Effects of tris (2-chloroethyl) phosphate exposure on gut microbiome using the simulator of the human intestinal microbial ecosystem (SHIME).

Tris (2-chloroethyl) phosphate (TCEP) has been widely used, and its health risk has received increasing attention. However, the rare research has been conducted on the effects of TCEP exposure on changes in the structure of the human gut microbiome and metabolic functions. In this experiment, Simulator of the human intestinal microbial ecosystem (SHIME) was applied to explore the influences of TCEP on the human gut bacteria community and structure. The results obtained from high-throughput sequencing of 16S rRNA gene have clearly revealed differences among control and exposure groups. High-dose TCEP exposure increased the Shannon and Simpson indexes in the results of α-diversity of the gut microbiome. At phylum level, Firmicutes occupied a higher proportion of gut microbiota, while the proportion of Bacteroidetes decreased. In the genus-level analysis, the relative abundance of Bacteroides descended with the TCEP exposure dose increased in the ascending colon, while the abundances of Roseburia, Lachnospira, Coprococcus and Lachnoclostridium were obviously correlated with exposure dose in each colon. The results of short chain fatty acids (SCFAs) showed a remarkable effect on the distribution after TCEP exposure. In the ascending colon, the control group had the highest acetate concentration (1.666 ± 0.085 mg⋅mL-1), while acetate concentrations in lose-dose medium-dose and high-doseTCEP exposure groups were 1.119 ± 0.084 mg⋅mL-1, 0.437 ± 0.053 mg⋅mL-1 and 0.548 ± 0.106 mg⋅mL-1, respectively. TCEP exposure resulted in a decrease in acetate and propionate concentrations, while increasing butyrate concentrations in each colon. Dorea, Fusicatenibacter, Kineothrix, Lachnospira, and Roseburia showed an increasing tendency in abundance under TCEP exposure, while they had a negatively correlation with acetate and propionate concentrations and positively related with butyrate concentrations. Overall, this study confirms that TCEP exposure alters both the composition and metabolic function of intestinal microbial communities, to arouse public concern about its negative health effects.

Functional reorganization of brain regions into a network in childhood absence epilepsy: A magnetoencephalography study.

OBJECTIVE: Epilepsy is considered as a network disorder. However, it is unknown how normal brain activity develops into the highly synchronized discharging activity seen in disordered networks. This study aimed to explore the epilepsy brain network and the significant re-combined brain areas in childhood absence epilepsy (CAE). METHODS: Twenty-two children with CAE were recruited to study the neural source activity during ictal-onset and interictal periods at frequency bands of 1-30 Hz and 30-80 Hz with magnetoencephalography (MEG) scanning. Accumulated source imaging (ASI) was used to analyze the locations of neural source activity and peak source strength. RESULTS: Most of the participants had more active source activity locations in the ictal-onset period rather than in the interictal period, both at 1-30 Hz and 30-80 Hz. The frontal lobe (FL), the temporo-parietal junction (T-P), and the parietal lobe (PL) became the main active areas of source activity during the ictal period, while the precuneus (PC), cuneus, and thalamus were relatively inactive. CONCLUSIONS: Some brain areas become more excited and have increased source activity during seizures. These significant brain regions might be re-combined to form an epilepsy network that regulates the process of absence seizures. SIGNIFICANCE: The study confirmed that important brain regions are reorganized in an epilepsy network, which provides a basis for exploring the network mechanism of CAE development. Imaging findings may provide a reference for clinical characteristics.

Influencing electroclinical features and prognostic factors in patients with anti-NMDAR encephalitis: a cohort follow-up study in Chinese patients.

The clinical manifestations of patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis in East China and factors associated with prognosis were analyzed. A retrospective study of 106 patients (58 females; 48 males) with anti-NMDAR encephalitis in East China was carried out from June 2015 to February 2019. Clinical features and factors influencing outcomes were reviewed. Behavioral changes were observed in 74.5% (79/106) of patients, and comprised the initial symptoms in 61.3% (65/106). Seizures were observed in 67% (71/106) of patients, and served as initial symptoms in 31.1% (33/106). A total of 54.9% (39/71) of seizures were focal seizures. More clinical symptoms were observed in female patients than in male patients (P = 0.000). Similarly, background activity (BA) with high cerebrospinal fluid (CSF) antibody titers at the peak stage was more severe in female patients than in male patients (P = 0.000). The Binary logistic regression and receiver operating characteristic (ROC) curve analyses revealed the factors associated with poor outcomes included consciousness disturbance (OR 4.907, 95% CI 1.653-14.562, P = 0.004; area: 65.4%, sensitivity: 44.2%, specificity: 86.5%, P = 0.014), EEG BA (OR 3.743, 95% CI 1.766-7.932, P = 0.001; area: 76.6%, sensitivity: 73%, specificity: 75%, P = 0.000), number of symptoms (OR 2.911, 95% CI 1.811-4.679, P = 0.000; area: 77.1%, sensitivity: 59.5%, specificity: 78.6%, P = 0.000) and CSF antibody titer (OR 31.778, 95% CI 8.891-113.57, P = 0.000; area: 83.9%, sensitivity: 89.2%, specificity: 78.6%, P = 0.000). EEG BA and number of symptoms were associated with CSF antibody titers. Consciousness disturbances, EEG BA, number of symptoms and CSF antibody titers served as predictors of poor outcomes.

Multifrequency Dynamics of Cortical Neuromagnetic Activity Underlying Seizure Termination in Absence Epilepsy.

PURPOSE: This study aimed to investigate the spectral and spatial signatures of neuromagnetic activity underlying the termination of absence seizures. METHODS: Magnetoencephalography (MEG) data were recorded from 18 drug-naive patients with childhood absence epilepsy (CAE). Accumulated source imaging (ASI) was used to analyze MEG data at the source level in seven frequency ranges: delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta (12-30 Hz), gamma (30-80 Hz), ripple (80-250 Hz), and fast ripple (250-500 Hz). RESULT: In the 1-4, 4-8, and 8-12 Hz ranges, the magnetic source during seizure termination appeared to be consistent over the ictal period and was mainly localized in the frontal cortex (FC) and parieto-occipito-temporal junction (POT). In the 12-30 and 30-80 Hz ranges, a significant reduction in source activity was observed in the frontal lobe during seizure termination as well as a decrease in peak source strength. The ictal peak source strength in the 1-4 Hz range was negatively correlated with the ictal duration of the seizure, whereas in the 30-80 Hz range, it was positively correlated with the course of epilepsy. CONCLUSION: The termination of absence seizures is associated with a dynamic neuromagnetic process. Frequency-dependent changes in the FC were observed during seizure termination, which may be involved in the process of neural network interaction. Neuromagnetic activity in different frequency bands may play different roles in the pathophysiological mechanism during absence seizures.

Altered cerebral blood flow in patients with anti-NMDAR encephalitis.

OBJECTIVE: This study aimed to identify to resting-state cerebral blood flow (CBF) connectivity alterations in patients with anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis. METHODS: Three-dimensional pseudo-continuous arterial spin labeling (pcASL) imaging was performed to measure the resting-state CBF in 23 patients with anti-NMDAR encephalitis at the peak stage of the disease and 32 healthy subjects. CBF was normalized to reduce variations among subjects. CBF was compared between the groups, and the correlations between the CBF alterations and clinical parameters were assessed. Differences in CBF connectivity in specific brain regions were also compared between groups. RESULTS: Compared with the healthy subjects, the patients with anti-NMDAR encephalitis exhibited increased CBF in the left insula (L_insula), left superior temporal lobe (L_STL), L_hippocampus, L_pallidum, bilateral putamen (Bi_putamen), and Bi_caudate, and decreased CBF in the bilateral precuneus (Bi_Pc) and bilateral occipital lobe (Bi_OL) (P < 0.05, FEW corrected). Compared with healthy subjects, the patients with anti-NMDAR encephalitis exhibited increased negative CBF connectivity between the Bi_Pc, Bi_OL and L_TL, L_insula (P < 0.05, FEW corrected). Anti-NMDAR encephalitis patients with behavioral changes exhibited higher CBF in the L_insula and lower CBF in the R_Pc, Bi_calcarine, Bi_cuneus, and Bi_lingual than patients without behavioral changes and health controls. The ROC curve shows changed CBF in the L_insula, and R_Pc, Bi_calcarine, Bi_cuneus, and Bi_lingual served as a predictor of behavioral changes in patients with anti-NMDAR encephalitis. CONCLUSIONS: Our results suggest that patients with anti-NMDAR encephalitis may exhibit both regional CBF abnormalities and deficits in CBF connectivity, which may underlie the clinical symptoms of anti-NMDAR encephalitis.

Dynamic Neuromagnetic Network Changes of Seizure Termination in Absence Epilepsy: A Magnetoencephalography Study.

Objective: With increasing efforts devoted to investigating the generation and propagation mechanisms of spontaneous spike and wave discharges (SWDs), little attention has been paid to network mechanisms associated with termination patterns of SWDs to date. In the current study, we aimed to identify the frequency-dependent neural network dynamics during the offset of absence seizures. Methods: Fifteen drug-naïve patients with childhood absence epilepsy (CAE) were assessed with a 275-Channel Magnetoencephalography (MEG) system. MEG data were recorded during and between seizures at a sampling rate of 6,000 Hz and analyzed in seven frequency bands. Source localization was performed with accumulated source imaging. Granger causality analysis was used to evaluate effective connectivity networks of the entire brain at the source level. Results: At the low-frequency (1-80 Hz) bands, activities were predominantly distributed in the frontal cortical and parieto-occipito-temporal junction at the offset transition periods. The high-frequency oscillations (HFOs, 80-500 Hz) analysis indicated significant source localization in the medial frontal cortex and deep brain areas (mainly thalamus) during both the termination transition and interictal periods. Furthermore, an enhanced positive cortico-thalamic effective connectivity was observed around the discharge offset at all of the seven analyzed bands, the direction of which was primarily from various cortical regions to the thalamus. Conclusions: Seizure termination is a gradual process that involves both the cortices and the thalamus in CAE. Cortico-thalamic coupling is observed at the termination transition periods, and the cerebral cortex acts as the driving force.

Neuromagnetic correlates of audiovisual word processing in the developing brain.

The brain undergoes enormous changes during childhood. Little is known about how the brain develops to serve word processing. The objective of the present study was to investigate the maturational changes of word processing in children and adolescents using magnetoencephalography (MEG). Responses to a word processing task were investigated in sixty healthy participants. Each participant was presented with simultaneous visual and auditory word pairs in "match" and "mismatch" conditions. The patterns of neuromagnetic activation from MEG recordings were analyzed at both sensor and source levels. Topography and source imaging revealed that word processing transitioned from bilateral connections to unilateral connections as age increased from 6 to 17 years old. Correlation analyses of language networks revealed that the path length of word processing networks negatively correlated with age (r = -0.833, p < 0.0001), while the connection strength (r = 0.541, p < 0.01) and the clustering coefficient (r = 0.705, p < 0.001) of word processing networks were positively correlated with age. In addition, males had more visual connections, whereas females had more auditory connections. The correlations between gender and path length, gender and connection strength, and gender and clustering coefficient demonstrated a developmental trend without reaching statistical significance. The results indicate that the developmental trajectory of word processing is gender specific. Since the neuromagnetic signatures of these gender-specific paths to adult word processing were determined using non-invasive, objective, and quantitative methods, the results may play a key role in understanding language impairments in pediatric patients in the future.

Disrupted topological organization of structural brain networks in childhood absence epilepsy.

Childhood absence epilepsy (CAE) is the most common paediatric epilepsy syndrome and is characterized by frequent and transient impairment of consciousness. In this study, we explored structural brain network alterations in CAE and their association with clinical characteristics. A whole-brain structural network was constructed for each participant based on diffusion-weighted MRI and probabilistic tractography. The topological metrics were then evaluated. For the first time, we uncovered modular topology in CAE patients that was similar to healthy controls. However, the strength, efficiency and small-world properties of the structural network in CAE were seriously damaged. At the whole brain level, decreased strength, global efficiency, local efficiency, clustering coefficient, normalized clustering coefficient and small-worldness values of the network were detected in CAE, while the values of characteristic path length and normalized characteristic path length were abnormally increased. At the regional level, especially the prominent regions of the bilateral precuneus showed reduced nodal efficiency, and the reduction of efficiency was significantly correlated with disease duration. The current results demonstrate significant alterations of structural networks in CAE patients, and the impairments tend to grow worse over time. Our findings may provide a new way to understand the pathophysiological mechanism of CAE.

Quantify neuromagnetic network changes from pre-ictal to ictal activities in absence seizures.

OBJECTIVE: The cortico-thalamo-cortical network plays a key role in childhood absence epilepsy (CAE). However, the exact interaction between the cortex and the thalamus remains incompletely understood. This study aimed to investigate the dynamic changes of frequency-dependent neural networks during the initialization of absence seizures. METHODS: Magnetoencephalography data from 14 patients with CAE were recorded during and between seizures at a sampling rate of 6000Hz and analyzed in seven frequency bands. Neuromagnetic sources were volumetrically scanned with accumulated source imaging. Effective connectivity networks of the entire brain, including the cortico-thalamo-cortical network, were evaluated at the source level through Granger causality analysis. RESULTS: The low-frequency (1-80Hz) activities showed significant frontal cortical and parieto-occipito-temporal junction source localization around seizures. The high-frequency (80-250Hz) oscillations showed predominant activities consistently localized in deep brain areas and medial frontal cortex. The increased cortico-thalamic effective connectivity was observed around seizures in both low- and high-frequency ranges. The direction was predominantly from the cortex to the thalamus at the early time, although the cortex that drove connectivity varied among subjects. CONCLUSIONS: The cerebral cortex plays a key role in driving the cortico-thalamic connections at the early portion of the initialization of absence seizures. The oscillatory activities in the thalamus could be triggered by networks from various regions in the cortex. SIGNIFICANCE: The dynamic changes of neural network provide evidences that absence seizures are probably resulted from cortical initialized cortico-thalamic network.

Altered Effective Connectivity Network in Childhood Absence Epilepsy: A Multi-frequency MEG Study.

Using multi-frequency magnetoencephalography (MEG) data, we investigated whether the effective connectivity (EC) network of patients with childhood absence epilepsy (CAE) is altered during the inter-ictal period in comparison with healthy controls. MEG data from 13 untreated CAE patients and 10 healthy controls were recorded. Correlation analysis and Granger causality analysis were used to construct an EC network at the source level in eight frequency bands. Alterations in the spatial pattern and topology of the network in CAE were investigated by comparing the patients with the controls. The network pattern was altered mainly in 1-4 Hz, showing strong connections within the frontal cortex and weak connections in the anterior-posterior pathways. The EC involving the precuneus/posterior cingulate cortex (PC/PCC) significantly decreased in low-frequency bands. In addition, the parameters of graph theory were significantly altered in several low- and high-frequency bands. CAE patients display frequency-specific abnormalities in the network pattern even during the inter-ictal period, and the frontal cortex and PC/PCC might play crucial roles in the pathophysiology of CAE. The EC network of CAE patients was over-connective and random during the inter-ictal period. This study is the first to reveal the frequency-specific alteration in the EC network during the inter-ictal period in CAE patients. Multiple-frequency MEG data are useful in investigating the pathophysiology of CAE, which can serve as new biomarkers of this disorder.

Structural Abnormalities in Childhood Absence Epilepsy: Voxel-Based Analysis Using Diffusion Tensor Imaging.

Purpose: Childhood absence epilepsy (CAE) is a common syndrome of idiopathic generalized epilepsy. However, little is known about the brain structural changes in this type of epilepsy, especially in the default mode network (DMN) regions. This study aims at using the diffusion tensor imaging (DTI) technique to quantify structural abnormalities of DMN nodes in CAE patients. Method: DTI data were acquired in 14 CAE patients (aged 8.64 ± 2.59 years, seven females and seven males) and 16 age- and sex-matched healthy controls. The data were analyzed using voxel-based analysis (VBA) and statistically compared between patients and controls. Pearson correlation was explored between altered DTI metrics and clinical parameters. The difference of brain volumes between patients and controls were also tested using unpaired t-test. Results: Patients showed significant increase of mean diffusivity (MD) and radial diffusivity (RD) in left medial prefrontal cortex (MPFC), and decrease of fractional anisotropy (FA) in left precuneus and axial diffusivity (AD) in both left MPFC and precuneus. In correlation analysis, MD value from left MPFC was positively associated with duration of epilepsy. Neither the disease duration nor the seizure frequency showed significant correlation with FA values. Between-group comparison of brain volumes got no significant difference. Conclusion: The findings indicate that structural impairments exist in DMN regions in children suffering from absence epilepsy and MD values positively correlate with epilepsy duration. This may contribute to understanding the pathological mechanisms of chronic neurological deficits and promote the development of new therapies for this disorder.

Multi-frequency analysis of brain connectivity networks in migraineurs: a magnetoencephalography study.

BACKGROUND: Although alterations in resting-state neural network have been previously reported in migraine using functional MRI, whether this atypical neural network is frequency dependent remains unknown. The aim of this study was to investigate the alterations of the functional connectivity of neural network and their frequency specificity in migraineurs as compared with healthy controls by using magnetoencephalography (MEG) and concepts from graph theory. METHODS: Twenty-three episodic migraine patients with and without aura, during the interictal period, and 23 age- and gender-matched healthy controls at resting state with eye-closed were studied with MEG. Functional connectivity of neural network from low (0.1-1 Hz) to high (80-250 Hz) frequency ranges was analyzed with topographic patterns and quantified with graph theory. RESULTS: The topographic patterns of neural network showed that the migraineurs had significantly increased functional connectivity in the slow wave (0.1-1 Hz) band in the frontal area as compared with controls. Compared with the migraineurs without aura (MwoA), the migraineurs with aura (MwA) had significantly increased functional connectivity in the theta (4-8 Hz) band in the occipital area. Graph theory analysis revealed that the migraineurs had significantly increased connection strength in the slow wave (0.1-1 Hz) band, increased path length in the theta (4-8 Hz) and ripple (80-250 Hz) bands, and increased clustering coefficient in the slow wave (0.1-1 Hz) and theta (4-8 Hz) bands. The clinical characteristics had no significant correlation with interictal MEG parameters. CONCLUSIONS: Results indicate that functional connectivity of neural network in migraine is significantly impaired in both low- and high-frequency ranges. The alteration of neural network may imply that migraine is associated with functional brain reorganization.

Neuromagnetic high-frequency oscillations correlate with seizure severity in absence epilepsy.

OBJECTIVE: This study quantified the clinical correlation of interictal and ictal neuromagnetic activities from low- to very-high-frequency ranges in childhood absence epilepsy (CAE). METHODS: Twelve patients with clinically diagnosed drug-naïve CAE were studied using a 275-channel whole-head magnetoencephalography (MEG) system. MEG data were digitized at 6000 Hz and analyzed at both sensor and source levels with multi-frequency analyses. RESULTS: Neuromagnetic changes from interictal to ictal periods predominantly occurred in medial prefrontal cortex and parieto-occipito-temporal junction in absence seizures. The changes were statistically significant in low-frequency bands only (<30 Hz, p<0.0001). There was a significant correlation between the source strength of ictal high-frequency oscillations (HFOs) in 200-1000 Hz and the number of daily seizures (r=0.734, p<0.01). CONCLUSIONS: CAE has focal neuromagnetic sources. The transition from interictal to ictal periods is associated with the elevation of low-frequency brain activities. The strength of HFOs reflects the severity of absence seizures. SIGNIFICANCE: Low- and high-frequency MEG signals reveal distinct brain activities in CAE. HFOs is a new biomarker for the study of absence seizures.

Sox17 facilitates the differentiation of mouse embryonic stem cells into primitive and definitive endoderm in vitro.

The Sox family of HMG (high mobility group)-box transcription factors are highly conserved in vertebrates. Sox members are involved in various developmental processes. Among them Sox17 has been demonstrated to function as an endoderm determinant in zebrafish and Xenopus, respectively. However, little is known about the role of Sox17 in mouse embryonic stem cell (ESC) differentiation. In our research, we investigated the effect of Sox17 on mouse ESC and embryoid body (EB) differentiation. The results demonstrated that Sox17 overexpression upregulated a set of endoderm-specific gene markers, suggesting that Sox17 overexpression induced an ESC differentiation program towards both primitive and definitive endoderm. We believe this finding brings new insights into the understanding of ESC differentiation and the organogenesis of endodermal derivatives.