miRNA-Coordinated Schizophrenia Risk Network Cross-Talk With Cardiovascular Repair and Opposed Gliomagenesis.

BACKGROUND: Schizophrenia risk genes are widely investigated, but a systemic analysis of miRNAs contributing to schizophrenia is lacking. METHODS: Schizophrenia-associated genetic loci profiles were derived from a genome-wide association study (GWAS) from the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC) dataset. Experimentally confirmed relationships between miRNAs and their target genes were retrieved from a miRTarBase. A competitive gene set association analysis for miRNA-target regulations was conducted by the Multi-marker Analysis of GenoMic Annotation (MAGMA) and further validated by literature-based functional pathway analysis using Pathway Studio. The association between the targets of three miRNAs and schizophrenia was further validated using a GWAS of antipsychotic treatment responses. RESULTS: Three novel schizophrenia-risk miRNAs, namely, miR-208b-3p, miR-208a-3p, and miR-494-5p, and their targetomes converged on calcium voltage-gated channel subunit alpha1 C (CACNA1C) and B-cell lymphoma 2 (BCL2), and these are well-known contributors to schizophrenia. Both miR-208a-3p and miR-208b-3p reduced the expression of the RNA-binding protein Quaking (QKI), whose suppression commonly contributes to demyelination of the neurons and to ischemia/reperfusion injury. On the other hand, both QKI and hsa-miR-494-5p were involved in gliomagenesis. CONCLUSION: Presented results point at an orchestrating role of miRNAs in the pathophysiology of schizophrenia. The sharing of regulatory networks between schizophrenia and other pathologies may explain higher cardiovascular mortality and lower odds of glioma previously reported in psychiatric patients.

Preparation of non-sintered fly ash filter (NSFF) for ammonia nitrogen adsorption.

In accordance with China's goal of 'treating wastes with wastes, turning wastes into treasure', a non-sintered fly ash filter (NSFF) with sewage sludge as additive was prepared. It consists of 70.9% fly ash, 7% sewage sludge, 9% cement, 7.1% CaO, 1% NaHCO3 and 5% sodium silicate solution. After mixing, 34 g/(100 g dry material) water was added, and then was granulated and steam cured under 80°C for 16 h. NSFF's main performance indexes include specific surface area (SSA) of 17.038 m2 g-1, filter media breaking rate (FMBR) of 2.2%, apparent density (AD) of 1140 kg m-3, and porosity of 41.67%, meeting the Chinese Standard CJ/T 299-2008. This NSFF has a larger SSA and a lower AD comparing with the other similar non-sintered fly ash ceramsite products. Moreover, leaching toxicity of the NSFF has met the Chinese Standards for Hazardous Wastes (GB5085.3-2007). Therefore, the NSFF is effective and safe to use as a water treatment filter media. The NSFF's adsorption characteristics for ammonia nitrogen was investigated. Results showed that the optimized parameters for ammonia nitrogen adsorption are as follows, NSFF dosage at 5 g, initial ammonia nitrogen concentration of 225 mg L-1, pH at 7, contact time of 12 h and temperature at 30°C. Under the optimum conditions, the adsorption capacity of NSFF for ammonia nitrogen was 4.25 mg g-1. The adsorption process can be best described by Langmuir isotherm and pseudo-second-order kinetic model. The proposed adsorption mechanism include adsorption and cation exchange.

The Single Nucleotide Polymorphism rs1014290 of the SLC2A9 Gene Is Associated with Uric Acid Metabolism in Parkinson's Disease.

Individuals with Parkinson's disease (PD) have lower uric acid levels than those without PD, and the CC genotype and C minor allele of a single nucleotide polymorphism (SNP), rs1014290 of SLC2A9, are associated with lower uric acid levels. We investigated the association of rs1014290 with uric acid metabolism in a cohort of PD cases (220) and controls (110) in a Han Chinese population. Uric acid levels were determined and rs1014290 was assayed using a mutation-sensitive on/off switch technology. PD uric acid levels (291.65 ± 76.29 µmol/L) were significantly lower than the controls (325.73 ± 74.23 µmol/L, P < 0.001, t-test). Individuals with rs1014290 TT and CT genotypes had higher uric acid levels, and those with the CC genotype had the lowest uric acid levels among both control and PD cases. The CC genotype and the C minor allele were statistically more frequent in the PD group compared to the control group. Those with the CC genotype had a statistically significant higher risk of PD than those with the TT or TC genotype (odds ratio [OR] = 2.249, 95% confidence interval [CI]: 1.129-4.480, and P = 0.021). Thus, SLC2A9 rs1014290 is related to lower uric acid levels in PD patients and can be a risk factor for PD in the Han population.

TLR2 signaling directs NO-dependent MMP-9 induction in mouse microglia.

Microglia are neural immune cells that produce pro-inflammatory proteins in the central nervous system. Dysregulation of microglia gene expression is linked to the chronic brain inflammation and the neurological disorders. Matrix metalloproteinase-9 (MMP-9) is a pro-inflammatory protease that regulates the neurotoxicity of glial cells in the brain and spinal cord. Recent studies showed the accumulation of MMP-9 at microglia-rich plaques associates with neurodegenerative diseases. However, the regulatory mechanism of MMP-9 expression in microglia inflammation is still unknown. Here we show that oxidized low-density lipoprotein (oxLDL) induces the expression and secretion of Pro-MMP-9 (92kDa) via TLR2 signaling pathway in mouse microglial cells. Depletion of TLR2 or its signaling mediators MyD88/TRAF6 blocks the agonist-induced MMP-9 expression. In addition, TLR2-dependent nitric oxide (NO) synthesis is also required for endogenous Pro-MMP-9 expression and secretion. Cell death assay indicates that the neurotoxicity of microglia is regulated by endogenous NO and TLR2 signaling pathway. Our findings establish a pathophysiological link between oxLDL and MMP-9 expression in microglia-related neuroinflammation.

Spatial patterns of intrinsic neural activity in depressed patients with vascular risk factors as revealed by the amplitude of low-frequency fluctuation.

To investigate spatial patterns of intrinsic neural activity of depressed patients with vascular risk factors using resting-state functional magnetic resonance imaging (fMRI) and to examine the relationship between regional activity abnormalities and symptom severity factor, we analyzed spatial patterns of spontaneous brain activity in 19 depressed patients with vascular risk factors and 18 healthy subjects. Intrinsic brain activity was measured by the amplitude of low-frequency fluctuations (ALFF) of the resting-state blood oxygen level dependent signal. Depressed patients with vascular risk factors showed decrease in ALFF in the limbic-cortical-striatal-pallidal-thalamic circuit. Specifically, the altered ALFF values (i.e., left insula and right superior frontal gyrus) were significantly correlated with depression severity in the depressed group. In addition, higher ALFF values in the right middle temporal gyrus and right superior temporal gyrus were observed in depressed patients with vascular risk factors. Our findings reveal distinct functional patterns of abnormal brain activity in depressed patients with vascular risk factors and have implications for the understanding of the pathophysiology of this understudied population.

Post-treatment of Bax-inhibiting peptide reduces neuronal death and behavioral deficits following global cerebral ischemia.

Cerebral ischemia is a major cause of adult disability and death worldwide. Evidence suggests that Bax-dependent initiation and activation of intrinsic apoptotic pathways contribute to ischemic brain injury. We investigated the Bax-inhibiting peptide VPALR, designed from the rat Ku70-Bax inhibiting domain, on the apoptotic neuronal cell death and behavioral deficits following global cerebral ischemia. The pentapeptide was infused into the left lateral ventricle of the rat brain by intracerebroventricular (i.c.v.) injection 1 h after cerebral ischemia, and results showed that it highly permeated hippocampal neurons and bound to Bax protein in vivo. Post-treatment with VPALR reduced the delayed neuronal damage by approximately 78% compared to the non-treated ischemic control and scrambled peptide-treated rats. TUNEL analysis revealed that VPALR markedly reduced the ischemia-induced increase in apoptotic neuronal death in rat hippocampal CA1 region. VPALR post-treatment also significantly attenuated Bax activation and its mitochondrial translocation as compared with scrambled peptide-treated animals. Concomitantly, Bax-inhibiting peptide-treated rats showed reduced cytochrome c release from mitochondria to cytosol and reduced caspase-3 activation in response to cerebral ischemia, indicating that activation of the intrinsic apoptotic pathway was reduced. Furthermore, Bax-inhibiting peptide improved spatial learning and memory performance in the Morris water maze, which was seriously affected by global cerebral ischemia. In conclusion, Bax inhibition by cell-permeable pentapeptides reduced apoptotic neuronal injury in the hippocampal CA1 region and behavioral deficits following global ischemia. These results suggest that Bax is a potential target for pharmacological neuroprotection and that Bax-inhibiting peptide may be a promising neuroprotective strategy for cerebral ischemia.

Neuroprotective effect and cognitive outcome of chronic lithium on traumatic brain injury in mice.

In vitro and in vivo studies have demonstrated that lithium treatment can protect neurons against excitotoxic and ischemic damage. Yet the possible beneficial effect of chronic low dose lithium on a model of traumatic brain injury (TBI) has not been intensively investigated. In this study, lithium (1 mmol/kg) was given daily, intraperitonealy, for 14 days before the onset of moderate controlled TBI and was continued until the mice were sacrificed. The results showed that in brain injured animals, chronic lithium treatment attenuated the loss of hemispheric tissue, cerebral edema and the expression of pro-inflammatory cytokine interleukin-1ß. The neuronal degeneration in hippocampal CA3 and dentate gyrus sub-regions was also attenuated in the chronic lithium-treated mice as shown by Fluoro-Jade B staining. Moreover, chronic lithium treatment enhanced spatial learning and memory performance of injured mice in the Morris water maze. Our current study extended the protective role of lithium in the model of TBI and suggested that chronic lithium treatment might be a helpful therapeutic strategy for brain injury with multiple beneficial effects.