Re-establishing immune tolerance in multiple sclerosis: focusing on novel mechanisms of mesenchymal stem cell regulation of Th17/Treg balance.

The T-helper 17 (Th17) cell and regulatory T cell (Treg) axis plays a crucial role in the development of multiple sclerosis (MS), which is regarded as an immune imbalance between pro-inflammatory cytokines and the maintenance of immune tolerance. Mesenchymal stem cell (MSC)-mediated therapies have received increasing attention in MS research. In MS and its animal model experimental autoimmune encephalomyelitis, MSC injection was shown to alter the differentiation of CD4+T cells. This alteration occurred by inducing anergy and reduction in the number of Th17 cells, stimulating the polarization of antigen-specific Treg to reverse the imbalance of the Th17/Treg axis, reducing the inflammatory cascade response and demyelination, and restoring an overall state of immune tolerance. In this review, we summarize the mechanisms by which MSCs regulate the balance between Th17 cells and Tregs, including extracellular vesicles, mitochondrial transfer, metabolic reprogramming, and autophagy. We aimed to identify new targets for MS treatment using cellular therapy by analyzing MSC-mediated Th17-to-Treg polarization.

The silencing of NREP aggravates OA cartilage damage through the TGF-ß1/Smad2/3 pathway in chondrocytes.

Background: Osteoarthritis (OA) is a common chronic degenerative joint disease. Due to the limited understanding of its complex pathological mechanism, there is currently no effective treatment that can alleviate or even reverse cartilage damage associated with OA. With improvement in public databases, researchers have successfully identified the key factors involved in the occurrence and development of OA through bioinformatics analysis. The aim of this study was to screen for the differentially expressed genes (DEGs) between the normal and OA cartilage through bioinformatics, and validate the function of the TGF-ß1/Smad2/3 pathway-related neuron regeneration related protein (NREP) in the articular cartilage. Methods: The DEGs between the cartilage tissues of OA patients and healthy controls were screened by bioinformatics, and functionally annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The expression levels of the DEG in human and murine OA cartilage was verified by reverse transcription-quantitative PCR (RT-qPCR), Western blotting and immunohistochemistry (IHC). RT-qPCR, Western-blotting, Cell Counting Kit-8(CCK8) and EdU assays were used to evaluate the effects of knocking down NREP in normal chondrocytes, and the molecular mechanisms were investigated by RT-qPCR, Western blotting and IHC. Results: In this study, we identified NREP as a DEG in OA through bioinformatics analysis, and found that NREP was downregulated in the damaged articular cartilage of OA patients and mouse model with surgically-induced OA. In addition, knockdown of NREP in normal chondrocytes reduced their proliferative capacity, which is the pathological basis of OA. At the molecular level, knock-down of NREP inactivated the TGF-ß1/Smad2/3 pathway, resulting in the downregulation of the anabolic markers Col2a1 and Sox9, and an increase in the expression of the catabolic markers MMP3 and MMP13. Conclusion: NREP plays a key role in the progression of OA by regulating the TGF-ß1/Smad2/3 pathway in chondrocytes, and warrants further study as a potential therapeutic target.

Research progress and hotspots on macrophages in osteoarthritis: A bibliometric analysis from 2009 to 2022.

BACKGROUND: Macrophages in the synovium, as immune cells, can be polarized into different phenotypes to play an anti-inflammatory role in the treatment of osteoarthritis. In this study, bibliometric methods were used to search the relevant literature to find valuable research directions for researchers and provide new targets for osteoarthritis prevention and early treatment. METHODS: Studies about the application of macrophages in the treatment of osteoarthritis were searched through the Web of Science core database from 2009 to 2022. Microsoft Excel 2019, VOSviewer, CiteSpace, R software, and 2 online websites were used to analyze the research status and predict the future development of the trend in research on macrophages in osteoarthritis. RESULTS: The number of publications identified with the search strategy was 1304. China and the United States ranked first in the number of publications. Shanghai Jiao Tong University ranked first in the world with 37 papers. Osteoarthritis and Cartilage was the journal with the most publications, and "exosomes," "stem cells," "macrophage polarization," "regeneration," and "innate immunity" may remain the research hotspots and frontiers in the future. CONCLUSION: The findings from the global trend analysis indicate that research on macrophages in the treatment of osteoarthritis is gradually deepening, and the number of studies is increasing. Exosomes may become a research trend and hotspot in the future.

[Study on application of posterior tibial slope angle in anterior cruciate ligament].

Posterior tibial slope angle (PTSA) is a risk factor for anterior cruciate ligament (ACL) injury and has attracted a lot of attention, but its mechanism of action and diagnosis are still not systematically studied in the field of sports medicine. In this paper, we believe that PTSA should be measured by full-length lower extremity films and combined with multiple imaging data for comprehensive assessment to reduce errors. A large PTSA may increases risk of anterior cruciate ligament injury, so patients with more than 12 degrees of PTSA should be treated by preserving meniscus as much as possible during ACL reconstruction and combining with tibial osteotomy if necessary, which could effectively prevent risk of ligament re-injury. At the same time, gait analysis has an important reference value for preoperative pathogenic pattern and postoperative rehabilitation function, so the author believes that it will have a guiding significance for the development of individualized rehabilitation strategy based on PTSA, in order to achieve the best treatment effect.

Sintering, Microstructure, and Mechanical Properties of TiTaNbZrHf High-Entropy Alloys Prepared by Cold Isostatic Pressing and Pressure-Less Sintering of Hydrides.

A TiTaNbZrHf refractory high-entropy alloy (RHEA) was synthesized through a cold isostatic pressing and a pressure-less sintering process in a hydrogen atmosphere using a powder mixture of metal hydride prepared either by mechanical alloying (MA) or by rotating mixing. This study investigates how differences in powder particle sizes impact the RHEA's microstructure and mechanical properties. HCP (a = b = 3.198 Å, c = 5.061 Å) and BCC2 (a = b = c = 3.40 Å) phases were observed in the microstructure of coarse powder TiTaNbZrHf RHEAs at 1400 °C. In contrast, fine powder RHEAs were found to possess two-phase structures of HCP and BCC1 (a = b = c = 3.36 Å) with a higher hardness of 431 HV, compression strength of 1620 MPa, and a plasticity of >20%.

Crosstalk between dendritic cells and regulatory T cells: Protective effect and therapeutic potential in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system related to autoimmunity and is characterized by demyelination, neuroinflammation, and neurodegeneration. Cell therapies mediated by dendritic cells (DCs) and regulatory T cells (Tregs) have gradually become accumulating focusing in MS, and the protective crosstalk mechanisms between DCs and Tregs provide the basis for the efficacy of treatment regimens. In MS and its animal model experimental autoimmune encephalomyelitis, DCs communicate with Tregs to form immune synapses and complete a variety of complex interactions to counteract the unbalanced immune tolerance. Through different co-stimulatory/inhibitory molecules, cytokines, and metabolic enzymes, DCs regulate the proliferation, differentiation and function of Tregs. On the other hand, Tregs inhibit the mature state and antigen presentation ability of DCs, ultimately improving immune tolerance. In this review, we summarized the pivotal immune targets in the interaction between DCs and Tregs, and elucidated the protective mechanisms of DC-Treg cell crosstalk in MS, finally interpreted the complex cell interplay in the manner of inhibitory feedback loops to explore novel therapeutic directions for MS.

Clinical Effect of Electroacupuncture on Acute Sleep Deprivation and Event-Related Potential Affecting the Inhibition Control of the Brain: Study Protocol for a Randomized Controlled Trial.

Background: Acute sleep deprivation (ASD) can effect mood, attention, memory, alertness and metabolism. Especially, it is often accompanied by cognitive impairment of the brain. Acupuncture is safe and effective for improving cognitive function, but its underlying mechanism is not fully understood. In this study, an event-related potential (ERP) technique will be employed to measure the behavioral, cognitive, and physiological changes produced by electroacupuncture intervention after ASD. Methods: We will recruit 60 healthy subjects. The participants will be randomly divided into a treatment group, a control group, a sham electroacupuncture group and a blank group, at a 1:1:1:1 ratio. The primary outcome will be determined by the change from baseline to 36 h in the MoCA score. The secondary results include the amplitude and latency of ERP N2 and P3, Go-hit rates, Go-RTs, No-Go-FA rates, the WCST, the Digit Span Subtest of the WAIS, the ESS score and FS-14. The 15 healthy subjects will not receive acupuncture treatment and ASD, but will receive EEG records and cognition functions test at the beginning and end of the experiment. Electroacupuncture intervention will be performed for 30 min once every 12 h, a total of three times. ERP measurements and other tests will be performed after baseline and ASD, and the statistician and outcome evaluator will be blinded to treatment allocation. Discussion: This study is expected to investigate the effectiveness of electroacupuncture in improving cognition for ASD. Trial Registration: ChiCTR2200055999.

[Lateral needling at Lianquan (CV 23) for post-stroke dysphagia: a randomized controlled trial].

OBJECTIVE: To observe the effect of lateral needling at Lianquan (CV 23) for post-stroke dysphagia, and explore its mechanism. METHODS: A total of 64 patients with post-stroke dysphagia were randomly divided into an observation group and a control group, 32 cases in each group. Both groups were treated with conventional basic treatment. The observation group was treated with lateral needling at CV 23, without needle retaining, once a day. The control group was treated with swallowing rehabilitation training, once a day. Both groups were treated for 5 days a week, with 2 days interval, 1 week as one course and 4 courses were required. Before and after treatment, the Kubota water swallowing test grade and standardized swallowing assessment (SSA) score were compared in the two groups. Before and after treatment, the video fluoroscopic swallowing study (VFSS) was used to measure the hyoid bone movement displacement and pharyngeal delivery time in the observation group. RESULTS: Compared before treatment, the Kubota water swallowing test grade after treatment was improved in the two groups (P<0.05), and the observation group was superior to the control group (P<0.05); the SSA scores after treatment were decreased in the two groups (P<0.05), and the observation group was lower than the control group (P<0.05). Compared before treatment, the hyoid bone movement displacement was increased and pharyngeal delivery time was shortened after treatment in the observation group (P<0.05). CONCLUSION: Lateral needling at CV 23 could improve dysphagia symptoms in patients with post-stroke dysphagia, its mechanism may be related to the increasing of hyoid bone movement displacement and shortening of pharyngeal delivery time.

Calcium-Related Gene Signatures May Predict Prognosis and Level of Immunosuppression in Gliomas.

Gliomas are the most common primary brain cancer. While it has been known that calcium-related genes correlate with gliomagenesis, the relationship between calcium-related genes and glioma prognosis remains unclear. We assessed TCGA datasets of mRNA expressions with differentially expressed genes (DEGs) and enrichment analysis to specifically screen for genes that regulate or are affected by calcium levels. We then correlated the identified calcium-related genes with unsupervised/supervised learning to classify glioma patients into 2 risk groups. We also correlated our identified genes with immune signatures. As a result, we discovered 460 calcium genes and 35 calcium key genes that were associated with OS. There were 13 DEGs between Clusters 1 and 2 with different OS. At the same time, 10 calcium hub genes (CHGs) signature model were constructed using supervised learning, and the prognostic risk scores of the 3 cohorts of samples were calculated. The risk score was confirmed as an independent predictor of prognosis. Immune enrichment analysis revealed an immunosuppressive tumor microenvironment with upregulation of checkpoint markers in the high-risk group. Finally, a nomogram was generated with risk scores and other clinical prognostic independent indicators to quantify prognosis. Our findings suggest that calcium-related gene expression patterns could be applicable to predict prognosis and predict levels of immunosuppression.

Insights Into the Research Status of Neuromedin U: A Bibliometric and Visual Analysis From 1987 to 2021.

Neuromedin U (NMU) is a regulatory peptide that is widely distributed throughout the body and performs a variety of physiological functions through its corresponding receptors. In recent years, NMU has become the focus of attention in various fields of research as its diverse and essential functions have gradually been elucidated. However, there have been no bibliometrics studies on the development trend and knowledge structure of NMU research. Therefore, in this study, we used VOSviewer software to statistically analyze scientific data from articles related to NMU to track the developmental footprint of this research field, including relevant countries, institutions, authors, and keywords. We retrieved a total of 338 papers related to NMU, written by 1,661 authors from 438 organizations of 41 countries that were published in 332 journals. The first study on NMU was reported by a group in Japan in 1985. Subsequently, nine articles on NMU were published from 1987 to 2006. A small leap in this field could be detected in 2009, with 30 articles published worldwide. Among the various countries in which this research has been performed, Japan and the United States have made the most outstanding contributions. Miyazato M, Kangawa K, and Mori K from the Department of Biochemistry, National Retrain and Cardiovascular Center Research Institute in Japan were the most productive authors who have the highest number of citations. Keyword analysis showed six clusters: central-nervous-system, homeostasis, energy metabolism, cancer, immune inflammation, and food intake. The three most highly cited articles were associated with inflammation. Overall, this study demonstrates the research trends and future directions of NMU, providing an objective description of the contributions in this field along with reference value for future research.

Preclinical studies and clinical trials on mesenchymal stem cell therapy for knee osteoarthritis: A systematic review on models and cell doses.

AIM: To provide a systematic analysis of the study design in knee osteoarthritis (OA) preclinical studies, focusing on the characteristics of animal models and cell doses, and to compare these to the characteristics of clinical trials using mesenchymal stem cells (MSCs) for the treatment of knee OA. METHOD: A systematic and comprehensive search was conducted using the PubMed, Web of Science, Ovid, and Embase electronic databases for research papers published in 2009-2020 on testing MSC treatment in OA animal models. The PubMed database and ClinicalTrials.gov website were used to search for published studies reporting clinical trials of MSC therapy for knee OA. RESULTS: In total, 9234 articles and two additional records were retrieved, of which 120 studies comprising preclinical and clinical studies were included for analysis. Among the preclinical studies, rats were the most commonly used species for modeling knee OA, and anterior cruciate ligament transection was the most commonly used method for inducing OA. There was a correlation between the cell dose and body weight of the animal. In clinical trials, there was large variation in the dose of MSCs used to treat knee OA, ranging from 1 × 106 to 200 × 106 cells with an average of 37.91 × 106 cells. CONCLUSION: Mesenchymal stem cells have shown great potential in improving pain relief and tissue protection in both preclinical and clinical studies of knee OA. Further high-quality preclinical and clinical studies are needed to explore the dose effectiveness relationship of MSC therapy and to translate the findings from preclinical studies to humans.

LncRNA TUG1 compromised neuronal mitophagy in cerebral ischemia/reperfusion injury by targeting sirtuin 1.

BACKGROUND: Mitophagy protects against cerebral ischemia/reperfusion (CI/R)-induced neuronal apoptosis via mitochondrial clearance. Although taurine-upregulated gene 1 (lncRNA TUG1) has been proposed to be involved in the neuronal apoptosis evoked by CI/R, its specific role in mitophagy during the progression of CI/R injury remains unknown. METHODS: The CI/R rat model was established using middle cerebral artery occlusion/reperfusion (MCAO/R). Human neuroblastoma cell line SH-SY5Y was subjected to oxygen-glucose deprivation and reoxygenation (OGD/R). Ubiquitination assay, co-immunoprecipitation assay, RNA pull-down, and RNA immunoprecipitation were used to determine the interplay among TUG1, sirtuin 1 (SIRT1), and F-box and WD repeat domain-containing 7 (FBXW7). RESULTS: The upregulation of the TUG1 level and downregulation of the mitophagy were observed in both MCAO/R-treated rats and OGD/R-treated cells. The administration of si-TUG1 (a siRNA directed against TUG1) potentiated mitophagy and suppressed neuronal apoptosis in OGD/R-treated cells. However, the neuroprotective effect of si-TUG1 was reversed by mitophagy inhibitor or SIRT1 knockdown in vitro. Functionally, TUG1 enhanced FBXW7-mediated SIRT1 ubiquitination by upregulating FBXW7 expression. The overexpression of FBXW7 abrogated the si-TUG1-reinforced mitophagy by decreasing SIRT1 expression, thus aggravating neuronal apoptosis in the OGD/R+si-TUG1-treated cells. In rats with MCAO/R, the interference of TUG1 clearly decreased neuronal apoptosis, lessened the infarct volume, and relieved the neurological deficits. CONCLUSION: TUG1 knockdown promotes SIRT1-induced mitophagy by suppressing FBXW7-mediated SIRT1 degradation, thus relieving the neuronal apoptosis induced by CI/R injury. LncRNA TUG1 promotes neuronal apoptosis through inhibition of mitophagy. TUG1 decreased SIRT1 expression by promoting FBXW7-mediated SIRT1 ubiquitination. FBXW7/SIRT1 axis mediated the effect of TUG1 on OGD/R-induced neuronal apoptosis by regulating mitophagy.

Cost Effectiveness of Pharmacological Management for Osteoarthritis: A Systematic Review.

BACKGROUND AND OBJECTIVE: Osteoarthritis (OA) is a highly prevalent, disabling disease requiring chronic management that is associated with an enormous individual and societal burden. This systematic review provides a global cost-effectiveness evaluation of pharmacological therapy for the management of OA. METHODS: Following Center for Reviews and Dissemination (CRD) guidance, a literature search strategy was undertaken using PubMed, EMBASE, Cochrane Library, Health Technology Assessment (HTA) database, and National Health Service Economic Evaluation database (NHS EED) to identify original articles containing cost-effectiveness evaluation of OA pharmacological treatment published before 4 November 2021. Risk of bias was assessed by two independent reviewers using the Joanna Briggs Institute (JBI) critical appraisal checklist for economic evaluations. The Quality of Health Economic Studies (QHES) instrument was used to assess the reporting quality of included articles. RESULTS: Database searches identified 43 cost-effectiveness analysis studies (CEAs) on pharmacological management of OA that were conducted in 18 countries and four continents, with one study containing multiple continents. A total of four classes of drugs were assessed, including non-steroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, symptomatic slow-acting drugs for osteoarthritis (SYSADOAs), and intra-articular (IA) injections. The methodological approaches of these studies showed substantial heterogeneity. The incremental cost-effectiveness ratios (ICERs) per quality-adjusted life-year (QALY) were (in 2021 US dollars) US$44.40 to US$307,013.56 for NSAIDS, US$11,984.84 to US$128,028.74 for opioids, US$10,930.17 to US$27,799.73 for SYSADOAs, and US$258.36 to US$58,447.97 for IA injections in different continents. The key drivers of cost effectiveness included medical resources, productivity, relative risks, and selected comparators. CONCLUSION: This review showed substantial heterogeneity among studies, ranging from a finding of dominance to very high ICERs, but most studies found interventions to be cost effective based on specific ICER thresholds. Important challenges in the analysis were related to the standardization and methodological quality of studies, as well as the presentation of results.

Ketogenic diet ameliorates cognitive impairment and neuroinflammation in a mouse model of Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is the most common neurodegenerative disorder that causes dementia and affects millions of people worldwide. Although it has devastating outcomes for patients and tremendous economic costs to society, there is currently no effective treatment available. AIMS: The high-fat, low-carbohydrate ketogenic diet (KD) is an established treatment for refractory epilepsy with a proven efficacy. Although the considerable interest has emerged in recent years for applying KD in AD patients, only few interventional studies in animals and humans have addressed the effects of KD on cognitive impairments, and the results were inconclusive. The aim of this study was to explore the impact of KD on cognitive functions and AD pathology in 5XFAD mice-a validated animal model of AD. RESULTS: Four months of a ketogenic diet improved spatial learning, spatial memory and working memory in 5XFAD mice. The improvement in cognitive functions was associated with a restored number of neurons and synapses in both the hippocampus and the cortex. Ketogenic diet treatment also reduced amyloid plaque deposition and microglial activation, resulting in reduced neuroinflammation. The positive effect of ketogenic diet on cognitive functions depended on the starting time and the duration of the diet. A shorter period (2 months) of ketogenic diet treatment had a weaker effect. Ketogenic diet initiated at late stage of AD (9 months of age) displayed no effect on cognitive improvement. CONCLUSIONS: These findings indicate positive effects of ketogenic diet on both cognitive function and histopathology in Alzheimer's disease, which could be due to reduced microglial activation and neuroinflammation. Our findings provide new insights and therapeutic interventions for the treatment of Alzheimer's disease.

Transcription Factor Signatures May Predict the Prognosis and Status of the Immune Microenvironment of Primary Lower-Grade Gliomas.

AIM: Transcription factor (TF) in glioma, including proliferation, invasion/migration, and tumor microenvironment, has been receiving increasing attention. However, there are still no systematical analyses based on global TF. Herein, using global TF target gene sets, we comprehensively investigated their relationship with prognosis and potential biological effect in lower-grade glioma (LGG). We aimed to develop a less-biased prognostic model and provide new insight for personalized management of this disease. METHODS: TF target gene sets were collected from MSigDB and GRID database followed by ssGSEA calculating normalized enrichment score. Comprehensive survival analysis was combined with Kaplan-Meier and Cox algorithms. Consensus cluster and lasso regression were performed to develop prognostic signatures with validation of ROC and independent external cohort. Approaches of xCell/CIBERSORT/TIMER were involved in analyzing the immune microenvironment. We also correlated identified prognostic signatures with tumor mutational burden (TMB) and m6A genes. RESULTS: Fourteen TFs were significantly screened based on survival. Patients were classified into 2 prognosis-related clusters based on 14-TFs features. The function of differentially expressed TF target genes between Cluster1/2 was enriched mostly on glioma invasion/migration. The prognostic model was trained by 6 out of 14-TFs followed by generating risk-score as an independent prognostic indicator. We found differences between the high/low-risk group in TMB and the immune microenvironment, where the high-risk group represented "hot-tumor". Besides, 6-TFs were correlated with m6A regulation genes. CONCLUSION: Our findings suggested that the 6-TFs model could be used to predict prognosis and predict the status of the immune microenvironment in LGG.

Identification of novel genetic biomarkers and treatment targets for arteriosclerosis-related abdominal aortic aneurysm using bioinformatic tools.

A large number of epidemiological studies have confirmed that arteriosclerosis (AS) is a risk factor for abdominal aortic aneurysm (AAA). However, the relationship between AS and AAA remains controversial. The objective of this work is to better understand the association between the two diseases by identifying the co-differentially expressed genes under both pathological conditions, so as to identify potential genetic biomarkers and treatment targets for atherosclerosis-related aneurysms. Differentially-expressed genes (DEGs) shared by both AS and AAA patients were identified by bioinformatics analyses of Gene Expression Omnibus (GEO) datasets GSE100927 and GSE7084. These DEGs were then subjected to bioinformatic analyses of protein-protein interaction (PPI), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Finally, the identified hub genes were further validated by qRT-PCR in AS (n = 4), AAA (n = 4), and healthy (n = 4) individuals. Differential expression analysis revealed a total of 169 and 37 genes that had increased and decreased expression levels, respectively, in both AS and AAA patients compared with healthy controls. The construction of a PPI network and key modules resulted in the identification of five hub genes (SPI1, TYROBP, TLR2, FCER1G, and MMP9) as candidate diagnostic biomarkers and treatment targets for patients with AS-related AAA. AS and AAA are indeed correlated; SPI1, TYROBP, TLR2, FCER1G and MMP9 genes are potential new genetic biomarkers for AS-related AAA.

Association of Circulating Follicular Helper T Cells and Serum CXCL13 With Neuromyelitis Optica Spectrum Disorders.

Background: Neuromyelitis optica spectrum disorders (NMOSDs) are severe inflammatory diseases mediated mainly by humoral and cellular immunity. Circulating follicular helper T (Tfh) cells are thought to be involved in the pathogenesis of NMOSD, and serum C-X-C motif ligand 13 (CXCL13) levels reflect the effects of Tfh cells on B-cell-mediated humoral immunity. Immune cell and cytokine changes during the dynamic relapsing and remitting processes in NMOSD require further exploration. Patients and methods: Blood samples were collected from 36 patients in acute and recovery phases of NMOSD, 20 patients with other noninflammatory neurological diseases (ONND) and 20 age- and sex-matched healthy volunteers. CD4+CXCR5+PD-1+ Tfh cells were detected by flow cytometry, and serum CXCL13 levels were assessed by enzyme-linked immunosorbent assay (ELISA). Results: The percentage of CD4+CXCR5+PD-1+ Tfh cells was significantly higher during the acute phase than during the recovery phase, and serum CXCL13 levels were significantly higher in patients in the acute and recovery phases of NMOSD than in the ONND and control groups. The Tfh cell percentage was positively correlated with CXCL13 levels, and both were positively correlated with Expanded Disability Status Scale (EDSS) scores and cerebrospinal fluid protein levels in patients with acute NMOSD. Conclusion: Circulating Tfh cells level has the potential to be a biomarker of disease severity.

Melamine Disrupts Acetylcholine-Mediated Neural Information Flow in the Hippocampal CA3-CA1 Pathway.

Considering the cognitive and synaptic deficits following intragastric administration of melamine, the aim of the current investigation was to test whether the hippocampal oscillations were affected. The local field potential (LFP) was recorded in the hippocampal CA3-CA1 pathway of Wistar rats during a spatial-dependent Y-maze task. The general partial directed coherence (gPDC) method was used to assess the directionality of neural information flow (NIF) between the CA3 and CA1 regions. The levels of acetylcholine (ACh) and its esterolytic protease, acetylcholinesterase (AChE), were detected in the hippocampus (HPC) following the behavioral test. The values of phase synchronization between the CA3 and CA1 regions in delta, low theta, and high theta oscillations were reduced significantly in the melamine-treated group. Moreover, the coupling directional index and the strength of CA3 driving CA1 were critically decreased in the above three frequency bands as well. Meanwhile, a reduction in ACh expression and an enhancement in AChE activity were found in the HPC of melamine-treated rats. Intrahippocampal infusion with ACh could mitigate the weakened neural coupling and directional NIF in parallel with spatial learning improvements. However, infusion of scopolamine, an acetylcholine receptor antagonist, could block the mitigative effects of ACh treatment in melamine rats. These findings provide first evidence that ACh-mediated neuronal coupling and NIF in the CA3-CA1 pathway are involved in spatial learning deficits induced by chronic melamine exposure.

Single-Cell Transcriptome Profiling Unravels Distinct Peripheral Blood Immune Cell Signatures of RRMS and MOG Antibody-Associated Disease.

Relapsing-remitting multiple sclerosis (RRMS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) are inflammatory demyelinating diseases of the central nervous system (CNS). Due to the shared clinical manifestations, detection of disease-specific serum antibody of the two diseases is currently considered as the gold standard for the diagnosis; however, the serum antibody levels are unpredictable during different stages of the two diseases. Herein, peripheral blood single-cell transcriptome was used to unveil distinct immune cell signatures of the two diseases, with the aim to provide predictive discrimination. Single-cell RNA sequencing (scRNA-seq) was conducted on the peripheral blood from three subjects, i.e., one patient with RRMS, one patient with MOGAD, and one patient with healthy control. The results showed that the CD19+ CXCR4+ naive B cell subsets were significantly expanded in both RRMS and MOGAD, which was verified by flow cytometry. More importantly, RRMS single-cell transcriptomic was characterized by increased naive CD8+ T cells and cytotoxic memory-like Natural Killer (NK) cells, together with decreased inflammatory monocytes, whereas MOGAD exhibited increased inflammatory monocytes and cytotoxic CD8 effector T cells, coupled with decreased plasma cells and memory B cells. Collectively, our findings indicate that the two diseases exhibit distinct immune cell signatures, which allows for highly predictive discrimination of the two diseases and paves a novel avenue for diagnosis and therapy of neuroinflammatory diseases.