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Harwell, United Kingdom

Becker J.,University of Oxford | Yau C.,University of Oxford | Hancock J.M.,MRC Harwell | Holmes C.C.,University of Oxford
Bioinformatics | Year: 2013

Motivation: The identification of nucleosomes along the chromatin is key to understanding their role in the regulation of gene expression and other DNA-related processes. However, current experimental methods (MNase-ChIP, MNase-Seq) sample nucleosome positions from a cell population and contain biases, making thus the precise identification of individual nucleosomes not straightforward. Recent works have only focused on the first point, where noise reduction approaches have been developed to identify nucleosome positions.Results: In this article, we propose a new approach, termed NucleoFinder, that addresses both the positional heterogeneity across cells and experimental biases by seeking nucleosomes consistently positioned in a cell population and showing a significant enrichment relative to a control sample. Despite the absence of validated dataset, we show that our approach (i) detects fewer false positives than two other nucleosome calling methods and (ii) identifies two important features of the nucleosome organization (the nucleosome spacing downstream of active promoters and the enrichment/depletion of GC/AT dinucleotides at the centre of in vitro nucleosomes) with equal or greater ability than the other two methods. © The Author 2013. Source


Goldman-Mellor S.,University of North Carolina at Chapel Hill | Goldman-Mellor S.,Duke University | Gregory A.M.,Goldsmiths, University of London | Caspi A.,Duke University | And 6 more authors.
Sleep | Year: 2014

Study Objectives: Insomnia is a highly prevalent condition that constitutes a major public health and economic burden. However, little is known about the developmental etiology of adulthood insomnia.Design: We examined whether indicators of psychological vulnerability across multiple developmental periods (psychiatric diagnoses in young adulthood and adolescence, childhood behavioral problems, and familial psychiatric history) predicted subsequent insomnia in adulthood.Setting and Participants: We used data from the ongoing Dunedin Multidisciplinary Health and Development Study, a population-representative birth cohort study of 1, 037 children in New Zealand who were followed prospectively from birth (1972-1973) through their fourth decade of life with a 95% retention rate.Measurements: Insomnia was diagnosed at age 38 according to DSM-IV criteria. Psychiatric diagnoses, behavioral problems, and family psychiatric histories were assessed between ages 5 and 38.Results: In cross-sectional analyses, insomnia was highly comorbid with multiple psychiatric disorders. After controlling for this concurrent comorbidity, our results showed that individuals who have family histories of depression or anxiety, and who manifest lifelong depression and anxiety beginning in childhood, are at uniquely high risk for age-38 insomnia. Other disorders did not predict adulthood insomnia.Conclusions: The link between lifelong depression and anxiety symptoms and adulthood insomnia calls for further studies to clarify the neurophysiological systems or behavioral conditioning processes that may underlie this association. Source


Collins-Hooper H.,University of Reading | Woolley T.E.,University of Oxford | Dyson L.,University of Oxford | Patel A.,University of Reading | And 6 more authors.
Stem Cells | Year: 2012

Skeletal muscle undergoes a progressive age-related loss in mass and function. Preservation of muscle mass depends in part on satellite cells, the resident stem cells of skeletal muscle. Reduced satellite cell function may contribute to the age-associated decrease in muscle mass. Here, we focused on characterizing the effect of age on satellite cell migration. We report that aged satellite cells migrate at less than half the speed of young cells. In addition, aged cells show abnormal membrane extension and retraction characteristics required for amoeboid-based cell migration. Aged satellite cells displayed low levels of integrin expression. By deploying a mathematical model approach to investigate mechanism of migration, we have found that young satellite cells move in a random "memoryless" manner, whereas old cells demonstrate superdiffusive tendencies. Most importantly, we show that nitric oxide, a key regulator of cell migration, reversed the loss in migration speed and reinstated the unbiased mechanism of movement in aged satellite cells. Finally, we found that although hepatocyte growth factor increased the rate of aged satellite cell movement, it did not restore the memoryless migration characteristics displayed in young cells. Our study shows that satellite cell migration, a key component of skeletal muscle regeneration, is compromised during aging. However, we propose clinically approved drugs could be used to overcome these detrimental changes. © AlphaMed Press. Source


Formstone C.J.,Kings College London | Moxon C.,Kings College London | Murdoch J.,MRC Harwell | Little P.,Imperial College London | Mason I.,Kings College London
Molecular and Cellular Neuroscience | Year: 2010

A characteristic of the 7TM-cadherins, Flamingo and Celsr1, is their asymmetric protein distribution and polarized activity at neighboring epithelial cell interfaces along defined axes of planar cell polarity. Here, we describe a novel distribution of Celsr1 protein to the basal surface of neuroepithelial cells within both the early neural tube and a less well-defined group of ventricular zone cells at the midline of the developing spinal cord. Importantly, this basal enrichment is lost in embryos homozygous for a mutant Celsr1 allele. We also demonstrate an intimate association between basal enrichment of Celsr1 protein and dorsal sensory tract morphogenesis, an intriguing spatio-temporal organization of Celsr1 protein along the apico-basal neuroepithelial axis suggestive of multiple Celsr1 protein isoforms and the existence of distinct cell surface Celsr1 protein species with direct signaling potential. Together, these data raise compelling new questions concerning the role of Celsr1 during neural development. © 2010 Elsevier Inc. Source


Stelma F.,MRC Harwell | Stelma F.,University of Groningen | Bhutta M.F.,MRC Harwell | Bhutta M.F.,University of Oxford
Journal of Laryngology and Otology | Year: 2014

Abstract Background: Hereditary sensorineural hearing loss is the most frequently occurring birth defect. It has profound effects for the individual and is a substantial burden on society. Insight into disease mechanisms can help to broaden therapeutic options and considerably lower lifetime social costs. In the past few decades, the identification of genes that can cause this type of hearing loss has developed rapidly. Objective: This paper provides a concise overview of the currently known genes involved in non-syndromic hereditary hearing loss and their function in the inner ear. Copyright © JLO (1984) Limited 2014. Source

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