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

Understanding the role of crystallographic shear on the electrochemical behavior of niobium oxyfluorides

The effects of shear planes in perovskite materials have been studied in order to identify their role in the electrochemical behavior of Li⁺ intercalation hosts. These planes modulate the structural stability and ionic transport pathways and therefore play an intimate role in the characteristics and performance of shear compounds. Herein, two Nb-based compounds, NbO₂F and Nb₃O₇F, were chosen as representative perovskite and shear derivatives respectively to investigate the role of crystallographic shear. A series of operando measurements, including X-ray diffraction and X-ray absorption spectroscopy, in conjunction with structural analysis, Raman spectroscopy, and detailed electrochemical studies identified the effect of shear planes. It was found that shear planes led to increased structural stability during Li⁺ (de)intercalation with shear layers being maintained, while perovskite layers were seen to degrade rapidly. However, disordering in the shear plane stacking introduced during delithiation ultimately led to poor capacity retention despite structural maintenance as Li⁺ diffusion channels are disrupted

Understanding the role of crystallographic shear on the electrochemical behavior of niobium oxyfluorides

The effects of shear planes in perovskite materials have been studied in order to identify their role in the electrochemical behavior of Li⁺ intercalation hosts. These planes modulate the structural stability and ionic transport pathways and therefore play an intimate role in the characteristics and performance of shear compounds. Herein, two Nb-based compounds, NbO₂F and Nb₃O₇F, were chosen as representative perovskite and shear derivatives respectively to investigate the role of crystallographic shear. A series of operando measurements, including X-ray diffraction and X-ray absorption spectroscopy, in conjunction with structural analysis, Raman spectroscopy, and detailed electrochemical studies identified the effect of shear planes. It was found that shear planes led to increased structural stability during Li⁺ (de)intercalation with shear layers being maintained, while perovskite layers were seen to degrade rapidly. However, disordering in the shear plane stacking introduced during delithiation ultimately led to poor capacity retention despite structural maintenance as Li⁺ diffusion channels are disrupted

Collaborative Interventions for Circulation and Depression (COINCIDE): Study protocol for a cluster randomized controlled trial of collaborative care for depression in people with diabetes and/or coronary heart disease

BACKGROUND: Depression is up to two to three times as common in people with long-term conditions. It negatively affects medical management of disease and self-care behaviors, and leads to poorer quality of life and high costs in primary care. Screening and treatment of depression is increasingly prioritized, but despite initiatives to improve access and quality of care, depression remains under-detected and under-treated, especially in people with long-term conditions. Collaborative care is known to positively affect the process and outcome of care for people with depression and long-term conditions, but its effectiveness outside the USA is still relatively unknown. Furthermore, collaborative care has yet to be tested in settings that resemble more naturalistic settings that include patient choice and the usual care providers. The aim of this study was to test the effectiveness of a collaborative-care intervention, for people with depression and diabetes/coronary heart disease in National Health Service (NHS) primary care, in which low-intensity psychological treatment services are delivered by the usual care provider - Increasing Access to Psychological Therapies (IAPT) services. The study also aimed to evaluate the cost-effectiveness of the intervention over 6 months, and to assess qualitatively the extent to which collaborative care was implemented in the intervention general practices. METHODS: This is a cluster randomized controlled trial of 30 general practices allocated to either collaborative care or usual care. Fifteen patients per practice will be recruited after a screening exercise to detect patients with recognized depression (≥10 on the nine-symptom Patient Health Questionnaire; PHQ-9). Patients in the collaborative-care arm with recognized depression will be offered a choice of evidence-based low-intensity psychological treatments based on cognitive and behavioral approaches. Patients will be case managed by psychological well-being practitioners employed by IAPT in partnership with a practice nurse and/or general practitioner. The primary outcome will be change in depressive symptoms at 6 months on the 90-item Symptoms Checklist (SCL-90). Secondary outcomes include change in health status, self-care behaviors, and self-efficacy. A qualitative process evaluation will be undertaken with patients and health practitioners to gauge the extent to which the collaborative-care model is implemented, and to explore sustainability beyond the clinical trial. DISCUSSION: COINCIDE will assess whether collaborative care can improve patient-centered outcomes, and evaluate access to and quality of care of co-morbid depression of varying intensity in people with diabetes/coronary heart disease. Additionally, by working with usual care providers such as IAPT, and by identifying and evaluating interventions that are effective and appropriate for routine use in the NHS, the COINCIDE trial offers opportunities to address translational gaps between research and implementation. TRIAL REGISTRATION NUMBER: ISRCTN80309252 TRIAL STATUS: Ope