Neurons are MHC Class I-Dependent Targets for CD8 T Cells upon Neurotropic Viral Infection

Following infection of the central nervous system (CNS), the immune system is faced with the challenge of eliminating the pathogen without causing significant damage to neurons, which have limited capacities of renewal. In particular, it was thought that neurons were protected from direct attack by cytotoxic T lymphocytes (CTL) because they do not express major histocompatibility class I (MHC I) molecules, at least at steady state. To date, most of our current knowledge on the specifics of neuron-CTL interaction is based on studies artificially inducing MHC I expression on neurons, loading them with exogenous peptide and applying CTL clones or lines often differentiated in culture. Thus, much remains to be uncovered regarding the modalities of the interaction between infected neurons and antiviral CD8 T cells in the course of a natural disease. Here, we used the model of neuroinflammation caused by neurotropic Borna disease virus (BDV), in which virus-specific CTL have been demonstrated as the main immune effectors triggering disease. We tested the pathogenic properties of brain-isolated CD8 T cells against pure neuronal cultures infected with BDV. We observed that BDV infection of cortical neurons triggered a significant up regulation of MHC I molecules, rendering them susceptible to recognition by antiviral CTL, freshly isolated from the brains of acutely infected rats. Using real-time imaging, we analyzed the spatio-temporal relationships between neurons and CTL. Brain-isolated CTL exhibited a reduced mobility and established stable contacts with BDV-infected neurons, in an antigen- and MHC-dependent manner. This interaction induced rapid morphological changes of the neurons, without immediate killing or impairment of electrical activity. Early signs of neuronal apoptosis were detected only hours after this initial contact. Thus, our results show that infected neurons can be recognized efficiently by brain-isolated antiviral CD8 T cells and uncover the unusual modalities of CTL-induced neuronal damage

Disease-Causing 7.4 kb Cis-Regulatory Deletion Disrupting Conserved Non-Coding Sequences and Their Interaction with the FOXL2 Promotor: Implications for Mutation Screening

To date, the contribution of disrupted potentially cis-regulatory conserved non-coding sequences (CNCs) to human disease is most likely underestimated, as no systematic screens for putative deleterious variations in CNCs have been conducted. As a model for monogenic disease we studied the involvement of genetic changes of CNCs in the cis-regulatory domain of FOXL2 in blepharophimosis syndrome (BPES). Fifty-seven molecularly unsolved BPES patients underwent high-resolution copy number screening and targeted sequencing of CNCs. Apart from three larger distant deletions, a de novo deletion as small as 7.4 kb was found at 283 kb 5′ to FOXL2. The deletion appeared to be triggered by an H-DNA-induced double-stranded break (DSB). In addition, it disrupts a novel long non-coding RNA (ncRNA) PISRT1 and 8 CNCs. The regulatory potential of the deleted CNCs was substantiated by in vitro luciferase assays. Interestingly, Chromosome Conformation Capture (3C) of a 625 kb region surrounding FOXL2 in expressing cellular systems revealed physical interactions of three upstream fragments and the FOXL2 core promoter. Importantly, one of these contains the 7.4 kb deleted fragment. Overall, this study revealed the smallest distant deletion causing monogenic disease and impacts upon the concept of mutation screening in human disease and developmental disorders in particular

Promoting remyelination in multiple sclerosis-recent advances

We review the current state of knowledge of remyelination in multiple sclerosis (MS), concentrating on advances in the understanding of the pathology and the regenerative response, and we summarise progress on the development of new therapies to enhance remyelination aimed at reducing progressive accumulation of disability in MS. We discuss key target pathways identified in experimental models, as although most identified targets have not yet progressed to the stage of being tested in human clinical trials, they may provide treatment strategies for demyelinating diseases in the future. Finally, we discuss some of the problems associated with testing this class of drugs, where they might fit into the therapeutic arsenal and the gaps in our knowledge

Review of the Competition for the best technological innovation in Serbia for 2020

The Competition for best technology innovation, organized by the Serbian Ministry of Education, Science and Technology Development, has been held since 2005. The public call for participation in the Competition is announced in February with the deadline to submit the application in March (or May, depending on the category), while the final round is completed at the end of December and is supported by the public media service. Any three-member team can apply. There are no limits in age, gender, education, or the field of the innovation: the most important is the marketable innovative solution itself

Mood disturbance and withdrawal severity in substitution treatment for opioid dependence: Their association and impact on continued illicit drug use

Objectives: This study explored the relationship between withdrawal severity and mood disturbance, and their links with continued illicit drug use during the first 3 months of opioid substitution treatment (ST). Methods: Sixteen participants undergoing opioid ST with methadone (n=7) or buprenorphine (n=9) were recruited through outpatient units in South Australia. In a within-groups repeated measures design, the Opiate Treatment Index was administered at baseline and again at 3 months. Participants also completed the Methadone Symptoms Checklist and the Profile of Mood States at baseline and fortnightly throughout the 3-month measurement period. Results: Withdrawal severity and mood disturbance were observed to co-vary over the 3 months. Statistically significant reductions in both withdrawal severity and mood disturbance were observed. The direction of association between withdrawal severity and mood disturbance was positive and was statistically significant at all measurement points. Continued use of illicit drugs was associated with higher levels of both mood disturbance and withdrawal severity. Conclusions: Withdrawal severity and mood disturbance co-vary over time and have important implications for treatment outcomes in ST. Copyright © 2010 by Lippincott Williams & Wilkins.Lisa Kettler, Mathew Nikic, David Newcombe and Robert Al