Glioblastoma (GBM) is the most prevalent and fatal form of brain tumor, which is associated with a poor prognosis. ATP-binding cassette subfamily F member 1 (ABCF1) is an E2 ubiquitin-conjugating enzyme, which is implicated in regulating immune responses and tumorigenesis. Aberrant E3 ubiquitylation has been evidenced in GBM. However, the role of ABCF1 in GBM needs to be further explored. The expression of ABCF1, CXC chemokine ligand 12 (CXCL12), and CXC chemokine receptor 4 (CXCR4) in GBM tissues was examined by the GEPIA tool, real-time PCR and Western blotting. HMC3, U251MG, and LN-229 cells were cultured and transfected with shRNA targeting ABCF1 and ABCF1 plasmids. The proliferative, migrative, and invasive ability of cells was detected. Western blotting was used to detect the levels of phosphorylated phosphatidylinositol 3-kinase (PI3K) and phosphorylated protein kinase B (AKT). We observed that GBM tissues had higher ABCF1, CXCL12, and CXCR4 expression levels. The expression levels of CXCL12 and CXCR4 were enhanced by ABCF1 overexpression, which were significantly reversed by silence of ABCF1 in GBM cells. Silencing ABCF1 or CXCR4 inhibition weakened the capacity of GBM cell growth, migration, and invasion, while ectopic ABCF1 expression or CXCL12 treatment enhanced the cellular function of GBM cells. Furthermore, p-PI3K and p-AKT protein levels were downregulated by ABCF1 knockdown or CXCR4 blockade, which were prompted by ABCF1 overexpression or CXCL12 supplement. The ABCF1-CXCL12-CXCR4 axis was identified as a key player in GBM cell survival and metastasis by activating the PI3K/AKT signaling pathway in GBM cells.

Post-infectious neuroinflammation has been implicated in multiple models of acute onset obsessive-compulsive disorder (OCD) including Sydenham's chorea (SC), pediatric acute-onset neuropsychiatric syndrome (PANS), and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). These conditions are associated with a range of autoantibodies which are thought to be triggered by an infections, most notably group A streptococci (GAS). Based on animal models using huma sera, these autoantibodies are thought to cross-react with neural antigens in the basal ganglia and modulate neuronal activity and behavior. As is true for many childhood neuroinflammatory diseases and rheumatological diseases, SC, PANS, and PANDAS lack clinically available, rigorous diagnostic biomarkers and randomized clinical trials. In this review article, we outline the accumulating evidence supporting the role neuroinflammation plays in these disorders. We describe work with animal models including patient-derived anti-neuronal autoantibodies, and we outline imaging studies that show alterations in the basal ganglia. In addition, we present research on metabolites, which are helpful in deciphering functional phenotypes, and on the implication of sleep in these disorders. Finally, we encourage future researchers to collaborate across medical specialties (e.g., pediatrics, psychiatry, rheumatology, immunology, and infectious disease) in order to further research on clinical syndromes presenting with neuropsychiatric manifestations.

Complex brain disorders like schizophrenia may have multifactorial origins related to mis-timed heritable and environmental factors interacting during neurodevelopment. Infections, inflammation, and autoimmune diseases are over-represented in schizophrenia leading to immune system-centered hypotheses. Complement component C4 is genetically and neurobiologically associated with schizophrenia, and its dual activity peripherally and in the brain makes it an exceptional target for biomarker development. Studies to evaluate the biomarker potential of plasma or serum C4 in schizophrenia do so to understand how peripheral C4 might reflect central nervous system (CNS)-derived neuroinflammation, synapse pruning and other mechanisms. This effort, however, has produced mostly conflicting results, with peripheral C4 sometimes elevated, reduced or unchanged between comparison groups. We undertook a pilot biomarker development study to systematically identify sociodemographic, genetic, and immune-related variables (autoimmune, infection-related, gastrointestinal (GI), inflammatory), which may be associated with plasma C4 levels in schizophrenia (SCH; n=335) and/or in non-psychiatric comparison subjects (NCs; n=233). As with previously inconclusive studies, we detected no differences in plasma C4 levels between SCH and NCs. In contrast, levels of general inflammation, C-Reactive Protein (CRP), were significantly elevated in SCH compared to NCs (ANOVA, F=20.74, p<0.0001), suggestive that plasma C4 and CRP may reflect different sources or causes of inflammation. In multivariate regressions of C4 gene copy number variants (CNVs), plasma C4 levels were correlated only for C4A (not C4B, C4L, C4S) and only in NCs (R Coeff=0.39, CI=0.01-0.77, R2=0.18, p<0.01; not SCH). Other variables associated with plasma C4 levels only in NCs included sex, double-stranded DNA (dsDNA) IgG, tissue-transglutaminase (TTG) IgG, and cytomegalovirus (CMV) IgG. Toxoplasma gondii IgG was the only variable significantly correlated with plasma C4 in SCH but not in NCs. Many variables were associated with plasma C4 in both groups (body mass index (BMI), race, CRP, N-methyl-D-aspartate receptor (NMDAR) NR2 subunit IgG, TTG IgA, lipopolysaccharide (LPS)-binding protein (LBP), and soluble CD14 (sCD14). While the direction of most C4 associations was positive, autoimmune markers tended to be inverse, and associated with reduced plasma C4 levels. When NMDAR NR2 autoantibody-positive individuals were removed, plasma C4 was elevated in SCH versus NCs (ANOVA, F=5.16, p<0.02). Our study was exploratory and confirmation of the many variables associated with peripheral C4 require replication. Our preliminary results point toward autoimmune factors and exposure to the pathogen, T. gondii, as possibly significant contributors to variability of total C4 protein levels in plasma of individuals with schizophrenia.

Understanding the long-term functional implications of gut microbial communities during the perinatal period is a bourgeoning area of research. Numerous studies have revealed the existence of a "gut-brain axis" and the impact of an alteration of gut microbiota composition in brain diseases. Recent research has highlighted how gut microbiota could affect brain development and behavior. Many factors in early life such as the mode of delivery or preterm birth could lead to disturbance in the assembly and maturation of gut microbiota. Notably, global rates of cesarean sections (C-sections) have increased in recent decades and remain important when considering premature delivery. Both preterm birth and C-sections are associated with an increased risk of neurodevelopmental disorders such as autism spectrum disorders; with neuroinflammation a major risk factor. In this review, we explore links between preterm birth by C-sections, gut microbiota alteration, and neuroinflammation. We also highlight C-sections as a risk factor for developmental disorders due to alterations in the microbiome.

PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections) is an acute onset or exacerbation of neuropsychiatric symptoms following a group A streptococcus (GAS) infection. It is believed to be a result of autoimmune response to streptococcal infection, but there is insufficient evidence to fully support this theory. Although this disease is primarily thought to be a disease of childhood, it is reported to occur also in adults. PANDAS is a well-defined clinical entity, but the neuropathology of this condition is not established yet. We describe the clinical course of a 26-year old female diagnosed with PANDAS. She committed suicide and her brain was bio-banked for further studies. We examined the banked tissue and used special stains, immunohistochemistry, and immunofluorescence analysis to characterize the neuropathology of this condition. Histology of temporal lobes, hippocampus, and basal ganglia shows mild astrogliosis, Alzheimer's type II astrocytes, and acute hypoxic ischemic changes. Immunostaining shows increased parenchymal/perivascular GFAP staining, and many vessels with mild increases in CD3, CD4 and CD25 stained lymphocytes in basal ganglia. The findings suggest that CD4 and CD25 positive T cells might have an important role in understanding the neuroinflammation and pathogenesis of this condition. The case represents the first neuropathological evaluation report for PANDAS.

The developmental condition of children after neonatal arterial ischemic stroke (NAIS) is characterized by cognitive and motor impairments. We hypothesized that independent walking age would be a predictor of later global cognitive functioning in this population. Sixty-one children with an available independent walking age and full-scale IQ score seven years after NAIS were included in this study. Full-scale IQ was assessed using the fourth edition of the Wechsler Intelligence Scale for Children (WISC-IV). Independent walking age was negatively correlated with full-scale IQ score at seven years of age (Pearson correlation coefficient of -0.27; 95% confidence interval from 0.48 to -0.01; p <0.05). Early motor function is correlated with later global cognitive functioning in children after NAIS. Assessing and promoting early motor ability is essential in this population.

Medulloblastoma (MB), the most common malignant pediatric brain tumor, comprises four molecularly and clinically distinct subgroups (termed WNT, SHH, Group3, and Group4). Prognosis varies based on genetic and pathological features associated with each molecular subgroup. WNT-MB, considered low-risk, are rarely metastatic and contain activating mutations in CTNNB1; Group3-MB, commonly classified as high-risk, are frequently metastatic and can contain genomic alterations resulting in elevated MYC expression. Here we compare model systems of low-risk WNT-MB and high-risk Group3-MB to identify tumor and microenvironment interactions that could contribute to features associated with prognosis. Compared to Group3-MB, we find that WNT-MB are enriched in gene sets related to extracellular matrix (ECM) regulation and cellular adhesion. Exogenous expression of MycT58A in a murine WNT-MB model significantly accelerates growth and results in metastatic disease. In addition to decreased ECM regulation and cell adhesion pathways, we also identified immune system interactions among the top down-regulated signaling pathways following MycT58A expression. Taken together, our data provides evidence that increased Myc-signaling can promote the growth and metastasis in a murine model of WNT-MB.

To explore the alterations in the white matter (WM) structural connectome in children with drug-naïve attention-deficit/hyperactivity disorder (ADHD). Forty-nine pediatric ADHD and 51 age- and gender-matched typically developing (TD) children aged 6-14 years old were enrolled. This cross-sectional study applied graph theoretical analysis to assess the white matter organization based on deterministic diffusion tensor imaging (DTI). WM structural connectivity was constructed in 90 cortical and subcor-tical regions, and topological parameters of the resulting graphs were calculated. Networks were compared between two groups. The digit cancellation test (DCT) was taken to evaluate clinical symptom severity in pediatric ADHD, using the concentration index and the total cancellation test scores. Then, a partial correlation analysis was performed to explore the re-lationship between significant topologic metrics and clinical symptom severity. Compared to TDs, ADHD showed an increase in the characteristic path length (Lp), normalized clustering coefficient (γ), small-worldness (σ), and a decrease in the global effi-ciency (Eglob) (all P <0.05). Furthermore, ADHD showed reduced nodal centralities mainly in the regions of default mode (DMN), central executive network (CEN), basal ganglia, and bilateral thalamus (all P <0.05). After performing Benjamini-Hochberg's procedure, only left orbital part of superior frontal gyrus (ORBsup.L) and left caudate (CAU) were statistically significant (P < 0.05, FDR-corrected). In addition, the concentration index of ADHD was negatively correlated with the nodal betweenness of the left orbital part of the middle frontal gyrus (ORBmid.L) (r = -0.302, P = 0.042). Our findings revealed an ADHD-related shift of WM network topology toward "regularization" pattern, characterized by decreased global network integration, which is also reflected by changed nodal centralities involving DMN, CEN, basal ganglia, and bilateral thalamus. ADHD could be understood by examining the dysfunction of large-scale spatially distributed neural networks.

Quantitative analysis of electroencephalography (qEEG) is a potential source of biomarkers for neonatal encephalopathy (NE). However, prior studies using qEEG in NE were limited in their generalizability due to individualized techniques for calculating qEEG features or labor-intensive pre-selection of EEG data. We piloted a fully automated method using commercially available software to calculate the suppression ratio (SR), absolute delta power, and relative delta, theta, alpha, and beta power from EEG of neonates undergoing 72 h of therapeutic hypothermia (TH) for NE between April 20, 2018, and November 4, 2019. We investigated the association of qEEG with degree of encephalopathy (modified Sarnat score), severity of neuroimaging abnormalities following TH (National Institutes of Child Health and Development Neonatal Research Network [NICHD-NRN] score), and presence of seizures. Thirty out of 38 patients met inclusion criteria. A more severe modified Sarnat score was associated with higher SR during all phases of TH, lower absolute delta power during all phases except rewarming, and lower relative delta power during the last 24 h of TH. In 21 patients with neuroimaging data, a worse NICHD-NRN score was associated with higher SR, lower absolute delta power, and higher relative beta power during all phases. QEEG features were not significantly associated with the presence of seizures after correction for multiple comparisons. Our results are consistent with those of prior studies using qEEG in NE and support automated qEEG analysis as an accessible, generalizable method for generating biomarkers of NE and response to TH. Additionally, we found evidence of an immature relative frequency composition in neonates with more severe brain injury, suggesting that automated qEEG analysis may have a use in the assessment of brain maturity.