Deep learning algorithm reveals two prognostic subtypes in patients with gliomas.

BACKGROUND: Gliomas are highly complex and heterogeneous tumors, rendering prognosis prediction challenging. The advent of deep learning algorithms and the accessibility of multi-omic data represent a new approach for the identification of survival-sensitive subtypes. Herein, an autoencoder-based approach was used to identify two survival-sensitive subtypes using RNA sequencing (RNA-seq) and DNA methylation (DNAm) data from The Cancer Genome Atlas (TCGA) dataset. The subtypes were used as labels to build a support vector machine model with cross-validation. We validated the robustness of the model on Chinese Glioma Genome Atlas (CGGA) dataset. DNAm-driven genes were identified by integrating DNAm and gene expression profiling analyses using the R MethylMix package and carried out for further enrichment analysis. RESULTS: For TCGA dataset, the model produced a high C-index (0.92 ± 0.02), low brier score (0.16 ± 0.02), and significant log-rank p value (p < 0.0001). The model also had a decent performance for CGGA dataset (CGGA DNAm: C-index of 0.70, brier score of 0.21; CGGA RNA-seq: C-index of 0.79, brier score of 0.18). Moreover, we identified 389 DNAm-driven genes of survival-sensitive subtypes, which were significantly enriched in the glutathione metabolism pathway. CONCLUSIONS: Our study identified two survival-sensitive subtypes of glioma and provided insights into the molecular mechanisms underlying glioma development; thus, potentially providing a new target for the prognostic prediction of gliomas and supporting personalized treatment strategies.

The Chinese Parkinson's Disease Registry (CPDR): Study Design and Baseline Patient Characteristics.

BACKGROUND: There is a lack of large multicenter Parkinson's disease (PD) cohort studies and limited data on the natural history of PD in China. OBJECTIVES: The objective of this study was to launch the Chinese Parkinson's Disease Registry (CPDR) and to report its protocol, cross-sectional baseline data, and prospects for a comprehensive observational, longitudinal, multicenter study. METHODS: The CPDR recruited PD patients from 19 clinical sites across China between January 2018 and December 2020. Clinical data were collected prospectively using at least 17 core assessment scales. Patients were followed up for clinical outcomes through face-to-face interviews biennially. RESULTS: We launched the CPDR in China based on the Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network (PD-MDCNC). A total of 3148 PD patients were enrolled comprising 1623 men (51.6%) and 1525 women (48.4%). The proportions of early-onset PD (EOPD, age at onset ≤50 years) and late-onset PD (LOPD) were 897 (28.5%) and 2251 (71.5%), respectively. Stratification by age at onset showed that EOPD manifested milder motor and nonmotor phenotypes and was related to increased probability of dyskinesia. Comparison across genders suggested a slightly older average age at PD onset, milder motor symptoms, and a higher rate of developing levodopa-induced dyskinesias in women. CONCLUSIONS: The CPDR is one of the largest multicenter, observational, longitudinal, and natural history studies of PD in China. It offers an opportunity to expand the understanding of clinical features, genetic, imaging, and biological markers of PD progression. © 2022 International Parkinson and Movement Disorder Society.

Discovery of novel MIF inhibitors that attenuate microglial inflammatory activation by structures-based virtual screening and in vitro bioassays.

Macrophage migration inhibitory factor (MIF) is a pluripotent pro-inflammatory cytokine and is related to acute and chronic inflammatory responses, immune disorders, tumors, and other diseases. In this study, an integrated virtual screening strategy and bioassays were used to search for potent MIF inhibitors. Twelve compounds with better bioactivity than the prototypical MIF-inhibitor ISO-1 (IC50 = 14.41 µM) were identified by an in vitro enzymatic activity assay. Structural analysis revealed that these inhibitors have novel structural scaffolds. Compound 11 was then chosen for further characterization in vitro, and it exhibited marked anti-inflammatory efficacy in LPS-activated BV-2 microglial cells by suppressing the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs). Our findings suggest that MIF may be involved in the regulation of microglial inflammatory activation and that small-molecule MIF inhibitors may serve as promising therapeutic agents for neuroinflammatory diseases.

Temporal and spatial characteristics of plantar pressure center trajectory for identifying early Parkinson's disease gait.

Gait analysis can be utilized as an effective method for identifying Parkinson's disease (PD) [1]. However, research methods based on the time-domain gait feature analysis are influenced by population characteristics such as individual height, age, and weight, which unfavorably affect PD diagnostic decision-making.

Corrigendum: High levels of Bifidobacteriaceae are associated with the pathogenesis of Parkinson's disease.

[This corrects the article DOI: 10.3389/fnint.2022.1054627.].

Age and Sex Affect Essential Tremor (ET) Plus: Clinical Heterogeneity in ET Based on the National Survey in China.

The new term essential tremor (ET) plus was proposed in the 2018 tremor consensus criteria. The National Survey of Essential Tremor Plus in China, a large multicenter registry study, aimed to evaluate the clinical features of pure ET and ET plus and explore possible factors related to ET plus. All patients with ET underwent neurological examination and neuropsychological assessment at 17 clinical sites. The diagnosis was made according to the 2018 consensus criteria. Clinicodemographic characteristics were analyzed. A total of 1160 patients were included, including 546 patients with pure ET and 614 patients with ET plus. The proportion of females was significantly higher in the ET plus than that in the pure ET (P = 0.001). The age at onset (AAO) of pure ET showed a bimodal distribution, with peaks in the 2nd and 5th decades. However, the AAO of the ET plus group demonstrated a skewed distribution, with a single peak in the 6th decade. Female sex (OR=1.645, P<0.001), older age (OR=1.023, P<0.001), lower educational level (OR=0.934, P<0.001), head tremor (OR=1.457, P<0.001), and higher the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS)-II scores (OR=1.134, P<0.001) were significantly associated with ET plus. Old age and female sex may contribute to ET plus development. Pure ET showed a bimodal distribution for AAO, whereas ET plus showed a unimodal distribution. It remains unclear whether pure ET and ET plus are merely different stages of a single disease or represent distinct disease entities.

High levels of Bifidobacteriaceae are associated with the pathogenesis of Parkinson's disease.

Background: The diagnosis of Parkinson's disease (PD) is complex and there are no biomarkers for early identification. Many studies have reported altered gut microbiota in patients with PD compared with healthy individuals. However, results from previous studies vary across countries. Aims: The aim of this study was to identify gut microbiota biomarkers that could be used as a marker for the diagnosis of PD. Methods: Firstly, the differential gut microbiota was obtained by meta-analysis, and then the results of meta-analysis were validated through metagenomic cohort. Finally, the ROC curve was drawn based on the metagenomic validation results. Results: The meta-analysis showed a lower relative abundance of Prevotellaceae (p < 0.00001) and Lachnospiraceae (p = 0.002), and a higher of Ruminococcaceae (p < 0.00001), Christensenellaceae (p = 0.03), Bifidobacteriaceae (p < 0.00001), and Verrucomicrobiaceae (p = 0.02) in patients with PD. Only Bifidobacteriaceae was also at high levels in the validation cohort of the metagenome. Meanwhile, three species from the Bifidobacteriaceae, including Scardovia_inopinata (p = 0.022), Bifidobacterium_dentium (p = 0.005), and Scardovia_wiggsiae (p = 0.024) were also high. The ROC curve showed that the three species (71.2%) from Bifidobacteriaceae had good predictive efficiency for PD. Conclusion: Elevated Bifidobacteriaceae may be associated with PD. Elevated three species from the Bifidobacteriaceae, including Scardovia_inopinata, Bifidobacterium_dentium and Scardovia_wiggsiae may provide new potential biomarkers for the diagnosis of PD.

Cross-Sectional Study on the Gut Microbiome of Parkinson's Disease Patients in Central China.

Gastrointestinal dysfunction plays an important role in the occurrence and development of Parkinson's disease (PD). This study investigates the composition of the gut microbiome using shotgun metagenomic sequencing in PD patients in central China. Fecal samples from 39 PD patients (PD group) and the corresponding 39 healthy spouses of the patients (SP) were collected for shotgun metagenomics sequencing. Results showed a significantly altered microbial composition in the PD patients. Bilophila wadsworthia enrichment was found in the gut microbiome of PD patients, which has not been reported in previous studies. The random forest (RF) model, which identifies differences in microbiomes, reliably discriminated patients with PD from controls; the area under the receiver operating characteristic curve was 0.803. Further analysis of the microbiome and clinical symptoms showed that Klebsiella and Parasutterella were positively correlated with the duration and severity of PD, whereas hydrogen-generating Prevotella was negatively correlated with disease severity. The Cluster of Orthologous Groups of protein database, the KEGG Orthology database, and the carbohydrate-active enzymes of gene-category analysis showed that branched-chain amino acid-related proteins were significantly increased, and GH43 was significantly reduced in the PD group. Functional analysis of the metagenome confirmed differences in microbiome metabolism in the PD group related to short-chain fatty acid precursor metabolism.

Altered gut microbiota in Parkinson's disease patients/healthy spouses and its association with clinical features.

INTRODUCTION: Increasing evidence shows that gut microbiota dysbiosis may play important roles in the occurrence and progression of Parkinson's disease (PD), but the findings are inconsistent. Besides, the effect of family environment on gut microbiota dysbiosis remains unclear. METHODS: We characterized the gut microbial compositions of 63 PD patients, 63 healthy spouses (HS) and 74 healthy people (HP) using 16S rRNA sequencing. Clinical phenotypes and microbial composition were analyzed comprehensively. RESULTS: There were markedly different microbial compositions among PD, HS and HP samples by alpha/beta diversity. We also found differential microbial compositions among Hoehn & Yahr stage/disease duration. Eight inflammation-associated microbial genera shared a continuously increase trend with increased Hoehn & Yahr stage and disease duration, indicating characteristic bacteria associated with deterioration in PD. Additionally, seven bacterial markers were identified for accurately differentiating PD patients from the controls (area under the curve [AUC]: 0.856). CONCLUSIONS: Our study shows altered gut microbiota in PD patients. Importantly, inflammation-associated microbial genera may play roles in PD progression. Differential microbial compositions in HS and HP samples demonstrate that the gut microbiota are also affected by family environment. Disease-associated metagenomics studies should consider the family environmental factor. Our research provides an important reference and improves the understanding of gut microbiota in PD patients.

[Protective effects of doxycycline upon dopaminergic neuron in LPS-induced rat model of Parkinson's disease].

OBJECTIVE: To explore the protective effect of doxycycline (DC) upon dopaminergic neuron in lipopolysaccharide (LPS)-induce rat model of Parkinson's disease (PD). METHODS: Sixty SD rats were randomly divided into three groups: control, LPS and doxycycline treatment. LPS was stereotatically injected into unilateral substantia nigra (SNc) of rats to establish the PD models. The damage to the substantia nigra DA neurons was observed by using tyrosine-hydroxylase (TH) immunohistochemical staining. Specific antibody OX6 (MHCII marker) was used to detect the changes in morphology and the numbers of microglia. The contents of dopamine and DOPAC in striatum were measured by high performance liquid chromatography (HPLC). Western blot were used to detect the expression of MHCII (Major histocompatibility complex class II) protein. RESULTS: After doxycycline treatment, the number of TH-positive cells remaining in the SNc increased from 38% +/- 5% to 79% +/- 4% (P < 0.01). The contents of dopamine and DOPAC in striatum increased from 4.89 +/- 0.27 and 0.70 +/- 0.07 to 7.00 +/- 0.34 and 1.10 +/- 0.10 respectively (P < 0.01); there was a significant decrease in rotational asymmetry in the doxycycline treatment group [(80 +/- 12) turns/30 min] when compared to the LPS group [(208 +/- 14) turns/30 min] (P < 0.01). However, the number of MHCII-positive microglia decreased significantly (LPS group: 835 +/- 82 vs doxycycline treatment group: 354 +/- 59, P < 0.01) after doxycycline treatment. Western blot were used to detect the expression of MHCII protein. The results showed that the expression of MHCII protein on microglia of LPS group increased significantly compared to the control group, but the expression of MHCII protein were inhibited significantly after doxycycline treatment in the doxycycline treatment group, as compared to the LPS group. CONCLUSIONS: Doxycycline might inhibit dopaminergic neuron degeneration by down-regulating the MHCII expression on microglia.

The Effect of Intensive Statin Therapy on Symptomatic Intracranial Arterial Stenosis.

BACKGROUND: The aim of this study was to observe the effect of intensive statin therapy on symptomatic intracranial arterial stenosis. METHODS: overall, 120 patients with symptomatic intracranial arterial stenosis were admitted to the Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang, China from January 2010 to May 2013. They were randomly divided into three groups and were given different doses of atorvastatin orally for 1 year or more, and followed up for 12 months. The three groups were assessed for clinical end-point event rates and changes in cerebral blood flow value before and after treatment to assess the effectiveness of intensive statin therapy. RESULTS: The incidence rates of end-point cerebrovascular events in the low-dose group (10 mg/d), the general-dose group (20 mg/d) and the intensive treatment group (40 mg/d) were 26.3%, 13.5% and 5.4% respectively during the 12-month follow-up after treatment. There was a significant difference between the low dose group and the intensive treatment group (P<0.05). The relative cerebral blood flow and relative cerebral blood volume of the three groups were significantly higher than those before treatment (P<0.05), and the relative time to peak for the intensive treatment group was shorter than that before treatment (P<0.001). CONCLUSION: Atorvastatin at 40 mg/d has a significant advantage compared with atorvastatin at 20 mg/d and 10 mg/d in reducing cerebrovascular events and improving cerebral blood flow.

Gene Expression Profile of Peripheral Blood Mononuclear Cells in Response to Intracerebral Hemorrhage.

RNA-sequencing, a powerful tool, yields a comprehensive view of whole transcriptome. Intracerebral hemorrhage (ICH) is a devastating form of stroke. To date, RNA-sequencing analysis of ICH has not been reported. Peripheral blood mononuclear cells (PBMCs) were used as a source of mRNA for gene expression profile analysis in stroke. In this study, we performed transcriptome analyses for PBMCs from four ICH patients and four healthy volunteers on Illumina platform. We identified 4040 significantly differentially expressed genes (DEGs). Functional annotation of DEGs with DAVID Bioinformatics Resources indicated that genes associated with cell apoptosis, autophagy, cell-cell adhesion, inflammatory response, protein binding, positive regulation of gene expression, and signal transduction were most significantly enriched by DEGs. Gene set enrichment analysis identified 40 significant Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including chemokine signaling, cytokine-cytokine receptor interaction, oxidative phosphorylation, and glutathione metabolism processes. These data point to a complex mechanism for ICH pathogenesis. Overall, the present study demonstrated an altered gene expression profile of PBMCs in response to acute ICH. Our study provided important information for understanding the molecular mechanisms of ICH pathogenesis at system-wide levels.

Diffusion on social networks: Survey data from rural villages in central China.

Empirical studies on social diffusions are often restricted by the access to data of diffusion and social relations on the same objects. We present a set of first-hand data that we collected in ten rural villages in central China through household surveys. The dataset contains detailed and comprehensive data of the diffusion of an innovation, the major social relationships and the household level demographic characteristics in these villages. The data have been used to study peer effects in social diffusion using simulation models, "Peer Effects and Social Network: The Case of Rural Diffusion in Central China" [1]. They can also be used to estimate spatial econometric models. Data are supplied with this article.

Correlations among heavy metals in blood and urine and their relations to depressive symptoms in Parkinson's disease patients.

OBJECTIVES: From our previous results, manganese (Mn) and iron (Fe) in the blood of Parkinson's disease (PD) patients without depression were higher than those of both the PD patients with depression and controls, the hypothesis that "two types of PD exist-PD without depression and affected by Mn and Fe, and PD with depression and unaffected by Mn or Fe" was induced. To investigate the hypothesis, correlations among blood and urine metals were compared in the subjects. METHODS: Subjects comprised PD patients with depression, PD patients without depression and controls recruited from an outpatient clinic in China. Morning blood and urine samples were used to measure concentrations of metals. RESULTS: In the controls, Mn, Fe and zinc (Zn) levels in blood strongly correlated with each other. The correlation coefficient between Mn and Zn in blood was significant in the PD patients with depression and the controls, but not in the PD patients without depression. Correlations of Fe between blood and urine in the PD patients without depression were significant, but not in the PD patients with depression and the controls. CONCLUSIONS: A common route of simultaneous intake of Mn, Fe and Zn could exist in our subjects, however in PD patients without depression, a large intake of Mn may have been from another route. Some results of the PD patients without depression were different from those of the PD patients with depression and the controls. Thus, two types of PD may exist.

Efficacy and safety of intensive statin therapy in Chinese patients with atherosclerotic intracranial arterial stenosis: a single-center, randomized, single-blind, parallel-group study with one-year follow-up.

OBJECTIVES: The purpose of this study is to validate the efficacy of intensive statin therapy for patients with atherosclerotic intracranial arterial stenosis (AICAS). METHODS: In this study, we performed a single-center, randomized, single-blind, parallel-group clinical trial. A total of 120 Chinese patients with AICAS were enrolled and randomly divided into three groups [low-dose atorvastatin therapy (LAT, 10mg/day), standard-dose atorvastatin therapy (SAT, 20mg/day), and intensive-dose atorvastatin therapy (IAT, 40mg/day) groups] in a 1:1:1 ratio. Evaluation variables, including changes in serum lipid profiles, degree of stenosis, and perfusion-related parameters derived from computed tomography perfusion (CTP) imaging from baseline to weeks 26 and 52, as well as the occurrence of cerebrovascular events during the study period, were used to compare the benefits of these three statin therapies. RESULTS: After 52 weeks of treatment, improvement of serum lipid profiles, degree of stenosis, and perfusion-related parameters were all significantly better in the IAT group. In addition, the cumulative probability of cerebrovascular events at 52 weeks was significantly lower in the IAT group than in the LAT group, although there was no statistical difference between the IAT group and the SAT group. The proportion of patients experiencing any adverse event was similar among the three treatment groups. Adverse events caused by IAT were generally mild; no serious adverse events occurred throughout the entire period of study. CONCLUSION: In conclusion, long-term use of IAT appears to be a safe and effective treatment at least for Chinese patients with AICAS.

Heavy metals in blood and urine and its relation to depressive symptoms in Parkinson's disease patients.

OBJECTIVES: Some heavy metals are suspected to be pathogenic to both Parkinson's disease (PD) and depression. Common background may exist in them. METHODS: Subjects comprised PD patients with depression, PD patients without depression and controls recruited from the outpatient clinic in China. Morning blood and urine samples were used to measure concentrations of metals and vitamins. RESULTS: Whole-blood manganese was significantly higher in the PD patients without depression than in both the PD patients with depression and the controls. Serum iron was significantly higher in the PD patients without depression than in the controls. Urine iron was also significantly higher in the PD patients without depression than in the controls. Serum copper was significantly lower in the PD patients with depression than in both the PD patients without depression and the controls. CONCLUSIONS: Excessive intake of iron and accumulation of manganese seemed to be involved in the etiology of non-depressive PD.