30 research outputs found

    Enhancer-driven chromatin interactions during development promote escape from silencing by a long non-coding RNA

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    <p>Abstract</p> <p>Background</p> <p>Gene regulation in eukaryotes is a complex process entailing the establishment of transcriptionally silent chromatin domains interspersed with regions of active transcription. Imprinted domains consist of clusters of genes, some of which exhibit parent-of-origin dependent monoallelic expression, while others are biallelic. The <it>Kcnq1 </it>imprinted domain illustrates the complexities of long-range regulation that coexists with local exceptions. A paternally expressed repressive non-coding RNA, <it>Kcnq1ot1</it>, regulates a domain of up to 750 kb, encompassing 14 genes. We study how the <it>Kcnq1 </it>gene, initially silenced by <it>Kcnq1ot1</it>, undergoes tissue-specific escape from imprinting during development. Specifically, we uncover the role of chromosome conformation during these events.</p> <p>Results</p> <p>We show that <it>Kcnq1 </it>transitions from monoallelic to biallelic expression during mid gestation in the developing heart. This transition is not associated with the loss of methylation on the <it>Kcnq1 </it>promoter. However, by exploiting chromosome conformation capture (3C) technology, we find tissue-specific and stage-specific chromatin loops between the <it>Kcnq1 </it>promoter and newly identified DNA regulatory elements. These regulatory elements showed <it>in vitro </it>activity in a luciferase assay and <it>in vivo </it>activity in transgenic embryos.</p> <p>Conclusions</p> <p>By exploring the spatial organization of the <it>Kcnq1 </it>locus, our results reveal a novel mechanism by which local activation of genes can override the regional silencing effects of non-coding RNAs.</p

    Lost in Translation? On the Need for Convergence in Animal and Human Studies on the Role of Dopamine in Diet-Induced Obesity

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    Purpose of Review: Animal and human studies suggest that diet-induced obesity and plasticity in the central dopaminergic system are linked. However, it is unclear whether observed changes depend on diet or obesity, and whether they are specific to brain regions and cognitive functions. Here, we focus on neural and cognitive changes in frontostriatal circuits. Recent Findings: Both diet and obesity affect dopaminergic transmission. However, site and direction of effects are inconsistent across species and studies. Non-specific changes are observed spanning all frontostriatal loops, from sensory input to motivated behaviour. Given the impact of peripheral signals on central dopaminergic signalling and the interaction between the frontostriatal loops, modulation of dopamine likely propagates through all loops and, thus, affects behaviour on various levels of complexity. Summary: To improve convergence between animal and human studies on diet-induced obesity, animal studies should include sophisticated cognitive measures and diets resembling human obesogenic diets, and human studies should adopt diet interventions and longitudinal designs.Peer reviewe

    Опыт внедрения электронного курса на базе платформы LMS Moodle с использованием содержания на английском языке

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    Представлен разработанный курс для смешанного обучения магистрантов направления "Инноватика" профиля "Информационные технологии в рекламе и связях с общественностью"

    Infectious causes of microcephaly: epidemiology, pathogenesis, diagnosis, and management.

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    Microcephaly is an important sign of neurological malformation and a predictor of future disability. The 2015-16 outbreak of Zika virus and congenital Zika infection brought the world's attention to links between Zika infection and microcephaly. However, Zika virus is only one of the infectious causes of microcephaly and, although the contexts in which they occur vary greatly, all are of concern. In this Review, we summarise important aspects of major congenital infections that can cause microcephaly, and describe the epidemiology, transmission, clinical features, pathogenesis, management, and long-term consequences of these infections. We include infections that cause substantial impairment: cytomegalovirus, herpes simplex virus, rubella virus, Toxoplasma gondii, and Zika virus. We highlight potential issues with classification of microcephaly and show how some infants affected by congenital infection might be missed or incorrectly diagnosed. Although Zika virus has brought the attention of the world to the problem of microcephaly, prevention of all infectious causes of microcephaly and appropriately managing its consequences remain important global public health priorities

    Genomic investigations of unexplained acute hepatitis in children

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    Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children
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