Integrated Bulk and Single-Cell RNA-Sequencing Reveals the Effects of Circadian Rhythm Disruption on the Metabolic Reprogramming of CD4+ T Cells in Alzheimer's Disease.

Although growing evidence suggests close correlations between Alzheimer's disease (AD) and circadian rhythm disruption (CRD), few studies have focused on the influence of circadian rhythm on levels of immune cells in AD. We aimed to delineate the mechanism underlying the effects of circadian related genes on T cell immune function in AD. A total of 112 brain samples were used to construct the CRD-related model by performing weighted gene co-expression network analysis and machine learning algorithms (LASSO, SVM-RFE, and RF). The ssGSEA method was used to calculate the CRDscore in order to quantify CRD status. Using single-cell transcriptome data of CSF cells, we investigated the CD4+ T cell metabolism and cell-cell communication in high- and low-risk CRD groups. Connectivity map (CMap) was applied to explore small molecule drugs targeting CRD, and the expression of the signature gene GPR4 was further validated in AD. The CRDscore algorithm, which is based on 23 circadian-related genes, can effectively classify the CRD status in AD datasets. The single-cell analysis revealed that the CD4+ T cells with high CRDscore were characterized by hypometabolism. Cell communication analysis revealed that CD4+ T cells might be involved in promoting CD8+ T cell adhesion under CRD, which may facilitate T cell infiltration into the brain parenchyma. Overall, this study indicates the potential connotation of circadian rhythm in AD, providing insights into understanding T cell metabolic reprogramming under CRD.

The occult spinal arachnoid web with inimitable imaging: a case report with 5 years of follow-up.

OBJECTIVES: The spinal arachnoid web (SAW) is intradural extramedullary thickened bands of the arachnoid tissue, causing a focal indentation of the spinal cord. In our study, we sought to provide a comprehensive description of the nonoperative progression of this condition, drawing from a 5-year follow-up based on our institutional experience. CASE PRESENTATION: A 67-year-old male patient, presenting with chest and back pain, was admitted to our hospital. During a constructive interference in steady state (CISS) sequence examination, a typical dorsal indentation of the spinal cord at thoracic vertebrae referred to as the "scalpel sign", was noted. Subsequently, a diagnosis of SAW was confirmed. The patient refused surgical intervention and underwent a series of three MR imaging sessions over 5 years. CONCLUSION: SAW is a rarely reported pathology with varying clinical presentation and whose etiology remains unknown. Secondary syrinx formation may be a consequence of chronically altered cerebrospinal fluid dynamics. The CISS sequence can visualize the SAW despite its comparatively thin width. The web is commonly curable, and treatment should be personalized and take into consideration the severity of symptoms, as well as clinical and radiological findings.

Mendelian randomization and colocalization analyses reveal an association between short sleep duration or morning chronotype and altered leukocyte telomere length.

Observational studies suggest certain sleep traits are associated with telomere length, but the causal nature of these associations is unclear. The study aimed to determine the causal associations between 11 sleep-related traits and leukocyte telomere length (LTL) through two-sample Mendelian randomization and colocalization analyses using the summary statistics from large-scale genome-wide association studies. Univariable Mendelian randomization indicates that genetically determined short sleep is associated with decreased LTL, while morning chronotype is associated with increased LTL. Multivariable Mendelian randomization further supports the findings and colocalization analysis identifies shared common genetic variants for these two associations. No genetic evidence is observed for associations between other sleep-related traits and LTL. Sensitivity MR methods, reverse MR and re-running MR after removing potential pleiotropic genetic variants enhance the robustness of the results. These findings indicate that prioritizing morning chronotype and avoiding short sleep is beneficial for attenuating telomere attrition. Consequently, addressing sleep duration and chronotype could serve as practical intervention strategies.

Women's reproductive traits and cerebral small-vessel disease: A two-sample Mendelian randomization study.

Background: Observational studies have suggested that women's reproductive factors (age at menarche (AAM), age at first birth (AFB), age at first sexual intercourse (AFS), age at natural menopause (ANM), and pregnancy loss) may influence the risk of cerebral small-vessel disease (CSVD) although the causality remains unclear. Methods: We conducted two-sample univariable Mendelian randomization (UVMR) and multivariable MR (MVMR) to simultaneously investigate the causal relationships between five women's reproductive traits and CSVD clinical [intracerebral hemorrhage (ICH) by location or small-vessel ischemic stroke (SVS)] and subclinical measures [white matter hyperintensities (WMH), fractional anisotropy (FA), and mean diffusivity (MD)], utilizing data from large-scale genome-wide association studies of European ancestry. For both UVMR and MVMR, the inverse-variance-weighted (IVW) estimates were reported as the main results. The MR-Egger, weighted median, generalized summary-data-based MR (GSMR), and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods for UVMR and MVMR-Egger, and the MVMR-robust methods for MVMR were used as sensitivity analyses. Sex-combined instruments for AFS and AFB were used to assess the impact of sex instrumental heterogeneity. Positive control analysis was implemented to measure the efficacy of selected genetic instruments. Results: We found no evidence to support causal associations between genetic liability for women's reproductive factors and the risk of CSVD in UVMR (all P-values > 0.05). Using MVMR, the results were consistent with the findings of UVMR after accounting for body mass index and educational attainment (all P-values > 0.05). Sensitivity analyses also provided consistent results. The putative positive causality was observed between AAM, ANM, and ovarian cancer, ensuring the efficacy of selected genetic instruments. Conclusion: Our findings do not convincingly support a causal effect of women's reproductive factors on CSVD. Future studies are warranted to investigate specific estrogen-related physiological changes in women, which may inform current researchers on the causal mechanisms involved in cerebral small-vessel disease progression.

Women's reproductive traits and major depressive disorder: A two-sample Mendelian randomization study.

BACKGROUND: Evidence suggested strong associations between women's reproductive factors and major depressive disorder (MDD), but their causalities are unclear. METHODS: Using female-specific SNPs as genetic instruments obtained from large-scale genome-wide association studies for women's reproductive traits, we designed two-sample univariable and multivariable Mendelian randomization (MR) analysis to evaluate the causal effects of women's reproductive traits on MDD. For both univariable MR (UVMR) and multivariable MR (MVMR), the inverse variance weighting estimates were reported as main results. MR-Egger, weighted median, and generalized summary-data-based MR (GSMR) methods for UVMR, and MVMR-Egger and MVMR-robust methods for MVMR were used as sensitivity analyses. Negative control analyses, MVMR of age at first birth (AFB) and age at first sexual intercourse (AFS) on MDD, and sex-combined genetic variants for AFB and AFS were performed to enhance the robustness of our study. RESULTS: There was substantial evidence for associations of genetically predicted later age at menarche (AAM) (odds ratio (OR) = 0.97, 95 % confidence interval (CI) = 0.94-0.99, P = 0.007), AFB (OR = 0.91, 95 % CI = 0.86-0.97, P = 0.002) and AFS (OR = 0.70, 95 % CI = 0.60-0.80, P < 0.001) with lower MDD risk in UVMR. After adjustment of BMI and educational attainment using MVMR, we found consistently significant causal effects of AAM (OR = 0.95, 95 % CI = 0.92-0.99, P = 0.006), AFB (OR = 0.88, 95 % CI = 0.84-0.91, P < 0.001) and AFS (OR = 0.71, 95 % CI = 0.64-0.79, P < 0.001) on MDD. CONCLUSIONS: Our results provide compelling evidence that early AAM, AFB, and AFS are risk factors for MDD. Promoting the cognition of reproductive health care for women may reduce the risk of MDD.

Women's reproductive traits and ischemic stroke: a two-sample Mendelian randomization study.

OBJECTIVE: We conducted a Mendelian randomization (MR) study to disentangle causal associations between women's reproductive behaviors and ischemic stroke (IS) and investigate the roles of two modifiable risk factors (body mass index (BMI) and educational attainment (EA)) in these associations. METHODS: Using summary-level data from large-scale genome-wide association studies, we performed univariable MR to examine whether there is genetic evidence that women's reproductive traits are causally associated with IS and its subtypes. Multivariable MR and MR mediation analysis were used to investigate whether BMI and EA are common mechanisms or mediators for these associations. A set of sensitivity analyses were conducted to test valid MR assumptions. RESULTS: We observed consistent and statistically significant associations across female and sex-combined analyses for earlier age at first birth (AFB) and age at first sexual intercourse (AFS) with a higher risk of IS and large-artery atherosclerotic stroke (LAS) risk in the primary analysis. The odds ratios of IS per 1 SD increase in genetically predicted early AFB and AFS were 0.93 (95% CI, 0.86-0.99; p = 0.046) and 0.83 (95% CI, 0.70-0.97, p = 0.020), respectively. Further analyses indicated that BMI played a shared role in AFS and IS/LAS while EA played a shared role in AFS/AFB and IS/LAS as well as a mediator in the path from AFS to IS/LAS. INTERPRETATION: These findings may inform prevention strategies and interventions directed toward relative women's reproductive behaviors and IS. Future studies are warranted to explore other factors related to EA which are responsible for these causalities.

Specific signature biomarkers highlight the potential mechanisms of circulating neutrophils in aneurysmal subarachnoid hemorrhage.

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating hemorrhagic stroke with high disability and mortality. Neuroinflammation and the immunological response after aSAH are complex pathophysiological processes that have not yet been fully elucidated. Therefore, attention should be paid to exploring the inflammation-related genes involved in the systemic response to the rupture of intracranial aneurysms. Methods: The datasets of gene transcriptomes were downloaded from the Gene Expression Omnibus database. We constructed a gene co-expression network to identify cluster genes associated with aSAH and screened out differentially expressed genes (DEGs). The common gene was subsequently applied to identify hub genes by protein-protein interaction analysis and screen signature genes by machine learning algorithms. CMap analysis was implemented to identify potential small-molecule compounds. Meanwhile, Cibersort and ssGSEA were used to evaluate the immune cell composition, and GSEA reveals signal biological pathways. Results: We identified 602 DEGs from the GSE36791. The neutrophil-related module associated with aSAH was screened by weighted gene co-expression network analysis (WGCNA) and functional enrichment analysis. Several small molecular compounds were predicted based on neutrophil-related genes. MAPK14, ITGAM, TLR4, and FCGR1A have been identified as crucial genes involved in the peripheral immune activation related to neutrophils. Six significant genes (CST7, HSP90AB1, PADI4, PLBD1, RAB32, and SLAMF6) were identified as signature biomarkers by performing the LASSO analysis and SVM algorithms. The constructed machine learning model appears to be robust by receiver-operating characteristic curve analysis. The immune feature analysis demonstrated that neutrophils were upregulated post-aSAH and PADI4 was positively correlated with neutrophils. The NETs pathway was significantly upregulated in aSAH. Conclusion: We identified core regulatory genes influencing the transcription profiles of circulating neutrophils after the rupture of intracranial aneurysms using bioinformatics analysis and machine learning algorithms. This study provides new insight into the mechanism of peripheral immune response and inflammation after aSAH.

Case Report: Unusual Varicella-Zoster Virus Meningoencephalitis With Meningomyelitis Mimicking Central Nervous System Leukemia.

Background: Varicella-Zoster Virus (VZV) is a human pathogen from the α-subfamily of herpesviruses. In immunocompromised patients, VZV may produce disease of the central nervous system (CNS). Clinical manifestations of CNS infection with VZV are non-specific and can mimic other infectious and non-infectious diseases. Due to similar symptoms, CNS infection with VZV represents a diagnostic challenge. Here, we report a case of a patient who showed laboratory and imaging manifestations mimicking the neoplastic etiology. Case: A 31-year-old man presented with a 3-day history of headache, 5-h of confusion, generalized tonic-clonic seizures, and transient fever. The patient has a history of acute myelogenous leukemia (AML). His cerebrospinal fluid (CSF) studies revealed markedly elevated protein (10.326 g/L) and atypical cells. Meanwhile, the MRI of brain, cervical, and thoracic spine was reported as extensive (frontal, parieto-occipital and temporal pachymeningeal, and falx cerebri) enhancement and irregular thickening. These examinations suggested a suspicion of CNS involvement of AML. However, based on further investigations with metagenomic next-generation sequencing, a final diagnosis of VZV meningoencephalitis with meningomyelitis was made. With acyclovir and foscarnet sodium therapy, repeated CSF studies revealed normal cell count and protein. No atypical cells were found. The repeated brain MRI also revealed obvious resolution of the previous abnormal pachymeningeal enhancement. Conclusion: This case highlights the importance of recognizing the unusual phenomenon of traditional tests in VZV meningoencephalitis with meningomyelitis, and timely using of further precise examinations to detect viral DNA, which is required to prevent missed diagnosis.

The prevalence and mortality of cryptococcal meningitis in patients with autoimmune diseases: a systematic review and meta-analysis.

Growing evidence suggests that autoimmune diseases (AIDs) are risk factors for cryptococcal meningitis (CM). Therefore, understanding the epidemiological and clinical profile of CM in patients with AIDs is important. This meta-analysis assessed the prevalence, clinical profiles, and clinical outcomes of CM in AIDs. Studies on CM in patients with AIDs were searched for in PubMed, EMBASE, Web of Science, and China National Knowledge Infrastructure, and meta-analyses were performed using the statistical program of R. Nineteen studies with 36,631 patients with AIDs were analyzed. The overall pooled CM prevalence was 0.4% (95% confidence interval [CI], 0.3-0.6%), 90.7% of which occurred in female patients. Thirteen studies with 77 patients with AIDs diagnosed with CM were analyzed, and the mortality rate was 26.7% (95% CI, 9.5-47.2%). Of patients with systemic lupus erythematosus, 30.1% of CM cases were initially misdiagnosed (95% CI, 0-65.6%). The primary symptom of CM with AIDs was headache (99.4%; 95% CI, 92.1-100%), followed by fever (93.7%; 95% CI, 82.8-100%) and vomiting (37.2%; 95% CI, 13.2-61.2%). The prevalence of CM infections among patients with AIDs should not be underestimated despite non-specific clinical presentations as there were fatal outcomes. Our results suggest that more research is needed to understand the relationship between AIDs and CM, and clinical trials are necessary to improve treatment strategies.