Exploring the potential molecular intersection of stroke and major depression disorder.

Stroke and major depression disorder are common neurological diseases, and a large number of clinical studies have shown that there is a close relationship between the two diseases, but whether the two diseases are linked at the genetic level needs to be further explored. The purpose of this study was to explore the comorbidity mechanism of stroke and major depression by using bioinformatics technology and animal experiments. From the GEO database, we gathered transcriptome data of stroke and depression mice (GSE104036, GSE131712, GSE81672, and GSE146845) and identified comorbid gene set through edgR and WGCNA analyses. Further analysis revealed that these genes were enriched in pathways associated with cell death. Programmed cell death gene sets (PCDGs) are generated from genes related to apoptosis, necroptosis, pyroptosis and autophagy. The intersection of PCDGs and comorbid gene set resulted in two hub genes, Mlkl and Nlrp3. Single-cell sequencing analysis indicated that Mlkl and Nlrp3 are mainly influential on endothelial cells and microglia, suggesting that the impairment of these two cell types may be a factor in the relationship between stroke and major depression. This was experimentally confirmed by RT-PCR and immunofluorescence staining. Our research revealed that two specific genes, namely, Mlkl and Nlrp3, play crucial roles in the complex mechanism that links stroke and major depression. Additionally, we have predicted six possible therapeutic agents and the outcomes of docking simulations of target proteins and drug molecules.

Silver dendrite metasurface SERS substrates prepared by photoreduction method for perfluorooctanoic acid detection.

Perfluorooctanoic acid (PFOA), a novel organic pollutant, has been shown to be toxic, persistent, bioaccumulative, long-range transportable, and globally prevalent. This article is based on surface enhanced Raman scattering (SERS) spectroscopy analysis technology. The monolayer of SiO2 was prepared by chemical reduction etching self-assembly method and silver dendrites were grown on it, thus forming the SERS substrate with silver dendrite Metasurface structure with Raman detection enhancement factor up to 2.32 × 105. The prepared silver dendrite Metasurface SERS substrate was applied to the qualitative and quantitative detection of PFOA, with a quantitative detection limit of 15.89 ppb. The results of this paper provide a new, simple, and quick method for the detection of PFOA in the environment.

Proteomic profiling of aqueous humor-derived exosomes in Vogt-Koyanagi-Harada disease and Behcet's uveitis.

Vogt-Koyanagi-Harada (VKH) disease and Behcet's uveitis (BU) are the two major vision-threatening uveitis entities. This study performed the first label-free quantitative proteomics on aqueous humor-derived exosomes from 84 patients with VKH or BU to determine their potential roles. Sixty-five differentially expressed proteins (DEPs) and 40 DEPs were detected in the VKH and BU groups, respectively. GO and KEGG analysis showed that DEPs were mainly enriched in the complement-related pathways. The complement C1q subcomponent subunit B (C1QB) was identified as a key exosomal protein, and its expression was significantly increased by western blotting in both diseases. Additionally, the integrated analysis based on the published scRNA-seq data showed that C1QB-containing exosomes were mainly produced by mononuclear macrophages in the anterior segment tissue. Overall, our proteomic profiling highlights that complement-related pathways may be actively involved in the pathogenesis of these two diseases. These pathways may also serve as treatment targets for both diseases.

A novel capsid-XL32-derived adeno-associated virus serotype prompts retinal tropism and ameliorates choroidal neovascularization.

Gene therapy has been adapted, from the laboratory to the clinic, to treat retinopathies. In contrast to subretinal route, intravitreal delivery of AAV vectors displays the advantage of bypassing surgical injuries, but the viral particles are more prone to be nullified by the host neutralizing factors. To minimize such suppression of therapeutic effect, especially in terms of AAV2 and its derivatives, we introduced three serine-to-glycine mutations, based on the phosphorylation sites identified by mass spectrum analysis, to the XL32 capsid to generate a novel serotype named AAVYC5. Via intravitreal administration, AAVYC5 was transduced more effectively into multiple retinal layers compared with AAV2 and XL32. AAVYC5 also enabled successful delivery of anti-angiogenic molecules to rescue laser-induced choroidal neovascularization and astrogliosis in mice and non-human primates. Furthermore, we detected fewer neutralizing antibodies and binding IgG in human sera against AAVYC5 than those specific for AAV2 and XL32. Our results thus implicate this capsid-optimized AAVYC5 as a promising vector suitable for a wide population, particularly those with undesirable AAV2 seroreactivity.

TET2-mediated upregulation of 5-hydroxymethylcytosine in LRRC39 promoter promotes Th1 response in association with downregulated Treg response in Vogt-Koyanagi-Harada disease.

DNA 5-Hydroxymethylcytosine (5-hmC), an oxidative reaction mediated by the ten-eleven translocation (TET) family, has been reported to play an essential role in the progression of auto-inflammatory and autoimmune diseases. By far, little is known about the effect of DNA 5-hmC and the TET family on the development of Vogt-Koyanagi-Harada (VKH) disease. In this study, we discovered that the global DNA 5-hmC level and the TET activity were elevated in association with the up-regulated expression of TET2 at both mRNA and protein levels in CD4+T cells from active VKH patients compared to healthy controls. Integrated analysis of DNA 5-hmC pattern and transcription profile of CD4+ T cells revealed that 6 candidate target genes were involved in the development of VKH disease. The promoter 5-hmC and mRNA levels of leucine rich repeat containing 39 (LRRC39) were verified to be elevated in active VKH patients. Functional experiments showed that TET2 could up-regulate LRRC39 mRNA expression by increasing the promoter 5-hmC level of LRRC39 in CD4+ T cells from active VKH patients. Up-regulated LRRC39 expression could increase the frequencies of IFN-γ+ and IL-17+ CD4+ T cells as well as the secretions of IFN-γ and IL-17 in association with the decreased frequency of CD4+CD25+FOXP3+ regulatory T (Treg) cells and the reduced production of IL-10. Additionally, restoration of LRRC39 rescued TET2-silencing-mediated reduced frequency of IFN-γ+ CD4+ T cells and increased frequency of CD4+CD25+FOXP3+ Treg cells. Collectively, our study reveals a novel axis, the TET2-5-hmC-LRRC39-Th1/Treg responses axis, in the pathogenesis of VKH and provides a potential target for further investigation into the epigenetic therapy of this disease.

A comprehensive analysis-based study of triphenyl phosphate-environmental explanation of glioma progression.

As BFRs have gradually been banned recently, organophosphorus flame retardants (OPFRs) have been manufactured and used in their place. Although OPFRs are considered the better alternatives to BFRs, many studies have discovered that OPFRs may be associated with various cancers, including prostate cancer, bladder cancer, hepatocellular carcinoma, and colorectal cancer. However, few studies have examined the relationship between OPFRs and gliomas. This study investigated the relationship between triphenyl phosphate (TPP) and glioma using bioinformatics analysis approaches. The comparative toxicogenomics database (CTD) and The Cancer Genome Atlas (TCGA) databases were accessed for TPP-related genes and gene expression data from glioma patients. The Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses show that TPP might be closely related to many pathways. Further, the analysis of protein-protein interactions revealed strong intrinsic relationships between TPP-related genes. In addition, the TPP-based prognostic prediction model demonstrated promising results in predicting the prognosis of patients with gliomas. Several TPP-related genes were closely related to glioma patients' overall survival rates. The proliferation and migration abilities of glioma cells were further demonstrated to be significantly enhanced by TPP. In a bioinformatics analysis, we also discovered that melatonin is highly correlated with the presence of TPP and gliomas. According to the cell proliferation and migration assays, exposure to melatonin and TPP inhibited the ability of glioma cells to invade compared with the TPP group.

Transcriptomic profiling of iris tissue highlights LCK signaling and T cell-mediated immunity in Behcet's uveitis.

Uveitis is the most common form of ocular lesions in Behcet's disease, severely affecting visual function. Molecular pathological changes of ocular lesions in patients with Behcet's uveitis (BU) are largely unknown. In this study, we performed the first comprehensive transcriptomic profiling of iris specimens from BU patients and healthy donors to provide an insight into intraocular immunopathogenesis. The mRNA sequencing identified 1633 differentially expressed genes (DEGs) between the BU group and healthy controls. GO functional enrichment analysis on DEGs showed that T cell activation was the most significantly enriched biological process. KEGG analysis of DEGs also revealed several prominently enriched T cell-related pathways, including the T cell receptor signaling pathway, Th17 cell differentiation, and Th1 and Th2 cell differentiation. The lymphocyte-specific protein tyrosine kinase (LCK) was identified as the key hub gene in the protein interaction network of DEGs. Western blot analysis further showed increased expression of active LCK in the BU group, suggesting activation of LCK signaling. Using publicly accessible single-cell RNA-sequencing data of the healthy iris, LCK was found to be expressed in clusters of activated T cells but not in other iris cell clusters, suggesting an overt association between LCK upregulation and T cell-mediated immune dysregulation. Additionally, 16 drugs were predicted to be potential inhibitors of LCK. Overall, these findings not only highlighted the central role of T cell-mediated immunity and previously unreported LCK signaling in intraocular immunopathogenesis but also revealed the potential value of LCK as a new therapeutic target for BU patients.

LncRNA Miat promotes neuropathic pain through miR-362-3p/BAMBI signaling axis.

The treatment of neuropathic pain (NP) has become an important subject to be studied and solved urgently in clinical practice. The role of long noncoding RNAs (lncRNAs) in NP development is becoming clear. Therefore, this study aimed to investigate the role and mechanism of lncRNA Miat in NP. In this study, chronic contractionary injury (CCI) mouse NP model was performed. Firstly, the effects of Miat on pain behavior in mice and the expression levels of pro-inflammatory cytokines and pro-inflammatory proteins in spinal cord tissue were explored by interfering with the expression of Miat. Then, Miat-targeted signaling pathway was predicted by bioinformatics and verified by dual luciferase reporter gene and RNA pull down. Finally, the mechanism of Miat was confirmed by the rescue experiments. Our results demonstrated that Miat knockdown alleviated paw withdrawal threshold, paw withdrawal latency, cold hyperalgesia frequency and neuroinflammation in CCI mice. MiR-362-3p was able to bind to Miat and BAMBI. Overall, Miat upregulated BAMBI by inhibiting miR-362-3p, thereby promoting the occurrence and development of NP. This study analyzed the possibility and effectiveness of targeting Miat for NP clinical treatment, in order to provide new ideas and technical methods for NP gene therapy.

Analysis of Clinical Features and Related Factors of Silent Aspiration in Hospitalized COPD Patients.

Context: Silent aspiration is a common complication of chronic obstructive pulmonary disease (COPD). COPD's acute-exacerbation phase may be associated with silent aspiration, impacting a patient's prognosis. Silent aspiration may be more likely to occur in patients in poor basic physical condition. Objective: The study intended to explore the clinical features and other factors related to silent aspiration in patients hospitalized with COPD. Design: The research team designed a retrospective study using data from medical records of patient's hospitalized with COPD. Setting: The study took place at the Sixth Hospital of Wuhan at the Affiliated Hospital of Jianghan University in Wuhan, China. Participants: Participants were 49 patients with acutely aggravated COPD who had been hospitalized between January 2019 and December 2019 at the hospital. Intervention: Participants had all received a radionuclide salivary test at the hospital in the past for silent aspiration. Based on the test results, 15 patients were included in the positive group, and 34 patients were included in the negative group. Outcome Measures: The study compared the two groups': (1) clinical features- respiratory difficulty on the modified Medical Research Council (mMRC) scale, rate of concomitant pneumonia, number of prior admissions to the intensive care unit (ICU), number of acute exacerbations within the year preceding the study, and proportion of patients with two or more acute exacerbations within the year preceding the study; (2) lung function-forced expiratory volume (FEV1), (FEV1%pre), and FEV1/ forced vital capacity (FVC %); (3) blood gases-partial pressure of oxygen (PaO2) and partial pressure of carbon dioxide (PaCO2); and (4) laboratory parameters-white blood cell (WBC) counts, C-reactive protein (CRP), procalcitonin (PCT), and percentage of neutrophils. The research team used univariate and multivariate, logistic regression analysis to identify risk factors for silent aspiration in hospitalized COPD patients. All participants were followed for a mean duration of 18.98 ± 3.09 months, with a range 12 to 24 months. Results: No patients died during the follow-up. No statistically significant differences existed between the groups in age, gender, course of illness, or other clinical variables (P > .05). The positive group had significantly lower scores on the mMRC than did the negative group. Some of the positive group's results were significantly higher than those of the negative group: (1) rate of concomitant pneumonia, (2) number of prior admissions to the ICU, (3) number of acute exacerbations within the year preceding the study, and (4) proportion of patients with two or more acute exacerbations within the year preceding the study (P < .05). No statistical differences existed between the groups in the FEV1, PaO2), PaCO2, WBCs, or percentage of neutrophils (P > .05). The FEV1%pre and FEV1/FVC%) were significantly lower and the CRP and PCT levels were significantly higher in the positive group than in the negative group (P < .05). Conclusion: The mMRC scores, concomitant pneumonia, and prior admission to the ICU were risk factors for silent aspiration in hospitalized COPD patients. Hospital staff should pay more attention to patients with those risk factors during hospitalizations.

Clinical Efficacy of Pulsed Radiofrequency Combined with Intravenous Lidocaine Infusion in the Treatment of Subacute Herpes Zoster Neuralgia.

Objective: Under the guidance of a digital subtraction angiography (DSA) machine, via fluoroscopic imaging techniques, patients diagnosed with herpes zoster neuralgia at the subacute stage, where self-reported pain lasts between 30 and 90 days, were treated with nerve pulsed radiofrequency surgery combined with intravenous lidocaine infusion or saline infusion as control. This study explores the clinical efficacy, safety, and clinical value of the combined treatment compared with nerve pulsed radiofrequency surgery alone. Methods: In this study, 72 patients diagnosed with herpes zoster neuralgia at the subacute stage were randomly divided into two groups with matched gender, age, and clinical symptoms. Both groups received pulsed radiofrequency surgery for the affected nerve segments under DSA fluoroscopy. Five days after the operation, 0.9% saline was administered daily for five consecutive days (50 ml per day, intravenous infusion) to group A (n = 36), and lidocaine was administered daily for five consecutive days (3 mg per kg per day, intravenous infusion) to group B (n = 36). Patients with poor pain control during the treatment were given 10 mg morphine tablets for pain relief to reach visual analog scale (VAS) ≤4 points. Data of the following categories were collected: VAS score, self-rating anxiety scale (SAS) score, depression self-rating scale (SDS) score, Pittsburgh sleep quality score (PSQI), 45 body area rating scale score, skin temperature measurement using infrared thermography, analgesic drug use before and after treatment at six different time points: before surgery (T 0), one day after surgery (T 1), three days after surgery (T 2), five days after surgery (T 3), one month after surgery (T 4), and two months after surgery (T 5). Blood was collected from all patients in the morning before surgery and right after the last intravenous infusion of lidocaine at T 3. Serum inflammatory indexes including white blood cell count, lymphocyte count, neutrophils count, erythrocyte sedimentation rate count, C-reactive protein (CRP) level, calcitonin gene-related peptide (CGRP) level, and interleukin-6(IL-6) level were determined. Lastly, the incidence of complications and adverse reactions throughout the study was recorded. Results: In total, 64 out of 72 patients completed the whole study. Two patients met the exclusion criteria in group A, one patient refused to participate, and one was lost to follow-up. Two patients met the exclusion criteria in group B, and two were lost to follow-up. Three patients in group B experienced vomiting during lidocaine treatment. The adverse symptom was relieved after symptomatic treatment. No patients in the two groups had severe complications such as hematoma at the puncture site, pneumothorax, and nerve injury. Compared with before treatment, the mean of VAS score, SAS score, SDS score, PSQI score, and skin temperature of both groups at each time point after interventional surgery were all significantly reduced. Furthermore, at each time point after surgery, the above indicators of group B patients were significantly lower than those of group A patients. After treatment, the consumption of analgesics in both groups was significantly lower than before treatment. Compared with group A, the consumption of analgesics was also significantly lower in group B. In addition, serum inflammatory indexes at the T 3 time point of the two groups of patients were lower than T 0. Among them, the erythrocyte sedimentation rate, CRP level, CGRP level, and interleukin-6 level of group B were significantly lower than those of group A. The incidence of postherpetic neuralgia (PHN) in group B patients (6.25%) was also lower than that in group A patients (25%). Conclusion: DSA-guided nerve pulse radiofrequency surgery combined with intravenous lidocaine infusion can effectively relieve pain in patients diagnosed with herpes zoster nerves at the subacute stage, reduce the number of analgesic drugs used in patients, reduce postherpetic neuralgia incidence rate, and improve sleep and quality of life.

Identification of Novel Risk Loci for Behçet's Disease-Related Uveitis in a Chinese Population in a Genome-Wide Association Study.

OBJECTIVE: To explore susceptibility loci associated with uveitis in Behçet's disease (BD). METHODS: We conducted a 2-stage study, consisting of a genome-wide association study (GWAS) stage and a replication stage, in a Chinese population. The GWAS stage included 978 cases with BD-related uveitis and 4,388 controls, and the replication stage included 953 cases with BD-related uveitis and 2,129 controls. Luciferase reporter analysis and chromatin immunoprecipitation assay were performed to explore the functional role of susceptibility genetic variants near ZMIZ1. RESULTS: Three independent HLA alleles (HLA-B51 [3.75 × 10-190 ], HLA-A26 [1.50 × 10-18 ], and HLA-C0704 [3.44 × 10-16 ]) were identified as having a genome-wide association with BD-related uveitis. In the non-HLA region, in addition to confirming 7 previously reported loci, we identified 22 novel susceptibility variants located in 16 loci. Meta-analysis of the Chinese cohort consisting of 1,931 cases and 6,517 controls and a published Japanese cohort of 611 cases and 737 controls showed genome-wide significant associations with ZMIZ1, RPS6KA4, IL10RA, SIPA1-FIBP-FOSL1, and VAMP1. Functional experiments demonstrated that genetic variants of ZMIZ1 were associated with enhanced transcription activity and increased expression of ZMIZ1. CONCLUSION: This GWAS study identified a novel set of genetic variants that are associated with susceptibility to uveitis in BD. These findings enrich our understanding of the contribution of genetic factors to the disease.

Development of revised diagnostic criteria for Fuchs' uveitis syndrome in a Chinese population.

BACKGROUND/AIMS: Fuchs' uveitis syndrome (FUS) is one of the frequently misdiagnosed uveitis entities, which is partly due to the absence of internationally recognised diagnostic criteria. This study was performed to develop and evaluate a set of revised diagnostic criteria for FUS. METHODS: The clinical data of Chinese patients with FUS and patients with non-FUS were collected and analysed from a tertiary referral centre between April 2008 and December 2020. A total of 593 patients with FUS and 625 patients with non-FUS from northern China were enrolled for the development of diagnostic criteria for FUS. Three hundred and seventy-seven patients with FUS and 503 patients with non-FUS from southern China were used to validate the criteria. Clinical symptoms and ocular signs were collected from all patients with FUS and patients with non-FUS. Multivariate two-step cluster analysis, logistic regression and decision tree algorithms in combination with the clinical judgement of uveitis experts were used to revise diagnostic criteria for FUS. RESULTS: Three essential findings including diffuse iris depigmentation, absence of posterior synechiae, mild inflammation in the anterior chamber at presentation and five associated findings including mostly unilateral involvement, cataract, vitreous opacities, absence of acute symptoms and characteristic iris nodules were used in the development of FUS diagnostic criteria. All essential findings were required for the diagnosis of FUS, and the diagnosis was further strengthened by the presence of associated findings. CONCLUSION: Revised diagnostic criteria for FUS were developed and validated by analysing data from Chinese patients and showed a high sensitivity (96.55%) and specificity (97.42%).

Detection of Fuchs' Uveitis Syndrome From Slit-Lamp Images Using Deep Convolutional Neural Networks in a Chinese Population.

Fuchs' uveitis syndrome (FUS) is one of the most under- or misdiagnosed uveitis entities. Many undiagnosed FUS patients are unnecessarily overtreated with anti-inflammatory drugs, which may lead to serious complications. To offer assistance for ophthalmologists in the screening and diagnosis of FUS, we developed seven deep convolutional neural networks (DCNNs) to detect FUS using slit-lamp images. We also proposed a new optimized model with a mixed "attention" module to improve test accuracy. In the same independent set, we compared the performance between these DCNNs and ophthalmologists in detecting FUS. Seven different network models, including Xception, Resnet50, SE-Resnet50, ResNext50, SE-ResNext50, ST-ResNext50, and SET-ResNext50, were used to predict FUS automatically with the area under the receiver operating characteristic curves (AUCs) that ranged from 0.951 to 0.977. Our proposed SET-ResNext50 model (accuracy = 0.930; Precision = 0.918; Recall = 0.923; F1 measure = 0.920) with an AUC of 0.977 consistently outperformed the other networks and outperformed general ophthalmologists by a large margin. Heat-map visualizations of the SET-ResNext50 were provided to identify the target areas in the slit-lamp images. In conclusion, we confirmed that a trained classification method based on DCNNs achieved high effectiveness in distinguishing FUS from other forms of anterior uveitis. The performance of the DCNNs was better than that of general ophthalmologists and could be of value in the diagnosis of FUS.

Prevalence and clinical features of systemic diseases in Chinese patients with uveitis.

PURPOSE: Systemic diseases are frequently associated with uveitis but are often not recognised by clinicians. An estimate of the prevalence in a large-scale uveitis population is essential for understanding the epidemiological profile and may be helpful for clinical practice. DESIGN: A nationwide survey. METHODS: Data were obtained from a national database which included the registration of uveitis cases from 23 provinces, 5 autonomous regions and 4 municipalities across mainland China. The primary outcome was identification of a systemic disease associated with uveitis. RESULTS: From April 2008 through August 2018, 15 373 uveitis patients were included in the study. Males accounted for 52.9%, and the mean (SD) age of uveitis onset was 35.4 (15.9) years. After standardisation for age, the prevalence of systemic disease among patients with uveitis was 30.8% (95% CI, 30.1% to 31.6%). Vogt-Koyanagi-Harada disease (VKH; age-standardised prevalence, 12.7%; 95% CI, 12.1% to 13.2%), Behçet's disease (BD; 8.7%; 95% CI, 8.3% to 9.2%), ankylosing spondylitis (AS; 5.0%; 95% CI, 4.6% to 5.3%) and juvenile idiopathic arthritis (JIA; 1.2%; 95% CI, 1.0% to 1.3%) were the most common entities among 36 different forms of systemic diseases identified. The prevalence was significantly higher in males (37.0%; 95% CI, 36.0% to 38.1%) than in females (23.6%; 95% CI, 22.6% to 24.6%), and also higher in bilateral uveitis patients (41.2%; 95% CI, 40.2% to 42.2%) compared with unilateral cases (14.3%; 95% CI, 13.4% to 15.2%), and was highest in panuveitis (59.5%; 95% CI, 58.2% to 60.8%). CONCLUSION: Approximately one third of uveitis patients in this nationwide survey have an associated systemic disease, whereby VKH, BD, AS and JIA are the most frequent entities seen in China.

Integrated Analysis of Key Pathways and Drug Targets Associated With Vogt-Koyanagi-Harada Disease.

Background: Vogt-Koyanagi-Harada (VKH) disease is a complex disease associated with multiple molecular immunological mechanisms. As the underlying mechanism for VKH disease is unclear, we hope to utilize an integrated analysis of key pathways and drug targets to develop novel therapeutic strategies. Methods: Candidate genes and proteins involved in VKH disease were identified through text-mining in the PubMed database. The GO and KEGG pathway analyses were used to examine the biological functions of the involved pathways associated with this disease. Molecule-related drugs were predicted through Drug-Gene Interaction Database (DGIdb) analysis. Results: A total of 48 genes and 54 proteins were associated with VKH disease. Forty-two significantly altered pathways were identified through pathway analysis and were mainly related to immune and inflammatory responses. The top five of significantly altered pathways were termed as "inflammatory bowel disease," "cytokine-cytokine receptor interaction," "allograft rejection," "antigen processing," and "presentation and Herpes simplex infection" in the KEGG database. IFN-γ and IL-6 were identified as the key genes through network analysis. The DGIdb analysis predicted 48 medicines as possible drugs for VKH disease, among which Interferon Alfa-2B was co-associated both with IFN-γ and IL-6. Conclusions: In this study, systematic analyses were utilized to detect key pathways and drug targets in VKH disease via bioinformatics analysis. IFN-γ and IL-6 were identified as the key mediators and possible drug targets in VKH disease. Interferon Alfa-2B was predicted to be a potentially effective drug for VKH disease treatment by targeting IFN-γ and IL-6, which warrants further experimental and clinical investigations.