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Abstract Background The Cardiometabolic Index (CMI) represents a novel anthropometric measurement, which combines characteristics of adiposity and lipids. Since obesity, lipid metabolism, and inflammation may collectively facilitate the occurrence of stroke, we hypothesize that a combination of elevated levels of the CMI and high-sensitivity C-reactive protein (hs-CRP) increases the risk of future stroke among middle-aged and older Chinese adults. Methods This study included 8,973 participants aged 45 years or older from the China Longitudinal Study on Health and Retirement (CHARLS), who were stroke-free and underwent baseline evaluations between 2011 and 2012, with followed-up at 2013, 2015 and 2018. The exposures were CMI and hs-CRP, with CMI calculated using the formula [waist circumference (cm)/height (cm)] × [triglycerides (mmol/L)/HDL-C (mmol/L)]. The primary outcome was the occurrence of new-onset stroke events. Cox proportional hazards models and restricted cubic spline (RCS) analyses were conducted to examine the associations between CMI, hs-CRP, and their combined effects on stroke risk. Sensitivity analysis was further implemented to verify the robustness of the results. Results A total of 629 participants (7.01%) suffered new-onset stroke during follow-up. The risk for stroke increased with each elevating quartile of baseline CMI levels, with adjusted HRs and 95% CIs being 1.27 (0.98–1.66), 1.41 (1.08–1.83), and 1.46 (1.09–1.96) for Q2, Q3, and Q4, respectively. Moreover, participants with levels of hs-CRP ≥ 2 mg/L also had significantly higher stroke incidence compared to those with CRP levels

Abstract Melanin concentrating hormone (MCH) controls many brain functions, such as sleep/wake cycle and memory, and modulates the inflammation response. Previous studies have shown that influenza A virus (IAV) infection-induced neuroinflammation leads to central nervous damage. This study investigated the potential effects of MCH against neuroinflammation induced by IAV infection and its mechanism. MCH (1 and 2 mg/ml) was administrated for 5 consecutive days before IAV infection. Pentobarbital-induced sleep tests, an open-field test, and a Morris water maze were performed to measure sleep quality, spatial learning and memory ability. Neuronal loss and microglial activation were observed with Nissl staining and immunofluorescence assay. The levels of inflammatory cytokines and the expression of the JNK/ERK signaling pathway were examined by ELISA and western blot. IAV infection led to poor sleep quality, impaired the ability of spatial learning and memory, caused neuronal loss and microglial activation in mice’s hippocampus and cortex. Meanwhile the level of inflammatory cytokines increased, and the JNK/ERK signaling pathway was activated after IAV infection. MCH administration significantly alleviated IAV-induced neuroinflammation, cognitive impairment, and sleep disorder, decreased the levels of inflammatory cytokines, and inhibited neuronal loss and microglial activation in the hippocampus and cortex by regulating the JNK/ERK signaling pathway. Therefore, MCH alleviated the neuroinflammation, spatial learning and memory impairment, and sleep disorder in IAV-infected mice by regulating the JNK/ERK signaling pathway.

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one of the most common inherited cerebral small vessel diseases caused by the NOTCH3 gene mutation. This mutation leads to the accumulation of NOTCH3 extracellular domain protein (NOTCH3ECD) into the cerebral arterioles, causing recurrent stroke, white matter lesions, and cognitive impairment. With the development of gene sequencing technology, cysteine-sparing mutations can also cause CADASIL disease, however, the pathogenicity and pathogenic mechanisms of cysteine-sparing mutations remain controversial.ObjectiveTo analyze the pathogenicity and pathological features of cysteine-sparing mutations in both in vitro and in vivo mouse models.MethodsA cysteine-sparing mutant of NOTCH3ECD R75Q was constructed by lentiviral transfection in vitro, and the NOTCH3 R75Q knock-in mouse model was constructed by CRISPR/Cas-mediated genome engineering in vivo. A cycloheximide pulse-chase experiment was used to analyze the degradation of NOTCH3 extracellular domain proteins, and the deposition characteristics of NOTCH3ECD were quantitatively analyzed by immunohistochemical staining. The characteristics of the smooth muscle cells and granular osmiophilic materials were observed using electron microscopy.ResultsWe elucidated that the NOTCH3 R75Q mutation is pathogenic. NOTCH3ECD R75Q was found to be resistant to protein degradation and more likely to cause abnormal aggregation of NOTCH3ECD, resulting in reduced cell activity in vitro. The NOTCH3 R75Q mouse model showed pathological characteristics of CADASIL, with age-dependent NOTCH3ECD, granular osmiophilic material, and degenerated smooth muscle cells detected in the brain.ConclusionTo our knowledge, this is the first study to analyze the pathogenicity of NOTCH3 R75Q cysteine-sparing mutations in both in vitro and in vivo models. We demonstrate that NOTCH3ECD induced by NOTCH3 R75Q mutation has toxic effects on cells and reveal the deposition characteristics of NOTCH3ECD in the brain. This provides a feasible model and lays the foundation for further studies on the pathogenesis and therapeutic strategies of NOTCH3 cysteine-sparing mutations.

Abstract Background Osteonecrosis of the femoral head (ONFH) is a prevalent orthopedic condition characterized by the disruption of blood supply to the femoral head, leading to ischemia of internal tissues, subchondral bone fractures, necrosis, and eventual collapse of the weight-bearing portion of the femoral head. This condition results in severe functional impairment, pain, and even disability of the hip joint. Existing animal models of ONFH have limitations in replicating the natural disease progression accurately. Thus, there is a critical need to develop a novel animal model capable of better simulating localized pressure on the human femoral head to facilitate ONFH-related research. Methods In this study, we present a novel approach for modeling ONFH, which involves integrating stress factors into the modeling process through the utilization of 3D printing technology and principles of biomechanics. A total of 36 animals were randomly assigned to six groups, where they received either the novel modeling technique or the traditional hormone induction method. Subsequently, an 8-week treatment period was implemented, followed by conducting micro-CT scans and histological evaluations to assess tissue outcomes. Results The study evaluated the cytotoxicity of the material used in the new model, and it was observed that the material did not exhibit any cytotoxic effects on cells. Additionally, the novel model successfully replicated the pathological features of ONFH, including femoral head collapse, along with a substantial presence of empty bone lacunae, cartilage defects, and subchondral bone fractures in the subchondral bone region. Conclusion In conclusion, our study provides evidence that the new model shows the ability to simulate the progression of the disease, making it a valuable tool for research in this field and can contribute to the development of better treatment strategies for this debilitating condition. It holds great promise for advancing our understanding of the pathogenesis of ONFH and the potential therapeutic interventions for this challenging clinical problem.

Abstract Background For a long time, the prevailing viewpoint suggests that shorter telomere contribute to chromosomal instability, which is a shared characteristic of both aging and cancer. The newest research presented that T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to some cancers. However, the relationship between genetically determined telomere length (TL) and immune cells remains unclear. Methods The two‐sample Mendelian randomization analysis was conducted to elucidate the potential causal relationship. The genetic data of TL and immune cells were obtained from the Genome‐Wide Association Study. The inverse variance weighted (IVW) method was used to estimate the effects primarily and another four methods were as a supplement. Sensitivity analysis was used to test the results. Results The IVW method showed a significant correlation between TL and the percentage of T cells in lymphocytes (odds ratio [OR]: 1.222, 95% confidence interval [CI]: 1.014–1.472, p = .035), indicating that shorter TL significantly increases the risk of low T cell percentage. Further analysis of T cell subsets indicated that shorter TL may primarily lead to a lower percentage of Natural Killer T cells (OR: 1.574, 95% CI: 1.281–1.935, p

IntroductionOne rare type of autoimmune disease is called neuromyelitis optica spectrum disorder (NMOSD) and the peripheral immune characteristics of NMOSD remain unclear.MethodsHere, single-cell RNA sequencing (scRNA-seq) is used to characterize peripheral blood mononuclear cells from individuals with NMOSD.ResultsThe differentiation and activation of lymphocytes, expansion of myeloid cells, and an excessive inflammatory response in innate immunity are observed. Flow cytometry analyses confirm a significant increase in the percentage of plasma cells among B cells in NMOSD. NMOSD patients exhibit an elevated percentage of CD8+ T cells within the T cell population. Oligoclonal expansions of B cell receptors are observed after therapy. Additionally, individuals with NMOSD exhibit elevated expression of CXCL8, IL7, IL18, TNFSF13, IFNG, and NLRP3.DiscussionPeripheral immune response high-dimensional single-cell profiling identifies immune cell subsets specific to a certain disease and identifies possible new targets for NMOSD.

Abstract Objective The purpose of the present study was to determine the learning curve for a novel seven-axis robot-assisted (RA) total knee arthroplasty (TKA) system and to explore whether it could provide superior short-term clinical and radiological outcomes compared with conventional surgery. Methods In the present retrospective study, 90 patients who underwent RA-TKA were included in robot-assisted system (RAS) group and 90 patients who underwent conventional TKA were included in the conventional group. The duration of surgery and robot-related complications were recorded to evaluate the learning curve through cumulative sum and risk-adjusted cumulative sum methods. The demographic data, preoperative clinical data, preoperative imaging data, duration of surgery, alignment of the prosthesis, lower limb force line alignment, Knee Society score, 10-cm visual analog scale pain score and range of motion were compared between the RAS and conventional groups. In addition, the proficiency group was compared with the conventional group using propensity score matching. Results RA-TKA was associated with a learning curve of 20 cases for the duration of surgery. There was no significant difference in indicators representing the accuracy of the prosthetic installation between the learning and proficiency phases in RA-TKA group patients. A total of 49 patients in the proficiency group were matched with 49 patients from the conventional group. The number of postoperative hip–knee–ankle (HKA) angle, component femoral coronal angle (CFCA), component tibial coronal angle (CTCA), and sagittal tibial component angle (STCA) outliers in the proficiency phase was lower than that in the conventional group, while deviations of the HKA angle, CFCA, CTCA, and STCA in the proficiency phase were significantly lower than those in the conventional group (P

Perivascular spaces are parts of the glymphatic pathway in the brain, which are microscopic but visible on magnetic resonance imaging when enlarged. Here, we described a case of a 16-year-old boy who presented with chronic headaches. Magnetic resonance imaging revealed giant perivascular spaces in the right centrum semiovale. Furtherly, we summarized the literature on classical and rare presentations of massive perivascular spaces and raised awareness that more clinical significance of the giant tumefactive perivascular spaces remains to be elucidated.

AimRed blood cell distribution width-to-albumin ratio (RAR) is a combined new indicator reflecting immunology and has been reported to predict the prognosis of inflammation-related diseases and brain diseases. However, the association and predictive value of RAR in the prognosis of patients with autoimmune encephalitis (AE) has not been reported.MethodsThis was a retrospective cohort study, and data were collected from the Henan Provincial People’s Hospital. RAR was categorized according to quartile. The prognosis was assessed using the modified Rankin Scale (mRS), and an mRS score of ≥3 was defined as a poor prognosis. The logistical regression model was used to explore the association between RAR and the prognosis, with results reported as odds ratio (OR) and 95% confidence interval (CI). The predictive value of RAR was evaluated by calculating the area under the receiving operating curve (AUC), sensitivity, specificity, and accuracy.ResultsA total of 175 eligible patients were included for analysis, and 51 patients were identified as having poor prognosis. After adjusting age, cancer, other diseases, histological subtype, antiepileptic therapy, anti-tumor treatment, ICU treatment, and length of stay, RAR in the highest quartile (Q4) was found to be significantly associated with the high odds of poor prognosis (OR = 5.63, 95%CI: 1.98–16.02) compared to RAR in the lowest quartile (Q1). In addition, RAR was identified as a predictor for the prognosis of AE patients (AUC = 0.660, 95%CI: 0.574–0.746).ConclusionThis study found the close association and predictive value of RAR for the prognosis of AE patients, indicating that RAR might help clinicians identify high-risk populations.

ObjectiveOsteonecrosis of the femoral head (ONFH) is a common orthopedic condition that will prompt joint dysfunction, significantly impacting patients’ quality of life. However, the specific pathogenic mechanisms underlying this disease remain elusive. The objective of this study is to examine the differentially expressed messenger RNAs (DE mRNAs) and key genes linked to ONFH, concurrently investigating the immune cell infiltration features in ONFH patients through the application of the CIBERSORT algorithm.MethodsMicroarray was applied to scrutinize mRNA expression profiles in both ONFH patients and healthy controls, with data integration sourced from the GEO database. DE mRNAs were screened using the Limma method. The biological functions of DE mRNAs were explored through the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, Gene Ontology (GO) functional analysis, and Gene Set Enrichment Analysis (GSEA). Additionally, support vector machine–recursive feature elimination (SVM-RFE) and the least absolute shrinkage and selection operator (LASSO) were employed to discern diagnostic biomarkers associated with the disease. Receiver operating characteristic (ROC) analysis was utilized to assess the statistical performance of the feature genes. The validation of key genes was performed using qRT-PCR in bone tissues obtained from ONFH patients and healthy controls. Osteogenic differentiation of BMSC was then performed and detected by alkaline phosphatase staining (ALP) and qRT-PCR to verify the correlation between key genes and osteogenic differentiation. Finally, immune cell infiltration analysis was executed to evaluate immune cell dysregulation in ONFH, concurrently exploring the correlation between the infiltration of immune cells and key genes.ResultsAfter consolidating the datasets, the Limma method revealed 107 DEGs, comprising 76 downregulated and 31 upregulated genes. Enrichment analysis revealed close associations of these DE mRNAs with functions such as cell migration, osteoblast differentiation, cartilage development and extracellular region. Machine learning algorithms further identified APOD, FBXO43 and LRP12 as key genes. ROC curves demonstrated the high diagnostic efficacy of these genes. The results of qRT-PCR showed that the expression levels of key genes were consistent with those of microarray analysis. In addition, the results of in vitro experiments showed that APOD was closely related to osteogenic differentiation of BMSC. Immune infiltration analysis suggested a close correlation between ONFH and imbalances in levels of Neutrophils, Monocytes, Macrophages M2, Dendritic cells activated and Dendritic cells resting.ConclusionAPOD is closely related to osteogenic differentiation of BMSCs and can be used as a diagnostic marker of ONFH. Immune cell infiltration significantly differs between controls and ONFH patients.

Venetoclax is a standard treatment for patients with chronic lymphocytic leukemia (CLL) following covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy, despite relatively limited prospective data in this setting. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that was designed to overcome the pharmacologic limitations of cBTKi and re-establish BTK inhibition. An unanchored matching-adjusted indirect comparison (MAIC) was conducted to estimate the treatment effect of pirtobrutinib versus venetoclax monotherapy in patients with cBTKi-pretreated CLL. Data from patients with CLL who were venetoclax-naïve and pretreated with cBTKi received pirtobrutinib (N=146) in the phase I/II BRUIN study were compared with the only identified trial of patients with CLL receiving venetoclax after a cBTKi (N=91), as administered as monotherapy until progression. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-emergent adverse events. Both unweighted and weighted analyses were conducted. PFS and OS of pirtobrutinib and venetoclax were comparable in both unweighted and weighted analyses (weighted hazard ratios for PFS: 1.01, 95% confidence interval [CI]: 0.58-1.73, P=0.98 and OS: 0.64, 95% CI: 0.25-1.67, P=0.34). ORR was significantly higher for pirtobrutinib (80.2% vs. 64.8%, P=0.01). Grade ≥3 treatment-emergent adverse events were lower in weighted analyses for pirtobrutinib versus venetoclax (all P

Aims: To summarize and clarify the current research status and indicate possible future directions in the field of autophagy in ischemic stroke, we performed a comprehensive and multidimensional bibliometric analysis of the literature in this field published from 2011 to 2022.Methods: We retrieved articles on the field of autophagy in ischemic stroke published between 2011 and 2022 from Web of Science Core Collection (WOSCC). VOSviewer (version 1.6.19) and CiteSpace (version 6.2.R2 Basic) were used to identify the leading topics as well as generate visual maps of Countries/regions, organizations, authors, journals, and keyword networks in the related field.Results: A total of 568 publications were contained in this research. The journal with the most publications were Front Pharmacol, Mol Neurobiol, and Neuroscience. China was the most productive country with respect to co-authorship, with the Capital Med Univ being the organization with the most. co-authorships. In terms of authorship analysis, eight of the top 10 most contributive authors were from China. The co-occurring author keywords can be divided into three main clusters, including “protective effect of autophagy in ischemic stroke,” “autophagy-targeted therapy for ischemic stroke,” and “mitochondrial function in cerebral ischemia-reperfusion injury”.Conclusion: This bibliometric analysis helps us reveal the current research hotspots in the research field of autophagy in ischemic stroke and guide future research directions. Subsequent trends in this special field are likely to identify and develop novel autophagy-targeted therapy strategies to effectively prevent and treat ischemic stroke.

ObjectiveTo investigate the value of 18F-FDG positron emission tomography/computed tomography (PET/CT) two time point imaging for the identification of the potential epileptogenic zone (EZ) in temporal lobe epilepsy (TLE).MethodsFifty-two patients with TLE were prospectively enrolled in the 18F-FDG PET/CT two time point imaging study. The early imaging was obtained approximately 40 min (43.44 ± 18.04 min) after 18F-FDG injection, and the delayed imaging was obtained about 2 to 3 h (160.46 ± 28.70 min) after the injection. Visual and semi-quantitative analysis of 18F-FDG uptake were performed at the two time points in EZ and contralateral symmetrical region. The mean standardized uptake value (SUVmean) of EZ and contralateral symmetrical region was calculated to determine the asymmetry index (AI) of the early and delayed images, as well as in the MRI positive and negative patient groups.ResultsSemi-quantitative analysis demonstrated that AI of the early and delayed 18F-FDG PET/CT images was 13.47 ± 6.10 and 16.43 ± 6.66, respectively. The ΔAI was 2.95 ± 3.05 in 52 TLE patients between the two time points. The AI of the EZ was significantly elevated in delayed images compared to the early images (p

Stroke is a severe and life-threatening disease, necessitating more research on new treatment strategies. Infiltrated T lymphocytes, an essential adaptive immune cell with extensive effector function, are crucially involved in post-stroke inflammation. Immediately after the initiation of the innate immune response triggered by microglia/macrophages, the adaptive immune response associated with T lymphocytes also participates in the complex pathophysiology of stroke and partially informs the outcome of stroke. Preclinical and clinical studies have revealed the conflicting roles of T cells in post-stroke inflammation and as potential therapeutic targets. Therefore, exploring the mechanisms that underlie the adaptive immune response associated with T lymphocytes in stroke is essential. The T-cell receptor (TCR) and its downstream signaling regulate T lymphocyte differentiation and activation. This review comprehensively summarizes the various molecules that regulate TCR signaling and the T-cell response. It covers both the co-stimulatory and co-inhibitory molecules and their roles in stroke. Because immunoregulatory therapies targeting TCR and its mediators have achieved great success in some proliferative diseases, this article also summarizes the advances in therapeutic strategies related to TCR signaling in lymphocytes after stroke, which can facilitate translation.

Abstract Objective Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune‐mediated disease that targets the myelin sheaths of the peripheral nerves. Fingolimod is a sphingosine 1 phosphate (S1P) receptor antagonist with a high affinity for S1P receptors through the Akt–mTOR pathway, and prior research has suggested that it might be helpful in autoimmune illnesses. Methods Chronic experimental autoimmune neuritis (c‐EAN) was induced by immunizing Lewis rats with the S‐palm P0(180–199) peptide, and then the treatment group was intraperitoneally injected with fingolimod (1 mg/kg) daily. Hematoxylin and eosin staining was used to assess the severity of nerve injury. Immunohistochemistry staining showed that fingolimod's anti‐inflammatory effects on c‐EAN rats might be realized through the NF‐κB signaling pathway. Tumor necrosis factor‐α (TNF‐α), interferon‐γ (INF‐γ), interleukin‐1beta (IL‐1β), interleukin 6 (IL‐6), inducible nitric oxide synthase (iNOS), and intercellular adhesion molecule‐1 (ICAM‐1) were measured to evaluate the inflammation levels, and pAkt, p‐S6, and p‐p65 were used to measure the abundance of downstream activation markers to determine whether the Akt/mTOR/NF‐κB signaling pathway was activated in the c‐EAN model. Results Fingolimod treatment reduced the inflammatory reaction and the expression of NF‐κB in sciatic nerves. It also decreased the mRNA levels of the proinflammatory cytokines TNF‐α, IFN‐γ, IL‐1β, IL‐6, iNOS, and ICAM‐1 and pAkt, p‐S6, and p‐p65, representing the Akt/mTOR/NF‐κB signaling pathway. Conclusion Our data showed that fingolimod could improve the disease course, alleviate the decrease in inflammation, and reduce proinflammatory cytokines through the Akt/mTOR/NF‐κB axis in c‐EAN rats, which could be beneficial for the development of CIDP‐related research.

Growth-regulating factors (GRFs) are a unique family of transcription factors with well-characterized functions in plant growth and development. However, few studies have evaluated their roles in the absorption and assimilation of nitrate. In this study, we characterized the GRF family genes of flowering Chinese cabbage (Brassica campestris), an important vegetable crop in South China. Using bioinformatics methods, we identified BcGRF genes and analyzed their evolutionary relationships, conserved motifs, and sequence characteristics. Through genome-wide analysis, we identified 17 BcGRF genes distributed on seven chromosomes. A phylogenetic analysis revealed that the BcGRF genes could be categorized into five subfamilies. RT-qPCR analysis showed that BcGRF1, 8, 10, and 17 expression clearly increased in response to nitrogen (N) deficiency, particularly at 8 h after treatment. BcGRF8 expression was the most sensitive to N deficiency and was significantly correlated with the expression patterns of most key genes related to N metabolism. Using yeast one-hybrid and dual-luciferase assays, we discovered that BcGRF8 strongly enhances the driving activity of the BcNRT1.1 gene promoter. Next, we investigated the molecular mechanism by which BcGRF8 participates in nitrate assimilation and N signaling pathways by expressing it in Arabidopsis. BcGRF8 was localized in the cell nucleus and BcGRF8 overexpression significantly increased the shoot and root fresh weights, seedling root length, and lateral root number in Arabidopsis. In addition, BcGRF8 overexpression considerably reduced the nitrate contents under both nitrate-poor and -rich conditions in Arabidopsis. Finally, we found that BcGRF8 broadly regulates genes related to N uptake, utilization, and signaling. Our results demonstrate that BcGRF8 substantially accelerates plant growth and nitrate assimilation under both nitrate-poor and -rich conditions by increasing the number of lateral roots and the expression of genes involved in N uptake and assimilation, providing a basis for crop improvement.

Introduction: Spinocerebellar ataxias 36 (SCA36) is the neurodegenerative disease caused by the GGCCTG Hexanucleotide repeat expansions in NOP56, which is too long to sequence using short-read sequencing. Single molecule real time (SMRT) sequencing can sequence across disease-causing repeat expansion. We report the first long-read sequencing data across the expansion region in SCA36.Methods: We collected and described the clinical manifestations and imaging features of Han Chinese pedigree with three generations of SCA36. Also, we focused on structural variation analysis for intron 1 of the NOP56 gene by SMRT sequencing in the assembled genome.Results: The main clinical features of this pedigree are late-onset ataxia symptoms, with a presymptomatic presence of affective and sleep disorders. In addition, the results of SMRT sequencing showed the specific repeat expansion region and demonstrated that the region was not composed of single GGCCTG hexanucleotides and there were random interruptions.Discussion: We extended the phenotypic spectrum of SCA36. We applied SMRT sequencing to reveal the correlation between genotype and phenotype of SCA36. Our findings indicated that long-read sequencing is well suited to characterize known repeat expansion.

IntroductionAnti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is a rare autoimmune disease, and the peripheral immune characteristics associated with anti-NMDARE antibodies remain unclear.MethodsHerein, we characterized peripheral blood mononuclear cells from patients with anti-NMDARE and healthy individuals by single-cell RNA sequencing (scRNA-seq).ResultsThe transcriptional profiles of 129,217 cells were assessed, and 21 major cell clusters were identified. B-cell activation and differentiation, plasma cell expansion, and excessive inflammatory responses in innate immunity were all identified. Patients with anti-NMDARE showed higher expression levels of CXCL8, IL1B, IL6, TNF, TNFSF13, TNFSF13B, and NLRP3. We observed that anti-NMDARE patients in the acute phase expressed high levels of DC_CCR7 in human myeloid cells. Moreover, we observed that anti-NMDARE effects include oligoclonal expansions in response to immunizing agents. Strong humoral immunity and positive regulation of lymphocyte activation were observed in acute stage anti-NMDARE patients.DiscussionThis high-dimensional single-cell profiling of the peripheral immune microenvironment suggests that potential mechanisms are involved in the pathogenesis and recovery of anti-NMDAREs.

Gibberellin and cytokinin synergistically regulate the stalk development in flowering Chinese cabbage. KNOX proteins were reported to function as important regulators of the shoot apex to promote meristem activity by synchronously inducing CTK and suppressing GA biosynthesis, while their regulatory mechanism in the bolting and flowering is unknown. In this study, 9 BcKNOX genes were identified and mapped unevenly on 6 out of 10 flowering Chinese cabbage chromosomes. The BcKNOXs were divided into three subfamilies on the basis of sequences and gene structure. The proteins contain four conserved domains except for BcKNATM. Three BcKNOX TFs (BcKNOX1, BcKNOX3, and BcKNOX5) displayed high transcription levels on tested tissues at various stages. The major part of BcKNOX genes showed preferential expression patterns in response to low-temperature, zeatin (ZT), and GA3 treatment, indicating that they were involved in bud differentiation and bolting. BcKNOX1 and BcKNOX5 showed high correlation level with gibberellins synthetase, and CTK metabolic genes. BcKONX1 also showed high correlation coefficients within BcRGA1 and BcRGL1 which are negative regulators of GA signaling. In addition, BcKNOX1 interacted with BcRGA1 and BcRGL1, as confirmed by yeast two-hybrid (Y2H) and biomolecular fluorescence complementation assay (BiFC). This analysis has provided useful foundation for the future functional roles’ analysis of flowering Chinese cabbage KNOX genes

Abstract Background Chronic cerebral hypoperfusion (CCH) is the leading cause of cerebral small vessel disease (CSVD). CCH is strongly associated with blood–brain barrier (BBB) dysfunction and white matter lesions (WMLs) in CSVD. However, the effects of CCH on BBB integrity and components and the cellular and molecular mechanisms underlying the effects of BBB dysfunction remain elusive. Whether maintaining BBB integrity can reverse CCH-induced brain damage has also not been explored. Methods In this study, we established a rat model of CSVD via permanent bilateral common carotid artery occlusion (2VO) to mimic the chronic hypoperfusive state of CSVD. The progression of BBB dysfunction and components of the BBB were assessed using immunostaining, Western blotting, transmission electron microscopy (TEM) and RNA sequencing. We also observed the protective role of imatinib, a tyrosine kinase inhibitor, on BBB integrity and neuroprotective function following CCH. The data were analyzed using one-way or two-way ANOVA. Results We noted transient yet severe breakdown of the BBB in the corpus callosum (CC) following CCH. The BBB was severely impaired as early as 1 day postoperation and most severely impaired 3 days postoperation. BBB breakdown preceded neuroinflammatory responses and the formation of WMLs. Moreover, pericyte loss was associated with BBB impairment, and the accumulation of serum protein was mediated by increased endothelial transcytosis in the CC. RNA sequencing also revealed increased transcytosis genes expression. BBB dysfunction led to brain damage through regulation of TGF-β/Smad2 signaling. Furthermore, imatinib treatment ameliorated serum protein leakage, oligodendrocyte progenitor cell (OPC) activation, endothelial transcytosis, microglial activation, and aberrant TGF-β/Smad2 signaling activation. Conclusions Our results indicate that reduced pericyte coverage leads to increased BBB permeability via endothelial transcytosis. Imatinib executes a protective role on the BBB integrity via inhibition of endothelial transcytosis. Maintenance of BBB integrity ameliorates brain damage through regulation of TGF-β/Smad2 signaling following CCH; therefore, reversal of BBB dysfunction may be a promising strategy for CSVD treatment.

ObjectiveTo explore prognostic indicators of lung adenocarcinoma with leptomeningeal metastases (LM) and provide an updated graded prognostic assessment model integrated with molecular alterations (molGPA).MethodsA cohort of 162 patients was enrolled from 202 patients with lung adenocarcinoma and LM. By randomly splitting data into the training (80%) and validation (20%) sets, the Cox regression and random survival forest methods were used on the training set to identify statistically significant variables and construct a prognostic model. The C-index of the model was calculated and compared with that of previous molGPA models.ResultsThe Cox regression and random forest models both identified four variables, which included KPS, LANO neurological assessment, TKI therapy line, and controlled primary tumor, as statistically significant predictors. A novel targeted-therapy-assisted molGPA model (2022) using the above four prognostic factors was developed to predict LM of lung adenocarcinoma. The C-indices of this prognostic model in the training and validation sets were higher than those of the lung-molGPA (2017) and molGPA (2019) models.ConclusionsThe 2022 molGPA model, a substantial update of previous molGPA models with better prediction performance, may be useful in clinical decision making and stratification of future clinical trials.

BackgroundWith promotion of COVID-19 vaccinations, there has been a corresponding vaccine hesitancy, of which older adolescents and young adults represent groups of particular concern. In this report, we investigated the prevalence and reasons for vaccine hesitancy, as well as potential risk factors, within older adolescents and young adults in China.MethodsTo assess these issues, an online survey was administered over the period from March 14 to April 15, 2021. Older adolescents (16–17 years old) and young adults (18–21 years old) were recruited nationwide from Wechat groups and results from a total of 2,414 respondents were analyzed. Socio-demographic variables, vaccine hesitancy, psychological distress, abnormal illness behavior, global well-being and social support were analyzed in this report.ResultsCompared to young adults (n = 1,405), older adolescents (n = 1,009) showed higher prevalence rates of COVID-19 vaccine hesitancy (16.5 vs. 7.9%, p < 0.001). History of physical diseases (p = 0.007) and abnormal illness behavior (p = 0.001) were risk factors for vaccine hesitancy among older adolescents, while only a good self-reported health status (p = 0.048) was a risk factor for young adults. Concerns over COVID-19 vaccine side effects (67.1%) and beliefs of invulnerability regarding infection risk (41.9%) were the most prevalent reasons for vaccine hesitancy. Providing evidence on the vaccine reduction of COVID-19 infection risk (67.5%), ensuring vaccine safety (56.7%) and the low risk of side effects (52.7%) were the most effective persuasions for promoting vaccinations.ConclusionIn China, older adolescents showed a higher prevalence for vaccine hesitancy than that of young adults. Abnormal illness behavior and history of physical diseases were risk factors for vaccine hesitancy among these older adolescents, while social support represents an important factor which could help to alleviate this hesitancy.

Background: Mutations in the NIPA1 gene cause hereditary spastic paraplegia (HSP) type 6 (SPG6), which is a rare type of HSP with a frequency of less than 1% in Europe. To date, less than 30 SPG6 families and limited NIPA1 mutations have been reported in different ethnic regions. The clinical features are variable.Methods: We screened for NIPA1 mutations by whole exome sequencing or next generation sequencing in 35 unrelated Chinese families with HSP. The clinical manifestations were evaluated.Results: Two variants of NIPA1 were identified in three index patients (3/35, 8.6%), two of whom carried a previously reported common variant c.316G > A (p.G106R), and the third patient harbored a novel likely pathogenic variant c.126C > G (p.N42K). Both variants were de novo in the three index patients. The phenotype was pure HSP in two patients and complicated HSP with epilepsy in the third one.Conclusion:NIPA1-related HSP is more common in China than it in Europe. Both pure and complicated form of HSP can be found. The variant c.316G > A is a hotspot mutation, and the novel variant c.126C > G expands the mutational spectrum. The phenomenon of de novo mutations in NIPA1 emphasizes the need to consider autosomal dominant HSP-related genes in sporadic patients.

PurposeThis study investigates the topological properties of brain functional networks in patients with isolated rapid eye movement sleep behavior disorder (iRBD).Participants and MethodsA total of 21 patients with iRBD (iRBD group) and 22 healthy controls (HCs) were evaluated using resting-state functional MRI (rs-fMRI) and neuropsychological measures in cognitive and motor function. Data from rs-fMRI were analyzed using graph theory, which included small-world properties, network efficiency, network local efficiency, nodal shortest path, node efficiency, and network connectivity, as well as the relationship between behavioral characteristics and altered brain topological features.ResultsRey-Osterrieth complex figure test (ROCFT-copy), symbol digital modalities test (SDMT), auditory verbal learning test (AVLT)-N1, AVLT-N2, AVLT-N3, and AVLT-N1-3 scores were significantly lower in patients with iRBD than in HC (P < 0.05), while trail making test A (TMT-A), TMT-B, and Unified Parkinson’s Disease Rating Scale Part-III (UPDRS-III) scores were higher in patients with iRBD (P < 0.05). Compared with the HCs, patients with iRBD had no difference in the small-world attributes (P > 0.05). However, there was a significant decrease in network global efficiency (P = 0.0052) and network local efficiency (P = 0.0146), while an increase in characteristic path length (P = 0.0071). There was lower nodal efficiency in occipital gyrus and nodal shortest path in frontal, parietal, temporal lobe, and cingulate gyrus. Functional connectivities were decreased between the nodes of occipital with the regions where they had declined nodal shortest path. There was a positive correlation between TMT-A scores and the nodal efficiency of the right middle occipital gyrus (R = 0.602, P = 0.014).ConclusionThese results suggest that abnormal behaviors may be associated with disrupted brain network topology and functional connectivity in patients with iRBD and also provide novel insights to understand pathophysiological mechanisms in iRBD.

The blood-brain barrier (BBB) comprises a single layer of endothelial cells and maintains a safe and homeostatic environment for proper neuronal function and synaptic transmission. BBB is not a discrete physical barrier, but a complex, dynamic, and adaptable interface. BBB continues to mature under the influence of the neural environment within a short period of time after birth. However, the basic mechanism of BBB formation and maintenance remains a mystery. Early studies have identified two structural characteristics of microvascular endothelium: special tight junctions (TJs) and a very low transcellular vesicle transport rate. Previous studies believed that BBB damage was mainly due to the destruction of tight junctions, and the role of vesicle transcytosis was neglected, so there was a lack of research on its impact on blood-brain barrier. It is urgent to get a better clarification of the unique structural and functional characteristics of the BBB endothelium to explain the role of BBB injury in neurological diseases. RNA sequencing was used to study the molecular characterization of cerebral cortex vascular endothelium by isolating them from neonatal, adolescent and adult rats. For investigation the maintenance mechanism of the BBB, we focused on the cellular and molecular regulation of barrier formation and the two characteristics of microvascular endothelial cells. Interestingly, we found that during the development of the blood-brain barrier, although the tight junctions gradually mature, endothelial cell transcytosis is gradually enhanced, resulting in an increase in the permeability of the blood-brain barrier. This study suggested that under physiological conditions, low vesicle transport is playing an important role in maintaining the integrity of the blood-brain barrier. This study not only summarized the unique characteristics of microvascular endothelial cells, but also illustrated a clarified mechanism of the development and maintenance of BBB which can provide new therapeutic opportunities for central nervous system drug delivery. Raw data of RNA sequencing were deposited in NCBI Sequence Read Archive database (PRJNA790676).

Abstract Background Traumatic brain injury (TBI) is a common neurotrauma leading to brain dysfunction and death. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) hold promise in the treatment of TBI. However, their efficacy is modest due to low survival and differentiation under the harsh microenvironment of the injured brain. MG53, a member of TRIM family protein, plays a vital role in cell and tissue damage repair. The present study aims to test whether MG53 preserves hUC-MSCs against oxidative stress and enhances stem cell survival and efficacy in TBI treatment. Methods In this study, we performed a series of in vitro and in vivo experiments in hUC-MSCs and mice to define the function of MG53 enhancing survival, neurogenesis, and therapeutic efficacy of stem cells in murine traumatic brain injury. Results We found that recombinant human MG53 (rhMG53) protein protected hUC-MSCs against H2O2-induced oxidative damage and stimulated hUC-MSC proliferation and migration. In a mouse model of contusion-induced TBI, intravenous administration of MG53 protein preserved the survival of transplanted hUC-MSCs, mitigated brain edema, reduced neurological deficits, and relieved anxiety and depressive-like behaviors. Co-treatment of MG53 and hUC-MSCs enhanced neurogenesis by reducing apoptosis and improving PI3K/Akt-GSK3β signaling. Conclusion MG53 enhances the efficacy of hUC-MSCs in the recovery of TBI, indicating that such adjunctive therapy may provide a novel strategy to lessen damage and optimize recovery for brain injury.

This paper presents a comprehensive study on dynamic properties and human-induced vibrations of a slender asymmetric steel-plated stress-ribbon footbridge via both experimental and analytical methods. Bridge modal test was conducted using both ambient vibration testing and impact methods. Modal properties of the bridge were identified based on stochastic subspace identification and peak-pick techniques. Results show that the bridge is characterized by closely spaced modes with low natural frequencies and small damping ratios (

Abstract Background Mishandling of intracellular chloride (Cl−) concentration ([Cl−]i) in cerebrovascular smooth muscle cells is implicated in several pathological processes, including hyperplasia and remodeling. We investigated the effects of ClC-2-mediated Cl− efflux on the proliferation of human brain vascular smooth muscle cells (HBVSMCs) induced by angiotensin II (AngII). Methods Cell proliferation and motility were determined using the CCK-8, bromodeoxyuridine staining, wound healing and invasion assays. ClC-2, PCNA, Ki67, survivin and cyclin D1 expression, and β-catenin and GSK-3β phosphorylation were examined using western blotting. Histological analyses were performed using hematoxylin and eosin staining and α-SMA staining. Results Our results showed that AngII-induced HBVSMC proliferation was accompanied by a decrease in [Cl−]i and an increase in ClC-2 expression. Inhibition of ClC-2 by siRNA prevented AngII from inducing the efflux of Cl−. AngII-induced HBVSMC proliferation, migration and invasion were significantly attenuated by ClC-2 downregulation. The inhibitory effects of ClC-2 knockout on HBVSMC proliferation and motility were associated with inactivation of the Wnt/β-catenin signaling pathway, as evidenced by inhibition of β-catenin phosphorylation and nuclear translocation, and decrease of GSK-3β phosphorylation and survivin and cyclin D1 expression. Recombinant Wnt3a treatment markedly reversed the effect of ClC-2 knockdown on HBVSMC viability. An in vivo study revealed that knockdown of ClC-2 with shRNA adenovirus ameliorated basilar artery remodeling by inhibiting Wnt/β-catenin signaling in AngII-treated mice. Conclusion This study demonstrates that blocking ClC-2-mediated Cl− efflux inhibits AngII-induced cerebrovascular smooth muscle cell proliferation and migration by inhibiting the Wnt/β-catenin pathway. Our data indicate that downregulation of ClC-2 may be a viable strategy in the prevention of hyperplasia and remodeling of cerebrovascular smooth muscle cells.

Abstract Background In the present study, a novel mutation in exon 46 at codon 2304 (G2304R) of the SYNE1 gene is described in a Chinese family (proband, mother, and sister) with Emery–Dreifuss muscular dystrophy-like, which clinically manifests as muscle weakness, muscle atrophy, joint contracture, and without significant cardiac abnormalities. Methods Clinical examination and neuroimaging of the captured target region and high-throughput sequencing were performed in a family of four generations. Muscle changes were evaluated using magnetic resonance imaging and muscle biopsies. Results Target region capture sequencing yielded a novel missense mutation in codon 2304 (G2304R), which is a heterozygous A to G point mutation at position 6910 (c.6910A > G) in exon 46 of SYNE1 leading to a glycine-to-arginine substitution (p.Gly2304Arg). The results were also identified by Sanger sequencing in three family members but not in the other three unaffected family members and 100 control subjects. Conclusions This mutation is probably pathogenic and is the first of its kind reported in a familial Emery–Dreifuss muscular dystrophy-like.

BackgroundAlzheimer’s disease (AD) and diabetes mellitus (DM) often coexist in patients because having one of these conditions increases risk for the other. These two diseases share several pathophysiological mechanisms, such as specific inflammatory signaling pathways, oxidative stress, and cell apoptosis. It is still unclear exactly which mechanisms associated with DM are responsible for increased AD risk. Studies have found that even transient elevation of brain Aβ levels can allow T2DM to slightly disrupt the neural milieu in a way that encourages pathologies associated with the onset of memory deficits and AD. A recent study argues that a potential common pathogenetic mechanism underlying both DM and AD is evidenced by the cooccurrence of amyloid brain legions and deposits containing both tau and Aβ in pancreatic β cells. Given these links, an investigation detailing disease mechanisms as well as treatment options for patients with cooccurring DM and AD is urgently needed. The biological effects of resveratrol relevant to DM and AD treatment include its abilities to modulate oxidative stress and reduce inflammation. A rat model of DM and concomitant AD was created for this study using intraperitoneal injection of streptozotocin and hippocampal injection of Aβ1–40 to characterize resveratrol’s potential protective action.ResultsResveratrol significantly increased the Sirt1 expression, inhibited the memory impairment, the increased acetylcholinesterase, malondialdehyde, interleukin-1β and interleukin 6 levels, and the decreased levels of choline acetyltransferase (ChAT), superoxide dismutase (SOD), and glutathione in this rat model of diabetes and concomitant AD. The Sirt 1 inhibitor EX527 partially reversed the effects of resveratrol.ConclusionThis study suggests that resveratrol may have a neuroprotective action through activation of Sirt1 signaling in diabetes and AD with concurrent onset.

Background: In recent years, the phenomenon of coexisting systemic autoimmune diseases (ADs) in patients with autoimmune encephalitis (AE) has been increasingly found, while its clinical significance remains unexplored. This study aimed to investigate the types and potential clinical associations of autoimmune comorbidities in patients with antibody-positive AE.Methods: A retrospective cohort study of patients with antibody-positive AE was conducted from 2011 to 2018. The demographics, clinical characteristics, and follow-up data were reviewed.Results: We enrolled 517 patients, among whom 45 were affected by one or more types of ADs, including Hashimoto's thyroiditis (HT) (n = 28), systemic lupus erythematosus (SLE) (n = 3), anaphylactoid purpura (n = 3), vitiligo (n = 3), Sjögren's syndrome (SS) (n = 2), chronic urticaria (n = 2), bullous pemphigoid (n = 1), uveitis (n = 1), myasthenia gravis (MG) (n = 1), and the coexistence of SLE and anaphylactoid purpura (n = 1). The proportion of patients with coexisting ADs was higher in those with anti–leucine-rich glioma-inactivated 1 (LGI1) encephalitis than in those with anti–N-methyl-d-aspartate receptor (NMDAR) encephalitis (13/111 vs. 16/307) (P = 0.021). In anti-NMDAR and anti-LGI1 encephalitis patients, there were no significant differences in the age at onset, sex ratio, proportion of patients with tumors, disease severity, or recurrence between the groups with and without ADs.Conclusions: One or more types of ADs developed in AE patients, and patients with anti-LGI1 encephalitis had a higher frequency of autoimmune comorbidities than those with anti-NMDAR encephalitis. And we found that autoimmune comorbidities did not affect the clinical course of AE.

Automated cell classification is an important yet a challenging computer vision task with significant benefits to biomedicine. In recent years, there have been several studies attempted to build an artificial intelligence-based cell classifier using label-free cellular images obtained from an optical microscope. Although these studies showed promising results, such classifiers were not able to reflect the biological diversity of different types of cell. While in terms of malignant cell, it is well-known that intracellular actin filaments are altered substantially. This is thought to be closely related to the abnormal growth features of tumor cells, their ability to invade surrounding tissues and also to metastasize. Therefore, being able to classify different types of cell based on their biological behaviors using automated technique is more advantageous. This article reveals the difference in the actin cytoskeleton structures between breast normal and cancer cells, which may provide new information regarding malignant changes and be used as additional diagnostic marker. Since the features cannot be well detected by human eyes, we proposed the application of convolutional neural network (CNN) in cell classification based on actin-labeled fluorescence microscopy images. The CNN was evaluated on a large number of actin-labeled fluorescence microscopy images of one human normal breast epithelial cell line and two types of human breast cancer cell line with different levels of aggressiveness. The study revealed that the CNN performed better in the cell classification task compared to a human expert.

Stem cell transplantation is a promising therapy for traumatic brain injury (TBI), but low efficiency of survival and differentiation of transplanted stem cells limits its clinical application. Histone deacetylase 1 (HDAC1) plays important roles in self-renewal of stem cells as well as the recovery of brain disorders. However, little is known about the effects of HDAC1 on the survival and efficacy of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in vivo. In this study, our results showed that HDAC1 silence promoted hUC-MSCs engraftment in the hippocampus and increased the neuroprotective effects of hUC-MSCs in TBI mouse model, which was accompanied by improved neurological function, enhanced neurogenesis, decreased neural apoptosis, and reduced oxidative stress in the hippocampus. Further mechanistic studies revealed that the expressions of phosphorylated PTEN (p-PTEN), phosphorylated Akt (p-Akt), and phosphorylated GSK-3β (p-GSK-3β) were upregulated. Intriguingly, the neuroprotective effects of hUC-MSCs with HDAC1 silence on behavioral performance of TBI mice was markedly attenuated by LY294002, an inhibitor of the PI3K/AKT pathway. Taken together, our findings suggest that hUC-MSCs transplantation with HDAC1 silence may provide a potential strategy for treating TBI in the future.

Background: Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Peripheral insulin resistance increases the risk for memory impairment and the development of AD. Objective: This study aims to assess changes in cognitive functions and the level of hyperphosphorylated tau proteins in central insulin-resistant rats. Methods: An in vivo central insulin-resistant (CIR) animal model was generated through intracerebroventricular injection of streptozotocin (STZ) into insulin-resistant (IR) rats that were induced by feeding a high-glucose/-protein/-fat diet. The Morris water maze test was used to assess changes in cognitive functions, pathological changes in the cornu ammonis 1 (CA1) region of the hippocampus were detected by immunohistochemistry, and the phosphorylation levels of tau proteins at specific sites were determined by Western blot analysis. Results: The escape latency time in the Morris water maze test was significantly prolonged; the number of phosphorylated tau proteins in the CA1 region of the hippocampus was significantly increased; and the phosphorylation levels of tau proteins at Ser199, Thr205, Thr212, Thr217 and Ser396 were significantly elevated in the CIR group compared with the IR and control groups. Conclusion: This study provides direct evidence that CIR plays an important role in AD pathogenesis by facilitating tau hyperphosphorylation.

ABSTRACT Objective: To investigate the predictive value of transcranial Doppler (TCD) ultrasound for cerebral small vessel disease in elderly patients. Methods: Transcranial Doppler ultrasound and magnetic resonance imaging (MRI) were performed on 184 elderly patients with cerebral small vessel disease. The relationship of clinical characteristics and TCD ultrasound parameters with severe white matter lesions (WMLs) in MRI were investigated by univariate analysis and multivariate analysis. Results: The univariate analysis showed that age, left middle cerebral artery (MCA) mean flow velocity, right MCA mean flow velocity and mean MCA pulsatility index were significantly correlated with severe WMLs (p < 0.05). The multivariate logistic regression analysis showed that only age (odds ratio: 1.21; 95%CI: 1.10–1.36; p < 0.01) and MCA pulsatility index (dominance ratio: 1.13; 95%CI: 1.06–1.80; p = 0.02) were significantly correlated with severe WMLs. The analysis of TCD ultrasound parameters showed that when the cut-off for MCA pulsatility index was 1.04, it could identify severe WMLs. The area under the curve was 0.70 (95%CI: 0.60–0.80). The sensitivity and specificity were 63.0% and 72.0%, respectively. The positive and negative predictive values were 35.4% and 86.6%, respectively. Conclusion: The MCA pulsatility index in TCD ultrasound is significantly correlated with severe WMLs; and TCD ultrasound can guide selective MRI for the detection of WMLs.