Transcriptomic analysis of embryonic mouse hypothalamic N38 cells exposed to high-energy protons and/or simulated microgravity.

Purpose: Space exploration poses unique challenges to astronauts, especially the effects of space radiation and microgravity (µG). Understanding molecular responses to these factors is crucial for ensuring astronaut health, and this study aimed to identify transcriptomic changes in mouse hypothalamic cell line N38 (mHypoE-N38) caused by simulated space environments. Method: Four experimental groups were established, namely, a ground condition group (GC; the control group), a proton irradiated group (the space radiation group), a simulated µG group, and a proton irradiated × simulated µG group (the combination group). RNA sequencing and quantitative real-time polymerase chain reaction were performed to investigate key altered genes and to validate them. Results: Three hundred and fifty-five differentially expressed genes were identified. Notably, the expressions of UCN2 and UGT1A5 genes were upregulated in all three experimental groups, suggesting a shared regulatory mechanism with potential consequences for brain function during space missions. Moreover, the study revealed significant alterations in genes belonging to the USP17 and ZSCAN4 families, indicating active response to DNA damage and telomere maintenance. PCR results validated that UGT1A5, USP17 family, and ZSCAN4 families (ZSCAN4C, ZSCAN4D, and ZSCAN4F) were significantly upregulated at the mRNA level in the combination group, while UCN2, ZSCAN4A, and ZSCAN4B were not reproduced. Conclusion: The present study on mHypoE-N38 cells exposed to space environments revealed a complex molecular narrative with disease-oriented implications. The knowledge gained might serve as a cornerstone for developing strategies to mitigate potential health risks associated with extended exposure to space-related stressors.

Therapeutic Potential of Intermittent Hypoxia in Atrial Fibrillation.

Intermittent hypoxia (IH) has been extensively studied in recent years, demonstrating adverse and beneficial effects on several physiological systems. However, the precise mechanism underlying its cardiac effects on the heart remains unclear. This study aims to explore the effect of treatment on atrial fibrillation under IH conditions, providing data that can potentially be used in the treatment of heart disease. An atrial fibrillation (AF) model was induced by injecting monocrotaline (MCT, 60 mg/kg) into rats. The study included 32 rats divided into four groups: Control, Control + IH, AF, and AF + IH. We evaluated molecular changes associated with AF using ELISA and Western blot and performed electrophysiological experiments to evaluate AF. Arrhythmia-related calcium and fibrosis markers were investigated. Phosphorylation levels of CaMKII, Phospholamban, and RyR2 all increased in the AF group but decreased in the IH-exposed group. Additionally, fibrosis marker expressions such as SMA, MMP2, MMP9, and TGF-ß increased in the AF group but were significantly downregulated with IH treatment. Connexin 43 and AQP4 expression were restored in the IH-treated group. These findings suggest that IH may prevent AF by downregulating the expression of calcium-handling proteins and fibrosis-associated proteins in an AF-induced rat model.

Neurologic Effects of SARS-CoV-2 Transmitted among Dogs.

SARS-CoV-2 induces illness and death in humans by causing systemic infections. Evidence suggests that SARS-CoV-2 can induce brain pathology in humans and other hosts. In this study, we used a canine transmission model to examine histopathologic changes in the brains of dogs infected with SARS-CoV-2. We observed substantial brain pathology in SARS-CoV-2-infected dogs, particularly involving blood-brain barrier damage resembling small vessel disease, including changes in tight junction proteins, reduced laminin levels, and decreased pericyte coverage. Furthermore, we detected phosphorylated tau, a marker of neurodegenerative disease, indicating a potential link between SARS-CoV-2-associated small vessel disease and neurodegeneration. Our findings of degenerative changes in the dog brain during SARS-CoV-2 infection emphasize the potential for transmission to other hosts and induction of similar signs and symptoms. The dynamic brain changes in dogs highlight that even asymptomatic individuals infected with SARS-CoV-2 may develop neuropathologic changes in the brain.

Smoking cessation strategies for women: An analysis of smoking cessation determinants among Korean female smokers participating in a smoking cessation outreach program.

Background: Although there is strong evidence that behavioral counseling improves quit rates, limited data are available on individualized smoking cessation counseling provided to female smokers because they often are hesitant to identify as smokers. This study aimed to elucidate factors related to smoking cessation among Korean women who participated in the smoking cessation outreach program. Methods: This retrospective descriptive study used data retrieved from the Korea Health Promotion Institute. The data included individual participant characteristics, supportive services received, and self-reported smoking cessation outcomes from June 1, 2015, to December 31, 2017. Results: Data from 709 women were analyzed. We found cessation rates of 43.3% (confidence interval [CI]=0.40, 0.47) at four weeks, 28.6% (CI=0.25, 0.32) at 12 weeks, and 21.6% (CI=0.19, 0.25) at six months. Significant determinants of quitting at six months were regular exercise (odds ratio [OR]=3.02; 95% CI=1.28, 3.29; P=0.009) and the number of counseling sessions during the first four weeks of the program (OR=1.26; 95% CI=1.04, 1.82; P=0.041). Conclusion: Providing intensive counseling during initial phase of smoking cessation program and regular exercise would be effective strategies for smoking cessation programs for women smokers to promote their health.

Gender Differences Among Out-of-School Korean Adolescents in a Counselor-Visiting Smoking Cessation Program.

ABSTRACT: The purpose of this study was to explore the determinants of self-reported smoking cessation among out-of-school Korean adolescents who participated in a counselor-visiting smoking cessation program. This retrospective descriptive study analyzed data from the Korea Health Promotion Institute. Participants were enrolled between June 1, 2015, and December 31, 2017, at a regional smoking cessation center in a counselor-visiting smoking cessation program for out-of-school adolescents. Participants consisted of 807 adolescents (70.3% male) with a mean age of 16.9 ± 1.2 years. Multiple logistic regression analysis showed that female gender (OR = 1.54-1.92), cohort year 2016 (OR = 1.69-1.90), smoking more than half a pack a day (OR = 0.44-0.50), strong motivation to quit (OR = 1.44), and number of counseling in person (OR = 1.97-2.10) were statistically significant independent contributors to quitting, based on follow-up assessments at 4 weeks, 12 weeks, and 6 months. This study explored smoking cessation outcomes of a government-driven smoking cessation program that targeted out-of-school adolescents and identified several risk factors that affect a successful outcome. More research is necessary to evaluate the efficacy of such smoking cessation programs for marginalized or understudied populations.

Galvanic vestibular stimulation down-regulated NMDA receptors in vestibular nucleus of PD model.

Parkinsonian symptoms relief by electrical stimulation is constructed by modulating neural network activity, and Galvanic vestibular stimulation (GVS) is known to affect the neural activity for motor control by activating the vestibular afferents. However, its underlying mechanism is still elusive. Due to the tight link from the peripheral vestibular organ to vestibular nucleus (VN), the effect by GVS was investigated to understand the neural mechanism. Using Sprague Dawley (SD) rats, behavioral response, extracellular neural recording, and immunohistochemistry in VN were conducted before and after the construction of Parkinson's disease (PD) model. Animals' locomotion was tested using rota-rod, and single extracellular neuronal activity was recorded in VN. The immunohistochemistry detected AMPA and NMDA receptors in VN to assess the effects by different amounts of electrical charge (0.018, 0.09, and 0.18 coulombs) as well as normal and PD with no GVS. All PD models showed the motor impairment, and the loss of TH+ neurons in medial forebrain bundle (mfb) and striatum was observed. Sixty-five neuronal extracellular activities (32 canal & 33 otolith) were recorded, but no significant difference in the resting firing rates and the kinetic responding gain were found in the PD models. On the other hand, the numbers of AMPA and NMDA receptors increased after the construction of PD model, and the effect by GVS was significantly evident in the change of NMDA receptors (p < 0.018). In conclusion, the increased glutamate receptors in PD models were down-regulated by GVS, and the plastic modulation mainly occurred through NMDA receptor in VN.

Machine Learning-Based Hearing Aid Fitting Personalization Using Clinical Fitting Data.

The initial software fitting prescribed by the fitting formula largely depends on the patient's hearing loss, which may not be the optimal preference for a particular user. Certain criteria must also be readjusted by an audiologist to meet the user-specific requirements. Therefore, this study focuses on the novel application of a neural network (NN) technique to build a suitable fitting algorithm with prescribed hearing loss and the corresponding preferred gain to minimize the gap between optimized fittings. The algorithm intended to learn the hearing preferences of an individual user such that the initial fitting may be optimized. These findings demonstrate the efficiency of the algorithm, with and without additional features. Using the clinical fitting data, the average mean square error (MSE) for the simple NN algorithm was 5.4183%. By adding additional features to the data, the algorithm performed better, and the average MSE was as low as 5.2530%. However, the algorithm outperformed Company A fitting software, as the MSE was the highest at 5.4748%. As the company's automatic fitting has a noticeable discrepancy with clinical fitting records, the impeccable results from this study can lead to a better path towards fitting satisfaction, thus benefiting the hearing-impaired community to a larger extent.

Factors Affecting the Extrusion Rate and Complications After Ventilation Tube Insertion: A Multicenter Registry Study on the Effectiveness of Ventilation Tube Insertion in Pediatric Patients With Chronic Otitis Media With Effusion-Part II.

OBJECTIVES: The impacts of ventilation tube (VT) type and effusion composition on the VT extrusion rate and complications in children with otitis media remain unclear. This part II study evaluated the factors affecting the extrusion rate, recurrence rate, and complications of VT insertion. METHODS: A prospective study was conducted between June 2014 and December 2016 (the EVENT study [analysis of the effectiveness of ventilation tube insertion in pediatric patients with chronic otitis media]), with follow-up data collected until the end of 2017. Patients aged <15 years diagnosed with otitis media with effusion who received VT insertion were recruited at 15 tertiary hospitals. The primary outcomes were time to extrusion of VT, time to effusion recurrence, and complications. RESULTS: Data from 401 patients were analyzed. After excluding the. RESULTS: of long-lasting tubes (Paparella type II and T-tubes), silicone tubes (Paparella type I) exhibited a significantly longer extended time to extrusion (mean, 400 days) than titanium tubes (collar-button-type 1.0 mm: mean, 312 days; P<0.001). VT material (hazard ratio [HR], 2.117, 95% confidence interval [CI], 1.254-3.572; P=0.005), age (HR, 3.949; 95% CI, 1.239-12.590; P=0.02), and effusion composition (P=0.005) were significantly associated with the time to recurrence of middle ear effusion. Ears with purulent (mean, 567 days) and glue-like (mean, 588 days) effusions exhibited a shorter time to recurrence than ears with serous (mean, 846 days) or mucoid (mean, 925 days) effusions. The revision VT rates during follow-up were 3.5%, 15.5%, 10.4%, and 38.9% in ears with serous, mucoid, glue-like, and purulent effusions, respectively (P<0.001). The revision surgery rates were higher among patients aged <7 years than among those aged ≥7 years. CONCLUSION: Silicone tubes (Paparella type I) were less prone to early extrusion than titanium 1.0 mm tubes. VT type, patient age, and effusion composition affected the time to recurrence of effusion.

Activation of NMDA receptors in brain endothelial cells increases transcellular permeability.

Neurovascular coupling is a precise mechanism that induces increased blood flow to activated brain regions, thereby providing oxygen and glucose. In this study, we hypothesized that N-methyl-D-aspartate (NMDA) receptor signaling, the most well characterized neurotransmitter signaling system which regulates delivery of essential molecules through the blood-brain barrier (BBB). Upon application of NMDA in both in vitro and in vivo models, increased delivery of bioactive molecules that was mediated through modulation of molecules involved in molecular delivery, including clathrin and caveolin were observed. Also, NMDA activation induced structural changes in the BBB and increased transcellular permeability that showed regional heterogeneity in its responses. Moreover, NMDA receptor activation increased endosomal trafficking and facilitated inactivation of lysosomal pathways and consequently increased molecular delivery mediated by activation of calmodulin-dependent protein kinase II (CaMKII) and RhoA/protein kinase C (PKC). Subsequent in vivo experiments using mice specifically lacking NMDA receptor subunit 1 in endothelial cells showed decreased neuronal density in the brain cortex, suggesting that a deficiency in NMDA receptor signaling in brain endothelial cells induces neuronal losses. Together, these results highlight the importance of NMDA-receptor-mediated signaling in the regulation of BBB permeability that surprisingly also affected CD31 staining.

Intermittent Hypoxia on the Attenuation of Induced Nasal Allergy and Allergic Asthma by MAPK Signaling Pathway Downregulation in a Mice Animal Model.

Intermittent hypoxia (IH) has been an issue of considerable research in recent years and triggers a bewildering array of both detrimental and beneficial effects in several physiological systems. However, the mechanisms leading to the effect are not yet clear. Consequently, we investigated the effects of IH on allergen-induced allergic asthma via the mitogen-activated protein kinase (MAPK) signaling pathway. Forty BALB/c mice were dived into four groups. We evaluated the influence of IH on the cell signaling system of the airway during the allergen-induced challenge in an animal model, especially through the MAPK (mitogen-activated protein kinase) pathway. The protein concentrations of p-ERK/ERK, p-JNK/JNK, p-p38/p38, and pMEK/MEK were significantly reduced in the allergen-induced+IH group, compared to the allergen-induced group (p-value < 0.05 as considered statistically significant). The number of eosinophils, neutrophils, macrophages, and lymphocytes in the bronchoalveolar lavage fluid and Dp (Dermatophagoides pteronyssinus)-specific IgG2a and interleukins 4, 5, 13, and 17 were significantly reduced in the Dp+IH group, compared to the Dp group. These findings suggest that the MAPK pathway might be associated with the beneficial effect of IH on the attenuation of allergic response in an allergen-induced mouse model.

Inertial-Measurement-Unit-Based Novel Human Activity Recognition Algorithm Using Conformer.

Inertial-measurement-unit (IMU)-based human activity recognition (HAR) studies have improved their performance owing to the latest classification model. In this study, the conformer, which is a state-of-the-art (SOTA) model in the field of speech recognition, is introduced in HAR to improve the performance of the transformer-based HAR model. The transformer model has a multi-head self-attention structure that can extract temporal dependency well, similar to the recurrent neural network (RNN) series while having higher computational efficiency than the RNN series. However, recent HAR studies have shown good performance by combining an RNN-series and convolutional neural network (CNN) model. Therefore, the performance of the transformer-based HAR study can be improved by adding a CNN layer that extracts local features well. The model that improved these points is the conformer-based-model model. To evaluate the proposed model, WISDM, UCI-HAR, and PAMAP2 datasets were used. A synthetic minority oversampling technique was used for the data augmentation algorithm to improve the dataset. From the experiment, the conformer-based HAR model showed better performance than baseline models: the transformer-based-model and the 1D-CNN HAR models. Moreover, the performance of the proposed algorithm was superior to that of algorithms proposed in recent similar studies which do not use RNN-series.

Brain Endothelial Cells Utilize Glycolysis for the Maintenance of the Transcellular Permeability.

Among the components of the blood-brain barrier (BBB), endothelial cells (ECs) play an important role in supplying limited materials, especially glucose, to the brain. However, the mechanism by which glucose is metabolized in brain ECs is still elusive. To address this topic, we assessed the metabolic signature of glucose utilization using live-cell metabolic assays and liquid chromatography-tandem mass spectrometry metabolomic analysis. We found that brain ECs are highly dependent on aerobic glycolysis, generating lactate as its final product with minimal consumption of glucose. Glucose treatment decreased the oxygen consumption rate in a dose-dependent manner, indicating the Crabtree effect. Moreover, when glycolysis was inhibited, brain ECs showed impaired permeability to molecules utilizing transcellular pathway. In addition, we found that the blockade of glycolysis in mouse brain with 2-deoxyglucose administration resulted in decreased transcellular permeability of the BBB. In conclusion, utilizing glycolysis in brain ECs has critical roles in the maintenance and permeability of the BBB. Overall, we could conclude that brain ECs are highly glycolytic, and their energy can be used to maintain the transcellular permeability of the BBB.

Detrimental effects of simulated microgravity on mast cell homeostasis and function.

Exposure to microgravity causes significant alterations in astronauts' immune systems during spaceflight; however, it is unknown whether microgravity affects mast cell homeostasis and activation. Here we show that microgravity negatively regulates the survival and effector function of mast cells. Murine bone marrow-derived mast cells (BMMCs) were cultured with IL-3 in a rotary cell culture system (RCCS) that generates a simulated microgravity (SMG) environment. BMMCs exposed to SMG showed enhanced apoptosis along with the downregulation of Bcl-2, and reduced proliferation compared to Earth's gravity (1G) controls. The reduction in survival and proliferation caused by SMG exposure was recovered by stem cell factor. In addition, SMG impaired mast cell degranulation and cytokine secretion. BMMCs pre-exposed to SMG showed decreased release of ß-hexosaminidase, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) upon stimulation with phorbol 12-myristate-13-acetate (PMA) plus calcium ionophore ionomycin, which correlated with decreased calcium influx. These findings provide new insights into microgravity-mediated alterations of mast cell phenotypes, contributing to the understanding of immune system dysfunction for further space medicine research.

Diagnostic evolution of vestibular neuritis after long-term monitoring.

INTRODUCTION: The diagnosis of vestibular neuritis is based on clinical and laboratory findings after exclusion of other disease. There are occasional discrepancies between clinical impressions and laboratory results. It could be the first vertigo episode caused by other recurrent vestibular disease, other than vestibular neuritis. OBJECTIVE: This study aimed to analyze the clinical features and identify the diagnostic evolution of patients with clinically suspected vestibular neuritis. METHODS: A total of 201 patients clinically diagnosed with vestibular neuritis were included in this study. Clinical data on the symptoms and signs of vertigo along with the results of vestibular function test were analyzed retrospectively. Patients were categorized in terms of the results of caloric testing (CP - canal paresis) group; canal paresis ≥25%; (MCP -minimal canal paresis) group; canal paresis <25%). Clinical features were compared between the two groups and the final diagnosis was reviewed after long-term follow up of both groups. RESULTS: Out of 201 patients, 57 showed minimal canal paresis (CP<25%) and 144 showed definite canal paresis (CP≥25%). A total of 48 patients (23.8%) experienced another vertigo episode and were re-diagnosed. Recurring vestibular symptoms were seen more frequently in patients with minimal canal paresis (p=0.027). Repeated symptoms were observed on the same affected side more frequently in the CP group. The proportion of final diagnosis were not different between two groups. CONCLUSIONS: Patients with minimal CP are more likely to have recurrent vertigo than patients with definite CP. There was no significant difference in the distribution of the final diagnoses between two groups when the vertigo recurs.

Control of hippocampal prothrombin kringle-2 (pKr-2) expression reduces neurotoxic symptoms in five familial Alzheimer's disease mice.

BACKGROUND AND PURPOSE: There is a scarcity of information regarding the role of prothrombin kringle-2 (pKr-2), which can be generated by active thrombin, in hippocampal neurodegeneration and Alzheimer's disease (AD). EXPERIMENTAL APPROACH: To assess the role of pKr-2 in association with the neurotoxic symptoms of AD, we determined pKr-2 protein levels in post-mortem hippocampal tissues of patients with AD and the hippocampi of five familial AD (5XFAD) mice compared with those of age-matched controls and wild-type (WT) mice, respectively. In addition, we investigated whether the hippocampal neurodegeneration and object memory impairments shown in 5XFAD mice were mediated by changes to pKr-2 up-regulation. KEY RESULTS: Our results demonstrated that pKr-2 was up-regulated in the hippocampi of patients with AD and 5XFAD mice, but was not associated with amyloid-ß aggregation in 5XFAD mice. The up-regulation of pKr-2 expression was inhibited by preservation of the blood-brain barrier (BBB) via addition of caffeine to their water supply or by treatment with rivaroxaban, an inhibitor of factor Xa that is associated with thrombin production. Moreover, the prevention of up-regulation of pKr-2 expression reduced neurotoxic symptoms, such as hippocampal neurodegeneration and object recognition decline due to neurotoxic inflammatory responses in 5XFAD mice. CONCLUSION AND IMPLICATIONS: We identified a novel pathological mechanism of AD mediated by abnormal accumulation of pKr-2, which functions as an important pathogenic factor in the adult brain via blood brain barrier (BBB) breakdown. Thus, pKr-2 represents a novel target for AD therapeutic strategies and those for related conditions.

Diagnostic evolution of vestibular neuritis after long-term monitoring / Evolução diagnóstica da neurite vestibular após monitoração de longo prazo

Abstract Introduction The diagnosis of vestibular neuritis is based on clinical and laboratory findings after exclusion of other disease. There are occasional discrepancies between clinical impressions and laboratory results. It could be the first vertigo episode caused by other recurrent vestibular disease, other than vestibular neuritis. Objective This study aimed to analyze the clinical features and identify the diagnostic evolution of patients with clinically suspected vestibular neuritis. Methods A total of 201 patients clinically diagnosed with vestibular neuritis were included in this study. Clinical data on the symptoms and signs of vertigo along with the results of vestibular function test were analyzed retrospectively. Patients were categorized in terms of the results of caloric testing (CP - canal paresis) group; canal paresis ≥25%; (MCP -minimal canal paresis) group; canal paresis <25%). Clinical features were compared between the two groups and the final diagnosis was reviewed after long-term follow up of both groups. Results Out of 201 patients, 57 showed minimal canal paresis (CP < 25%) and 144 showed definite canal paresis (CP ≥ 25%). A total of 48 patients (23.8%) experienced another vertigo episode and were re-diagnosed. Recurring vestibular symptoms were seen more frequently in patients with minimal canal paresis (p = 0.027). Repeated symptoms were observed on the same affected side more frequently in the CP group. The proportion of final diagnosis were not different between two groups. Conclusions Patients with minimal CP are more likely to have recurrent vertigo than patients with definite CP. There was no significant difference in the distribution of the final diagnoses between two groups when the vertigo recurs.

Resumo Introdução O diagnóstico de neurite vestibular é baseado em achados clínicos e laboratoriais após exclusão de outra doença. Existem discrepâncias ocasionais entre a impressão clínica e os resultados laboratoriais. Pode ser o primeiro episódio de vertigem causado por outra doença vestibular recorrente, além da neurite vestibular. Objetivo Analisar as características clínicas e identificar a evolução diagnóstica de pacientes com suspeita clínica de neurite vestibular. Método Foram incluídos neste estudo 201 pacientes com diagnóstico clínico de neurite vestibular. Os dados clínicos sobre os sintomas e sinais de vertigem e os resultados dos testes de função vestibular foram analisados retrospectivamente. Os pacientes foram categorizados de acordo com os resultados das provas calóricos (Grupo PC: paresia do canal ≥ 25%; Grupo PMC: paresia mínima do canal < 25%). As características clínicas foram comparadas entre os dois grupos e o diagnóstico final foi revisado após o acompanhamento de longo prazo de ambos os grupos. Resultados De 201 pacientes, 57 apresentaram paresia mínima do canal (PC < 25%) e 144 apresentaram paresia definitiva do canal (PC ≥ 25%). Quarenta e oito pacientes (23,8%) apresentaram outro tipo de vertigem e foram diagnosticados novamente. Sintomas vestibulares recorrentes foram observados com mais frequência nos pacientes com paresia mínima do canal (p = 0,027). Sintomas recorrentes no mesmo lado afetado foram observados com mais frequência no Grupo PC. A proporção de diagnóstico final não foi diferente entre os dois grupos. Conclusão Os pacientes com paresia mínima do canal foram mais propensos a apresentar vertigem recorrente que os pacientes com paresia do canal definitiva. Não houve diferença significante na distribuição dos diagnósticos finais entre os dois grupos quando houve recorrência da vertigem.

The effects of real and simulated microgravity on cellular mitochondrial function.

Astronauts returning from space shuttle missions or the International Space Station have been diagnosed with various health problems such as bone demineralization, muscle atrophy, cardiovascular deconditioning, and vestibular and sensory imbalance including visual acuity, altered metabolic and nutritional status, and immune system dysregulation. These health issues are associated with oxidative stress caused by a microgravity environment. Mitochondria are a source of reactive oxygen species (ROS). However, the molecular mechanisms through which mitochondria produce ROS in a microgravity environment remain unclear. Therefore, this review aimed to explore the mechanism through which microgravity induces oxidative damage in mitochondria by evaluating the expression of genes and proteins, as well as relevant metabolic pathways. In general, microgravity-induced ROS reduce mitochondrial volume by mainly affecting the efficiency of the respiratory chain and metabolic pathways. The impaired respiratory chain is thought to generate ROS through premature electron leakage in the electron transport chain. The imbalance between ROS production and antioxidant defense in mitochondria is the main cause of mitochondrial stress and damage, which leads to mitochondrial dysfunction. Moreover, we discuss the effects of antioxidants against oxidative stress caused by the microgravity environment space microgravity in together with simulated microgravity (i.e., spaceflight or ground-based spaceflight analogs: parabolic flight, centrifugal force, drop towers, etc.). Further studies should be taken to explore the effects of microgravity on mitochondrial stress-related diseases, especially for the development of new therapeutic drugs that can help increase the health of astronauts on long space missions.

Spike Proteins of SARS-CoV-2 Induce Pathological Changes in Molecular Delivery and Metabolic Function in the Brain Endothelial Cells.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the coronavirus disease (COVID-19), is currently infecting millions of people worldwide and is causing drastic changes in people's lives. Recent studies have shown that neurological symptoms are a major issue for people infected with SARS-CoV-2. However, the mechanism through which the pathological effects emerge is still unclear. Brain endothelial cells (ECs), one of the components of the blood-brain barrier, are a major hurdle for the entry of pathogenic or infectious agents into the brain. They strongly express angiotensin converting enzyme 2 (ACE2) for its normal physiological function, which is also well-known to be an opportunistic receptor for SARS-CoV-2 spike protein, facilitating their entry into host cells. First, we identified rapid internalization of the receptor-binding domain (RBD) S1 domain (S1) and active trimer (Trimer) of SARS-CoV-2 spike protein through ACE2 in brain ECs. Moreover, internalized S1 increased Rab5, an early endosomal marker while Trimer decreased Rab5 in the brain ECs. Similarly, the permeability of transferrin and dextran was increased in S1 treatment but decreased in Trimer, respectively. Furthermore, S1 and Trimer both induced mitochondrial damage including functional deficits in mitochondrial respiration. Overall, this study shows that SARS-CoV-2 itself has toxic effects on the brain ECs including defective molecular delivery and metabolic function, suggesting a potential pathological mechanism to induce neurological signs in the brain.

Hypergravity-induced malfunction was moderated by the regulation of NMDA receptors in the vestibular nucleus.

Gravity alteration is one of the critical environmental factors in the space, causing various abnormal behaviors related with the malfunctioned vestibular system. Due to the high plastic responses in the central vestibular system, the behavioral failures were resolved in a short period of time (in approx. 72 h). However, the plastic neurotransmission underlying the functional recovery is still elusive. To understand the neurotransmitter-induced plasticity under hypergravity, the extracellular single neuronal recording and the immunohistochemistry were conducted in the vestibular nucleus (VN). The animals were grouped as control, 24-h, 72-h, and 15-day exposing to 4G-hypergravity, and each group had two subgroups based on the origins of neuronal responses, such as canal and otolith. The averaged firing rates in VN showed no significant difference in the subgroups (canal-related: p > 0.105, otolith-related: p > 0.138). Meanwhile, the number of NMDAr was significantly changed by the exposing duration to hypergravity. The NMDAr decreased in 24 h (p = 1.048 × 10-9), and it was retrieved in 72 h and 15 days (p < 4.245 × 10-5). Apparently, the reduction and the retrieval in the number of NMDAr were synchronized with the generation and recovery of the abnormal behaviors. Thus, the plasticity to resolve the hypergravity-induced malfunctional behaviors was conducted by regulating the number of NMDAr.

Neural Interruption by Unilateral Labyrinthectomy Biases the Directional Preference of Otolith-Related Vestibular Neurons.

BACKGROUND: The directional preference of otolith-related vestibular neurons elucidates the neuroanatomical link of labyrinths, but few direct experimental data have been provided. METHODS: The directional preference of otolith-related vestibular neurons was measured in the vestibular nucleus using chemically induced unilateral labyrinthectomy (UL). For the model evaluation, static and dynamic behavioral tests as well as a histological test were performed. Extracellular neural activity was recorded for the neuronal responses to the horizontal head rotation and the linear head translation. RESULTS: Seventy-seven neuronal activities were recorded, and the total population was divided into three groups: left UL (20), sham (35), and right UL (22). Based on directional preference, two sub-groups were again classified as contra- and ipsi-preferred neurons. There was no significance in the number of those sub-groups (contra-, 15/35, 43%; ipsi-, 20/35, 57%) in the sham (p = 0.155). However, more ipsi-preferred neurons (19/22, 86%) were observed after right UL (p = 6.056 × 10-5), while left UL caused more contra-preferred neurons (13/20, 65%) (p = 0.058). In particular, the convergent neurons mainly led this biased difference (ipsi-, 100% after right UL and contra-, 89% after left UL) (p < 0.002). CONCLUSIONS: The directional preference of the neurons depended on the side of the lesion, and its dominance was mainly led by the convergent neurons.