Effects of different seat inclination angles on lumbar dynamic response and injury during lunar-earth reentry.

The inclination angle of the spacecraft seat is related to the astronaut's reentry angle, which in turn affects the safety of the astronauts. This study quantitatively analyzed the effects of different seat inclination angles on astronauts' lumbar spine injuries using the finite element method during the Lunar-Earth reentry. Firstly, a finite element model of the astronaut's lumbar spine was constructed based on reverse engineering technology, and the effectiveness of the model was verified through mesh sensitivity, vertebral range of motion, and spinal impact experiments. Then, simulation calculations were carried out for different seat inclination angles (0°, 10°, 20°, and 30°) under the typical reentry return loads of Chang'e 5T1 (CE-5T1) and Apollo 10, and the prediction and evaluation of lumbar spine injuries were conducted in conjunction with the biological tissue injury criteria. The results indicated that the stress on the vertebrae and annulus fibrosus increased under both reentry loads with the rise of the seat inclination angle, but the increasing rates decreased. When the acceleration peak of CE-5T1 approached 9G, the risk of tissue injury was higher under the seat angle exceeded 20°. According to the Multi-Axis Dynamic Response Criteria for spinal injury, neither of the two load conditions would directly cause injury to the astronauts' lumbar spine when the seat inclination angle was below 30°. The study findings provide a numerical basis for designing and improving the spacecraft's inclination angle in crewed lunar missions, ensuring the safety of astronauts.

Simulation and analysis of chest loads on crews during Lunar-Earth re-entry returns.

The safety of crews is the primary concern in the manned lunar landing project, particularly during re-entry as the manned spacecraft returns from a direct Lunar-Earth trajectory. This paper analyzed the crew's chest biomechanical response to assess potential injuries caused by acceleration loads during the re-entry phase. Initially, a sophisticated finite element model of the chest was constructed, whose effectiveness was verified by experiments involving vertebral range of motion, rib lateral rupture, and chest frontal impact. The model was then subjected to the return re-entry loads simulating the Apollo and Chang'e 5 T1 (CE-5T1) test returner to specifically analyze the correlation between the acceleration load and the injury of the crew's chest tissues and organs. The results indicate that the biomechanical response of crew chest bone tissue under the two return missions is within the threshold value and will not directly cause damage. Compared to the Apollo mission, the CE-5T1 mission's load poses a higher risk to internal organs. These findings can enhance the crew's safety and provide reliable assurance for future space exploration.

Phase-amplitude coupling of Go/Nogo task-related neuronal oscillation decreases for humans with insufficient sleep.

Phase-amplitude coupling (PAC) across frequency might be associated with the long-range synchronization of brain networks, facilitating the spatiotemporal integration of multiple cell assemblies for information transmission during inhibitory control. However, sleep problems may affect these cortical information transmissions based on cross-frequency PAC, especially when humans work in environments of social isolation. This study aimed to evaluate changes in the theta-beta/gamma PAC of task-related electroencephalography (EEG) for humans with insufficient sleep. Here, we monitored the EEG signals of 60 healthy volunteers and 18 soldiers in the normal environment, performing a Go/Nogo task. Soldiers also participated in the same test in isolated cabins. These measures demonstrated theta-beta PACs between the frontal and central-parietal, and robust theta-gamma PACs between the frontal and occipital cortex. Unfortunately, these PACs significantly decreased when humans experienced insufficient sleep, which was positively correlated with the behavioral performance of inhibitory control. The evaluation of theta-beta/gamma PAC of Go/Nogo task-related EEG is necessary to help understand the different influences of sleep problems in humans.

Proxalutamide reduces SARS-CoV-2 infection and associated inflammatory response.

Early in the COVID-19 pandemic, data suggested that males had a higher risk of developing severe disease and that androgen deprivation therapy might be associated with protection. Combined with the fact that TMPRSS2 (transmembrane serine protease 2), a host entry factor for the SARS-CoV-2 virus, was a well-known androgen-regulated gene, this led to an upsurge of research investigating androgen receptor (AR)-targeting drugs. Proxalutamide, an AR antagonist, was shown in initial clinical studies to benefit COVID-19 patients; however, further validation is needed as one study was retracted. Due to continued interest in proxalutamide, which is in phase 3 trials, we examined its ability to impact SARS-CoV-2 infection and downstream inflammatory responses. Proxalutamide exerted similar effects as enzalutamide, an AR antagonist prescribed for advanced prostate cancer, in decreasing AR signaling and expression of TMPRSS2 and angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor. However, proxalutamide led to degradation of AR protein, which was not observed with enzalutamide. Proxalutamide inhibited SARS-CoV-2 infection with an IC50 value of 97 nM, compared to 281 nM for enzalutamide. Importantly, proxalutamide inhibited infection by multiple SARS-CoV-2 variants and synergized with remdesivir. Proxalutamide protected against cell death in response to tumor necrosis factor alpha and interferon gamma, and overall survival of mice was increased with proxalutamide treatment prior to cytokine exposure. Mechanistically, we found that proxalutamide increased levels of NRF2, an essential transcription factor that mediates antioxidant responses, and decreased lung inflammation. These data provide compelling evidence that proxalutamide can prevent SARS-CoV-2 infection and cytokine-induced lung damage, suggesting that promising clinical data may emerge from ongoing phase 3 trials.

Cognitive Load Moderates the Effects of Total Sleep Deprivation on Working Memory: Evidence from Event-Related Potentials.

Purpose: The function of working memory (WM) is impaired by total sleep deprivation (TSD) and cognitive load. However, it is unclear whether the load modulates the effect of TSD on WM. We conducted a pilot study to investigate the effects of 36 h of TSD on WM under different load levels. Materials and methods: Twenty-two male students aged 18-25 years were enrolled, who underwent two types of sleep conditions (baseline and 36 h TSD), where they performed two N-back WM tasks (one-back task and two-back task) with simultaneous electroencephalography recordings. Results: Repeated measures analysis of variance (ANOVA) indicated that, with the increasing load, the reaction time increased and the accuracy decreased. After TSD, the correct number per unit time decreased. The significant interaction effect of the P3 amplitudes between the load level and the sleep condition showed that the reduction in the amplitude of P3 in the two-back task due to TSD was more obvious than that in the one-back task. Conclusions: Our results provided evidence for the moderation of load on the impairment of TSD on WM. The degree of TSD-induced impairment for a higher load was greater than that for a lower load. The current study provides new insights into the mechanisms by which sleep deprivation affects cognitive function.

Impeded frontal-occipital communications during Go/Nogo tasks in humans owing to mental workload.

Human brains rely on oscillatory coupling mechanisms for regulating access to prefrontal cognitive resources, dynamically communicating between the frontal and remote cortex. We worry that communications across cortical regions will be impeded when humans in extreme space environments travel with mental load work, affecting the successful completion of missions. Here, we monitored crews of workers performing a Go/Nogo task in space travel, accompanied by acquisitions of electroencephalography (EEG) signals. These data demonstrated that when the target stimulus suddenly changed to the non-target stimulus, an instantaneous communication mechanism between the frontal and occipital cortex was established by theta-gamma phase-amplitude coupling (PAC). However, this frontal-occipital communication was impeded because of the mental workload of space travel. 86 healthy volunteers who participated in the ground imitation further indicated that mental workload caused decoupled theta-gamma PAC during the Go/Nogo task, impeding frontal-occipital communications and behavioral performance. We also found that the degree of theta-gamma PAC coupling in space was significantly lower than on the ground, indicating that mental workload and other hazards worsen the impeded frontal-occipital communications of humans. These results could guide countermeasures for the inadaptability of humans working in spaceflight.

Brain signatures of error awareness during cognitive tasks for humans in the flight environment.

At present, many scientific experiments are carried out in extreme conditions. Pilots need to perform high-intensity tasks for a long time. Human error is an essential factor affecting mission execution. To deeply study the physiological characteristics of different erroneous states of consciousness, we used an improved double-choice Oddball paradigm to collect brain electrophysiological signals of volunteers and pilots in missions and analyze event-related potential (ERP), time-frequency, and brain function spectrum, extracting EEG indicators sensitive to error awareness. The results showed that, in the 300∼500 ms time window, the error awareness type was correlated with Pe amplitude. Meanwhile, the time-frequency and brain functional spectrum analysis showed that the amplitude of the aware errors α-ERS oscillation, the functional spectral density of the α-band, and the uncertain errors were more prominent than unaware errors. The error awareness of the pilots showed the same EEG sensitivity characteristics in flight as in the ground volunteer experiment, and the characteristic sensitivity value was higher than that of the ground participants. We analyzed the EEG indicators sensitive to error awareness and determined the differences in EEG characteristics when pilots have error awareness on the ground and in flight. This study provides theoretical guidance for the follow-up research on the intervention measures against error awareness and determines the target point positioning.

Extreme conditions affect neuronal oscillations of cerebral cortices in humans in the China Space Station and on Earth.

Rhythmical oscillations of neural populations can reflect working memory performance. However, whether neuronal oscillations of the cerebral cortex change in extreme environments, especially in a space station, remains unclear. Here, we recorded electroencephalography (EEG) signals when volunteers and astronauts were executing a memory task in extreme working conditions. Our experiments showed that two extreme conditions affect neuronal oscillations of the cerebral cortex and manifest in different ways. Lengthy periods of mental work impairs the gating mechanism formed by theta-gamma phase-amplitude coupling of two cortical areas, and sleep deprivation disrupts synaptic homeostasis, as reflected by the substantial increase in theta wave activity in the cortical frontal-central area. In addition, we excluded the possibility that nutritional supply or psychological situations caused decoupled theta-gamma phase-amplitude coupling or an imbalance in theta wave activity increase. Therefore, we speculate that the decoupled theta-gamma phase-amplitude coupling detected in astronauts results from their lengthy periods of mental work in the China Space Station. Furthermore, comparing preflight and inflight experiments, we find that long-term spaceflight and other hazards in the space station could worsen this decoupling evolution. This particular neuronal oscillation mechanism in the cerebral cortex could guide countermeasures for the inadaptability of humans working in spaceflight.

Changes in ventromedial prefrontal cortex functional connectivity are correlated with increased risk-taking after total sleep deprivation.

There is evidence indicating that people are more likely to take risks when they are sleep-deprived than during resting wakefulness (RW). The ventromedial prefrontal cortex (vmPFC) could have a crucial psychophysiological role in this phenomenon. However, the intrinsic patterns of functional organization of the human vmPFC and their relationship with risk-taking during sleep deprivation (SD) are unclear. This study investigated the relationship between functional connectivity in the vmPFC and cerebral cortex and the risk-taking tendency after SD. The study participants were 21 healthy college students who underwent functional magnetic resonance imaging twice in the resting state, once during RW and once after 36 h of SD. The vmPFC was analyzed bilaterally for functional connectivity between the regions of interest. Correlation analysis was performed to evaluate changes in functional connectivity between the vmPFC and the cerebral cortex and risk-taking before and after SD. A single night of SD produced a definite deficit in functional connectivity between the vmPFC and thalamus bilaterally and an increase in functional connectivity between the vmPFC and dorsolateral prefrontal cortex (dlPFC) and the parietal lobe. We also found that the likelihood of risk-taking was positively correlated with increased functional connectivity between the vmPFC and dlPFC and negatively correlated with decreased functional connectivity between the vmPFC and thalamus bilaterally. These results demonstrate that lack of sleep substantially impairs functional connectivity between the vmPFC and the cerebral cortex, which in turn predicts the risk-taking behavior found after SD.

Comfort Evaluation of Slow-Recovery Ejection Seat Cushions Based on Sitting Pressure Distribution.

Sitting discomfort not only affects the health of pilots carrying out long-endurance missions but also affects operational performance. The experimental objects included four ejection seat cushions: N1 was a fast-recovery foam as the comparison group, and the experimental groups were slow-recovery foams with different indentation force deflection (IFD), named N2 (hard), N3 (mid), and N4 (soft). The sitting comfort of 20 participants was tested on the four cushions by using subjective rating and sitting pressure distribution analysis. The results showed that compared with fast-recovery cushion N3 and N4 slow-recovery cushions have lower contact pressure and more uniform pressure distribution. Slow-recovery cushions that were too soft or too hard would reduce the comfort. No matter from the subjective rating or the analysis of the contact pressure data, the N3 cushion with a thickness of 3 cm and 65% IFD of 280 N had the highest comfort. In addition, the seat pressure distribution (SPD%) has a significant correlation with the subjective rating (p = 0.019, R = -0.98), which is more suitable for evaluating the comfort of the cushions. However, the slow-recovery cushions would show a decrease in support after a period of sitting, while the fast-recovery cushion could always maintain constant support.

Activity of preclinical and phase I clinical trial of a novel androgen receptor antagonist GT0918 in metastatic breast cancer.

PURPOSE: To evaluate GT0918, a 2nd-generation AR antagonist, for its AR down-regulation activity among breast cancer patients. METHODS: The effect of GT0918 on AR protein expression was evaluated in AR expression breast cancer cells and in breast cancer xenograft model. A 3 + 3 phase I dose-escalation study was launched in Peking University Cancer Hospital. The endpoints included dose finding, safety, pharmacokinetics, and antitumor activity. RESULTS: GT0918 was demonstrated to effectively suppress the expression of AR protein and the growth of AR-positive breast cancer tumors in mouse xenograft tumor models. All patients treated with GT0918 were at a QD dose-escalation of five dose levels from 100 to 500 mg. The most common treatment-related AEs of any grade were asthenia, anemia, decreased appetite, increased blood cholesterol, increased blood triglycerides, decreased white blood cell count, and increased low-density lipoprotein. Grade 3 AEs were fatigue (2 of 18, 11.1%), aspartate aminotransferase increase (1 of 18, 5.6%), alanine aminotransferase increase (1 of 18, 5.6%), and neutrophil count decrease (1 of 18, 5.6%). Clinical benefit rate (CBR) in 16 weeks was 23.1% (3/13). Among 7 AR-positive patients, 6 can evaluate efficacy, and 2 completed 23.5- and 25-cycle treatment, respectively (as of 2020/1/20). PK parameters showed a fast absorption profile of GT0918 in the single-dose study. GT0918 and its major metabolite reached steady-state serum concentration levels at day 21 after multiple dosing. CONCLUSION: GT0918 can effectively inhibit AR-positive breast cancer tumor growth. GT0918 was demonstrated well tolerated with a favorable PK profile. The suitable dose of GT0918 was 500 mg QD and may provide clinical benefits for AR-positive mBC.

Effect of lighting illuminance and colour temperature on mental workload in an office setting.

The mental workload of subjects was tested under different lighting conditions, with colour temperatures ranging from 3000 to 6500 K and illuminance ranging from 300 to 1000 lx. We used both psychological and physiological responses for evaluation. The former was based on NASA Task Load Index (NASA-TLX, NASA), and the latter was based on the electroencephalogram (EEG) P3b analysis of event-related potentials using the "oddball" paradigm experimental task. The results show that as illuminance increases, and the response time becomes longer with a colour temperature of 3000 K (P < 0.01). However, when the colour temperature is set at 6500 K, the response time becomes shorter as the illuminance increases (P < 0.01). P3b amplitudes were significantly affected by colour temperature (P = 0.009) and illuminance (P = 0.038) levels. The highest amplitudes occurred at 3000 K and 750 lx, which is consistent with the trend shown by the subjective scale. The data analysis of error rates is not significant. These results suggest that an office environment with a colour temperature of 3000 K and illumination of 750 lx, which exerts the lowest mental workload, is the most suitable for working. However, the interaction between colour temperature and illuminance in affecting the mental workload of participants is not clear. This work provides more appropriate lighting choices with colour temperature and illuminance to reduce people's mental workload in office settings.

[The Antileukemia Activity of ZSTK474 on U937 Cells].

OBJECTIVE: To investigate the antileukemia activity of phosphatidylinositol-3 kinase (PI3K) inhibitor ZSTK474 on human leukemia cell line U937. METHODS: MTT, soft agar assay, flow cytometric analysis and western blot were used to detect the effect of ZSTK474 on U937 cell proliferation, tumorigenicity, cell cycle, cell apoptosis and phosphorylation levels of the key factor of PI3K/AKT pathway. Chou-Talalay method was used to evaluate the combination of ZSTK474 with Cytarabine or Homoharringtonine. RESULTS: PI3K inhibitor ZSTK474 could inhibit the proliferation and tumorigenicity of U937 cell, induce G1 cell cycle arrest and promote cell apoptosis, and enhance intracellular ROS production and decrease MMP, downregulate Cyclin D1, p-Rb, BCL-2 and upregulate p27, caspase-9, caspase-3, PARP and BAX. Furthermore, the phosphorylation of PDK1, GSK-3ß, AKT and mTOR could be downregulated by ZSTK474. The combination of ZSTK474 with Homoharringtonine was synergistic. CONCLUSION: ZSTK474 can inhibit the pathway of PI3K/AKT, ZSTK474 alone or in combination with Homoharringtonine shows potential antileukemia activity on U937 cells.

Decreased resting-state alpha-band activation and functional connectivity after sleep deprivation.

Cognitive abilities are impaired by sleep deprivation and can be recovered when sufficient sleep is obtained. Changes in alpha-band oscillations are considered to be closely related to sleep deprivation. In this study, power spectrum, source localization and functional connectivity analyses were used to investigate the changes in resting-state alpha-band activity after normal sleep, sleep deprivation and recovery sleep. The results showed that the global alpha power spectrum decreased and source activation was notably reduced in the precuneus, posterior cingulate cortex, cingulate gyrus, and paracentral lobule after sleep deprivation. Functional connectivity analysis after sleep deprivation showed a weakened functional connectivity pattern in a widespread network with the precuneus and posterior cingulate cortex as the key nodes. Furthermore, the changes caused by sleep deprivation were reversed to a certain extent but not significantly after one night of sleep recovery, which may be due to inadequate time for recovery sleep. In conclusion, large-scale resting-state alpha-band activation and functional connectivity were weakened after sleep deprivation, and the inhibition of default mode network function with the precuneus and posterior cingulate cortex as the pivotal nodes may be an important cause of cognitive impairment. These findings provide new insight into the physiological response to sleep deprivation and determine how sleep deprivation disrupts brain alpha-band oscillations.

Study of mental workload imposed by different tasks based on teleoperation.

To explore mental workload and methods for dynamically monitoring mental workload imposed by complex tasks, this study constructed a virtual operating environment according to three cognitive steps: perception, judgment-making and action execution. Dynamic characteristics of mental workload were then analyzed employing subjective questionnaires, performance data and electroencephalography (EEG) characteristics. The analysis of non-linear dynamic characteristics of EEG signals showed that the fractal box dimension features of EEG signals are quite sensitive to the level of mental workload, exercising a significant impact on the four brain areas. The sample entropy is also quite sensitive to the level of mental workload, exercising a significant impact on the frontal, central and occipital areas. Based on this study, operational tasks can be dynamically assigned according to the state of personnel load and the safety and efficiency of the operation of the human-machine system can be ensured.

Preclinical profile and phase I clinical trial of a novel androgen receptor antagonist GT0918 in castration-resistant prostate cancer.

PURPOSE: We conducted preclinical experiments and phase I clinical trial to investigate the safety, pharmacokinetics (PK) and antitumour effects of GT0918 in castration-resistant prostate cancer (CRPC). EXPERIMENTAL DESIGN: An androgen receptor (AR) competitive binding assay was performed, followed by evaluation of GT0918 on AR protein expression. The efficacy of GT0918 was investigated in a castration-resistant xenograft model. A phase I dose-escalation study of GT0918 in CRPC was also carried out to evaluate its safety, PK and antitumour efficacy. RESULTS: GT0918 was demonstrated to inhibit the binding of androgen to AR more potently than MDV3100, and to effectively reduce the AR protein level. GT0918 inhibited the transcriptional activity of wild-type AR and AR with clinically relevant ligand-binding domain mutations. Furthermore, GT0918 significantly inhibited the growth of prostate cancer. A total of 16 patients was treated with GT0918 at five dose levels. Among these 16 patients, 10 and 2 patients, respectively, completed a three-cycle and six-cycle treatment, in which MTD was not reached. All the treatment-related adverse events were grade I, including hypercholesterolemia, hypertriglyceridemia, fatigue and anaemia. PK parameters showed that drug exposure increased with dose proportionally from 50 to 300 mg and a saturation was observed between 300 and 400 mg. PSA declines of ≥30% and ≥50% were, respectively, observed in six and two cases. All the 12 patients with metastatic soft tissue lesions confirmed stable disease. CONCLUSIONS: GT0918, a full AR antagonist without agonist effect, has high binding affinity to AR with AR protein down-regulation activity. GT0918 is demonstrated to be well tolerated with a favourable PK profile and exhibits promising antitumour activity in CRPC. CLINICALTRIALS: gov identifier CTR20150501.

Decreased Information Replacement of Working Memory After Sleep Deprivation: Evidence From an Event-Related Potential Study.

Working memory (WM) components are altered after total sleep deprivation (TSD), both with respect to information replacement and result judgment. However, the electrophysiological mechanisms of WM alterations following sleep restriction remain largely unknown. To identify such mechanisms, event-related potentials were recorded during the n-back WM task, before and after 36 h sleep deprivation. Thirty-one young volunteers participated in this study and performed a two-back WM task with simultaneous electroencephalography (EEG) recording before and after TSD and after 8 h time in bed for recovery (TIBR). Repeated measures analysis of variance revealed that, compared to resting wakefulness, sleep deprivation induced a decrease in the P200 amplitude and induced longer reaction times. ERP-component scalp topographies results indicated that such decrease primarily occurred in the frontal cortex. The N200 and P300 amplitudes also decreased after TSD. Our results suggest that decreased information replacement of WM occurs after 36 h of TSD and that 8 h TIBR after a long period of TSD leads to partial restoration of WM functions. The present findings represent the EEG profile of WM during mental fatigue.

Evaluation on Directed Functional Brain Connectivity during the Expert Rifle Pre-shot Period.

Experts require long-term and intense practice to acquire extraordinary motor skills that be known as the brain function regulator. However, the brain function network mechanism of rifle shooters is still unclear. The generalized orthogonalized partial directed coherence (gOPDC) algorithm and local efficiency significance analysis method (LESA) was applied to quantify the difference in directed functional networks between expert and novice rifle shooters during the pre-shot period. The more directed functional connections were observed in alpha and low-beta frequency bands as compared to other bands. Moreover, comparing with the novice's fluctuant connection, the values of connection (P3→C3) strength were increasing steadily in the experts during the pre-shot period. Fewer connections in left hemisphere networks were obtained in the experts than in the novices. The results validated the "neural efficiency" hypothesis in experts. Moreover, the strength of the functional connection (P3→C3) in the alpha and beta bands serves as a distinguishing feature between experts and novices.

[Efficient connectivity analysis of electroencephalogram in the pre-shot phase of rifle shooting based on causality method].

The directed functional connectivity in cerebral cortical is the key to understanding the pattern of the behavioral tissue. This process was studied to explore the directed functional network of rifle shooters at cerebral cortical rhythms from electroencephalogram (EEG) data, aiming to provide neurosciences basis for the future development of accelerating rifle skill learning method. The generalized orthogonalized partial directed coherence (gOPDC) algorithm was used to calculate the effective directed functional connectivity of the experts and novices in the pre-shot period. The results showed that the frontal, frontal-central, central, parietal and occipital regions were activated. Moreover, the more directed functional connections numbers in right hemispheres were observed compared to the left hemispheres. Furthermore, as compared to experts, novices had more activated regions, the stronger strength of connections and the lower value of the global efficiency during the pre-shot period. Those indirectly supported the conclusion that the novices needed to recruit more brain resources to accomplish tasks, which was consistent with "neural efficiency" hypothesis of the functional cerebral cortical in experts.