Development of CO2-switchable deep eutectic solvent-based liquid-liquid microextraction approach: Application in urinary excretion and tissue distribution studies.

BACKGROUND: Pharmacokinetic studies are pivotal in drug development, focusing on absorption, distribution, and excretion of active compounds. Effective sample preparation methods play a crucial role in these studies. Traditional techniques like protein precipitation and liquid-liquid extraction often involve toxic solvents and are time-consuming. Recently, deep eutectic solvent (DES) has emerged as an eco-friendly alternative due to its high efficiency, low cost, and low toxicity. This study introduces a novel sample pretreatment method using CO2-switchable DES in liquid-liquid microextraction (LLME) to enhance speed, accuracy, and sensitivity in complex biological samples analysis. RESULTS: A liquid-liquid microextraction sample pretreatment method based on switchable DES combined with high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was established for the analysis of urine and tissue samples. The method was optimized through systematic investigation of key parameters, including DES type, volume, molar ratio, pH, vortex time, gas purge time, and salt addition. The resulting procedure exhibited satisfying linearity (r2 ≥ 0.9958), good precision (RSD ≤6.01 %), desirable recovery (52.44%-98.12 %) and matrix effect (86.22%-119.30 %), and the accuracy and precision of stability were within the ±15 % limit. The proven methods were further applied to urinary excretion study and tissue distribution study of Nelumbinis plumula (NP) extract. The results indicated that the total cumulative excretion of liensinine, isoliensinine and neferine in urine within 240 h was 4.96 %, 0.66 % and 0.44 %, respectively. The tissue distribution study showed that alkaloids mainly distribute in liver, kidney, and spleen. SIGNIFICANCE: This research introduces a groundbreaking technique distinguished by its simplicity, speed, cost-effectiveness, and environmental friendliness. This approach, utilizing CO2-switchable DES as an extraction solvent for LLME, integrates deproteinization and removal of interfering molecules into a single step. This integration showcases its efficiency and convenience, demonstrating significant promise for various applications in the analysis of biological samples. Additionally, this study provides the first report on urinary excretion and tissue distribution of alkaloids from NP using a DES-LLME method. These findings offer valuable insights into the in vivo behavior of herbal medicine, enhancing understanding of pharmacological actions and facilitating clinical rational administration.

The Analysis of ceRNA Networks and Tumor Microenvironment in Endometrial Cancer.

Background: Endometrial carcinoma is a life-threatening and aggressive tumor that affects women worldwide. ceRNAs and carcinoma-infiltrating immunocytes can be associated with tumor formation and progression. Therefore, investigating the unique mechanisms underlying endometrial carcinoma is crucial. Methods: Prognostic nomograms were constructed based on the differentially expressed genes between normal and tumor tissues. Twenty types of tumor immune infiltrating cells in uterine corpus endometrial carcinoma (UCEC) were examined using CIBERSORT. To identify the potential signaling pathways, the associations among essential ceRNA network genes and important immunocytes were investigated using the co-expression assay. Results: Differential analysis identified 3636 mRNAs, 249 miRNAs, and 252 lncRNAs unique to UCEC. The ceRNA network was constructed using the interplays between 19 lncRNA-miRNA pairs and 434 miRNA-mRNA pairs. Furthermore, CIBERSORT and ceRNA integration analysis revealed that immune cells, including dendritic cells and natural killer cells, and associated ceRNAs such as LRP8, HDGF, PPARGC1B, and TEAD1 can appropriately predict prognosis. A receiver operating characteristic curve was constructed to predict patient outcomes. Conclusions: Using a nomogram, we predicted the outcomes of patients with UCEC Furthermore, we revealed its significance in improving clinical management.

Protective effects of docosahexaenoic acid supplementation on cognitive dysfunction and hippocampal synaptic plasticity impairment induced by early postnatal PM2.5 exposure in young rats.

PM2.5 exposure is a challenging environmental issue that is closely related to cognitive development impairment; however, currently, relevant means for prevention and treatment remain lacking. Herein, we determined the preventive effect of docosahexaenoic acid (DHA) supplementation on the neurodevelopmental toxicity induced by PM2.5 exposure. Neonatal rats were divided randomly into three groups: control, PM2.5, and DHA + PM2.5 groups. DHA could ameliorate PM2.5-induced learning and memory dysfunction, as well as reverse the impairment of hippocampal synaptic plasticity, evidenced by enhanced long-term potentiation, recovered synaptic ultrastructure, and increased expression of synaptic proteins. Moreover, DHA increased CREB phosphorylation and BDNF levels and attenuated neuroinflammation and oxidative stress, reflected by lower levels of IBA-1, IL-1ß, and IL-6 and increased levels of SOD1 and Nrf2. In summary, our findings demonstrated that supplementation of DHA effectively mitigated the cognitive dysfunction and synaptic plasticity impairment induced by early postnatal exposure to PM2.5. These beneficial effects may be attributed to the upregulation of the CREB/BDNF signaling pathway, as well as the reduction of neuroinflammation and oxidative stress.

FgGmtB Plays an Important Role in Growth, Reproduction, Virulence and Deoxynivalenol Biosynthesis of Fusarium graminearum.

GDP-mannose transporters (GMTs) have been implicated in the virulence of some important pathogenic fungi, and guanosine diphosphate (GDP) mannose transporters transport GDP-mannose from the cytosol to the Golgi lumen prior to mannosylation, where mannose attaches to the modified protein. GMTs could be potential targets for new antifungal drugs, as disruption of any step in GDP-mannose biosynthesis can affect fungal viability, growth, or virulence. To date, the GDP-mannose transporter has been extensively studied in yeast, but its biological function in fungi, particularly F. graminearum, is still unclear. In this experimental study, the role of the GDP-mannose transporter in F. graminearum was investigated by analysing the VRG4 gene. FgGmtA and FgGmtB were blastp-derived from their Scvrg4 protein sequences and proved to be their functional homologues. The mutant and complementary strains of FgGmtA, FgGmtB and FgGmtA&B genes were generated and used to evaluate the effect of the two GMTs genes on mycelial growth, asexual reproduction, sexual reproduction, cell wall sensitivity, glyphosate synthesis and drug susceptibility. Only in the FgGmtB and FgGmtA&B mutants was the rate of mycelial growth slowed, conidium production increased, sexual reproduction impaired, cell wall sensitivity increased, glycemic content decreased, and drug sensitivity reduced. The results of the pathogenicity assessment of GMTs showed that only FgGmtB affects the patogenicity of F. graminearum. At the same time, the effect of GMTs on the ability of rhinoceros to synthesise DON toxins was investigated and the results showed that the ability of ΔFgGmtB and ΔFgGmtA&B mutants to produce the DON toxin was significantly reduced, and the expression of toxin-related genes was also reduced.

A case report of vaginal delivery in the second trimester of severe uterine prolapse complicated with cervical incarceration.

BACKGROUND: Uterine prolapse is a rare complication of pregnancy, and there is still no consensus on the choice of delivery method. METHODS: The patient's reproductive history included an abortion and eutocic delivery of a girl weighing 3200 g; the current pregnancy was the third pregnancy. Her cervical region was outside the vaginal opening and was red in color, with evident enlargement (6 × 4 cm) and a broken surface. The cervical area also showed white discharge. According to her Transvaginal ultrasonography revealed a fetus in the uterine cavity at approximately 19 weeks of gestation. Gynecological examination revealed prolapse of both the anterior and posterior vaginal walls. Evaluation of the pelvic organ prolapse-Q scores showed that the patient had uterine prolapse at stage IV. RESULTS: Vaginal delivery was performed smoothly after oral administration mifepristone and misoprostol tablets for a few days, obtaining a dead female fetus in cephalic, 25 cm in length. The cervix of the pregnant woman did not prolapse during the delivery. CONCLUSION: For pregnancy with uterine prolapse and cervical incarceration, transvaginal delivery is a potential treatment option. Maintenance of cervical retraction and oral mifepristone administration with misoprostol tablets is crucial during this delivery. This treatment can minimize the risk of cervical lacerations and uterine rupture, helping surgeons to complete the operation successfully.

A peptide from the Japanese encephalitis virus failed to induce the production of anti-N-methyl-d-aspartate receptor antibodies via molecular mimicry in mice.

Background: The development of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis following viral encephalitis, such as Japanese encephalitis, has received increasing attention in recent years. However, the mechanism of anti-NMDAR antibody production following Japanese encephalitis has not been explored. Methods: A peptide from the Japanese encephalitis virus (JEV), which shares a similar amino acid sequence with GluN1, was identified by sequence comparison. We then explored whether active subcutaneous immunization with the JEV peptide could induce the production of anti-NMDAR antibodies and related pathophysiological and behavioral changes in mice. In addition, a published active immune model of anti-NMDAR encephalitis using a GluN1 peptide was used as the positive control. Results: A 6-amino-acid sequence with 83 % similarity between the envelope protein of the JEV (HGTVVI) and GluN1 (NGTHVI) was identified, and the sequence included the N368/G369 region. Active immunization with the JEV peptide induced a substantial and specific immune response in mice. However, anti-NMDAR antibodies were not detected in the serum of mice immunized with the JEV peptide by ELISA, CBA, and TBA. Moreover, mice immunized with the JEV peptide presented no abnormities related to anti-NMDAR antibodies according to western blotting, patch clamp, and a series of behavioral tests. In addition, active immunization with a recently reported GluN1 peptide failed to induce anti-NMDAR antibody production in mice. Conclusions: In this study, the attempt of active immunization with the JEV peptide to induce the production of anti-NMDAR antibodies via molecular mimicry failed. The pathogenesis of anti-NMDAR encephalitis following Japanese encephalitis remains to be elucidated.

The effect of ice-cold water spray following the model for symptom management on postoperative thirst in patients admitted to intensive care unit: A randomized controlled study.

BACKGROUND: Postoperative thirst is common in patients admitted to the intensive care unit. Existing methods like wet cotton swabs or oral care prove ineffectual or operationally intricate. Currently, an efficacious postoperative thirst alleviation method remains elusive. Exploring a prompt, safe, and efficacious solution is of paramount importance. OBJECTIVE: To assess the effect of ice-cold water spray applied following a symptom management model on postoperative thirst and to establish a framework for mitigating thirst in intensive care unit patients. RESEARCH DESIGN: Single-center randomized controlled study. SETTING: Surgical intensive care unit in a university-affiliated hospital. MAIN OUTCOME MEASURES: 56 intensive care unit patients were selected and equally randomized. The experimental group received ice-cold water spray in conjunction with eight symptom management strategies, while the control group underwent standard care involving wet cotton swabs. Thirst intervention was initiated 0.5 hours after postoperative extubation, followed by subsequent interventions at 2-hour, 4-hour, and 6-hour intervals post-extubation. Thirst intensity, oral comfort, and the duration of relief from thirst were assessed and compared between groups before and 0.5 hours after each thirst intervention. RESULTS: Across different interventions, the experimental group exhibited superior scores in thirst intensity and oral comfort compared to the control group. Additionally, the nursing time required to alleviate thirst in the experimental group was significantly shorter than that in the control group (P < 0.01). CONCLUSION: Ice-cold water spray following the model for symptom management can effectively mitigate the postoperative thirst intensity in intensive care unit patients, improve oral comfort, and reduce the nursing time for relieving thirst. IMPLICATIONS FOR CLINICAL PRACTICE: Clinical nurses can employ ice-cold water spray following the model for symptom management to ameliorate postoperative thirst intensity in ICU patients while enhancing oral comfort. Furthermore, the utilization of ice-cold water spray can reduce the nursing time required for relieving postoperative thirst in intensive care unit patients.

Genome-wide identification of the GRF family in sweet orange (Citrus sinensis) and functional analysis of the CsGRF04 in response to multiple abiotic stresses.

BACKGROUND: Citrus is one of the most valuable fruits worldwide and an economic pillar industry in southern China. Nevertheless, it frequently suffers from undesirable environmental stresses during the growth cycle, which severely restricts the growth, development and yield of citrus. In plants, the growth-regulating factor (GRF) family of transcription factors (TF) is extensively distributed and plays an vital part in plant growth and development, hormone response, as well as stress adaptation. However, the systematic identification and functional analysis of GRF TFs in citrus have not been reported. RESULTS: Here, a genome-wide identification of GRF TFs was performed in Citrus sinensis, 9 members of CsGRFs were systematically identified and discovered to be scattered throughout 5 chromosomes. Subsequently, physical and chemical properties, phylogenetic relationships, structural characteristics, gene duplication events, collinearity and cis-elements of promoter were elaborately analyzed. In particular, the expression patterns of the CsGRF genes in response to multiple phytohormone and abiotic stress treatments were investigated. Predicated on this result, CsGRF04, which exhibited the most differential expression pattern under multiple phytohormone and abiotic stress treatments was screened out. Virus-induced gene silencing (VIGS) technology was utilized to obtain gene silenced plants for CsGRF04 successfully. After the three stress treatments of high salinity, low temperature and drought, the CsGRF04-VIGS lines showed significantly reduced resistance to high salinity and low temperature stresses, but extremely increased resistance to drought stress. CONCLUSIONS: Taken together, our findings systematically analyzed the genomic characterization of GRF family in Citrus sinensis, and excavated a CsGRF04 with potential functions under multiple abiotic stresses. Our study lay a foundation for further study on the function of CsGRFs in abiotic stress and hormone signaling response.

Efficacy of cyclobutrifluram in controlling Fusarium crown rot of wheat and resistance risk of three Fusarium species to cyclobutrifluram.

Cyclobutrifluram (TYMIRIUM® technology), a new succinate dehydrogenase inhibitor (SDHI) fungicide, is currently being registered by SYNGENTA for controlling Fusarium crown rot (FCR) of wheat in China. The application of 15 or 30 g of active ingredient/100 kg seed of cyclobutrifluram significantly reduced pre-emergence damping-off, discoloration on the stem base and formation of whiteheads caused by FCR. The EC50 values of cyclobutrifluram for 60 isolates of F. pseudograminearum, 30 isolates of F. asiaticum and 30 isolates of F. graminearum ranged from 0.016 to 0.142 mg L-1, 0.010 to 0.041 mg L-1 and 0.012 to 0.059 mg L-1, respectively. One hundred and seven cyclobutrifluram-resistant (CR) mutants were obtained from three Fusarium species isolates, with ten types of mutations identified in Sdh genes. Three Fusarium species isolates exhibited similar resistance mechanisms, with the most prevalent mutations, SdhC1A83V and SdhC1R86K, accounting for 61.68% of mutants. The CR mutants possessed comparable or slightly impaired fitness compared to the corresponding parental isolates. The CR mutants carrying FpSdhBH248Y/Q/D exhibited increased sensitivity to fluopyram. An overall moderate risk of resistance development in three Fusarium species was recommended for cyclobutrifluram.

Autophagy alleviates hippocampal neuroinflammation by inhibiting the NLRP3 inflammasome in a juvenile rat model exposed particulate matter.

Ambient fine particulate matter (PM) is a global public and environmental problem. PM is closely associated with several neurological diseases, which typically involve neuroinflammation. We investigated the impact of PM exposure on neuroinflammation using both in vivo (in a juvenile rat model with PM exposure concentrations of 1, 2, and 10 mg/kg for 28 days) and in vitro (in BV-2 and HT-22 cell models with PM concentrations of 50-200 µg/ml for 24 h). We observed that PM exposure induced the activation of the NLRP3 inflammasome, leading to the production of IL-1ß and IL-18 in the rat hippocampus and BV-2 cells. Furthermore, inhibition of the NLRP3 inflammasome with MCC950 effectively reduced neuroinflammation and ameliorated hippocampal damage. In addition, autophagy activation was observed in the hippocampus of PM-exposed rats, and the promotion of autophagy by rapamycin (Rapa) effectively attenuated the NLRP3-mediated neuroinflammation induced by PM exposure. However, autophagic flow was blocked in BV-2 cells exposed to PM, and Rapa failed to ameliorate NLRP3 inflammasome activation. We found that autophagy was activated in HT-22 cells exposed to PM and that treatment with Rapa reduced the release of reactive oxygen species (ROS) and malondialdehyde (MDA), as well as cell apoptosis. In a subsequent coculture model of BV-2 and HT-22 cells, we observed the activation of the NLRP3 inflammasome in BV-2 cells when the HT-22 cells were exposed to PM, and this activation was alleviated when PM-exposed HT-22 cells were pretreated with Rapa. Overall, our study revealed that PM exposure triggered hippocampal neuroinflammation by activating the NLRP3 inflammasome. Notably, autophagy mitigated NLRP3 inflammasome activation, potentially by reducing neuronal ROS and apoptosis. This research emphasized the importance of reducing PM exposure and provided valuable insight into its neurotoxicity.

Genome analyses reveal the secondary metabolites potentially influence the geographical distribution of Fusarium pseudograminearum populations.

Fusarium crown rot (FCR), caused by Fusarium pseudograminearum, significantly impacts wheat yield and quality in China's Huanghuai region. The rapid F. pseudograminearum epidemic and FCR outbreak within a decade remain unexplained. In this study, two high-quality, chromosome-level genomes of F. pseudograminearum strains producing 3-acetyl-deoxynivalenol (3AcDON) and 15-acetyl-deoxynivalenol (15AcDON) toxins were assembled. Additionally, 38 related strains were resequenced. Genomic differences such as single nucleotide polymorphisms (SNPs), insertions/deletions (indels), and structural variations (SVs) among F. pseudograminearum strains were analyzed. The whole-genome SNP locus based population classification mirrored the toxin chemotype (3AcDON and 15AcDON)-based classification, indicating the presence of genes associated with the trichothecene toxin gene cluster. Further analysis of differential SNP, indel, and SV loci between the 3AcDON and 15AcDON populations revealed a predominant connection to secondary metabolite synthesis genes. Notably, the majority of the secondary metabolite biosynthesis gene cluster (SMGC) loci were located in SNP-dense genomic regions, suggesting high mutability and a possible contribution to F. pseudograminearum population structure and environmental adaptability. This study provides insightful perspectives on the distribution and evolution of F. pseudograminearum, and for forecasting the spread of wheat FCR, thereby aiding in the development of preventive measures and control strategies.

Ambient particulate matter exposure induces ferroptosis in hippocampal cells through the GSK3B/Nrf2/GPX4 pathway.

Epidemiological studies have established a robust correlation between exposure to ambient particulate matter (PM) and various neurological disorders, with dysregulation of intracellular redox processes and cell death being key mechanisms involved. Ferroptosis, a cell death form characterized by iron-dependent lipid peroxidation and disruption of antioxidant defenses, may be involved in the neurotoxic effects of PM exposure. However, the relationship between PM-induced neurotoxicity and ferroptosis in nerve cells remains to be elucidated. In this study, we utilized a rat model (exposed to PM at a dose of 10 mg/kg body weight per day for 4 weeks) and an HT-22 cell model (exposed to PM at concentrations of 50, 100, and 200 µg/mL for 24 h) to investigate the potential induction of ferroptosis by PM exposure. Furthermore, RNA sequencing analysis was employed to identify hub genes that potentially contribute to the process of ferroptosis, which was subsequently validated through in vivo and in vitro experiments. The results revealed that PM exposure increased MDA content and Fe2+ levels, and decreased SOD activity and GSH/GSSG ratio in rat hippocampal and HT-22 cells. Through RNA sequencing analysis, bioinformatics analysis, and RT-qPCR experiments, we identified GSK3B as a possible hub gene involved in ferroptosis. Subsequent investigations demonstrated that PM exposure increased GSK3B levels and decreased Nrf2, and GPX4 levels in vivo and in vitro. Furthermore, treatment with LY2090314, a specific inhibitor of GSK3B, was found to mitigate the PM-induced elevation of MDA and ROS and restore SOD activity and GSH/GSSG ratio. The LY2090314 treatment promoted the upregulation of Nrf2 and GPX4 and facilitated the nuclear translocation of Nrf2 in HT-22 cells. Moreover, treatment with LY2090314 resulted in the upregulation of Nrf2 and GPX4, along with the facilitation of nuclear translocation of Nrf2. This study suggested that PM-induced ferroptosis in hippocampal cells may be via the GSK3B/Nrf2/GPX4 pathway.

Enhancing ROS-Inducing Nanozyme through Intraparticle Electron Transport.

Iron oxide nanoparticles (IONPs) have garnered significant attention as a promising platform for reactive oxygen species (ROS)-dependent disease treatment, owing to their remarkable biocompatibility and Fenton catalytic activity. However, the low catalytic activity of IONPs is a major hurdle in their clinical translation. To overcome this challenge, IONPs of different compositions are examined for their Fenton reaction under pharmacologically relevant conditions. The results show that wüstite (FeO) nanoparticles exhibit higher catalytic activity than magnetite (Fe3 O4 ) or maghemite (γ-Fe2 O3 ) of matched size and coating, despite having a similar surface oxidation state. Further analyses suggest that the high catalytic activity of wüstite nanoparticles can be attributed to the presence of internal low-valence iron (Fe0 and Fe2+ ), which accelerates the recycling of surface Fe3+ to Fe2+ through intraparticle electron transport. Additionally, ultrasmall wüstite nanoparticles are generated by tuning the thermodecomposition-based nanocrystal synthesis, resulting in a Fenton reaction rate 5.3 times higher than that of ferumoxytol, an FDA-approved IONP. Compared with ferumoxytol, wüstite nanoparticles substantially increase the level of intracellular ROS in mouse mammary carcinoma cells. This study presents a novel mechanism and pivotal improvement for the development of highly efficient ROS-inducing nanozymes, thereby expanding the horizons for their therapeutic applications.

Effects of minocycline on dendrites, dendritic spines, and microglia in immature mouse brains after kainic acid-induced status epilepticus.

PURPOSE: This study aimed to investigate whether minocycline could influence alterations of microglial subtypes, the morphology of dendrites and dendritic spines, the microstructures of synapses and synaptic proteins, or even cognition outcomes in immature male mice following status epilepticus (SE) induced by kainic acid. METHODS: Golgi staining was performed to visualize the dendrites and dendritic spines of neurons of the hippocampus. The microstructures of synapses and synaptic proteins were observed using transmission electron microscopy and western blotting analysis, respectively. Microglial reactivation and their markers were evaluated using flow cytometry. The Morris water maze (MWM) test was used to analyze spatial learning and memory ability. RESULTS: Significant partial spines increase (predominate in thin spines) was observed in the dendrites of neurons after acute SE and partial loss (mainly in thin spines) was presented by days 14 and 28 post-SE. The postsynaptic ultrastructure was impaired on the 7th and 14th days after SE. The proportion of M1 microglia increased significantly only after acute SE Similarly, the proportion of M2 microglia increased in the acute stage with high expression levels of all surface markers. In contrast, a decrease in M2 microglia and their markers was noted by day 14 post-SE. Minocycline could reverse the changes in dendrites and synaptic proteins caused by SE, and increase the levels of synaptic proteins. Meanwhile, minocycline could inhibit the reactivation of M1 microglia and the expression of their markers, except for promoting CD200R. In addition, treatment with minocycline could regulate the expression of M2 microglia and their surface markers, as well as ameliorating the impaired spatial learning and memory on the 28th day after SE. CONCLUSIONS: Dendritic spines and microglia are dynamically changed after SE. Minocycline could ameliorate the impaired cognition in the kainic acid-induced mouse model by decreasing the damage to dendrites and altering microglial reactivation.

Autoimmune encephalitis antibody profiles and clinical characteristics of children with suspected autoimmune encephalitis.

AIM: To identify the spectrum of autoimmune encephalitis antibody biomarkers (AE-Abs) in children with suspected autoimmune encephalitis and explore the clinical features indicating AE-Abs presence. METHOD: We included children with suspected autoimmune encephalitis who underwent AE-Abs tests at the Children's Hospital of Chongqing Medical University between June 2020 and June 2022. Clinical features suggestive of AE-Abs were analysed based on AE-Abs test results. RESULTS: A total of 392 children were tested for AE-Abs with suspected autoimmune encephalitis. Of these, 49.5% were male, with a median age of 7 years 11 months (6 months-17 years 11 months); 93.6% (367/392) of all patients had both serum and cerebrospinal fluid (CSF) tests performed. The antibody-positive rate in the cohort was 23.7% (93/392), the serum antibody-positive rate was 21.9% (84/384), and the CSF antibody-positive rate was 20.8% (78/375). Eleven different AE-Abs were detected. Serum analysis revealed that N-methyl-D-aspartate receptor immunoglobulin-G (NMDAR-IgG) (15.1%) was greater than myelin oligodendrocyte glycoprotein (MOG)-IgG (14.6%) and glial fibrillary acidic protein (GFAP)-IgG (3.3%). CSF analysis revealed that NMDAR-IgG (16.3%) was greater than MOG-IgG (13.8%) and GFAP-IgG (3.3%). Compared with antibody-negative patients, antibody-positive patients were more often female (odds ratio [OR] 1.86, p = 0.03), with memory impairment (OR 2.91, p = 0.01) and sleep disorders (OR 2.08, p = 0.02). INTERPRETATION: In children, the most frequent AE-Abs detected were NMDAR-IgG and MOG-IgG. Female sex, memory impairment, and sleep disorders predict a higher likelihood of AE-Abs.

Identification of novel proteins for sleep apnea by integrating genome-wide association data and human brain proteomes.

BACKGROUND: Sleep apnea is regarded as a significant global public health issue. The relationship between sleep apnea and nervous system diseases is intricate, yet the precise mechanism remains unclear. METHODS: In this study, we conducted a comprehensive analysis integrating the human brain proteome and transcriptome with sleep apnea genome-wide association study (GWAS), employing genome-wide association study (PWAS), transcriptome-wide association study (TWAS), Mendelian randomization (MR), and colocalization analysis to identify brain proteins associated with sleep apnea. RESULTS: The discovery PWAS identified six genes (CNNM2, XRCC6, C3orf18, CSDC2, SQRDL, and DGUOK) whose altered protein abundances in the brain were found to be associated with sleep apnea. The independent confirmatory PWAS successfully replicated four out of these six genes (CNNM2, C3orf18, CSDC2, and SQRDL). The transcriptome level TWAS analysis further confirmed two out of the four genes (C3orf18 and CSDC2). The subsequent two-sample Mendelian randomization provided compelling causal evidence supporting the association of C3orf18, CSDC2, CNNM2, and SQRDL with sleep apnea. The co-localization analysis further supported the association between CSDC2 and sleep apnea (posterior probability of hypothesis 4 = 0.75). CONCLUSIONS: In summary, the integration of brain proteomic and transcriptomic data provided multifaceted evidence supporting causal relationships between four specific brain proteins (CSDC2, C3orf18, CNNM2, and SQRDL) and sleep apnea. Our findings provide new insights into the molecular basis of sleep apnea in the brain, promising to advance understanding of its pathogenesis in future research.

FgSdhC Paralog Confers Natural Resistance toward SDHI Fungicides in Fusarium graminearum.

Fusarium graminearum exhibited natural resistance to a majority of succinate dehydrogenase inhibitor fungicides (SDHIs) and the molecular mechanisms responsible for the natural resistance were still unknown. Succinate dehydrogenase subunit C (SdhC) is an essential gene for maintaining succinate-ubiquinone oxidoreductase (SQR) function in fungi. In F. graminearum, a paralog of FgSdhC named as FgSdhC1 was identified. Based on RNA-Seq and qRT-PCR assay, we found that the expression level of FgSdhC1 was very low but upregulated by SDHIs treatment. Based on reverse genetics, we demonstrated that FgSdhC1 was an inessential gene in normal growth but was sufficient for maintaining SQR function and conferred natural resistance or reduced sensitivity toward SDHIs. Additionally, we found that the standard F. graminearum isolate PH-1 had high sensitivity to a majority of SDHIs. A single nucleotide variation (C to T) in the FgSdhC1 of isolate PH-1, resulting in a premature termination codon (TAA) replacing the fourth amino acid glutamine (Q), led to the failure of FgSdhC1 to perform functions of conferring nature resistance. These results established that a dispensable paralogous gene determined SDHIs resistance in natural populations of F. graminearum.

TREM2 mitigates NLRP3-mediated neuroinflammation through the NF-κB and PI3k/Akt signaling pathways in juvenile rats exposed to ambient particulate matter.

Ambient particulate matter (PM) is a global public and environmental problem. PM is closely associated with several neurological disorders that typically involve neuroinflammation. There have been few studies on the effect of PM on neuroinflammation to date. In this study, we used a juvenile rat model (PM exposure was conducted at a dose of 10 mg/kg body weight per day for 4 weeks) and a BV-2 cell model (PM exposure was conducted at concentrations of 50, 100, 150, and 200 µg/ml for 24 h) to investigate PM-induced neuroinflammation mediated by NLRP3 inflammasome activation and the role of TREM2 in this process. Our findings revealed that PM exposure reduced TREM2 protein and mRNA levels in the rat hippocampus and BV-2 cells. TREM2 overexpression attenuated PM-induced spatial learning and memory deficits in rats. Moreover, we observed that TREM2 overexpression in vivo and in vitro effectively mitigated the increase in NLRP3 and pro-Caspase1 protein expression, as well as the secretion of IL-1ß and IL-18. Exposure to PM increased the expression of NF-κB and decreased the phosphorylation of PI3k/Akt in vivo and in vitro, and this process was effectively reversed by overexpressing TREM2. Our results indicated that PM exposure could reduce TREM2 expression and induce NLRP3 inflammasome-mediated neuroinflammation and that TREM2 could mitigate NLRP3 inflammasome-mediated neuroinflammation by regulating the NF-κB and PI3k/Akt signaling pathways. These findings shed light on PM-induced neuroinflammation mechanisms and potential intervention targets.

High Atherogenic Risk in Ketosis-Prone Type 2 Diabetic Individuals with Ketosis Episodes: A Cross-Sectional Study.

Purpose: Diabetes is an important contributor to the progression of atherosclerosis (AS). We aimed to investigate the correlation between ketosis episodes and lipid-related parameters in patients with new-onset ketosis-prone type 2 diabetes (KPT2D), further attempting to assess the impact of ketosis episodes on AS. Patients and Methods: A cross-sectional study of 147 subjects with new-onset diabetes was performed, including 65 KPT2D subjects (KPT2D group) and 82 non-ketotic type 2 diabetes (T2D) (T2D group) subjects. Anthropometric and biochemical parameters were measured in all subjects. Calculation of atherogenic index of plasma (AIP) by traditional lipid parameters. Results: The AIP (P = 0.008) level and the percentage of AIP ≥ 0.24 (P = 0.026) in subjects with KPT2D were higher than in subjects with T2D. The apoA1 (P = 0.001) levels were significantly lower in patients with KPT2D than in patients with T2D. In the KPT2D group, plasma ketones were positively correlated with AIP (P = 0.023) and negatively correlated with apoA1 (P = 0.002). Univariate logistic regression suggested that plasma ketone (OR = 1.704, P = 0.040) was an important related factor for the AS in subjects with KPT2D. Multiple linear regression suggested plasma ketone was significantly positive with AIP (ß = 0.437, P = 0.020). In multiple linear regression analysis suggests that apolipoprotein A1 (ß = -0.335, P = 0.033) is strongly associated with ketotic episodes in newly diagnosed ketosis-prone type 2 diabetic patients. Conclusion: Ketosis episodes in patients with KPT2D were significantly and positively associated with elevated AIP levels and reduced apoA1 levels. Frequent ketosis episodes may accelerate the progression of AS.