Immunity and AAV-Mediated Gene Therapy for Muscular Dystrophies in Large Animal Models and Human Trials

Adeno-associated viral (AAV) vector-mediated gene replacement for the treatment of muscular dystrophy represents a promising therapeutic strategy in modern medicine. One major obstacle in using AAV vectors for in vivo gene delivery is the development of host immune responses to the viral capsid protein and transgene products as evidenced in animal models and human trials for a range of genetic diseases. Here, we review immunity against AAV vector and transgene in the context of gene delivery specific to muscles for treating muscular dystrophies and non-muscle diseases in large animal models and human trials, factors that influence the intensity of the immune responses, and immune modulatory strategies to prevent unwanted immune responses and induce tolerance to the vector and therapeutic gene for a successful gene therapy

What young people want from health-related online resources: a focus group study

The growth of the Internet as an information source about health, particularly amongst young people, is well established. The aim of this study was to explore young people's perceptions and experiences of engaging with health-related online content, particularly through social media websites. Between February and July 2011 nine focus groups were facilitated across Scotland with young people aged between 14 and 18 years. Health-related user-generated content seems to be appreciated by young people as a useful, if not always trustworthy, source of accounts of other people's experiences. The reliability and quality of both user-generated content and official factual content about health appear to be concerns for young people, and they employ specialised strategies for negotiating both areas of the online environment. Young people's engagement with health online is a dynamic area for research. Their perceptions and experiences of health-related content seem based on their wider familiarity with the online environment and, as the online environment develops, so too do young people's strategies and conventions for accessing it

Immune Responses to rAAV6: The Influence of Canine Parvovirus Vaccination and Neonatal Administration of Viral Vector

Recombinant adeno-associated viral (rAAV) vectors promote long-term gene transfer in many animal species. Significant effort has focused on the evaluation of rAAV delivery and the immune response in both murine and canine models of neuromuscular disease. However, canines provided for research purposes are routinely vaccinated against canine parvovirus (CPV). rAAV and CPV possess significant homology and are both parvoviruses. Thus, any immune response generated to CPV vaccination has the potential to cross-react with rAAV vectors. In this study, we investigated the immune response to rAAV6 delivery in a cohort of CPV-vaccinated canines and evaluated multiple vaccination regimens in a mouse model of CPV-vaccination. We show that CPV-vaccination stimulates production of neutralizing antibodies with minimal cross-reactivity to rAAV6. In addition, no significant differences were observed in the magnitude of the rAAV6-directed immune response between CPV-vaccinated animals and controls. Moreover, CPV-vaccination did not inhibit rAAV6-mediated transduction. We also evaluated the immune response to early rAAV6-vaccination in neonatal mice. The influence of maternal hormones and cytokines leads to a relatively permissive state in the neonate. We hypothesized that immaturity of the immune system would permit induction of tolerance to rAAV6 when delivered during the neonatal period. Mice were vaccinated with rAAV6 at 1 or 5 days of age, and subsequently challenged with rAAV6 exposure during adulthood via two sequential IM injections, 1 month apart. All vaccinated animals generated a significant neutralizing antibody response to rAAV6-vaccination that was enhanced following IM injection in adulthood. Taken together, these data demonstrate that the immune response raised against rAAV6 is distinct from that which is elicited by the standard parvoviral vaccines and is sufficient to prevent stable tolerization in neonatal mice

Inspædia: [Almost] Everything About Simplicity, Playfulness and Inspiration

The aim of this paper is to disclose the new research developments and the results from the systematization of experience and user interaction with the Inspædia (a new web knowledge “Agora”), to inspire a dynamic, collaborative, and interactive intelligence among the inspædiers. We will explain in detail and describe the design process and discuss the ultimate design interaction concept & development regarding (almost everything about) simplicity and playfulness of the inspædiers’ experience to transform relevant information (related > meanfull > useful) in productive knowledge (inspiration > insight > foresight) in a very easy and quick way (usability: learnability; understandability; operability; attractiveness...), with a smile in the face (satisfaction) and a wow in the mind (or in the soul).Inspædia is the natural consequence and development of the prototype resulting from the research in Design PhD thesis Innovation, design et cetera (FA/UTL, 2012). Therefore, it is being developed with the Science Without Borders Program (2013-2016) with a Special Visiting Researcher fellowship grant of CAPES (Brazil), and under the post-doctoral in Design at the Faculty of Architecture, University of Lisbon (FA/UL); CIAUD – Reseach Centre of Architecture, Urbanism and Design (FA/UL); Faculty of Sciences and Technology, Nova University of Lisbon (FCT/UNL); NOVA-LINCS (FCT/UNL) and CITAD - Research Centre for Territory, Architecture and Design (FAA/ULL). The Inspædia research project was ranked in first place in Design scientific area and obtained a post-doctoral fellowship by FCT – Foundation for Science and Technology (Portugal). The project has been internationally disseminated at international Design conferences with indexed publications. It was presented and published both at AHFE 2014 (Krakow) and AHFE 2015 (Las Vegas). It was part of the biennial Experimentadesign tangential events in 2013 (EXD'13), 2015 (EXD'15) and was presented, by invitation, at the International Congress DESIGN I-CON (2015). During the last year we prototyped and tested (usability testing) with some inspædiers different approaches to achieve users’ needs > desires > expectations) in a challenging way, in order to provide the most powerful and memorable user experience

Networking the nucleus

The nuclei of differentiating cells exhibit several fundamental principles of self-organization. They are composed of many dynamical units connected physically and functionally to each other—a complex network—and the different parts of the system are mutually adapted and produce a characteristic end state. A unique cell-specific signature emerges over time from complex interactions among constituent elements that delineate coordinate gene expression and chromosome topology. Each element itself consists of many interacting components, all dynamical in nature. Self-organizing systems can be simplified while retaining complex information using approaches that examine the relationship between elements, such as spatial relationships and transcriptional information. These relationships can be represented using well-defined networks. We hypothesize that during the process of differentiation, networks within the cell nucleus rewire according to simple rules, from which a higher level of order emerges. Studying the interaction within and among networks provides a useful framework for investigating the complex organization and dynamic function of the nucleus

Synchronous online CPD: empirical support for the value of webinars in career settings

The careers profession in England is facing unprecedented challenges. Initiatives to improve service delivery while keeping costs low are attractive and online training holds the promise of high impact at low cost. The present study employs a qualitative methodology to evaluate a series of online ‘webinars’ conducted with 15 careers advisers. Results showed that the technology itself could impede learning, and participants missed out on the peer-to-peer interaction that takes place in a ‘bricks and mortar’ setting, but overall participants found that access to relevant, good quality training from the convenience of their workplace more than compensated for the challenges. The article offers conceptual support for the viability of online learning through the theory of equivalency, andragogy and transactional distance theory, and makes recommendations for practice

A duplication at chromosome 11q12.2–11q12.3 is associated with spinocerebellar ataxia type 20

Spinocerebellar ataxia type 20 (SCA20) has been linked to chromosome 11q12, but the underlying genetic defect has yet to be identified. We applied single-nucleotide polymorphism genotyping to detect structural alterations in the genomic DNA of patients with SCA20. We found a 260 kb duplication within the previously linked SCA20 region, which was confirmed by quantitative polymerase chain reaction and fiber fluorescence in situ hybridization, the latter also showing its direct orientation. The duplication spans 10 known and 2 unknown genes, and is present in all affected individuals in the single reported SCA20 pedigree. While the mechanism whereby this duplication may be pathogenic remains to be established, we speculate that the critical gene within the duplicated segment may be DAGLA, the product of which is normally present at the base of Purkinje cell dendritic spines and contributes to the modulation of parallel fiber-Purkinje cell synapses