NOVEL ROLES OF MICRORNAS IN HEPATITIS C

Approximately, 170 million people are infected by hepatitis C virus (HCV) worldwide, and of these, nearly 85% will develop chronic hepatitis C (CHC). Despite finding new anti-viral treatment that increase response rate from 45 % to 65-70 %, investigations continue to find more effective treatments for hepatitis C because of side effects and limitations of current treatment. It is known that miR-122 enhances HCV replication by binding to two closely spaced target sites in the 5’-UTR of the viral genome, which leads to an increase in abundance of HCV RNA. We found that miR-122 down- regulates Occludin (OCLN), one of the key HCV receptors, by directly targeting 3’-UTR of OCLN mRNA. We also found that interaction of miR-122 with 3’-UTR of OCLN mRNA eventually results in a decrease in HCV entry. In accordance with our in vitro study, we found an inverse correlation between pre-treatment levels of miR-122 and HCV RNA levels in patients with CHC. This is a new finding of our study which is consonant with our hypothesis that miR-122 may play an antiviral role in uninfected hepatocytes and early stages of HCV infection. Protein Kinase R (PKR), a double- stranded RNA-dependent protein kinase, is among the well-known members of cellular antiviral proteins transcriptionally induced by IFNs in response to viral infection. We found that miR-122 down- regulates PRKRA expression by targeting 3’-UTR of PRKRA mRNA in uninfected Huh7.5 cells. This down-regulation led to decrease in phosphorylation of PKR. Our results are consonant with the notion that, in infected hepatocytes, miR-122 preferentially binds to 5’-UTR of HCV RNA rather than to the3’-UTR of PRKRA, and this is the main factor that increases HCV replication. Based on our findings, both in vitro and in CHC patients, we speculate that miR-122 could play a dual role in HCV infection; in uninfected hepatocytes miR-122 plays an antiviral role through down-regulation of OCLN while, in infected hepatocytes, miR-122 increases HCV replication through binding to the 5’-UTR of HCV RNA. Our results suggest that miR-122 mimics may be more beneficial than miR-122 inhibitors in the earlier stages of infection or as a prophylactic approach when few or no hepatocytes are infected with HCV. Both responses to treatment as well as spontaneous outcome of HCV infection are critically affected by host genetic factors. We found that pre-treatment levels of hepatic miR-29b were significantly lower in CHC patients with early viral response (EVR) than those without EVR. This novel finding could be very important both for predicting the outcome of disease as well as suggesting new treatment approaches for chronic hepatitis C. Low levels of miR-29b in early responders to HCV therapy might potentially benefit future therapeutic interventions involving the use of miR-29 antagomirs. We also showed that miR-29b level serves as an independent factor for predicting advanced stages of fibrosis in patients with CHC. These findings are unexpected, because miR-29b has been shown to exhibit anti-fibrotic effects in vitro. Hence, caution should be exercised in extrapolating in vitro observations to subjects with CHC. Higher levels of mir-29b in these patients may suggest a role of over-expression of miR-29b as an anti-fibrotic factor in advanced degree of liver fibrosis as a healing process for liver. Broader translational and in vitro studies are needed to unravel the importance of miR-29b in prognosis and treatment of hepatitis C

Legalon-SIL downregulates HCV core and NS5A in human hepatocytes expressing full-length HCV

AIM: To determine the effect of Legalon-SIL (LS) on hepatitis C virus (HCV) core and NS5A expression and on heme oxygenase-1 (HMOX-1) and its transcriptional regulators in human hepatoma cells expressing full length HCV genotype 1b

Dynamic Functional Connectivity Predicts Treatment Response to Electroconvulsive Therapy in Major Depressive Disorder

Background: Electroconvulsive therapy (ECT) is one of the most effective treatments for major depressive disorder. Recently, there has been increasing attention to evaluate the effect of ECT on resting-state functional magnetic resonance imaging (rs-fMRI). This study aims to compare rs-fMRI of depressive disorder (DEP) patients with healthy participants, investigate whether pre-ECT dynamic functional network connectivity network (dFNC) estimated from patients rs-fMRI is associated with an eventual ECT outcome, and explore the effect of ECT on brain network states. Method: Resting-state functional magnetic resonance imaging (fMRI) data were collected from 119 patients with depression or depressive disorder (DEP) (76 females), and 61 healthy (HC) participants (34 females), with an age mean of 52.25 (N = 180) years old. The pre-ECT and post-ECT Hamilton Depression Rating Scale (HDRS) were 25.59 ± 6.14 and 11.48 ± 9.07, respectively. Twenty-four independent components from default mode (DMN) and cognitive control network (CCN) were extracted, using group-independent component analysis from pre-ECT and post-ECT rs-fMRI. Then, the sliding window approach was used to estimate the pre-and post-ECT dFNC of each subject. Next, k-means clustering was separately applied to pre-ECT dFNC and post-ECT dFNC to assess three distinct states from each participant. We calculated the amount of time each subject spends in each state, which is called “occupancy rate” or OCR. Next, we compared OCR values between HC and DEP participants. We also calculated the partial correlation between pre-ECT OCRs and HDRS change while controlling for age, gender, and site. Finally, we evaluated the effectiveness of ECT by comparing pre- and post-ECT OCR of DEP and HC participants. Results: The main findings include (1) depressive disorder (DEP) patients had significantly lower OCR values than the HC group in state 2, where connectivity between cognitive control network (CCN) and default mode network (DMN) was relatively higher than other states (corrected p = 0.015), (2) Pre-ECT OCR of state, with more negative connectivity between CCN and DMN components, is linked with the HDRS changes (R = 0.23 corrected p = 0.03). This means that those DEP patients who spent less time in this state showed more HDRS change, and (3) The post-ECT OCR analysis suggested that ECT increased the amount of time DEP patients spent in state 2 (corrected p = 0.03). Conclusion: Our finding suggests that dynamic functional network connectivity (dFNC) features, estimated from CCN and DMN, show promise as a predictive biomarker of the ECT outcome of DEP patients. Also, this study identifies a possible underlying mechanism associated with the ECT effect on DEP patients

Viral and host determinants in hepatitis B

The outcome of hepatitis B infection is highly variable, ranging from acute disease resulting in the elimination of infection to persistent infection that can lead to cirrhosis or hepatocellular carcinoma. The factors determining the outcome in an individual are not fully known but may be classified into viral and host factors. Frequencies of hemochromatosis gene mutations were assessed in 75 Iranian subjects with chronic hepatitis B infection. The major C282Y mutation was significantly more frequent in subjects infected with hepatitis B virus (HBV) (4%) than in 194 control subjects (0%, P=0.02). Our results reports, for the first time, a higher prevalence of C282Y mutation in a group of HBsAg positive patients comparing to healthy individuals and may support the role of the major HFE mutation (C282Y) in increasing the likelihood of development of liver disease in individuals with chronic HBV infection. To clarify the role of viral factors in the clinical variability of chronic hepatitis B the precore and core promoter regions of HBV strains were characterized from 30 patients with HBeAg negative chronic hepatitis B (e-CHB) and 42 anti-HBe positive asymptomatic carriers (ASCs). G1896A precore stop mutants, detected in 77% of e-CHB patients and in 85% of ASCs, showed no association with viral load or aminotransferase levels. 20% of e-CHB patients and 31 % of ASCs harbored T1762 A1764 promotor mutants. These mutants in association with G1757 were linked to higher viral load in the patients, than those associated with A1757, 105.2+1.8 VS 103.2+0.8 copies/ml (P=0.004). Interestingly, the most common BCP mutations were T1764 G1766 double mutants, which were present in 33% of e-CHB patients and in 29% of ASCs. The T1764 G1766 double mutant was only present in strains with A 1717 (p<0 .001), Which is more frequent in genotype D strains than in strains belonging to other genotypes. On the other hand, the T1762 A1764 double mutation was more frequently found in association with G1757 than A1757 Thus position 1757 affects the emergence of promoter double mutants and would predict a relative genotypic restriction of both the T1762 A1764 and the T1764 G1766 double mutants. To investigate the role of mutations in different immune epitopes of hepatitis B core antigen (HBcAg) in HBeAg negative chronic hepatitis B (eCHB), amino acid 1-150 of HBcAg were characterized for HBV strains from 29 patients and 48 ASCs from Iran. Amino acid substitutions were found to cluster in eight different regions: residues 21-27, 35-40, 49-59, 6470, 77-87, 91-95, 105-116, and 130-135 of HBcAg. Residue 21, in an HLA-A2 CD8 epitope, was the most variable amino acid. Region 64-70, which is known to form part of a CD4 T cell epitope, was found to be the most variable region often with a Glu64Asp substitution. This was associated with other amino acid substitutions at positions 51-97 (P<0.001). An inverse relation was found between viral load and mutations in the region 18-27 and none of the patients with these mutants had a viral load > 106 viral particles ml-1 (p<0.0001). It is possible that CTLs of patients with higher viral load could be exhausted because of this load and there are fewer mutations in CTL epitope of isolates of patients with higher viral load comparing to patients harboring isolates with lower replication reflecting a more vigorous CTL response and thereby a milder state of disease in the ASCs. Core promoter mutations that occur in initial phase of seroconversion might temporarily increase viral load with specific CTL exhaustion as a consequence in some infected individuals

Investigation of Brain Functional Networks in Children Suffering from Attention Deficit Hyperactivity Disorder

Here is the pre-processed EEG dataset for ADHD and the Healthy control group while they were facing four facial emotions (Angry, Happy, Neutral, and Sad). They saw 60 images of facial expression for each emotions. Each participant's data is put in a folder named from P1 to P52. P31 and P43 have been removed from the data list due to noisy data. P15 to P17, P22 to P43, and P51 and P52 are labeled as ADHD group and the rest are healthy group. In each folder (e.g., P1) there are five folders. A refers to Angry epochs, H refers to happy epochs, N refers to neutral epochs, and S refers to Sad epoch, as well as the channel location. The matrix for each emotions is with the size of 62*1536*60 refering to channels*samples*epochs Cite: Dini, H., Farnaz.Ghassemi & Sendi, M.S.E. Investigation of Brain Functional Networks in Children Suffering from Attention Deficit Hyperactivity Disorder. Brain Topogr 33, 733–750 (2020). https://doi.org/10.1007/s10548-020-00794-