Fluoride pollution—whether of geological or anthropogenic origin—disrupts gut microbiota–host homeostasis and compromises the intestinal barrier. We established an acute high-fluoride mouse model via intragastric NaF, integrating metagenomics, metabolomics, and molecular biological techniques to clarify the underlying mechanism of enhanced intestinal permeability caused by fluoride exposure in vivo. Mechanistically, high fluoride exposure activates the RhoA/ROCK signaling pathway, increases the level of phosphorylated myosin light chain (p-MLC), induces filamentous actin (F-actin) rearrangement, and disrupts the apical junctional complex (AJC)—characterized by downregulated expression or abnormal localization of AJC-related proteins (ZO-1, Claudin-1, β-catenin, Occludin). It also alters the morphology of intestinal epithelial cells, ultimately increasing ileal permeability. At the microbiota level, high fluoride disrupted the ileal microbiota; specifically, at the species level, Bifidobacterium sp. SO1 and Schaalia turicensis were identified as the key species with high specificity and high occupancy under fluoride exposure. Lactobacillus and Akkermansia were abnormally enriched in the intestines of mice exposed to fluoride. Metabolomic analysis revealed that high fluoride exposure enriched multiple pathways including linoleic acid metabolism and sphingolipid metabolism, altering the levels of 11 cytoskeleton-related metabolites. Correlation analysis confirmed that Bifidobacterium sp. SO1 and Schaalia turicensis were strongly correlated with damage phenotypes, pathway molecules, and metabolites, indicating that these two strains are closely associated with cytoskeleton changes and increased intestinal permeability under high fluoride exposure. Collectively, our findings reveal that gut microbiota drive fluoride-induced intestinal barrier dysfunction through the “microbiota–RhoA/ROCK–cytoskeleton” axis, highlighting a novel host–microbe interaction mechanism underlying environmental toxin–mediated gut injury.

High-altitude environments (> 2500 m) with low oxygen, low pressure, variable climate, large diurnal temperature differences, and high solar and ultraviolet radiation are risky to human health. Mice’s intestinal microbiota changes at high altitude may affect cognition via the gut–brain axis. Short-term high-altitude exposure may have positive effects on organisms. This study explores if short-term high-altitude exposure can protect working memory from restraint stress (RS) and the role of intestinal microbiota in this process. Forty-eight C57BL/6 mice aged eight weeks were divided into four groups: the Control group, RS group (S group), high altitude exposed group (HA group), and high-altitude exposed with RS group (HA-S group). High altitude was simulated via exposure to a low-pressure oxygen chamber at a simulated altitude of 3500–4000 m for 14 days. RS was simulated from days 22–29 and followed by the novel object recognition test to assess working memory. Blood for serum, prefrontal cortex, ileal sections for molecular analysis, and intestinal contents for 16S rRNA sequencing were collected. Compared to control mice that were not exposed to high altitude and did not experience RS, mice that were also exposed to high altitude and experienced restraint stress had significantly greater working memory deficits, whereas mice exposed only to high altitude did not show significant differences in working memory performance. Different gut microbial community structures were observed in these groups, with high altitude-exposed mice exhibiting higher α-diversity. In addition, the difference in β-diversity between restraint stress and high altitude exposed mice was significantly higher, indicating significant differences in microbial community composition. The major bacterial phyla identified were Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria, with Lactobacillus being more abundant in the restraint stress group, while Bifidobacterium and Muribaculum were relatively more abundant in the high-altitude exposed with restraint stress group, but the relative abundance of Lactobacillus was lower. Short-term high-altitude exposure might possibly protect working memory function by modulating intestinal function through the microbiota–gut–brain axis, with Lactobacillus perhaps contributing to alleviate working memory dysfunction induced by stress. This study may enhance our understanding of the microbiota-gut-brain axis in high-altitude environments and could offer new preventive and therapeutic insights for high-altitude-related health issues, possibly benefiting workers and explorers in such environments.

Rationale: Chronic exposure to high-fluoride drinking water impairs intestinal structure and function, potentially damaging extraluminal tissues via the gut-organ axis. However, how lifelong exposure to naturally occurring moderate-to-high-fluoride water affects intestinal cells and their underlying mechanisms remain unclear. Methods: Single-cell RNA sequencing identified cellular heterogeneity and candidate risk genes in the mouse ileum after 56 weeks of 50-ppm fluoride exposure. Cellchart was employed to analyze fluoride-altered cell communication patterns, and gut bacterial richness was ablated using broad-spectrum antibiotics to validate high fluoride-disrupted intercellular signaling pathways. Results: Fluoride exposure disrupted enterocyte trans-differentiation, affected metabolic health by restricting nutrient absorption, and activated antibacterial activity in enterocytes at the villus base. Downregulation of genes associated with rapid goblet-cell emptying and transmembrane mucin 3 in goblet cell impairs mucus and glycocalyx formation. Antimicrobial peptides, lectins, and lysozymes were reduced in fluoride-exposed Paneth and goblet cells. Fluorescence in situ hybridization demonstrated bacterial invasion of the epithelium following mucus barrier damage. Immunologically, fluoride-exposed T cells exhibit high scores for apoptosis, cell cycle suppression, inflammation, and high gut-homing gene expression. Fluoride exposure promoted somatic hypermutation and affinity selection in B-lineage cells while expanding plasma cells with high developmental potential. Ligand-receptor analysis revealed that activated enterocytes presented antigens to T cells via the MHC-II L-R signaling pathway, triggering downstream responses such as upregulating proinflammatory factors and cytotoxic molecules, and remodeling B-lineage cells. Broad-spectrum antibiotics depleted gut microbiota, reducing fluoride-induced gut microbial overgrowth and suppressing MHCII signaling in enterocytes and T/B cell activation-thereby decreasing proinflammatory cytokines and immunoglobulins. Conclusions: High-fluoride exposure disrupts the intestinal mucus barrier and gut microbiota homeostasis, leading to bacterial invasion of the epithelium that activates MHC-II signaling in absorptive enterocytes. Upregulated MHC-II signaling triggers intestinal immune cell activation and inflammation. These results reveal new intercellular interactions and communication hubs in intestinal cells under fluoride exposure.

IntroductionHigh-altitude environments have significant effects on brain function, particularly a decline in cognitive function, due to insufficient oxygen supply. The microbiome-gut-brain axis (MGBA) plays an important role in regulating cognitive function, but its specific mechanism of action in high-altitude environments is unclear. Therefore, the aim of this study was to investigate whether the probiotic Lactobacillus johnsonii HL79 could alleviate high altitude-induced cognitive dysfunction in mice by modulating the gut microbiota.Methods and resultsSixty C57BL/6 mice aged 8 weeks were randomly divided into four groups: control, high altitude exposure (HA), HL79-treated (P), and high altitude exposure plus HL79-treated (HAP). the HA and HAP groups were exposed to a low-pressure oxygen chamber at a simulated altitude of 3,500–4,000 m for 20 weeks, while the Control and P groups were maintained at the normal barometric pressure level. Probiotic HL79 was given daily by gavage in the P and HAP groups, while saline gavage was given daily in the other two groups. The cognitive functions of the mice were assessed by new object recognition test and elevated plus maze test. The results showed that HL79 treatment significantly improved the working memory abilities of high altitude exposed mice. In addition, HL79 treatment improved antioxidant capacity, decreased malondialdehyde (MDA) content, and increased superoxide dismutase (SOD) and catalase (CAT) activities in serum and whole brain tissue. Gut microbiota analysis showed that HL79 was able to modulate the structure of gut microbiota and increase the relative abundance of beneficial flora in high altitude environment.ConclusionLactobacillus johnsonii HL79 significantly ameliorated cognitive dysfunction in high altitude-exposed mice by modulating the gut microbiota and antioxidant capacity, further confirming the important role of MGBA in high altitude environment.

High fluoride exposure was widely demonstrated to be related with brain memory impairment. Since the absorption of F- enters the body mainly through the gastrointestinal tract, studying the effects of excessive intake of fluoride on brain memory function in various gut microbiome states might have profound implications for the prevention of fluorosis because growing evidence revealed the significance of the “microbiota-gut-brain” axis (MGBA). In the present study, we aimed to illustrate the potential mechanism of gut microbiota on high fluoride exposure-induced hippocampal lesions and spatial memory dysfunction in mice by the various intestinal microecological environments, which were constructed by antibiotic treatment. Mice fed with normal (CG1 and Exp1 groups) or sodium-fluoride (CG2 and Exp2 groups; 24 mg/kg sodium fluoride per mouse) by gavage administration with or without antibiotic treatments, a combination of metronidazole (1 g/L) and ciprofloxacin (0.2 g/L) in drinking water. Mice gavaged with excessive sodium fluoride alone exhibited reduced weight gain, hippocampal tissue damages, spatial memory levels dysfunction, impaired intestinal permeability, decreased inflammatory cytokines expression and antioxidant capability in the hippocampal and ileal tissues. In contrast, antibiotic intervention significantly reversed these high fluoride exposure-induced hippocampal and ileal changes.16S rRNA high throughput sequencing found that ileal microbiota were dominated by abundant taxa, which is conducive to constructing microbial interaction networks and module communities, and identifying keystone species targeted by high fluoride exposure compared with colonic microbiome. In addition, the microbial community composition and assembly mechanism of ileal microbiome under the effects of antibiotics were suitable for revealing the characteristics of high fluoride environment. In the later analysis, Lactobacillus, Staphylococcus, Muribaculaceae and Robinsoniella were considered as the keystone species targeted by high fluoride-exposed mice based on the analysis of network node properties and niche overlap of ileal microbes. Spearman rank correlation demonstrated that these keystone species had significant effects on hippocampal memory levels and intestinal health, as well as microbial communities functions. Compared to previous researches, this study further revealed intestinal microbial coummunity mediated the underlying mechanism through antibiotic treatment against high fluoride-induce hippocampal spatial memory impairment.

Based on the microbiota-gut-brain axis (MGBA) hypothesis, probiotics play an increasingly important role in treating various psychiatric disorders. Schizophrenia (SCZ) is a common mental disease with a complex pathogenesis and is challenging to treat. Although studies have elucidated the mechanisms associated with the interactions between the microbiota-gut-brain axis and SCZ, few have specifically used probiotics as a therapeutic intervention for SCZ. Accordingly, the current study determines whether L. johnsonii YH1136 effectively prevents SCZ-like behavior in mice and identifies the associated key microbes and metabolites. An SCZ mouse model was established by intraperitoneal injection of MK-801; L. johnsonii YH1136 was administered via oral gavage. L. johnsonii YH1136 significantly improves abnormal behaviors, including psychomotor hyperactivity and sociability and alleviates aberrant enzyme expression associated with tryptophan metabolism in SCZ mice. Additionally, L. johnsonii YH1136 upregulates hippocampal brain-derived neurotrophic factor (BDNF) levels while downregulating tryptophan 2,3-dioxygenase (TDO2), indoleamine-pyrrole 2,3-dioxygenase 1 (IDO1), kynurenine aminotransferase 1 (KAT1). Subsequent 16S rRNA sequencing of intestinal contents suggests that L. johnsonii YH1136 modulates the gut flora structure and composition by increasing the relative abundance of Lactobacillus and decreasing Dubosiella in SCZ mice. N-acetylneuraminic acid and hypoxanthine are the key serum metabolites mediating the interaction between the MGBA and SCZ. These results partially reveal the mechanism underlying the effects of L. johnsonii YH1136 on SCZ-like behavior in mice, supporting the development of therapeutic L. johnsonii probiotic formulations against SCZ.

Plateau environment represents a common terrestrial characterized by multistress conditions including hypobaric hypoxia, low temperature, and intense radiation, yet sustain over 100 million permanent or transient inhabitants. While this extreme environment exerts profound impacts on cerebral architecture and gut microbiota homeostasis, precipitating cognitive deficits and microbiome-derived intestinal pathologies, the mechanistic interplay between plateau environment adaptation and microbial dynamics remains contentious. Here, we employ a microbiota-gut-brain axis framework to investigate whether probiotic intervention can ameliorate hippocampal impairments induced by simulated plateau environment exposure (3500-4000 m) in mice. Through simulated plateau environment exposure experiments, we revealed that extreme high-altitude conditions induced hippocampal memory dysfunction in mice, exacerbated oxidative stress damage in hippocampal tissues, and altered synaptic plasticity-related biomarkers including CREB transcription factor, BDNF protein levels, and electrophysiological power spectra. Administration of HL79 alleviated these burdens, including memory dysfunction and tissue damage, though complete reversal was not achieved. Combined hippocampal transcriptomic analyses suggested that HL79's beneficial effects primarily involved modulation of lipid-related gene expression in the hippocampus, consistent with prior reports of plateau environmental impacts on gene expression. Serum metabolomic results further reinforced this inference that differential metabolites regulated by HL79 are mainly enriched in bile secretion, taurine and hypotaurine metabolism, linoleic acid metabolism, and PPAR signaling pathways, though the precise regulatory mechanisms require further elucidation. This research provides a novel microbiota-gut-brain axis-based regulatory strategy for adaptation to extreme plateau environments and offers new evidence for understanding the relationship between gut microbiota and plateau environment adaptation at high elevations.

Motor imagery (MI) is a cognitive process wherein an individual mentally rehearses a specific movement without physically executing it. Recently, MI-based brain-computer interface (BCI) has attracted widespread attention. However, accurate decoding of MI and understanding of neural mechanisms still face huge challenges. These seriously hinder the clinical application and development of BCI systems based on MI. Thus, it is very necessary to develop new methods to decode MI tasks. In this work, we propose a multi-branch convolutional neural network (MBCNN) with a temporal convolutional network (TCN), an end-to-end deep learning framework to decode multi-class MI tasks. We first used MBCNN to capture the MI electroencephalography signals information on temporal and spectral domains through different convolutional kernels. Then, we introduce TCN to extract more discriminative features. The within-subject cross-session strategy is used to validate the classification performance on the dataset of BCI Competition IV-2a. The results showed that we achieved 75.08% average accuracy for 4-class MI task classification, outperforming several state-of-the-art approaches. The proposed MBCNN-TCN-Net framework successfully captures discriminative features and decodes MI tasks effectively, improving the performance of MI-BCIs. Our findings could provide significant potential for improving the clinical application and development of MI-based BCI systems.

BackgroundHyperuricemia (HUA) is a prevalent metabolic disorder whose development is associated with intestinal microbiota. Therefore, probiotics have emerged as a potential and safe approach for lowering uric acid (UA) levels. However, the underlying mechanisms of many effective probiotic strains remain unknown.Methods and resultsC57BL/6 mice were randomly divided into two groups: control and model groups. The model group received 12 weeks of potassium oxonate. Through 16s sequencing we found that HUA resulted in a significant decrease in the total diversity of all intestinal segments. When each intestinal segment was analyzed individually, the reduction in diversity was only significant in the cecum and colon sections. RDA analysis showed that lactobacilli in the rat colon exhibited a strong correlation with model group, suggesting that Lactobacillus may play an important role in HUA. Consequently, the preventive effects of Lactobacillus johnsonii YH1136 against HUA were investigated. C57BL/6 mice were randomly divided into three groups: control, model and YH1136 groups. The results showed that administering Lactobacillus johnsonii YH1136 effectively reduced serum UA levels in vivo by inhibiting hepatic xanthine oxidase (XOD) activity and promoting renal ABCG2 transporter expression. Moreover, supplementation with Lactobacillus johnsonii YH1136 significantly ameliorated pathological damage in the kidney and liver, thereby reducing UA accumulation.ConclusionHyperuricemia is accompanied by an altered composition of multiple gut bacteria, of which Lactobacillus is a key genus. Lactobacillus johnsonii YH1136 may ameliorate renal involvement in HUA via the gut-kidney axis.

Autism spectrum disorder (ASD) is a developmental disorder involving regional changes and local neural disturbances. However, few studies have investigated the dysfunctional phenomenon across different age stages. This study explores the structural and functional brain changes across different developmental stages in individuals with ASD, focusing on childhood (6–12 years), adolescence (12–18 years), and adulthood (18 + years). Using a comprehensive set of neuroimaging metrics, including modulated and non-modulated voxel-based morphometry (VBM), regional homogeneity (ReHo), amplitude of low-frequency fluctuation (ALFF), and fractional ALFF (fALFF), we identified significant stage-specific alterations in both VBM and functional measurements. Our results reveal that ASD is associated with progressive and stage-specific abnormalities in brain structure and function, with distinct patterns emerging at each developmental stage. Specifically, we observed significant modulated VBM reductions in the precuneus, lentiform nucleus, and inferior parietal lobule, accompanied by increases in the midbrain and sub-gyral regions. Moreover, we observed unmodulated VBM increment in regions including lentiform nucleus and thalamus. Functionally, ReHo analyses demonstrated disrupted local synchronization in the medial frontal gyrus, while ALFF and fALFF metrics highlighted altered spontaneous brain activity in the sub-gyral and sub-lobar. Finally, correlation analyses revealed that stage-specific findings are closely linked to clinical social- and behavior-related scores, with VBM in the inferior parietal lobule and putamen as well as ReHo in supplemental motor area being significantly associated with restrictive repetitive behaviors in childhood. These findings underscore the importance of considering age-specific brain changes when studying ASD and suggest that targeted interventions may be necessary at different developmental stages.

Fluoride exposure is widespread worldwide and poses a significant threat to organisms, particularly to their gastrointestinal tracts. However, due to limited knowledge of the mechanism of fluoride induced intestinal injury, it has been challenging to develop an effective treatment. To address this issue, we used a series of molecular biology in vitro and in vivo experiments. NaF triggered m6A mediated ferroptosis to cause intestinal damage. Mechanistically, NaF exposure increased the m6A level of SLC7A11 mRNA, promoted YTHDF2 binding to m6A-modified SLC7A11 mRNA, drove the degradation of SLC7A11 mRNA, and led to a decrease in its protein expression, which eventually triggers ferroptosis. Moreover, NaF aggravated ferroptosis of the colon after antibiotics destroyed the composition of gut microbiota. 16 S rRNA sequencing and SPEC-OCCU plots, Zi-Pi relationships, and Spearman correlation coefficients verified that Lactobacillus murinus (ASV54, ASV58, and ASV82) plays a key role in the response to NaF-induced ferroptosis. Collectively, NaF-induced gut microbiota alteration mediates severe intestinal cell injury by inducing m6A modification-mediated ferroptosis. Our results highlight a key mechanism of the gut in response to NaF exposure and suggest a valuable theoretical basis for its prevention and treatment.

Download This Paper Open PDF in Browser Add Paper to My Library Share: Permalink Using these links will ensure access to this page indefinitely Copy URL The Enhancement of P300 Amplitude and Event-Related Gaba Release by Decision-Making in the Mpfc of Mice Neuroscience 29 Pages Posted: 27 Feb 2024 Publication Status: Under Review See all articles by Peimin YuanPeimin YuanUniversity of Electronic Science and Technology of China (UESTC)Qinjun LiuUniversity of Electronic Science and Technology of China (UESTC)Chanlin YiUniversity of Electronic Science and Technology of China (UESTC)Chunli ChenUniversity of Electronic Science and Technology of China (UESTC)Zhaojin ChenUniversity of Electronic Science and Technology of China (UESTC)Xi CaoSichuan Agricultural UniversityFali LiUniversity of Electronic Science and Technology of China (UESTC)Hesong WangSouthern Medical UniversityPeng XuUniversity of Electronic Science and Technology of China (UESTC)Ke ChenUniversity of Electronic Science and Technology of China (UESTC)Yang XiaUniversity of Electronic Science and Technology of China (UESTC)Daqing GuoUniversity of Electronic Science and Technology of China (UESTC)Bin ZhuUniversity of Electronic Science and Technology of China (UESTC) Abstract Although P300 (P3) is widely accepted as a useful tool in both medical and engineering fields, the mechanism it generates from cognition, and its neurochemical substrates, remain largely unknown. In the present study, the influence of exogenous stimuli and endogenous decision-making processes on P3 was obtained. According to the event-related potentials (ERPs) recorded from the medial prefrontal cortex (mPFC) of trained awake mice in the oddball paradigm, a significantly larger P3 fluctuation was observed in trials in which a low-probability target stimulus was presented or with the lick of mice. This result suggested that the presentation of stimuli and the decisions of mice may be able to influence P3 generation. The other purpose of this study is to explore the role of γ-aminobutyric acid (GABA) in the formation of P3 components during the ERP process. Enhanced P3 amplitude was detected along with stronger event-related GABA release (ERGR) after mice were stimulated by target tones or made the response decision. The results in this study indicated that P3 was influenced by the decision-making process and that GABA engaged directly with an earlier time in the P3 process. Note: Funding declaration: This work was supported by the STI 2030-Major Projects (#2022ZD0208500), the Key R&D projects of Science & Technology Department of Sichuan Province (#2023YFS0324), and Sichuan Science and Technology Program (Grant No. 2022NSFSC1481) Conflict of Interests: No Ethical Approval: All experimental procedures were in accordance with SfN’s Policies on the Use of Animals and Humans in Neuroscience Research, and experimental protocols were approved by the Ethical Committee on Animal Experimentation of the University of Electronic Science and Technology of China (UESTC). Keywords: Event-related potential, GABA, odd-ball paradigm, decision-making Suggested Citation: Suggested Citation Yuan, Peimin and Liu, Qinjun and Yi, Chanlin and Chen, Chunli and Chen, Zhaojin and Cao, Xi and Li, Fali and Wang, Hesong and Xu, Peng and Chen, Ke and Xia, Yang and Guo, Daqing and Zhu, Bin, The Enhancement of P300 Amplitude and Event-Related Gaba Release by Decision-Making in the Mpfc of Mice. Available at SSRN: https://ssrn.com/abstract=4732204 Peimin Yuan University of Electronic Science and Technology of China (UESTC) ( email ) 610054China Qinjun Liu University of Electronic Science and Technology of China (UESTC) ( email ) 610054China Chanlin Yi University of Electronic Science and Technology of China (UESTC) ( email ) 610054China Chunli Chen University of Electronic Science and Technology of China (UESTC) ( email ) 610054China Zhaojin Chen University of Electronic Science and Technology of China (UESTC) ( email ) 610054China Xi Cao Sichuan Agricultural University ( email ) Fali Li University of Electronic Science and Technology of China (UESTC) ( email ) Hesong Wang Southern Medical University ( email ) Peng Xu University of Electronic Science and Technology of China (UESTC) ( email ) Ke Chen University of Electronic Science and Technology of China (UESTC) ( email ) 610054China Yang Xia University of Electronic Science and Technology of China (UESTC) ( email ) 610054China Daqing Guo University of Electronic Science and Technology of China (UESTC) ( email ) 610054China Bin Zhu (Contact Author) University of Electronic Science and Technology of China (UESTC) ( email ) 610054China Download This Paper Open PDF in Browser Do you have negative results from your research you’d like to share? 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Millions of residents in areas with high-fluoride drinking water supply ingest excessive levels of fluoride for long periods. This study investigated the mechanisms and impacts of lifelong exposure to naturally occurring moderate-high-fluoride drinking water on spatial-memory function by studying mice in controlled experiments. Spatial-memory deficits and disorders of hippocampal neuronal electrical activity were observed in mice exposed to 25-ppm or 50-ppm-fluoride drinking water for 56 weeks, but not in adult or old mice exposed to 50 ppm fluoride for 12 weeks. Ultrastructural analysis showed severely damaged hippocampal mitochondria, evidenced by reduced mitochondrial membrane potential and ATP content. Mitochondrial biogenesis was impaired in fluoride-exposed mice, manifesting as a significantly reduced mtDNA content, mtDNA-encoded subunits mtND6 and mtCO1, and respiratory complex activities. Fluoride reduced expression of Hsp22, a beneficial mediator of mitochondrial homeostasis, and decreased levels of signaling for the PGC-1 alpha/TFAM pathway-which regulates mitochondrial biogenesis-and the NF-kappa beta/STAT3 pathway-which regulates mitochondrial respiratory chain enzyme activity. Hippocampus-specific Hsp22-overexpression improved fluoride-induced spatial-memory deficits by activating the PGC-1 alpha/TFAM and STAT3 signaling pathways, while Hsp22-silencing aggravated the deficits by inhibiting both pathways. Downregulation of Hsp22 plays a vital role in fluoride-induced spatialmemory deficits by impacting mtDNA-encoding subsets and mitochondrial respiratory chain enzyme activity.

The giant panda is a unique vulnerable mammal in western China, and its main cause of death is digestive system diseases regardless of whether these animals are in the wild or in captivity. The relationship between the intestinal flora and the host exerts a significant impact on the nutrition and health of the giant pandas.

Fluoride is a common contaminant of groundwater and agricultural commodity, which poses challenges to animal and human health. A wealth of research has demonstrated its detrimental effects on intestinal mucosal integrity; however, the underlying mechanisms remain obscure. This study aimed to investigate the role of the cytoskeleton in fluoride-induced barrier dysfunction. After sodium fluoride (NaF) treatment of the cultured Caco-2 cells, both cytotoxicity and cytomorphological changes (internal vacuoles or massive ablation) were observed. NaF lowered transepithelial electrical resistance (TEER) and enhanced paracellular permeation of fluorescein isothiocyanate dextran 4 (FD-4), indicating Caco-2 monolayers hyperpermeability. In the meantime, NaF treatment altered both the expression and distribution of the tight junction protein ZO-1. Fluoride exposure increased myosin light chain II (MLC2) phosphorylation and triggered actin filament (F-actin) remodeling. While inhibition of myosin II by Blebbistatin blocked NaF-induced barrier failure and ZO-1 discontinuity, the corresponding agonist Ionomycin had effects comparable to those of fluoride, suggesting that MLC2 serves as an effector. Given the mechanisms upstream of p-MLC2 regulation, further studies demonstrated that NaF activated RhoA/ROCK signaling pathway and myosin light chain kinase (MLCK), strikingly increasing the expression of both. Pharmacological inhibitors (Rhosin, Y-27632 and ML-7) reversed NaF-induced barrier breakdown and stress fiber formation. The role of intracellular calcium ions ([Ca2+]i) in NaF effects on Rho/ROCK pathway and MLCK was investigated. We found that NaF elevated [Ca2+]i, whereas chelator BAPTA-AM attenuated increased RhoA and MLCK expression as well as ZO-1 rupture, thus, restoring barrier function. Collectively, abovementioned results suggest that NaF induces barrier impairment via Ca2+-dependent RhoA/ROCK pathway and MLCK, which in turn triggers MLC2 phosphorylation and rearrangement of ZO-1 and F-actin. These results provide potential therapeutic targets for fluoride-induced intestinal injury.

Background: Colorectal cancer (CRC) is a harmful cancer with high morbidity and poor prognosis. There is growing evidence that RNA methylation is closely related to the occurrence of cancer and its malignant biological behavior. N6-methyladenosine (m6A) methylation is the most common RNA modification in eukaryotes, and its multiple regulatory mechanisms in CRC have been elucidated from multiple perspectives. At the same time, the role of 5-methylcytosine (m5C), another important and widely distributed methylation modification, in CRC is far from being elucidated. Methods: In this study, we used RNA immunoprecipitation sequencing combined with bioinformatics methods to identify the m5C peaks on messenger RNA (mRNA) in HCT15 cells and sh-NSUN2 HCT15 cells, understand which transcripts are modified by m5C, and characterize the distribution of m5C modifications. In addition, we performed further bioinformatics analysis of the detected data to initially clarify the potential function of these m5C-modified transcripts. Results: We found significant differences in the distribution of m5C between HCT15 cells and sh-NSUN2 HCT15 cells, suggesting that m5C is likely to play a key role in the occurrence and development of CRC. Furthermore, Gene Ontology (GO) enrichment analysis showed that genes altered by m5C were mainly enriched in phylogeny, synaptic membrane, and transcription factor binding. The Kyoto Encyclopedia of Genes and Genomes (KEGG)pathway analysis showed that the genes altered by m5C are enriched in ECM receptor interaction pathway, the circadian pathway, and the cAMP signaling pathway. Conclusion: Here, our study preliminarily revealed the different distribution patterns of m5C between HCT15 cell and sh-NSUN2 HCT15 cell. Our results open a new window to understand the role of m5C RNA methylation of mRNA in the development of CRC.

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Approximately 400 million people work and live in high-altitude areas and suffer from memory dysfunction worldwide. Until now, the role of the intestinal flora in plateau-induced brain damage has rarely been reported. To address this, we investigated the effect of intestinal flora on spatial memory impairment induced by high altitudes based on the microbiome-gut-brain axis theory. C57BL/6 mice were divided into three groups: control, high-altitude (HA), and high-altitude antibiotic treatment (HAA) group. The HA and HAA groups were exposed to a low-pressure oxygen chamber that simulated an altitude of 4000 m above sea level (m. a. s.l.) for 14 days, with the air pressure in the chamber set at 60-65 kPa. The results showed that spatial memory dysfunction induced by the high-altitude environment was aggravated by antibiotic treatment, manifesting as lowered escape latency and hippocampal memory-related proteins (BDNF and PSD-95). 16 S rRNA sequencing showed a remarkable separation of the ileal microbiota among the three groups. Antibiotic treatment exacerbated the reduced richness and diversity of the ileal microbiota in mice in the HA group. Lactobacillaceae were the main target bacteria and were significantly reduced in the HA group, which was exacerbated by antibiotic treatment. Meanwhile, reduced intestinal permeability and ileal immune function in mice exposed high-altitude environ-ment was also aggravated by antibiotic treatment, as indicated by the lowered tight junction proteins and IL-1 & beta; and IFN-& gamma; levels. Furthermore, indicator species analysis and Netshift co-analysis revealed that Lactobacillaceae (ASV11) and Corynebacteriaceae (ASV78, ASV25, and ASV47) play important roles in high-altitude exposure-induced memory dysfunction. Interestingly, ASV78 was negatively correlated with IL-1 & beta; and IFN-& gamma; levels, indicating that ASV78 may be induced by reduced ileal immune function, which mediates high-altitude envi-ronment exposure-induced memory dysfunction. This study provides evidence that the intestinal flora is effective in preventing brain dysfunction caused by exposure to high-altitude environments, suggesting a relationship between the microbiome-gut-brain axis and altitude exposure.

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder characterized by a core deficit in social processes. However, it is still unclear whether the core clinical symptoms of the disorder can be reflected by the temporal variability of resting-state network functional connectivity (FC). In this article, we examined the large-scale network FC temporal variability at the local region, within-network, and between-network levels using the fuzzy entropy technique. Then, we correlated the network FC temporal variability to social-related scores. We found that the social behavior correlated with the FC temporal variability of the precuneus, parietal, occipital, temporal, and precentral. Our results also showed that social behavior was significantly negatively correlated with the temporal variability of FC within the default mode network, between the frontoparietal network and cingulo-opercular task control network, and the dorsal attention network. In contrast, social behavior correlated significantly positively with the temporal variability of FC within the subcortical network. Finally, using temporal variability as a feature, we construct a model to predict the social score of ASD. These findings suggest that the network FC temporal variability has a close relationship with social behavioral inflexibility in ASD and may serve as a potential biomarker for predicting ASD symptom severity.