Differential expression of exosomal microRNAs in prefrontal cortices of schizophrenia and bipolar disorder patients

Exosomes are cellular secretory vesicles containing microRNAs (miRNAs). Once secreted, exosomes are able to attach to recipient cells and release miRNAs potentially modulating the function of the recipient cell. We hypothesized that exosomal miRNA expression in brains of patients diagnosed with schizophrenia (SZ) and bipolar disorder (BD) might differ from controls, reflecting either disease-specific or common aberrations in SZ and BD patients. The sources of the analyzed samples included McLean 66 Cohort Collection (Harvard Brain Tissue Resource Center), BrainNet Europe II (BNE, a consortium of 18 brain banks across Europe) and Boston Medical Center (BMC). Exosomal miRNAs from frozen postmortem prefrontal cortices with well-preserved RNA were isolated and submitted to profiling by Luminex FLEXMAP 3D microfluidic device. Multiple statistical analyses of microarray data suggested that certain exosomal miRNAs were differentially expressed in SZ and BD subjects in comparison to controls. RT-PCR validation confirmed that two miRNAs, miR-497 in SZ samples and miR-29c in BD samples, have significantly increased expression when compared to control samples. These results warrant future studies to evaluate the potential of exosome-derived miRNAs to serve as biomarkers of SZ and BD

Single detector-dual scintillator anti-comptom probes

Anti¬-Compton spectrometers have many applications in the fields of safeguards, medicine and security. One of the most important applications is in the location of low energy gamma sources in the presence of high-¬energy gamma background or the location of high-¬energy gamma radiation sources hidden within the same spread of radiation background. In most situations space constraints limit the application of large size detectors or classical anti¬-Compton spectrometers. We have designed a compact anti-¬Compton spectrometer based on a single chip, dual silicon photodetector optically coupled to isolated, annular scintillators. Preliminary room temperature testing with Csl(TI) and LYSO scintillators demon¬strate the readout capabilities of the spectrometer concept. We have measured an outstanding energy resolution of 12 % and 8 % for the 511 keV line from a 22Na source used to excite a LYSO and Csl(TI) respectively. The other variants of Si-Csl(TI) probes is also discussed

Median and 90th percentile of False Discovery Rates (FDR) in order left-to-right of threshold value and number of statistically significant results for all three groups (C, BD, and SZ).

<p>The Y-axis is an estimate of the percentage of false positives. High-ranked miRNA (at the left) have a low rate of false positives, while lower-ranked miRNA (moving toward the right) have higher rates of false positives.</p

Student’s t-test comparison of qPCR Delta-CT.

<p>miR-29c expression is significantly increased in BD samples, and miR-497 in SZ samples.</p><p>BD =  bipolar disorder; SZ =  schizophrenia.</p

Analyzed human prefrontal cortices (BA9).

<p>SZ =  schizophrenia; BD =  bipolar disorder; C =  controls.</p><p>BB =  Braak and Braak.</p><p>L =  Luminex; P =  qPCR.</p

SAM test of <i>Luminex</i> miRNA expression data for all 3 examined groups of cases: SZ, BD, and C.

<p>The list of 198 miRNAs were narrowed from 312 microRNA using a linear regression model and subsequently ranked by z-score test statistics. Local FDR evaluates false discoveries by assigning samples to random groups to test for statistical significance by chance. The relevance of FDR is determined using q-values, an analog of the p-value. The 21 top-ranked miRNAs have a q-value equal to 0%, meaning that it is highly unlikely for this miRNAs to be expressed differentially by chance among the three groups examined.</p><p>SZ =  schizophrenia; BD =  bipolar disorder; C =  controls.</p

Misclassification rate analysis.

<p>(A) Controls (red) have the most variable miRNA expression. The expression data have less variability in BD (green) and the least in SZ (blue; misclassification rate  = 0), resulting in stronger predictive power within their respective clinical groups.</p

Covariate effects of medications on highly-ranked miRNAs in SAM (top-21 in Table 2 and top-12 in Table 3).

<p>Covariate effects of medications on highly-ranked miRNAs in SAM (top-21 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0048814#pone-0048814-t002" target="_blank">Table 2</a> and top-12 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0048814#pone-0048814-t003" target="_blank">Table 3</a>).</p

In comparison to controls, the expression of miR-29c and miR-497 is significantly increased in BD and SZ samples, respectively.

<p>Average exosomal RNA extracted from BA9 cortices of BD samples show a 2.77 fold increase of miR-29c in comparison to controls (A). SZ samples reveal 2.35 fold increase of miR-497 when compared to controls (B). Error bars indicate S.E.M.</p