The CLIF Project : the repository as part of a content lifecycle

At the heart of meeting institutional needs for managing digital content is the need to understand the different activities that the content goes through, from planning and creation through to disposal or preservation. Digital content is created using a variety of authoring tools. Once created the content is often stored somewhere different, made accessible in possibly more than one way, altered as required, and then moved for deletion or preservation at an appropriate point. Different systems can be involved at different points: one of these may be a repository. To embed repositories in the content lifecycle, and prevent them becoming yet another content silo within the institution, they thus need to be integrated with other systems that support other parts of this lifecycle. In this way the content can be moved between systems as required, minimising the constraints of any one system. The JISC-funded CLIF (Content Lifecycle Integration Framework) project, which concluded in March 2011, was a joint venture between Library and Learning Innovation (LLI) at the University of Hull and the Centre for e-Research (CeRch) at King’s College London. It undertook an extensive literature review and worked with creators of digital content at the two host institutions to understand how they would like to deal with the interaction of the authoring, collaboration and delivery of materials using three systems used within Higher Education institutions that are targeted at the management of digital content from different perspectives and for different purposes: the Fedora Commons repository software, Microsoft SharePoint, and the virtual learning environment, Sakai. Each of these systems addresses a range of lifecycle stages in the functionality provided; yet they were not designed to encompass the whole lifecycle. Armed with this background information, the project team went on to design and produce software that would allow the transfer of digital content between the systems to meet lifecycle requirements: Fedora and SharePoint, on the one hand, Fedora and Sakai on the other. The CLIF software has been designed to try and allow the maximum flexibility in how and when users can transfer material from one system to another, integrating the tools in such a way that they seem to be natural extensions of the basic systems. This open source software is available for others to investigate and work with. This article draws on several of the pieces of documentation produced by the project

Gene Therapy for Dopamine Dyshomeostasis: From Parkinson's to Primary Neurotransmitter Diseases

Neurological disorders encompass a broad range of neurodegenerative and neurodevelopmental diseases that are complex and almost universally without disease modifying treatments. There is, therefore, significant unmet clinical need to develop novel therapeutic strategies for these patients. Viral gene therapies are a promising approach, where gene delivery is achieved through viral vectors such as adeno-associated virus and lentivirus. The clinical efficacy of such gene therapies has already been observed in two neurological disorders of pediatric onset; for spinal muscular atrophy and aromatic L-amino acid decarboxylase (AADC) deficiency, gene therapy has significantly modified the natural history of disease in these life-limiting neurological disorders. Here, we review recent advances in gene therapy, focused on the targeted delivery of dopaminergic genes for Parkinson's disease and the primary neurotransmitter disorders, AADC deficiency and dopamine transporter deficiency syndrome (DTDS). Although recent European Medicines Agency and Medicines and Healthcare products Regulatory Agency approval of Upstaza (eladocagene exuparvovec) signifies an important landmark, numerous challenges remain. Future research will need to focus on defining the optimal therapeutic window for clinical intervention, better understanding of the duration of therapeutic efficacy, and improved brain targeting. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Dopamine Transporter Deficiency Syndrome (DTDS): Expanding the Clinical Phenotype and Precision Medicine Approaches

Infantile parkinsonism-dystonia due to dopamine transporter deficiency syndrome (DTDS) is an ultrarare childhood movement disorder caused by biallelic loss-of-function mutations in the SLC6A3 gene. Advances in genomic analysis have revealed an evolving spectrum of SLC6A3-related neurological and neuropsychiatric disorders. Since the initial clinical and genetic characterisation of DTDS in 2009, there have been thirty-one published cases with a variety of protein-truncating variants (nonsense variants, splice-site changes, and deletions) and missense changes. Amino acid substitutions result in mutant proteins with impaired dopamine transporter function due to reduced transporter activity, impaired dopamine binding, reduced cell-surface expression, and aberrant posttranslational protein modification with impaired glycosylation. In this review, we provide an overview of the expanding clinical phenotype of DTDS and the precision therapies in development, including pharmacochaperones and gene therapy

Prime orbit theorems for closed orbits and knots in hyperbolic dynamical systems

This thesis consists of four chapters, each with its own notation and references. Chapters 1, 2 and 3 are independent pieces of research. Chapter 0 is an introduction which sets out the definitions and results needed in the main part of the thesis. In Chapter 1, we derive asymptotic formulae for the number of closed orbits of a toral automorphism which is ergodic, but not necessarily hyperbolic. Previously, such formulae were known only in the hyperbolic case. The proof uses an analogy with the Prime Number Theorem. We also give a new proof of the uniform distribution of periodic points. In Chapter 2, we derive various asymptotic formulae for the numbers of closed orbits in the Lorenz and Smale horseshoe templates with given knot invariants, (specifically braid index and genus). We indicate how these estimates can be applied to more complicated flows by giving a bound for the genus of knotted periodic orbits in the ' figure of eight template'. In Chapter 3, we prove a dynamical version of the Chebotarev density theorem for group extensions of geodesic flows on compact manifolds of variable negative curvature. Specifically, the group is taken to be the weak direct sum of a finite abelian group. We outline an application to twisted orbits

Knowledge-based semantic annotation and retrieval of multimedia content

aceMedia is a 4 year EC part-funded FP6 Integrated Project, ending in December 2007. The project has developed tools to enable users to manage and share both personal and purchased content across PC, STB and mobile platforms. Knowledge-based analysis and ontologies have been successfully exploited in an end-to-end system to enable automated semantic annotation and retrieval of multimedia content. The paper briefly describes the objectives of aceMedia and the application of knowledge-based analysis in the project

Harmonising research reporting in the UK – experiences and outputs from UKRISS

The Jisc-funded UK Research Information Shared Service (UKRISS) project investigated the reporting of research information across the UK HE sector and assessed the feasibility of a national infrastructure based on CERIF with the objective of increasing the efficiency, productivity and reporting quality across the sector. A core reporting profile was developed that would enable harmonised reporting on RCUK-funded research, taking into account the HE-BCI survey as well as REF reporting elements. In this paper we describe the UKRISS modelling approach and provide some insight into the UKRISS reporting objects to support understanding of their formal CERIF representations, i.e. the selection of underlying CERIF entities; the challenges with managing objects and aggregations in CERIF. Example data extracts demonstrate the work

Specific inhibition of c-Jun N-terminal kinase delays preterm labour and reduces mortality

Preterm labour (PTL) is commonly associated with infection and/or inflammation. Lipopolysaccharide (LPS) from different bacteria can be used to independently or mutually activate Jun N-terminal kinase (JNK)/AP1- or NF-kB-driven inflammatory pathways that lead to PTL. Previous studies using Salmonella abortus LPS, which activates both JNK/AP-1 and NF-kB, showed that selective inhibition of NF-kB delays labour and improves pup outcome. Where labour is induced using Escherichia coli LPS (O111), which upregulates JNK/AP-1 but not NF-kB, inhibition of JNK/AP-1 activation also delays labour. In this study, to determine the potential role of JNK as a therapeutic target in PTL, we investigated the specific contribution of JNK signalling to S. Abortus LPS-induced PTL in mice. Intrauterine administration of S. Abortus LPS to pregnant mice resulted in the activation of JNK in the maternal uterus and fetal brain, upregulation of pro-inflammatory proteins COX-2, CXCL1, and CCL2, phosphorylation of cPLA2 in myometrium, and induction of PTL. Specific inhibition of JNK by co-administration of specific D-JNK inhibitory peptide (D-JNKI) delayed LPS-induced preterm delivery and reduced fetal mortality. This is associated with inhibition of myometrial cPLA2 phosphorylation and proinflammatory proteins synthesis. In addition, we report that D-JNKI inhibits the activation of JNK/JNK3 and caspase-3, which are important mediators of neural cell death in the neonatal brain. Our data demonstrate that specific inhibition of TLR4-activated JNK signalling pathways has potential as a therapeutic approach in the management of infection/inflammation-associated PTL and prevention of the associated detrimental effects to the neonatal brain

Microfluidic production of nanogels as alternative triple transfection reagents for the manufacture of adeno-associated virus vectors

Adeno-associated viral vectors (AAVs) have proved a mainstay in gene therapy, owing to their remarkable transduction efficiency and safety profile. Their production, however, remains challenging in terms of yield, the cost-effectiveness of manufacturing procedures and large-scale production. In this work, we present nanogels produced by microfluidics as a novel alternative to standard transfection reagents such as polyethylenimine-MAX (PEI-MAX) for the production of AAV vectors with comparable yields. Nanogels were formed at pDNA weight ratios of 1 : 1 : 2 and 1 : 1 : 3, of pAAV cis-plasmid, pDG9 capsid trans-plasmid and pHGTI helper plasmid respectively, where vector yields at a small scale showed no significant difference to those of PEI-MAX. Weight ratios of 1 : 1 : 2 showed overall higher titers than 1 : 1 : 3, where nanogels with nitrogen/phosphate ratios of 5 and 10 produced yields of ≈8.8 × 10^{8} vg mL^{-1} and ≈8.1 × 10^{8} vg mL^{-1} respectively compared to ≈1.1 × 10^{9} vg mL^{-1} for PEI-MAX. In larger scale production, optimised nanogels produced AAV at a titer of ≈7.4 × 10^{11} vg mL^{-1}, showing no statistical difference from that of PEI-MAX at ≈1.2 × 10^{12} vg mL^{-1}, indicating that equivalent titers can be achieved with easy-to-implement microfluidic technology at comparably lower costs than traditional reagents

7 Essays on Impact

Edited by Dr Andrew Dean, Dr Michael Wykes & Hilary Stevens, University of ExeterThrough the Jisc-funded DESCRIBE Project we have sought to undertake a rigorous assessment of current standards relating to the evidence of impacts arising from Higher Education research. This document contains seven valuable essays each exploring the topic of Impact. Each essay is distinct and we have sought to enable selected thought-leaders and Impact experts to both review the status quo, and to look to the future, making suggestions and recommendations for the development of Impact in the sector. DESCRIBE has been managed by the University of Exeter’s Research and Knowledge Transfer team in partnership with the Marchmont Observatory. We have sought to combine the latest thinking on research Impact with examples and recommendations which are practical and rooted in the art of the possible.JISC DIINN1