Investigating the mechanisms directing oligodendrocyte precursor cell (OPC) development in the zebrafish hindbrain

Oligodendrocytes are the myelinating cells of the central nervous system (CNS) and are implicated in the pathobiology of many CNS diseases including multiple sclerosis and schizophrenia. Oligodendrocyte precursor cells (OPCs) are capable of migrating long distances, but the mechanisms governing the migration of OPCs to their axonal destinations are not fully understood. We sought to understand the extrinsic and intrinsic factors that contribute to the migration of a subset of OPCs in the zebrafish hindbrain. We utilized the zebrafish transgenic tg(olig2:gfp) line to mark OPCs and characterise their normal migration patterns. These cells normally first migrate in a ventral direction, after which they migrate away from the midline dorsolaterally to populate the hindbrain. However, how these cells initiate migration in a ventral direction is not known. We have found that removing Hedgehog signalling at the onset of their migratory phase results in a failure of OPCs to migrate in their normal ventral fashion, while increasing Hedgehog signalling results in hypermigration of these cells. This suggests that Hedgehog might not just be important for OPC fate specification, via induction of transcription factors such as olig2, but may also be actively involved in the development of these cells post-specification. We propose that Sonic Hedgehog acts as a chemoattractant to drive the initial ventral migration of hindbrain OPCs and furthermore provide evidence that it may function at least in part by inducing disc1, a schizophrenia risk factor gene, which has known roles in neural crest and neuronal migration. With several studies supporting a role of DISC1 in neuronal migration it has been hypothesised that DISC1 could also play a role in the process of myelination. White matter abnormalities are consistently reported in schizophrenia patients, and it is hypothesised that OPC migratory defects may cause these documented white matter abnormalities due to early genetic dysfunction. This thesis has provided evidence for a link between a well characterised schizophrenia risk factor gene, early OPC migration events and a fundamental signalling pathway

The electronic frailty index as an indicator of community healthcare service utilisation in the older population

Background: older people with frailty are particularly high users of healthcare services, however a lack of standardised recording of frailty in different healthcare electronic datasets has limited investigations into healthcare service usage and demand of the older frail population. Objectives: to investigate the community service demand of frail patients using the electronic frailty index (eFI) as a measure of frailty. Study design and setting a retrospective cohort study using anonymised linked healthcare patient data from primary care, community services and acute hospitals in Norfolk. Participants: patients aged 65 and over who had an eFI assessment score established in their primary care electronic patient record in Norwich based General Practices. Results: we include data from 22,859 patients with an eFI score. Frailty severity increased with age and was associated with increased acute hospital admission within a 6-month window. Patients with a frail eFI score were also more likely to have a community service referral within a 6-month window of frailty assessment, with a RR of 1.84 (1.76–1.93) for mild frailty, 1.96 (1.83–2.09) for moderate frailty and 2.95 (2.76–3.14) for severe frailty scores. We also found that frail patients had more community referrals per patient then those classified as fit and required more care plans per community referral. Conclusions: eFI score was an indicator of community service use, with increasing severity of frailty being associated with higher community healthcare requirements. The eFI may help planning of community services for the frail population

Scratch.

Scratch investigated the use of physical space as a site and representation of narrative and dramatic structure. It was commissioned by and collaboratively developed with BBC Radio Drama. Boyd Davis directed the project and devised and undertook the evaluation with 40 trial listeners. It was unprecedented in being location-sensitive without being tied to any particular place, building on research undertaken for Dragons (Boyd Davis REF Output 4). It used pre-recorded audio on GPS-enabled mobile devices allowing sounds to be virtually attached to locations in an outdoor space. As participants moved, they encountered scenes forming a coherent drama; the same place behaved differently if visited more than once. This translocational approach opened novel artistic possibilities that were exploited through team expertise in narrative, sound design and advanced interaction. It was also significant for the economics of broadcast media, a more viable proposition than the many locative experiences that have been site-specific: a factor of great interest to the BBC. The public performance selected for BBC FreeThinking, September 2008 in Liverpool, that year’s European Capital of Culture, was reported in a co-written 2009 conference presentation at ISEA, Belfast (2009) and in a co-written short chapter in Spierling and Szilas (eds.), Interactive Storytelling (2008). Boyd Davis reported the findings to BBC executives (http://researchonline.rca.ac.uk/1000/), for whom an additional trial was run in London in 2009. He used mixed methods, open but capable of rigorous analysis, to feed back to the makers of the drama and to guide BBC policy. Abigail le Fleming (Producer BBC Radio Drama) confirms that ‘through this collaboration, the Radio Drama department became the first BBC unit to experiment with GPS technologies’. The work ‘brought us to tackle non-linear narratives in ways that we would not have otherwise done… invaluable in terms of the questions that it raised for radio drama.

Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy

Acknowledgments Blood biochemistry analysis and serum analysis were performed by the Easter Bush Pathology Department, University of Edinburgh. Animal husbandry was performed by Centre for Integrative Physiology bio-research restructure technical staff, University of Edinburgh. Assistance with intravenous injections was provided by Ian Coldicott (University of Sheffield) and Hannah Shorrock (University of Edinburgh). Human blood cDNA was a gift to GH from Kathy Evans, University of Edinburgh. Imaging was performed at the IMPACT imaging facility, University of Edinburgh, with technical assistance from Anisha Kubasik-Thayil. The authors would also like to thank Lyndsay Murray for technical discussions relating to qRT-PCR analysis. This work was supported by funding from the SMA Trust and the Anatomical Society (via grants to THG); the Euan MacDonald Centre for Motor Neurone Disease Research (via grants to THG and SHP); the Wellcome Trust (via grants to EJNG and THG); Muscular Dystrophy UK (via grants to THG and CGB); a Elphinstone Scholarship from the University of Aberdeen (to SHP); and The French Muscular Dystrophy Association (via grants to CM and JC).Peer reviewedPublisher PD

UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy

Deafferentation of motor neurons as a result of defective sensory-motor connectivity is a critical early event in the pathogenesis of spinal muscular atrophy, but the underlying molecular pathways remain unknown. We show that restoration of ubiquitin-like modifier-activating enzyme 1 (UBA1) was sufficient to correct sensory-motor connectivity in the spinal cord of mice with spinal muscular atrophy. Aminoacyl-tRNA synthetases, including GARS, were identified as downstream targets of UBA1. Regulation of GARS by UBA1 occurred via a non-canonical pathway independent of ubiquitylation. Dysregulation of UBA1/GARS pathways in spinal muscular atrophy mice disrupted sensory neuron fate, phenocopying GARS-dependent defects associated with Charcot-Marie-Tooth disease. Sensory neuron fate was corrected following restoration of UBA1 expression and UBA1/GARS pathways in spinal muscular atrophy mice. We conclude that defective sensory motor connectivity in spinal muscular atrophy results from perturbations in a UBA1/GARS pathway that modulates sensory neuron fate, thereby highlighting significant molecular and phenotypic overlap between spinal muscular atrophy and Charcot-Marie-Tooth disease.</p

“Dolls or teddies?”: constructing lesbian identity through community-specific practice.

The concept of ‘community’ often presents a problem for queer linguists. ‘The gay community’ is often viewed as an impossible site for research due to its imagined status, whilst local communities of gay people have been considered too heterogeneous and idiosyncratic to draw conclusions from. In this article, however, it is argued that both of these aspects of community can, and should, be a central focus of an investigation into language and sexual identity. Through the analysis of a conversation emerging from a lesbian group, using a sociocultural linguistics framework, it is argued here that the community of practice approach can play a crucial role in understanding how ideologies from ‘the gay community’ are used to construct a coherent sexual identity on a local level. The analysis reveals how the group engages in practices that enable them to construct micro-level personas in direct response to broader, ideological structures of heteronormativity