounds of the oddball paradigm, revealed a higher amplitude in 1.8 G. A model established by Kohn et al. (2018) describing changes in neural communication with decreasing gravity can be used here as an explanatory approach. The fluid shift increases the intracranial pressure, decreases membrane viscosity and influences the open state probability of ion channels. This leads to an increase in the resting membrane potential, and the threshold for triggering an action potential can be reached more easily. The question now arises whether the observed changes are linear or whether they depend on a specific threshold., (© 2023. The Author(s).)

INTRODUCTION: Prior study has indicated that individuals of varied age, medical history, and limited-to-no experience tolerate spaceflight conditions. We sought to expand upon the understanding of layperson response to hypergravity conditions expected in commercial spaceflight by exposing subjects, following minimal training, to centrifuge-simulated, high-fidelity commercial spaceflight profiles. We further explored how these individuals perform in simulated operational activities during and following hypergravity. METHODS: Volunteer subjects participated in up to five centrifuge runs (maximum +4.0 G z , +4.5 G x , 6.1 G resultant; onset rate <0.5 G z · s -1 , ≤1 G x · s -1 ). Profiles included two winged spacecraft simulations with sequential and combined +G x /+G z and two capsule simulations representing nominal +G x launch and reentry. The final profile simulated a capsule launch abort, with a more dynamic cycling of +G x exposures and oscillatory multi-axis exposures simulating parachutes and water motion. Touchscreen tablets were used to administer pattern-replication tasks during and after profiles. RESULTS: A total of 46 subjects participated, including 4 diabetics and 9 with cardiac disease. There was increased frequency of motion sickness, subjectively associated with capsule-type profiles, and increased termination of participation compared to prior studies. There was no association between medical history, age, sex, or motion sickness history and tolerance or noncompletion. Tablet test errors were common; accuracy and time to completion were associated with age. There was no association between any time metric or accuracy and sex. DISCUSSION: This study improves understanding of layperson tolerance in commercial spaceflight analog conditions, and the capsular profiles broaden the applicability of the findings. The frequency of task errors highlights the potential for mistakes in operational activities when performed by laypersons. Blue RS, Ong KM, Ray K, Menon A, Mateus J, Auñón-Chancellor S, Shah R, Powers W. Layperson physiological tolerance and operational performance in centrifuge-simulated spaceflight . Aerosp Med Hum Perform. 2023; 94(8):584-595.

The study examined intra- and interlimb variations in cutaneous vessel responsiveness to acute and repeated transmural pressure elevations. In 11 healthy men, red blood cell flux was assessed via laser-Doppler flowmetry on both glabrous and nonglabrous skin regions of an arm (finger and forearm) and leg (toe and lower leg), across a wide range of stepwise increasing distending pressures imposed in the vessels of each limb separately. The pressure-flux cutaneous responses were evaluated before and after 5 wk of intermittent (40 min, 3 sessions per week) exposures to hypergravity (∼2.6-3.3 G; G training). Before and after G training, forearm and lower leg blood flux were relatively stable up to ∼210 and ∼240 mmHg distending pressures, respectively; and then they increased two- to threefold ( P < 0.001). Finger blood flux dropped promptly ( P < 0.001), regardless of the G training ( P = 0.64). At ≤120-mmHg distending pressures, toe blood flux enhanced by ∼40% ( P ≤ 0.05); the increase was augmented after the G training ( P = 0.01). At high distending pressures, toe blood flux dropped by ∼70% in both trials ( P < 0.001). The present results demonstrate that circulatory autoregulation is more pronounced in glabrous skin than in nonglabrous skin, and in nonglabrous sites of the leg than in those of the arm. Repetitive high-sustained gravitoinertial stress does not modify the pressure-flow relationship in the dependent skin vessels of the arm nor in the nonglabrous sites of the lower leg. Yet it may partly inhibit the myogenic responsiveness of the toe's glabrous skin.

INTRODUCTION: With increasing engagement of commercial spaceflight participants in spaceflight activities, the evaluation of individuals with medical conditions not previously characterized in the spaceflight environment is of particular interest. Factors such as acceleration forces experienced during launch, reentry, and landing of spacecraft could pose an altered risk profile in some individuals due to known disease. Bleeding diatheses present a unique concern in the spaceflight environment given hypergravity exposure and, particularly, the potential for injury resulting from transient or impact acceleration. CASE REPORT: A 26-yr-old Caucasian man with severe hemophilia A and no detectable endogenous Factor VIII (FVIII) volunteered for participation in hypergravity exposures simulating spaceflight. His treatment regimen included 50 IU · kg -1 FVIII-Fc fusion protein intravenous administration every 96 h, with supplemental FVIII administration as needed for injury or bleeding. The subject experienced two profiles at the National Aerospace Training and Research Center (NASTAR), with maximum exposure +4.0 G z , +4.5 G x , 6.1 G resultant, and maximum onset rate <0.5 G z · s -1 and +1 G x · s -1 . The subject reported no abnormal events during the profiles other than brief mild vertigo. No petechial hemorrhage, ecchymosis, or other bleeding was noted during or after profiles. Supplemental FVIII was not required before, during, or after exposure. DISCUSSION: Inherited bleeding disorders present several potential concerns that must be evaluated prior to spaceflight participation. Cautious review and management of medical history, adherence and barriers to treatment, duration of spaceflight and longitudinal management concerns, and a thorough and detailed risk/benefit assessment may provide a future pathway for inclusion of individuals with hematological disorders in commercial spaceflight. Reeves IA, Blue RS, Auñon-Chancellor S, Harrison MF, Shah R, Powers WE. Tolerance of centrifuge-simulated commercial spaceflight in a subject with hemophilia A . Aerosp Med Hum Perform. 2023; 94(6):470-474.

Hypothermia has been observed during hypergravity load in mice and rats. This response is beneficial for maintaining blood glucose level, although food intake decreases. However, saving glucose is not enough to maintain blood glucose level during hypergravity load. In this study, we examined the contribution of humoral factors related to glycolysis in maintaining blood glucose level in a 2 G environment. Increased plasma corticosterone levels were observed in mice with intact peripheral vestibular organs, but not in mice with vestibular lesions. Plasma glucagon levels did not change, and decrease in plasma adrenaline levels was observed in mice with intact peripheral vestibular organs. Accordingly, it is possible that increase in plasma corticosterone level and hypothermia contribute to prevent hypoglycemia in a 2 G environment., (© 2022. The Author(s).)

BACKGROUND: Optimal human performance and health is dependent on steady blood supply to the brain. Hypergravity (+G z ) may impair cerebral blood flow (CBF), and several investigators have also reported that microgravity (0 G) may influence cerebral hemodynamics. This has led to concerns for safe performance during acceleration maneuvers in aviation or the impact long-duration spaceflights may have on astronaut health. METHODS: A systematic PEO (Population, Exposure, Outcome) search was done in PubMed and Web of Science, addressing studies on how elevated +G z forces or absence of such may impact cerebral hemodynamics. All primary research containing anatomical or physiological data on relevant intracranial parameters were included. Quality of the evidence was analyzed using the GRADE tool. RESULTS: The search revealed 92 eligible articles. It is evident that impaired CBF during +G z acceleration remains an important challenge in aviation, but there are significant variations in individual tolerance. The reports on cerebral hemodynamics during weightlessness are inconsistent, but published data indicate that adaptation to sustained microgravity is also characterized by significant variations among individuals. DISCUSSION: Despite a high number of publications, the quality of evidence is limited due to observational study design, too few included subjects, and methodological challenges. Clinical consequences of high +G z exposure are well described, but there are significant gaps in knowledge regarding the intracranial pathophysiology and individual hemodynamic tolerance to both hypergravity and microgravity environments. Saehle T. Cerebral hemodynamics during exposure to hypergravity (+G z ) or microgravity (0 G) . Aerosp Med Hum Perform. 2022; 93(7):581-592.

Despite decades of experience from high-gravitoinertial (G) exposures in aircraft and centrifuges, information is scarce regarding primary cardiovascular adaptations to +Gz loads in relaxed humans. Thus, effects of G-training are typically evaluated after regimens that are confounded by concomitant use of anti-G straining maneuvers, anti-G suits, and pressure breathing. Accordingly, the aim was to evaluate cardiovascular adaptations to repeated +Gz exposures in the relaxed state. Eleven men underwent 5 wk of centrifuge G training, consisting of 15 × 40 min +Gz exposures at G levels close to their individual relaxed G-level tolerance. Before and after the training regimen, relaxed G-level tolerance was investigated during rapid onset-rate (ROR) and gradual onset-rate (GOR) G exposures, and cardiovascular responses were investigated during orthostatic provocation and vascular pressure-distension tests. The G training resulted in: 1 ) a 13% increase in relaxed ROR G tolerance ( P < 0.001), but no change in GOR G tolerance, 2 ) increased pressure resistance in the arteries and arterioles of the legs ( P < 0.001), but not the arms, and 3 ) a reduced initial drop in arterial pressure upon ROR high G, but no change in arterial pressure under basal resting conditions or during GOR G loading, or orthostatic provocation. The results suggest +Gz adaptation via enhanced pressure resistance in dependent arteries/arterioles. Presumably, this reflects local adaptations to high transmural pressures, resulting from the +Gz-induced exaggeration of the intravascular hydrostatic pressure gradients.

Microgravity acts on cellular systems on several levels. Cells of the immune system especially react rapidly to changes in gravity. In this study, we performed a correlative metabolomics analysis on short-term and long-term microgravity effects on primary human macrophages. We could detect an increased amino acid concentration after five minutes of altered gravity, that was inverted after 11 days of microgravity. The amino acids that reacted the most to changes in gravity were tightly clustered. The observed effects indicated protein degradation processes in microgravity. Further, glucogenic and ketogenic amino acids were further degraded to Glucose and Ketoleucine. The latter is robustly accumulated in short-term and long-term microgravity but not in hypergravity. We detected highly dynamic and also robust adaptative metabolic changes in altered gravity. Metabolomic studies could contribute significantly to the understanding of gravity-induced integrative effects in human cells.

Using rotors to expose animals to different levels of hypergravity is an efficient means of understanding how altered gravity affects physiological functions, interactions between physiological systems and animal development. Furthermore, rotors can be used to prepare space experiments, e.g., conducting hypergravity experiments to demonstrate the feasibility of a study before its implementation and to complement inflight experiments by comparing the effects of micro- and hypergravity. In this paper, we present a new platform called the Gravitational Experimental Platform for Animal Models (GEPAM), which has been part of European Space Agency (ESA)'s portfolio of ground-based facilities since 2020, to study the effects of altered gravity on aquatic animal models (amphibian embryos/tadpoles) and mice. This platform comprises rotors for hypergravity exposure (three aquatic rotors and one rodent rotor) and models to simulate microgravity (cages for mouse hindlimb unloading and a random positioning machine (RPM)). Four species of amphibians can be used at present. All murine strains can be used and are maintained in a specific pathogen-free area. This platform is surrounded by numerous facilities for sample preparation and analysis using state-of-the-art techniques. Finally, we illustrate how GEPAM can contribute to the understanding of molecular and cellular mechanisms and the identification of countermeasures.

Background Hypergravity may promote human hemostasis thereby increasing thrombotic risk. Future touristic suborbital spaceflight will expose older individuals with chronic medical conditions, who are at much higher thromboembolic risk compared with professional astronauts, to hypergravity. Therefore, we tested the impact of hypergravity on hemostasis in healthy volunteers undergoing centrifugation. Methods and Results We studied 20 healthy seated men before and after 15 minutes under 3 Gz hypergravity on a long-arm centrifuge. We obtained blood samples for hemostasis testing before, immediately after, and 30 minutes after centrifugation. Tests included viscoelastic thromboelastometry, platelet impedance aggregometry, endothelial activation markers, blood rheology testing, microparticle analyses, and clotting factor analysis. Exposure to hypergravity reduced plasma volume by 12.5% ( P =0.002) and increased the red blood cell aggregation index ( P <0.05). With hypergravity, thrombelastographic clotting time of native blood shortened from 719±117 seconds to 628±89 seconds ( P =0.038) and platetet reactivity increased ( P =0.045). Hypergravity shortened partial thromboplastin time from 28 (26-29) seconds to 25 (24-28) seconds ( P <0.001) and increased the activity of coagulation factors (eg, factor VIII 117 [93-134] versus 151 [133-175] %, P <0.001). Tissue factor concentration was 188±95 pg/mL before and 298±136 pg/mL after hypergravity exposure ( P =0.023). Antithrombin ( P =0.005), thrombin-antithrombin complex ( P <0.001), plasmin-alpha2-antiplasmin complex (0.002), tissue-plasminogen activatior ( P <0.001), and plasminogen activator inhibitor-1 ( P =0.002) increased with centrifugation. Statistical adjustment for plasma volume attenuated changes in coagulation. Conclusions Hypergravity triggers low-level hemostasis activation through endothelial cell activation, increased viscoelasticity, and augmented platelet reactivity, albeit partly counteracted through endogenous coagulation inhibitors release. Hemoconcentration may contribute to the response.

We compared voluntary oscillatory sway for eight subjects tested in 1.8- g and 1- g gravito-inertial force (GIF) levels of parabolic flight. Subjects performed voluntary forward-backward (FB) and lateral left-right (LR) swaying as the forces and moments under the soles of each foot were measured. We calculated the experimental values of three parameters: two ankle stiffness parameters K S AP and K S ML acting in orthogonal FB and LR directions and one parameter K ED related to leg pivot shifting. Simulations of the engaged leg model (Bakshi A, DiZio P, Lackner JR. J Neurophysiol 121: 2042-2060, 2019; Bakshi A, DiZio P, Lackner JR. J Neurophysiol 121: 2028-2041, 2019) correctly predicted the experimentally determined stability bounds of upright balance and also the scaling of the postural parameters as a function of GIF magnitude. The effective stiffness, K S AP , at the ankles played the primary role to prevent falling in FB swaying and both model predictions, and experimental data showed K S AP to scale up in proportion to GIF magnitude. For LR swaying, the model predicted a 3:4 scaling of anterior-posterior stiffness to change in GIF magnitude, which was borne out by the experimental data. Simulations predict stability (nonfalling) not to depend on lateral stiffness, K S ML , which was experimentally found not to depend on the GIF magnitude. Both model and experiment showed that the geometry-dependent pivot shift parameter K ED was invariant to a change in GIF magnitude. Thus the ELM explains voluntary sway and balance in altered GIF magnitude conditions, rotating environments with Coriolis perturbations of sway, as well as normal terrestrial conditions. NEW & NOTEWORTHY A nonparallel leg model of balance, the engaged leg model (ELM), was previously developed to characterize adaptive balance control in a rotating environment. Here we show the ELM also explains sway in hypergravity. It predicts the changes in balance control parameters with changes in gravity. ELM is currently the only balance model applicable to artificial and hypergravity conditions. ELM can also be applied to terrestrial clinical situations for pathologies that generate postural asymmetries.

Gravity in the head-to-toe direction, known as +Gz (G force), forces blood to pool in the lower body. Fighter pilots experience decreases in blood pressure when exposed to hypergravity in flight. Human centrifuge has been used to examine the G tolerance and anti-G straining maneuver (AGSM) techniques of military pilots. Some factors that may affect G tolerance have been reported but are still debated. The aim of this study was to investigate the physiological responses and anthropometric factors correlated with G tolerance. We retrospectively reviewed the training records of student pilots who underwent high G training. Variables were collected to examine their correlations with the outcome of 7.5G sustained for 15 s (7.5G profile). There were 873 trainees who underwent 7.5G profile training, 44 trainees (5.04%) could not sustain the test for 15 s. The group with a small heart rate (HR) increase (less than 10%) during the first 1-5 s of the 7.5G profile had a nearly ten-fold higher failing chance compared with the large HR increase group (adjusted odds ratio: 9.91; 95% confidence interval: 4.11-23.88). The chances of failure were inversely related to the HR increase percentage ( p for trend <0.001). Factors, including body mass index, relaxed and straining G tolerance, and AGSM, were found to be negatively correlated with the outcome.

The gravity is necessary for living organisms to operate various biological events including hippocampus-related functions of learning and memory. Until now, it remains inconclusive how altered gravity is associated with hippocampal functions. It is mainly due to the difficulties in generating an animal model experiencing altered gravity. Here, we demonstrate the effects of hypergravity on hippocampus-related functions using an animal behavior and electrophysiology with our hypergravity animal model. The hypergravity (4G, 4 weeks) group showed impaired synaptic efficacy and long-term potentiation in CA1 neurons of the hippocampus along with the poor performance of a novel object recognition task. Our studies suggest that altered gravity affects hippocampus-related cognitive functions, presumably through structural and functional adaptation to various conditions of gravity shift.

Background: we aimed at investigating the influence of weightlessness and hypergravity by means of parabolic flight on the levels of the heart failure biomarkers H-FABP, sST2, IL-33, GDF-15, suPAR and Fetuin-A., Methods: 14 healthy volunteers (males: eight; mean age: 28.9) undergoing 31 short-term phases of weightlessness and hypergravity were included. At different time points (baseline, 1 h/24 h after parabolic flight), venous blood was drawn and analyzed by the use of ELISA., Results: sST2 evidenced a significant decrease 24 h after parabolic flight (baseline vs. 24, p = 0.009; 1 h vs. 24 h, p = 0.004). A similar finding was observed for GDF-15 (baseline vs. 24 h, p = 0.002; 1 h vs. 24 h, p = 0.025). The suPAR showed a significant decrease 24 h after parabolic flight (baseline vs. 24 h, p = 0.1726; 1 h vs. 24 h, p = 0.009). Fetuin-A showed a significant increase at 1 h and 24 h after parabolic flight (baseline vs. 24 h, p = 0.007; 1 h vs. 24 h, p = 0.04). H-FABP and IL-33 showed no significant differences at all time points., Conclusion: Our results suggest a reduction in cardiac stress induced by exposure to gravitational changes. Moreover, our findings indicate an influence of gravitational changes on proliferative processes and calcium homeostasis.

Extended travel in deep space poses potential hazards to the reproductive function of female and male astronauts, including exposure to cosmic radiation, microgravity, increased gravity (hypergravity), psychological stress, physical stress and circadian rhythm disruptions. This Review focuses on the effects of microgravity, hypergravity and cosmic radiation. Cosmic radiation contains protons, helium nuclei and high charge and energy (HZE) particles. Studies performed on Earth in which rodents were exposed to experimentally generated HZE particles have demonstrated a high sensitivity of ovarian follicles and spermatogenic cells to HZE particles. Exposure to microgravity during space flight and to simulated microgravity on Earth disrupts spermatogenesis and testicular testosterone synthesis in rodents, whereas the male reproductive system seems to adapt to exposure to moderate hypergravity. A few studies have investigated the effects of microgravity on female reproduction, with findings of disrupted oestrous cycling and in vitro follicle development being cause for concern. Many remaining data gaps need to be addressed, including the effects of microgravity, hypergravity and space radiation on the male and female reproductive tracts, hypothalamic-pituitary regulation of reproduction and prenatal development of the reproductive system as well as the combined effects of the multiple reproductive hazards encountered in space.

The overall objective of this study was to test the hypothesis that +Gz (hypergravity/positive acceleration) and microgravity can both aggravate intervertebral disc degeneration (IVDD). Due to +Gz and microgravity, many pilots develop IVDD. However, the lack of animal models of IVDD under conditions of simulated +Gz and microgravity has hampered research on the onset and prevention of IVDD. Rabbits were randomly allotted to a control group, microgravity group, +Gz group, or mixed (+Gz + microgravity) group. A tail-suspension model was utilized to simulate a microgravity environment and an animal centrifuge to mimic +Gz conditions. After exposure to the above conditions for 4, 8, and 24 weeks, the body weights (BW) of animals in the control group gradually increased over time, while those of animals in the microgravity and mixed groups both decreased (p < 0.001). As compared with the control group, the proteoglycan content of animals in the other three groups was significantly reduced (F = 192.83, p < 0.001). The imageological, histopathological, and immunohistochemical changes to the L6-S1 intervertebral disc samples suggests that the effects of +Gz and microgravity can aggravate IVDD over time. The mixed effects of +Gz and microgravity had the greatest effect on degeneration and +Gz had a particularly greater effect than microgravity.

INTRODUCTION: Exposure to high G force is a known safety hazard in military aviation as well as civilian aerobatic flight. Tolerance to high G forces has been well studied in military pilots, but there is little research directed at civilian pilots who may have medications or medical conditions not permitted in military pilots. METHODS: In this case-control study, we identified 89 fatal high-G aerobatic accidents and 4000 fatal control accidents from 1995 through 2018 from the NTSB accident database and the FAA autopsy database. We retrieved medications and medical conditions from the FAA's pilot medical databases. Logistic regression models were used to explore the associations of drugs, medical conditions, height, and medical waivers with high-G accidents. RESULTS: Seven drugs (alprazolam, clonidine, ethanol, meclizine, phentermine, triamterene, and zolpidem) reached statistical significance in our models, but had such small case counts that we consider these findings to be uncertain, except for ethanol, which was found in seven cases. Of these, only triamterene was known to the FAA. Statistically significant medical predictors included only alcohol abuse (seven cases) and liver disease (only two cases). DISCUSSION: Our analysis found that the drug ethanol and the condition alcohol abuse are significantly associated with high-G accidents. Seven other factors were statistically significant, but should only be considered as hypothesis generating due to very low case counts. Our study does not suggest that restricting pilots with otherwise permissible medications or medical conditions from aerobatics is warranted. Mills WD, Greenhaw RM, Wang JMP. A medical review of fatal high-G U.S. aerobatic accidents . Aerosp Med Hum Perform. 2019; 90(11):959-965.

BACKGROUND: UK Royal Air Force fast jet aircrew use three different anti-G systems, however, little objective comparison of the G protection they provide exists. The G-protection afforded by each system and associated hemodynamic responses were investigated. METHODS: Ten subjects performed centrifuge acceleration exposures using Mk-10 (S1) and Mk-4 (S2) five-bladder anti-G trousers (AGT) and full coverage AGT plus pressure breathing for G-protection (PBG; S3). Measurements of relaxed G tolerance (RGT), eye-level blood pressure (BP eye ), lower body blood volume (LBV), stroke volume (SV) and total peripheral resistance (TPR) were made during gradual onset runs (GOR) and rapid onset runs (ROR). The subjective effort required to maintain clear vision at +7 and +8 G z provided an indication of the protection provided by the system. RESULTS: All systems moderated decreases in SV and BP eye and increases in LBV under increased +G z . S3 provided the greatest mean RGT during GOR (+6.2 G z ) and ROR (+6 G z ), reduced the effort required to maintain clear vision at up to +8 G z , prevented venous pooling and afforded the greatest rise in TPR. The majority of indices revealed no difference between S1 and S2 although RGT during the ROR was greater with S2 (+0.25 G z ). DISCUSSION: S3 effectively prevented pooling of blood in the lower limbs under +G z , despite the use of PBG, and offers an advantage over five-bladder AGT. Given the similarities of S1 and S2, it was unsurprising that the majority of indices measured were similar. The objective measurement of hemodynamic parameters provides useful information for comparing the G-protection provided by anti-G systems. Pollock RD, Firth RV, Storey JA, Phillips KE, Connolly DM, Green NDC, Stevenson AT. Hemodynamic responses and G protection afforded by three different anti-G systems. Aerosp Med Hum Perform. 2019; 90(11):925-933.

INTRODUCTION: Physical conditioning may improve aircrew performance during exposure to high +G z acceleration, although few studies have directly assessed this. The present study investigated the effects of a 12-wk Aircrew Conditioning Programme (ACP) on markers of G tolerance. The ACP comprises aerobic and muscle strengthening exercise performed twice weekly and targets improved fitness and reduced injury risk. METHODS: There were 36 UK Royal Air Force and Royal Navy aircrew who volunteered; 17 performed the ACP (Ex) and 19 acted as a control group (Con). Centrifuge testing was performed before and after the intervention. Relaxed G tolerance (RGT) and straining G tolerance (SGT), which had the addition of muscle tensing, were assessed. G endurance was also determined via repeated simulated air combat maneuvers (SACMs). During these centrifuge runs a number of physiological variables were recorded. RESULTS: During the G profile to determine RGT, neither RGT, HR, nor blood pressure responses were affected by the ACP. During SGT profiles, a lower HR at a given +G z (+5.5 G z ) level following the ACP was observed (Ex: pre 146.0 ± 4.4, post 136.9 ± 5.6 bpm; Con: pre 148.0 ± 3.2, post 153.1 ± 3.3 bpm). BP was maintained and there was a tendency toward an improved SGT. The ACP increased the proportion of individuals completing the number of SACM profiles, although no meaningful differences were found between groups in other variables. CONCLUSION: Overall the ACP has no negative effect on RGT, reduced the physiological strain associated with a given level of +G z (during SGT), and tended to improve the ability to tolerate repeated G z exposure. Slungaard E, Pollock RD, Stevenson AT, Green NDC, Newham DJ, Harridge SDR. Aircrew conditioning programme impact on +Gz tolerance . Aerosp Med Hum Perform. 2019; 90(9):764-773.

Gravitational stress in general and microgravity (µg) in particular are regarded as major stress factors responsible for immune system dysfunction in space. To assess the effects of alternating µg and hypergravity (hyper-g) on immune cells, the attachment of peripheral blood mononuclear cells (PBMCs) to adhesion molecules under flow conditions and the antigen-induced immune activation in whole blood were investigated in parabolic flight (PF). In contrast to hyper-g (1.8 g) and control conditions (1 g), flow and rolling speed of PBMCs were moderately accelerated during µg-periods which were accompanied by a clear reduction in rolling rate. Whole blood analyses revealed a "primed" state of monocytes after PF with potentiated antigen-induced pro-inflammatory cytokine responses. At the same time, concentrations of anti-inflammatory cytokines were increased and monocytes displayed a surface molecule pattern that indicated immunosuppression. The results suggest an immunologic counterbalance to avoid disproportionate immune responses. Understanding the interrelation of immune system impairing and enhancing effects under different gravitational conditions may support the design of countermeasures to mitigate immune deficiencies in space.

INTRODUCTION: Changes in gravity or body position provoke changes in hydrostatic pressure in the arterial system and in venous return. Potential asymmetries between left (Q LV ) and right ventricular (Q RV ) cardiac output during transient gravity changes were investigated. It was hypothesized that blood volume is temporarily stored in the pulmonary vessels, with amount and duration depending on the level and directions of gravity. METHODS: Eight healthy, male subjects (32 ± 3 yr, 182 ± 7 cm, 82 ± 6 kg) were tested on a tilt seat (TS), in a long arm human centrifuge (laHC), and during parabolic flights (PF). The gravitational changes during PF were reconstructed by changing gravity in a laHC and different body positions on a TS. All participants were tested in the seated, resting position. Heart rate and blood pressure were recorded continuously and Q LV was calculated, applying the Modelflow Algorithm. Gas exchange was measured breath-by-breath. Q RV was calculated from these data according to the Fick Principle. Four sequences were superimposed and analyzed by ANOVA with the factors Time, Ventricle (Q RV , Q LV ), and Mode (TS, PF, laHC). RESULTS: After reductions in gravity Q RV and Q LV were transiently desynchronized. ANOVA showed no main effect for Mode, but significant changes were found for Time and Ventricle and all interactions. DISCUSSION: Phases of reduced gravity seem to lead to transiently increased storage of blood volume inside the pulmonary vascular system. A more detailed understanding of these mechanisms might help to describe the compliance of the pulmonary vascular system in diseases of the pulmonary circulation. Hoffmann U, Koschate J, Appell Coriolano H-J, Drescher U, Thieschäfer L, Dumitrescu D, Werner A. Adaptation of systemic and pulmonary circulation to acute changes in gravity and body position . Aerosp Med Hum Perform. 2019; 90(8):688-695.

The control of bipedal stance and the capacity to regain postural equilibrium after its deterioration in variable gravities are crucial prerequisites for manned space missions. With an emphasize on natural orthograde posture, computational techniques synthesize muscle activation patterns of high complexity to a simple synergy organization. We used nonnegative matrix factorization to identify muscle synergies during postural recovery responses in human and to examine the functional significance of such synergies for hyper-gravity (1.75 g) and hypo-gravity (0.25 g). Electromyographic data were recorded from leg, trunk and arm muscles of five human exposed to five modes of anterior and posterior support surface translations during parabolic flights including transitional g-levels of 0.25, 1 and 1.75 g. Results showed that in 1 g four synergies accounted for 99% of the automatic postural response across all muscles and perturbation directions. Each synergy in 1 g was correlated to the corresponding one in 0.25 and 1.75 g. This study therefore emphasizes the similarity of the synergy organization of postural recovery responses in Earth, hypo- and hyper-gravity conditions, indicating that the muscle synergies and segmental strategies acquired under terrestrial habits are robust and persistent across variable and acute changes in gravity levels.

INTRODUCTION: High-gravity (G) training is used to educate trainee pilots about anti-G straining maneuvers (AGSM) in an environment similar to that of a real fighter aircraft, and to enhance their G tolerance. The success or failure of high-G training could be multifactorial, but most previous studies have only focused on the effect of pilots' physical condition. METHODS: A total of 138 male trainee pilots participated in this study. All trainee pilots had received AGSM training from experienced instructors and then underwent centrifuge high-G training. Participants completed questionnaire surveys about body size, lifestyle, self-reported AGSM proficiency, resilience (Connor-Davidson Resilience Scale, CD-RISC), and depression level (Center for Epidemiologic Studies Depression Scale, CES-D). RESULTS: Of the 138 subjects, 100 (72.5%) successfully completed high-G training without experiencing G-induced loss of consciousness (G-LOC) within two trials; these were allocated to the success group. The remaining 38 (27.5%) subjects who completed the training after three or more attempts, or who failed to complete the training at all, were allocated to the failure group. Multivariate analyses revealed that the success of centrifuge training was positively associated with age and self-reported AGSM proficiency, and negatively associated with depression level. DISCUSSION: The success of high-G training was significantly associated with self-reported AGSM proficiency and depression level. Instructors should emphasize the importance of AGSM proficiency and offer practice-based learning to trainee pilots. In addition, they should pay attention to not only trainee pilots' physical condition, but also their psychological status. Yun C, Oh S, Shin YH. AGSM proficiency and depression are associated with success of high-G training in trainee pilots. Aerosp Med Hum Perform. 2019; 90(7):613-617.

Functional studies of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hCMs) under different gravity conditions contribute to aerospace medical research. To study the effects of altered gravity on hCMs, we exposed them to acute hypergravity and microgravity phases in the presence and absence of the β-adrenoceptor isoprenalin (ISO), L-type Ca 2+ channel (LTCC) agonist Bay-K8644, or LTCC blocker nifedipine, and monitored their beating rate (BR). These logistically demanding experiments were executed during the 66th Parabolic Flight Campaign of the European Space Agency. The hCM cultures were exposed to 31 alternating hypergravity, microgravity, and hypergravity phases, each lasting 20-22 s. During the parabolic flight experiment, BR and cell viability were monitored using the xCELLigence real-time cell analyzer Cardio Instrument ® . Corresponding experiments were performed on the ground (1 g ), using an identical set-up. Our results showed that BR continuously increased during the parabolic flight, reaching a 40% maximal increase after 15 parabolas, compared with the pre-parabolic (1 g ) phase. However, in the presence of the LTCC blocker nifedipine, no change in BR was observed, even after 31 parabolas. We surmise that the parabola-mediated increase in BR was induced by the LTCC blocker. Moreover, the increase in BR induced by ISO and Bay-K8644 during the pre-parabola phase was further elevated by 20% after 25 parabolas. This additional effect reflects the positive impact of the parabolas in the absence of both agonists. Our study suggests that acute alterations of gravity significantly increase the BR of hCMs via the LTCC.

Background: Exposure to high sustained +Gz (head-to-foot inertial load) is known to have harmful effects on pilots' body in flight. Although clinical data have shown that liver dysfunction occurs in pilots, the precise cause has not been well defined., Aim: To investigate rat liver function changes in response to repeated +Gz exposure., Methods: Ninety male Wistar rats were randomly divided into a blank control group (BC group, n = 30), a +6 Gz/5 min stress group (6GS group, n = 30), and a +10 Gz/5min stress group (10GS group, n = 30). The 6GS and 10GS groups were exposed to +6 Gz and +10 Gz, respectively, in an animal centrifuge. The onset rate of +Gz was 0.5 G/s. The sustained time at peak +Gz was 5 min for each exposure (for 5 exposures, and 5-min intervals between exposures for a total exposure and non-exposure time of 50 min). We assessed liver injury by measuring the portal venous flow volume, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), liver tissue malondialdehyde (MDA), Na + -K + -ATPase, and changes in liver histology. These parameters were recorded at 0 h, 6 h, and 24 h after repeated +Gz exposures., Results: After repeated +Gz exposures in the 6GS and the 10GS groups, the velocity and flow signal in the portal vein (PV) were significantly decreased as compared to the BC group at 0 h after exposure. Meanwhile, we found that the PV diameter did not change significantly. However, rats in the 6GS group had a much higher portal venous flow volume than the 10GS group at 0 h after exposure. The 6GS group had significantly lower ALT, AST, and MDA values than the 10GS group 0 h and 6 h post exposure. The Na + -K + -ATPase activity in the 6GS group was significantly higher than that in the 10GS group 0 h and 6 h post exposure. Hepatocyte injury, determined pathologically, was significantly lower in the 6GS group than in the 10GS group., Conclusion: Repeated +Gz exposures transiently cause hepatocyte injury and affect liver metabolism and morphological structure., Competing Interests: Conflict-of-interest statement: The authors declare that there are no conflicts of interest to disclose.

Gravitational stress occurs during space flights or certain physical activities including extreme sports, where the change in experienced gravitational acceleration can reach large magnitudes. These changes include reduction and increase in the physical forces experienced by the body and may potentially induce pathogenic alterations of physiological processes. The immune system is known to regulate most functions in the human organism and previous studies suggest an impairment of the immune function under gravitational stress. However, systematic studies aiming to investigate the effect of gravitational stress on cellular immune response in humans are lacking. Since parabolic flights are considered as feasible model to investigate a short-term impact of gravitational changes, we evaluated the influence of gravitational stress on the immune system by analyzing leukocyte numbers before and after parabolic flight maneuvers in human blood. To correct for circadian effects, samples were taken at the corresponding time points on ground the day before the flight. The parabolic flight maneuvers led to changes in numbers of different leukocyte subsets. Naïve and memory T and B cell subsets decreased under gravitational stress and lower numbers of basophils and eosinophils were observed. Only circulating neutrophils increased during the parabolic flight. The observed changes could not be attributed to stress-induced cortisol effects, since cortisol levels were not affected. Our data demonstrate that the gravitational stress by parabolic flights can affect all parts of the human immune system. Consequently, it is possible that gravitational stress can have clinically relevant impacts on the control of immune responses., Competing Interests: Authors MK, AP, JV are employees of Beckman Coulter GmbH. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors have no further competing interests to declare.

Globally, approximately a billion patients are estimated to suffer from neurological disorders. Although there are many therapeutic candidates for the central nervous system, treatment of brain disorders is restricted by the blood-brain barrier (BBB), which is a highly selective membrane that protects the brain from exogenous substances. This study was undertaken to develop a novel strategy to overcome the BBB and improve the efficiency of drug delivery to the brain by mechanical load increase using hypergravity. Human cerebral microvascular endothelial cells were exposed three times to 20 min hypergravity (10g), with a 20-min rest period between each exposure. The applied hypergravity reversibly decreased the cellular metabolic activity and increased the permeation rate of fluorescein sodium salt, fluorescein isothiocyanate-labeled dextran (FD-4), and fluorescein-labeled jacalin. Following the exposure to hypergravity, we also observed structural changes of the cytoskeleton and tight junctions, and an alteration in the expression levels of related genes. These results indicate that increased mechanical load due to the applied hypergravity affects the cytoskeletal arrangement and tight junctions, thereby weakening the cell barrier function and enhancing the permeability of the paracellular pathway. Thus, the mechanical load increase by hypergravity has the potential of being used as a novel strategy to overcome the BBB for brain drug delivery., (© 2018 Wiley Periodicals, Inc.)

Background: +Gz tolerance is traditionally determined in centrifuges with open-loop G control, i.e., the centrifuge is under operator control (open loop), and thus the test subject is unable to influence the Gz load. In modern centrifuges, however, the subject is commonly able to continuously control the Gz load (closed loop). It is a widespread opinion among fighter pilots that +Gz tolerance is higher under closed- than open-loop G control. The aims were to investigate whether +Gz tolerance is higher in closed- than open-loop G control, and whether it is possible to use closed-loop G control during precise determination of +Gz tolerance., Methods: Relaxed +Gz tolerance was determined in eight men during rapid Gz-onset rate (ROR) under three conditions: 1) OL-VFB, open loop with visual feedback; 2) OL-NFB, open loop with no visual feedback; and 3) CL, closed loop. Straining +Gz tolerance was determined in 10 men during ROR in OL and CL conditions., Results: Relaxed +Gz tolerance did not differ between CL (3.66 Gz), OL-VFB (3.70 Gz) and OL-NFB (3.64 Gz). Straining +Gz tolerance was similar in the CL (8.5 Gz) and OL (8.6 Gz) conditions. In the CL condition, the Gz load varied substantially and was on average lower than in the OL conditions, at any stipulated G-time profile., Discussion: There is no systematic difference in relaxed or straining +Gz tolerance as determined in closed- vs. open-loop G-controlled systems. During closed-loop control, precision and reproducibility are too low to recommend it for accurate determination of relaxed G tolerance.Grönkvist M, Levin B, Eiken O. G tolerance during open- vs. closed-loop G-time control. Aerosp Med Hum Perform. 2018; 89(9):798-804.

One of the most important laboratory animal species is the nematode Caenorhabditis elegans, which has been used in a range of research fields such as neurobiology, body development, and molecular biology. The scientific progress obtained by employing C. elegans as a model in these areas has encouraged its use in new fields. One of the new potential applications concerns the biological responses to hyperacceleration stress (g-force), but only a few studies have evaluated the response of multicellular organisms to extreme hypergravity conditions at the order of magnitude 10 5  x g, which is the theorized force experienced by rocks ejected from Mars (or similar planets). Therefore, we subjected the nematode C. elegans to 400,000 x g (equivalent to that force) and evaluated viability, general morphology, and behavior of C. elegans after exposure to this stress. The metabolic activity of this nematode in response to the gravitational spectrum of 50-400,000 x g was also evaluated by means of the MTT assay. Surprisingly, we found that this organism showed no decrease in viability, no changes in behavior and development, and no drastic metabolic depression after hyperacceleration. Thus, we demonstrated for the first time that this multicellular research model can withstand extremely high g-forces, which prompts the use of C. elegans as a new model for extreme hypergravity. Key Words: Caenorhabditis elegans-Hypergravity-Ultracentrifugation-Acceleration-Panspermia-Astrobiology. Astrobiology 18, 825-833.

The effects of hypergravity on the gene expression of the hypothalamic feeding-related neuropeptides in sham-operated (Sham) and vestibular-lesioned (VL) mice were examined by in situ hybridization histochemistry. Corticotrophin-releasing hormone (CRH) in the paraventricular nucleus was increased significantly in Sham but not in VL mice after 3 days of exposure to a 2 g environment compared with a 1 g environment. Significant decreases in pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript and significant increases in neuropeptide Y, agouti-related protein in the arcuate nucleus and orexin in the lateral hypothalamic area were observed in both Sham and VL mice. After 2 weeks of exposure, CRH and POMC were increased significantly in Sham but not in VL mice. After 8 weeks of exposure, the hypothalamic feeding-related neuropeptides were comparable between Sham and VL mice. These results suggest that the hypothalamic feeding-related neuropeptides may be affected during the exposed duration of hypergravity via vestibular inputs., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Embryonic developmental studies under microgravity conditions in space are very limited. To study the effects of short-term altered gravity on embryonic development processes, we exposed mouse embryonic stem cells (mESCs) to phases of hypergravity and microgravity and studied the differentiation potential of the cells using wide-genome microarray analysis. During the 64th European Space Agency's parabolic flight campaign, mESCs were exposed to 31 parabolas. Each parabola comprised phases lasting 22 s of hypergravity, microgravity, and a repeat of hypergravity. On different parabolas, RNA was isolated for microarray analysis. After exposure to 31 parabolas, mESCs (P31 mESCs) were further differentiated under normal gravity (1 g) conditions for 12 days, producing P31 12-day embryoid bodies (EBs). After analysis of the microarrays, the differentially expressed genes were analyzed using different bioinformatic tools to identify developmental and nondevelopmental biological processes affected by conditions on the parabolic flight experiment. Our results demonstrated that several genes belonging to GOs associated with cell cycle and proliferation were downregulated in undifferentiated mESCs exposed to gravity changes. However, several genes belonging to developmental processes, such as vasculature development, kidney development, skin development, and to the TGF-β signaling pathway, were upregulated. Interestingly, similar enriched and suppressed GOs were obtained in P31 12-day EBs compared with ground control 12-day EBs. Our results show that undifferentiated mESCs exposed to alternate hypergravity and microgravity phases expressed several genes associated with developmental/differentiation and cell cycle processes, suggesting a transition from the undifferentiated pluripotent to a more differentiated stage of mESCs.

Introduction: The purpose of this study was to analyze posterior-to-anterior spinal stiffness in Earth, hyper-, and microgravity conditions during both prone and upright postures., Case Report: During parabolic flight, the spinal stiffness of the L3 vertebra of a healthy 37-yr-old man was measured in normal Earth gravity (1.0 g), hypergravity (1.8 g), and microgravity (0.0 g) conditions induced in the prone and upright positions. Differences in spinal stiffness were significant across all three gravity conditions in the prone and upright positions. Most effect sizes were large; however, in the upright posture, the effect size between Earth gravity and microgravity was medium. Significant differences in spinal stiffness between the prone and upright positions were found during Earth gravity and hypergravity conditions. No difference was found between the two postures during microgravity conditions., Discussion: Based on repeated measurements of a single individual, our results showed detectable changes in posterior-to-anterior spinal stiffness. Spinal stiffness increased during microgravity and decreased during hypergravity conditions. In microgravity conditions, posture did not impact spinal stiffness. More data on spinal stiffness in variable gravitational conditions is needed to confirm these results.Swanenburg J, Meier ML, Langenfeld A, Schweinhardt P, Humphreys BK. Spinal stiffness in prone and upright postures during 0-1.8 g induced by parabolic flight. Aerosp Med Hum Perform. 2018; 89(6):563-567.

Background: The present study aimed to find out if possible differences in early military flight career +Gz exposure level could predict permanent flight duty limitations (FDL) due to spinal disorders during a pilot's career., Methods: The study population consisted of 23 pilots flying with Gz limitation (max limitation ranging from +2 Gz to +5 Gz) due to spinal disorders and 50 experienced (+1000 flight hours) symptomless controls flying actively in operative missions in the Finnish Air Force. Data obtained for all subjects included the level of cumulative Gz exposure measured sortie by sortie with fatigue index (FI) recordings and flight hours during the first 5 yr of the pilot's career., Results: The mean (± SD) accumulation of FI in the first 5 yr of flying high-performance aircraft was 8.0 ± 1.8 among the pilots in the FDL group and 7.7 ± 1.7 in the non-FDL group. There was no association between flight duty limitations and early career cumulative +Gz exposure level measured with FI or flight hours., Discussion: According to the present findings, it seems that the amount of cumulative +Gz exposure during the first 5 yr of a military pilot's career is not an individual risk factor for spinal disorders leading to flight duty limitation. Future studies conducted with FI recordings should be addressed to reveal the relationship between the actual level of +Gz exposure and spinal disorders, with a longer follow-up period and larger sample sizes.Honkanen T, Sovelius R, Mäntysaari M, Kyröläinen H, Avela J, Leino TK. +Gz exposure and spinal injury-induced flight duty limitations. Aerosp Med Hum Perform. 2018; 89(6):552-556.

Introduction: The rate of intervertebral disc degeneration (IVDD) is influenced by environmental factors. Extracellular matrix (ECM) destruction and apoptosis of intervertebral disc cells are major characteristics of IVDD. ECM degradation is closely linked to up-regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMP). This study aimed to elucidate the molecular biological changes during IVDD under conditions of weightlessness and hypergravity., Methods: A total of 120 rabbits were divided randomly into four groups: control group, weightlessness group, hypergravity group, and mixed (hypergravity + weightlessness) group. Tail-suspension was used to simulate a weightless environment, and an animal centrifuge (+7 Gz three times for 60 s) was used to mimic hypergravity conditions. After exposure to the above conditions for 30, 60, and 90 d, respectively, 10 rabbits were selected from each group for immunohistochemical determination of MMP-1, MMP-3, and TIMP-1 expression. TUNEL staining was also carried out to detect apoptotic cells in each group at each time point., Results: MMP-1, MMP-3, and TIMP-1 were rarely expressed in the control group, but were positively expressed in the other three groups. The strongest expression was in the mixed group at every time point, followed by the hypergravity group, and then the weightlessness group. Cell apoptosis index followed a similar trend to MMPs and TIMP-1 expression., Discussion: The results suggested that weightlessness and hypergravity may both aggravate IVDD over time, with hypergravity having a particularly marked effect.Wu D, Zheng C, Wu J, Huang R, Chen X, Zhang T, Zhang L. Molecular biological effects of weightlessness and hypergravity on intervertebral disc degeneration. Aerosp Med Hum Perform. 2017; 88(12):1123-1128.

The inner ears of all vertebrates are designed to perceive auditory and vestibular inputs. Although a tremendous diversity in the inner ear can be found even among bony fishes, the morphologies of the utricle and of the semicircular canals are rather conservative among vertebrates. Fish show kinetoses under reduced gravity (spinning movements and looping responses) and are regarded model organisms concerning the performance of the otolithic organs. Otoliths can be analysed easily because they are compact, in contrast to the otoconial masses of other vertebrates. Here, late-larval Oreochromis mossambicus were subjected to 0.0001 × g and 0.04 × g aboard a sounding rocket, their behaviour was observed and morphometrical analyses on otoliths were carried out. Fish swimming kinetotically at 0.0001 × g had a higher asymmetry of utricular otoliths (gravity perception) but not of saccular otoliths (hearing process) than specimens behaving normally at this gravity level (p = 0.0055). Also, asymmetries of lapilli in animals swimming normally at 0.0001 × g were lower than asymmetries in specimens swimming normally at 0.04 × g (p = 0.06). This supports the "otolith asymmetry hypothesis", an explanation for the susceptibility to kinetosis, particularly concerning the utricular otoliths. It would be interesting to identify processes generating asymmetric otoliths, also in regard to human motion sickness.

Background: G-induced loss of consciousness (G-LOC) is mainly caused by failure to sustain an oxygenated blood supply to the pilot's brain because of the sudden acceleration in the direction of the +Gz axis, and is considered a critical safety issue. The purpose of this study was to develop G-LOC warning algorithms based on monitoring electromyograms (EMG) of the gastrocnemius muscle on the calf., Methods: EMG data was retrieved from a total of 67 pilots and pilot trainees of the Korean Air Force during high-G training on a human centrifugal simulator. Seven EMG features were obtained from root mean square (RMS), integrated absolute value (IAV), and mean absolute value (MAV) for muscle contraction, slope sign changes (SSC), waveform length (WL), zero crossing (ZC), and median frequency (MF) for muscle contraction and fatigue., Results: Out of seven EMG features, IAV and WL showed a rapid decay before G-LOC. Based on these findings, this study developed two algorithms which can detect G-LOC during flight and provide warning signals to the pilots. The probability of G-LOC occurrence was detected through monitoring the decay trend for representing muscle endurance and climb rate of the IAV and WL value during sudden acceleration above 6 G, representing muscle power. The sensitivity of the algorithms using IAV and WL features was 100% and the specificity was 66.7%., Discussion: This study suggests that a G-LOC detecting and warning system may be a customized, real-time countermeasure by improving the accuracy of detecting G-LOC.Kim S, Cho T, Lee Y, Koo H, Choi B, Kim D. G-LOC warning algorithms based on EMG features of the gastrocnemius muscle. Aerosp Med Hum Perform. 2017; 88(8):737-742.

Introduction: Hypergravitational exposures during human centrifugation are known to provoke dysrhythmias, including sinus dysrhythmias/tachycardias, premature atrial/ventricular contractions, and even atrial fibrillations or flutter patterns. However, events are generally short-lived and resolve rapidly after cessation of acceleration. This case report describes a prolonged ectopic ventricular rhythm in response to high G exposure., Case Report: A previously healthy 30-yr-old man voluntarily participated in centrifuge trials as a part of a larger study, experiencing a total of 7 centrifuge runs over 48 h. Day 1 consisted of two +Gz runs (peak +3.5 Gz, run 2) and two +Gx runs (peak +6.0 Gx, run 4). Day 2 consisted of three runs approximating suborbital spaceflight profiles (combined +Gx and +Gz). Hemodynamic data collected included blood pressure, heart rate, and continuous three-lead electrocardiogram. Following the final acceleration exposure of the last Day 2 run (peak +4.5 Gx and +4.0 Gz combined, resultant +6.0 G), during a period of idle resting centrifuge activity (resultant vector +1.4 G), the subject demonstrated a marked change in his three-lead electrocardiogram from normal sinus rhythm to a wide-complex ectopic ventricular rhythm at a rate of 91-95 bpm, consistent with an accelerated idioventricular rhythm (AIVR). This rhythm was sustained for 2 m, 24 s before reversion to normal sinus. The subject reported no adverse symptoms during this time., Discussion: While prolonged, the dysrhythmia was asymptomatic and self-limited. AIVR is likely a physiological response to acceleration and can be managed conservatively. Vigilance is needed to ensure that AIVR is correctly distinguished from other, malignant rhythms to avoid inappropriate treatment and negative operational impacts.Suresh R, Blue RS, Mathers C, Castleberry TL, Vanderploeg JM. Sustained accelerated idioventricular rhythm in a centrifuge-simulated suborbital spaceflight. Aerosp Med Hum Perform. 2017; 88(8):789-793.

Introduction: Exposure to sustained +Gz acceleration with inadequate G protection can result in G-induced loss of consciousness (G-LOC) or almost loss of consciousness (A-LOC). The UK Royal Air Force (RAF) last conducted a survey of G-LOC within their military aircrew in 2005 with interventions subsequently introduced. The aim of this study was to repeat the 2005 survey in order to evaluate the impact of those interventions., Methods: An anonymous questionnaire requesting details of G-LOC and A-LOC events was mailed to all RAF pilots (N = 1878) and weapons systems operators (WSOs) (N = 473), irrespective of aircraft currently flown., Results: The questionnaire was returned by 809 aircrew (34.4% response rate). There were 120 (14.8%) aircrew who reported at least one episode of G-LOC and 260 (32.2%) reported at least one episode of A-LOC. The reported prevalence of G-LOC in the previous 2005 survey was 20.1% (N = 454). There was an increased reporting of G-LOC in the Hawk, Tucano, and Grob Tutor aircraft, with 5 G-LOC and 19 A-LOC events reported in the Grob Tutor compared to none in 2005., Discussion: The prevalence of reported G-LOC has decreased in the surveyed populations, which may be due to the introduction of centrifuge training, but also may be influenced by patterns of G exposure and other factors. Scope for further reduction remains through correct execution of the anti-G straining maneuver (AGSM) with centrifuge training early in flying training and use of a structured conditioning program to increase the general strength of muscles involved in the AGSM.Slungaard E, McLeod J, Green NDC, Kiran A, Newham DJ, Harridge SDR. Incidence of G-induced loss of consciousness and almost loss of consciousness in the Royal Air Force. Aerosp Med Hum Perform. 2017; 88(6):550-555.

The influence of environmental stressors on the pathogenesis of gastrointestinal disease has received increased awareness. Stress affects different physiological functions of the gastrointestinal tract, including gastric acid secretion and mucosal blood flow. Repeated exposures of rapid-onset, highly-sustained hypergravity cause severe physical stress in the pilot. Although the effects of exposure to hypergravity on cardiovascular and cerebral functions have been the subjects of numerous studies, crucial information regarding pathophysiological changes in the gastrointestinal tract following hypergravity exposure is lacking. In this study, we investigated the effects of acute exposure to hypergravity on gastric secretory activity and gastrin release. Male Sprague-Dawley rats were exposed to +10Gz three times for 3 min. Gastric juice and blood were collected. The volume and total acidity of gastric juice, and the plasma gastrin level was measured. Acute exposure to +10Gz significantly decreased the gastric juice parameters. The gastric juice volume and total acidity of hypergravity-exposed rats were 3.54 ± 0.32 mL/100 g and 84.90 ± 5.17 mEq/L, respectively, which were significantly lower than those of the nonexposed rats (4.62 ± 0.39 mL/100 g and 97.37 ± 5.42 mEq/L; P < 0.001 and P < 0.001, respectively). In contrast, plasma gastrin level was not significantly altered following hypergravity exposure. We demonstrated that acute exposure to hypergravity led to a significant decrease in the gastric juice volume and acidity but did not alter the plasma gastrin level.

Background: Due to spatial disorientation reported in space, spatial memory and navigation performances could be more largely impaired by gravity changes. Hippocampus, a key structure for spatial memory, receives inputs from gravity-sensing otolith organs., Objective: To determine the key molecules in the rat hippocampus that contribute to an adaptation to altered gravity in terms of spatial memory performance., Methods: Gene expression of hippocampus and spatial memory after continuous two-weeks exposure to 2 G hypergravity (HG) were examined using a microarray analysis followed by real-time PCR methods and radial arm maze testing, respectively. Serum cortisol levels during HG load were measured as a stress marker., Results: Accuracy to enter the correct arms in HG rats was significantly lower than that of controls, indicating an impaired spatial memory due to gravity changes. Microarray analysis followed by real-time PCR confirmed an upregulation of insulin like growth factor binding protein 2 (IGFBP2) gene. Serum cortisol level was the same level as controls at the last day of hypergravity, suggesting the adaptation to HG-induced stress., Conclusions: Given that the IGF systems are involved in neurotrophic and synaptic plasticity mechanisms, IGF system might contribute to the adaptation to altered gravity in terms of spatial memory.

Background: Binge alcohol consumption elicits mitochondrial dysfunction in hepatocytes. An understanding of the effect of ethanol (EtOH) exposure after hypergravity stress on liver function may assist in the implementation of pathophysiological countermeasures for aerospace missions. This study investigated whether a combination of hypergravity stress and binge alcohol intake has a detrimental effect on AMP-activated protein kinase (AMPK) and other molecules necessary for hepatocyte survival., Methods: The mice were orally administered a single dose of EtOH (5 g/kg body weight, 20% EtOH) immediately after a load to +9 Gz hypergravity for 1 hour using a small animal centrifuge and sacrificed 24 hours after treatment. For the multiple-dose model, 3 consecutive daily treatments were carried out. Immunoblottings were carried out on liver homogenates., Results: Binge alcohol intake in mice immediately after a 1-hour exposure to a +9 Gz hypergravity load repressed hepatic Akt and PARP-1 levels at 24 hours posttreatment. Moreover, it sustainably diminished the level of AMPKα, a key regulator of energy metabolism, as compared to each individual treatment. Similarly, the combination of alcohol and hypergravity suppressed the levels of STAT3, FOXO1/3, C/EBPβ, and CREB, transcription factors necessary for cell survival. Similar changes were not detected after 3 consecutive daily combinatorial treatments, indicating that repetitive training with hypergravity loads provides hepatoprotective effects in a binge alcohol model., Conclusions: These results show that binge alcohol exposure in mice immediately following a +9 Gz hypergravity stress persistently decreased AMPKα and other key molecules required for hepatocyte survival, and these changes may be reversed by repetitive hypergravity loads., (Copyright © 2016 by the Research Society on Alcoholism.)

Gravity changes concurrently affect muscle and bone as well as induce alterations in vestibular signals. However, the role of vestibular signals in the changes in muscle and bone induced by gravity changes remains unknown. We therefore investigated the effects of vestibular lesions (VL) on the changes in muscle and bone induced by 3 g hypergravity for 4 weeks in C57BL/6J mice. Quantitative computed tomography analysis revealed that hypergravity increased muscle mass surrounding the tibia and trabecular bone mineral content, adjusting for body weight in mice. Hypergravity did not affect cortical bone and fat masses surrounding the tibia. Vestibular lesions blunted the increases in muscle and bone masses induced by hypergravity. Histological analysis showed that hypergravity elevated the cross-sectional area of myofiber in the soleus muscle. The mRNA levels of myogenic genes such as MyoD, Myf6, and myogenin in the soleus muscle were elevated in mice exposed to hypergravity. Vestibular lesions attenuated myofiber size and the mRNA levels of myogenic differentiation markers enhanced by hypergravity in the soleus muscle. Propranolol, a β-blocker, antagonized the changes in muscle induced by hypergravity. In conclusion, this study is the first to demonstrate that gravity changes affect muscle and bone through vestibular signals and subsequent sympathetic outflow in mice., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Objectives: We investigated the dose-effect relationship between wide changes in gravity from 0 to 2.0 Gz (Δ0.5 Gz) and cerebral blood flow (CBF), to test our hypothesis that CBF has a linear relationship with levels of gravity., Subjects and Methods: Ten healthy seated men were exposed to 0, 0.5, 1.0, 1.5, and 2.0 Gz for 21 min, by using a tilt chair and a short-arm human centrifuge. Steady-state CBF velocity (CBFV) in the middle cerebral artery by transcranial Doppler ultrasonography, mean arterial pressure (MAP) at the heart level (MAPHeart), heart rate, stroke volume, cardiac output and respiratory conditions were obtained for the last 6 min at each gravity level. Then, MAP in the middle cerebral artery (MAPMCA), reflecting cerebral perfusion pressure, was estimated., Results: Steady-state CBFV decreased stepwise from 0.5 to 2.0 Gz. Steady-state heart rate, stroke volume, estimated MAPMCA and end-tidal carbon dioxide pressure (ETCO2) also changed stepwise from hypogravity to hypergravity. On the other hand, steady-state MAPHeart and cardiac output did not change significantly. Steady-state CBFV positively and linearly correlated with estimated MAPMCA and ETCO2 in most subjects., Conclusion: The present study demonstrated stepwise gravity-induced changes in steady-state CBFV from 0.5 to 2.0 Gz despite unchanged steady-state MAPHeart. The combined effects of reduced MAPMCA and ETCO2 likely led to stepwise decreases in CBFV. We caution that a mild increase in gravity from 0 to 2.0 Gz reduces CBF, even if arterial blood pressure at the heart level is maintained.

This study was designed to examine the expression of hypoxia-inducible factor-1α (HIF-1α) and the level and activity of endothelial nitric oxide synthase (eNOS) in the hearts and livers of mice exposed to hypergravity. Hypergravity-induced hypoxia and the subsequent post-exposure reoxygenation significantly increased cardiac HIF-1α levels. Furthermore, the levels and activity of cardiac eNOS also showed significant increase immediately following hypergravity exposure and during the reoxygenation period. In contrast, the expression of phosphorylated Akt (p-Akt) and phosphorylated extracellular signal-regulated kinase (p-ERK) showed significant elevation only during the reoxygenation period. These data raise the possibility that the increase in cardiac HIF-1α expression induced by reoxygenation involves a cascade of signaling events, including activation of the Akt and ERK pathways. In the liver, HIF-1α expression was significantly increased immediately after hypergravity exposure, indicating that hypergravity exposure to causes hepatocellular hypoxia. The hypergravity-exposed livers showed significantly higher eNOS immunoreactivity than did those of control mice. Consistent with these results, significant increases in eNOS activity and nitrate/nitrite levels were also observed. These findings suggest that hypergravity-induced hypoxia plays a significant role in the upregulation of hepatic eNOS., Competing Interests: The authors declare that they have no conflicts of interest.