Neurotrophin gene augmentation by electrotransfer to improve cochlear implant hearing outcomes

This Review outlines the development of DNA-based therapeutics for treatment of hearing loss, and in particular, considers the potential to utilize the properties of recombinant neurotrophins to improve cochlear auditory (spiral ganglion) neuron survival and repair. This potential to reduce spiral ganglion neuron death and indeed re-grow the auditory nerve fibres has been the subject of considerable pre-clinical evaluation over decades with the view of improving the neural interface with cochlear implants. This provides the context for discussion about the development of a novel means of using cochlear implant electrode arrays for gene electrotransfer. Mesenchymal cells which line the cochlear perilymphatic compartment can be selectively transfected with (naked) plasmid DNA using array - based gene electrotransfer, termed ‘close-field electroporation’. This technology is able to drive expression of brain derived neurotrophic factor (BDNF) in the deafened guinea pig model, causing re-growth of the spiral ganglion peripheral neurites towards the mesenchymla cells, and hence into close proximity with cochlear implant electrodes within scala tympani. This was associated with functional enhancement of the cochlear implant neural interface (lower neural recruitment thresholds and expanded dynamic range, measured using electrically - evoked auditory brainstem responses). The basis for the efficiency of close-field electroporation arises from the compression of the electric field in proximity to the ganged cochlear implant electrodes. The regions close to the array with highest field strength corresponded closely to the distribution of bioreporter cells (adherent human embryonic kidney (HEK293)) expressing green fluorescent reporter protein (GFP) following gene electrotransfer. The optimization of the gene electrotransfer parameters using this cell-based model correlated closely with in vitro and in vivo cochlear gene delivery outcomes. The migration of the cochlear implant electrode array-based gene electrotransfer platform towards a clinical trial for neurotrophin-based enhancement of cochlear implants is supported by availability of a novel regulatory compliant mini-plasmid DNA backbone (pFAR4; plasmid Free of Antibiotic Resistance v.4) which could be used to package a ‘humanized’ neurotrophin expression cassette. A reporter cassette packaged into pFAR4 produced prominent GFP expression in the guinea pig basal turn perilymphatic scalae. More broadly, close-field gene electrotransfer may lend itself to a spectrum of potential DNA therapeutics applications benefitting from titratable, localised, delivery of naked DNA, for gene augmentation, targeted gene regulation, or gene substitution strategies

The influence of interactions with students for the development of new academics as teachers in higher education

The aim of the current investigation was to provide an insight into how new lecturers in higher education develop as teachers and to identify some of the main influences upon this development. A qualitative, longitudinal design with three semi-structured interviews over a 2-year period was employed with eleven new teachers from a range of higher education institutions and settings. The analysis used case studies, alongside a thematic analysis, to provide fine-grained and idiosyncratic insights into the teachers’ development. The principal finding from the current study was the identification that instances of interactions with students, acted as a core influence upon the new teachers’ development. These instances appeared to provide the teachers with richer and fuller feedback about their teaching. This feedback supported their reflection and influenced the way in which they thought about teaching. Based on these findings it is suggested that teacher development could be enhanced by focussing upon specific instances of interactions with students as these instances provide specific and tangible moments that allow individuals to reflect upon and discuss their conceptions of teaching

Estimating and Modelling Bias of the Hierarchical Partitioning Public-Domain Software: Implications in Environmental Management and Conservation

BACKGROUND: Hierarchical partitioning (HP) is an analytical method of multiple regression that identifies the most likely causal factors while alleviating multicollinearity problems. Its use is increasing in ecology and conservation by its usefulness for complementing multiple regression analysis. A public-domain software "hier.part package" has been developed for running HP in R software. Its authors highlight a "minor rounding error" for hierarchies constructed from >9 variables, however potential bias by using this module has not yet been examined. Knowing this bias is pivotal because, for example, the ranking obtained in HP is being used as a criterion for establishing priorities of conservation. METHODOLOGY/PRINCIPAL FINDINGS: Using numerical simulations and two real examples, we assessed the robustness of this HP module in relation to the order the variables have in the analysis. Results indicated a considerable effect of the variable order on the amount of independent variance explained by predictors for models with >9 explanatory variables. For these models the nominal ranking of importance of the predictors changed with variable order, i.e. predictors declared important by its contribution in explaining the response variable frequently changed to be either most or less important with other variable orders. The probability of changing position of a variable was best explained by the difference in independent explanatory power between that variable and the previous one in the nominal ranking of importance. The lesser is this difference, the more likely is the change of position. CONCLUSIONS/SIGNIFICANCE: HP should be applied with caution when more than 9 explanatory variables are used to know ranking of covariate importance. The explained variance is not a useful parameter to use in models with more than 9 independent variables. The inconsistency in the results obtained by HP should be considered in future studies as well as in those already published. Some recommendations to improve the analysis with this HP module are given

The exceptional value of intact forest ecosystems

As the terrestrial human footprint continues to expand, the amount of native forest that is free from significant damaging human activities is in precipitous decline. There is emerging evidence that the remaining intact forest supports an exceptional confluence of globally significant environmental values relative to degraded forests, including imperilled biodiversity, carbon sequestration and storage, water provision, indigenous culture and the maintenance of human health. Here we argue that maintaining and, where possible, restoring the integrity of dwindling intact forests is an urgent priority for current global efforts to halt the ongoing biodiversity crisis, slow rapid climate change and achieve sustainability goals. Retaining the integrity of intact forest ecosystems should be a central component of proactive global and national environmental strategies, alongside current efforts aimed at halting deforestation and promoting reforestation

Post-doctoral research fellowship as a health policy and systems research capacity development intervention: a case of the CHESAI initiative

BACKGROUND: Building capacity in health policy and systems research (HPSR), especially in low- and middle-income countries, remains a challenge. Various approaches have been suggested and implemented by scholars and institutions using various forms of capacity building to address challenges regarding HPSR development. The Collaboration for Health Systems Analysis and Innovation (CHESAI) – a collaborative effort between the Universities of Cape Town and the Western Cape Schools of Public Health – has employed a non-research based post-doctoral research fellowship (PDRF) as a way of building African capacity in the field of HPSR by recruiting four post-docs. In this paper, we (the four post-docs) explore whether a PDRF is a useful approach for capacity building for the field of HPSR using our CHESAI PDRF experiences. METHODS: We used personal reflections of our written narratives providing detailed information regarding our engagement with CHESAI. The narratives were based on a question guide around our experiences through various activities and their impacts on our professional development. The data analysis process was highly iterative in nature, involving repeated meetings among the four post-docs to reflect, discuss and create themes that evolved from the discussions. RESULTS: The CHESAI PDRF provided multiple spaces for our engagement and capacity development in the field of HPSR. These spaces provided us with a wide range of learning experiences, including teaching and research, policy networking, skills for academic writing, engaging practitioners, co-production and community dialogue. Our reflections suggest that institutions providing PDRF such as this are valuable if they provide environments endowed with adequate resources, good leadership and spaces for innovation. Further, the PDRFs need to be grounded in a community of HPSR practice, and provide opportunities for the post-docs to gain an in-depth understanding of the broader theoretical and methodological underpinnings of the field. CONCLUSION: The study concludes that PDRF is a useful approach to capacity building in HPSR, but it needs be embedded in a community of practice for fellows to benefit. More academic institutions in Africa need to adopt innovative and flexible support for emerging leaders, researchers and practitioners to strengthen our health systemsIS

A Neuron-Glial Perspective for Computational Neuroscience

International audienceThere is growing excitement around glial cells, as compelling evidence point to new, previously unimaginable roles for these cells in information processing of the brain, with the potential to affect behavior and higher cognitive functions. Among their many possible functions, glial cells could be involved in practically every aspect of the brain physiology in health and disease. As a result, many investigators in the field welcome the notion of a Neuron-Glial paradigm of brain function, as opposed to Ramon y Cayal's more classical neuronal doctrine which identifies neurons as the prominent, if not the only, cells capable of a signaling role in the brain. The demonstration of a brain-wide Neuron-Glial paradigm however remains elusive and so does the notion of what neuron-glial interactions could be functionally relevant for the brain computational tasks. In this perspective, we present a selection of arguments inspired by available experimental and modeling studies with the aim to provide a biophysical and conceptual platform to computational neuroscience no longer as a mere prerogative of neuronal signaling but rather as the outcome of a complex interaction between neurons and glial cells

The microbiome mediates epiphyseal bone loss and metabolomic changes after acute joint trauma in mice

ObjectiveTo compare the early responses to joint injury in conventional and germ-free mice.DesignPost-traumatic osteoarthritis (PTOA) was induced using a non-invasive anterior cruciate ligament rupture model in 20-week old germ-free (GF) and conventional C57BL/6 mice. Injury was induced in the left knees of n = 8 GF and n = 10 conventional mice. To examine the effects of injury, n = 5 GF and n = 9 conventional naïve control mice were used. Mice were euthanized 7 days post-injury, followed by synovial fluid recovery for global metabolomic profiling and analysis of epiphyseal trabecular bone by micro-computed tomography (μCT). Global metabolomic profiling assessed metabolic differences in the joint response to injury between GF and conventional mice. Magnitude of trabecular bone volume loss measured using μCT assessed early OA progression in GF and conventional mice.ResultsμCT found that GF mice had significantly less trabecular bone loss compared to conventional mice, indicating that the GF status was protective against early OA changes in bone structure. Global metabolomic profiling showed that conventional mice had greater variability in their metabolic response to injury, and a more distinct joint metabolome compared to their corresponding controls. Furthermore, differences in the response to injury in GF compared to conventional mice were linked to mouse metabolic pathways that regulate inflammation associated with the innate immune system.ConclusionsThese results suggest that the gut microbiota promote the development of PTOA during the acute phase following joint trauma possibly through the regulation of the innate immune system