Neuroscience
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Autism Spectrum Disorders (ASD) are caused by disrupted neurodevelopment leading to socio-communication and behavioural abnormalities. Although genetic anomalies like Copy Number Variations (CNV) have been implicated in ASD, their overall genomic landscape and pathogenicity remain elusive. Therefore, we created a CNV map for ASD using 9337 cases and 5650 controls from SFARI database, statistically marked genomic regions with high and low frequencies of CNVs (i.e., common and rare CNV regions respectively), performed gene function enrichment for CNV genes, built functional networks, pathways and examined their expression in brain tissues. ⋯ While common CNV regions were found in loci 15q11.2, 16p11.2, 22q11.21, 15q13.2-13.3, rare CNV regions in loci 4p16.3, 9q34.3, 7q11.23, 17p11.2 contributed significantly to protein interaction networks and were highly expressed in brain. Enriched CNV genes were clustered in six functional categories with either direct roles in neurodevelopment or auxiliary roles like cellular signalling via MAPK pathway, cytoskeletal organization and transport or immune regulation. Mechanisms through which these molecular systems could independently or in combination trigger an ASD phenotype were predicted.
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Excessive expression of vascular endothelial growth factor (VEGF) is a common cause of blood-brain barrier (BBB) breakdown that triggers severe complications following traumatic brain injury (TBI). It has been shown that inhibition of VEGF activities may attenuate cerebral edema in pathological conditions. Vascular endothelial growth inhibitor (VEGI; also known as TNFSF15), a cytokine produced largely by vascular endothelial cells, is capable of downregulating VEGF expression and inhibiting VEGF receptor-2 (VEGFR2) activation. ⋯ VEGI treatment resulted in a marked decrease of BBB permeability and concomitant restoration of normal ratios of VEGF/VEGI and Angpt2/Angpt1. Consistently, alleviated edema, decreased neuron cell death, and improved neurological functions were observed when the experimental animals were treated with VEGI in the early phase of TBI. Our findings suggest that administration of VEGI recombinant protein at early phases of TBI is beneficial to stabilization of the disease conditions.
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The complexity of brain activity has recently been investigated using the Hurst exponent (H), which describes the extent to which functional magnetic resonance imaging (fMRI) blood oxygen-level dependent (BOLD) activity is simple vs. complex. For example, research has demonstrated that fMRI activity is more complex before than after consumption of alcohol and during task than resting state. The measurement of H in fMRI is a novel method that requires the investigation of additional factors contributing to complexity. ⋯ Multiple regression analyses demonstrated that eigenvector centrality was the most robust predictor of complexity, whereby greater centrality was associated with increased complexity (lower H). Regions known to be highly connected, including the thalamus and hippocampus, notably were among the highest in centrality and complexity. This research has led to a greater understanding of how brain region characteristics such as DTI centrality relate to the novel Hurst exponent approach for assessing brain activity complexity, and implications for future research that employ these measures are discussed.
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Mutations in γ-aminobutyric acid A receptor (GABAA) subunits and sodium channel genes, especially GABRG2 and SCN1A, have been reported to be associated with febrile seizures (FS) and genetic epilepsy with febrile seizures plus (GEFS+). GEFS+ is a well-known family of epileptic syndrome with autosomal dominant inheritance in children. Its most common phenotypes are febrile seizures often with accessory afebrile generalized tonic-clonic seizures, febrile seizures plus (FS+), severe epileptic encephalopathy, as well as other types of generalized or localization-related seizures. ⋯ In summary, mutations in the GABAA receptor can lead to a decrease in numbers of receptors, which may cause the impairment of GABAergic pathway signaling. This data has been the first time to reveal that GABRG2 mutations would affect the function of other genes, and based on this finding we hope this work would also provide a new direction for the research of GABRG2 in GEFS+. It also may provide a molecular basis for the severity of epilepsy, and guide the clinical medication for the treatment of the epilepsy focused on the function on GABAA receptors, which, might be a new strategy for genetic diagnosis and targeted treatment of epilepsy.
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Accumulation of amyloid-β (Aβ) in brain tissue contributes to the pathophysiology of Alzheimer's disease (AD). We recently reported that intrahippocampal transplantation of mouse bone marrow-derived microglia-like (BMDML) cells suppresses brain amyloid pathology and cognitive impairment in a mouse model of AD. How these transplanted cells interact with resident microglia remains unknown. ⋯ Brain TGF-β1 levels and resident microglial TGF-β1R expression were increased by intrahippocampal injection of BMDML cells in a mouse model of AD. Cotreatment with the TGF-βR1 inhibitor suppressed the ability of transplanted BMDML cells to increase microglial TGF-β1R expression and decrease hippocampal Aβ levels. Taken together, these findings suggested that transplanted BMDML cells secreted TGF-β1 to stimulate Aβ phagocytosis by resident microglia and decrease brain Aβ pathology.