Viral delivery of antioxidant genes as a therapeutic strategy in experimental models of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with no effective treatment to date. Despite its multi-factorial aetiology, oxidative stress is hypothesized to be one of the key pathogenic mechanisms. It is thus proposed that manipulation of the expression of antioxidant genes that are downregulated in the presence of mutant SOD1 may serve as a therapeutic strategy for motor neuronal protection. Lentiviral vectors expressing either PRDX3 or NRF2 genes were tested in the motor neuronal-like NSC34 cell line, and in the ALS tissue culture model, NSC34 cells expressing the human SOD1(G93A) mutation. The NSC34 SOD1(G93A) cells overexpressing either PRDX3 or NRF2 showed a significant decrease in endogenous oxidation stress levels by 40 and 50% respectively compared with controls, whereas cell survival was increased by 30% in both cases. The neuroprotective potential of those two genes was further investigated in vivo in the SOD1(G93A) ALS mouse model, by administering intramuscular injections of adenoassociated virus serotype 6 (AAV6) expressing either of the target genes at a presymptomatic stage. Despite the absence of a significant effect in survival, disease onset or progression, which can be explained by the inefficient viral delivery, the promising in vitro data suggest that a more widespread CNS delivery is needed

The Impact of Accretion Disk Winds on the Optical Spectra of Cataclysmic Variables

Many high-state non-magnetic cataclysmic variables (CVs) exhibit blue-shifted absorption or P-Cygni profiles associated with ultraviolet (UV) resonance lines. These features imply the existence of powerful accretion disk winds in CVs. Here, we use our Monte Carlo ionization and radiative transfer code to investigate whether disk wind models that produce realistic UV line profiles are also likely to generate observationally significant recombination line and continuum emission in the optical waveband. We also test whether outflows may be responsible for the single-peaked emission line profiles often seen in high-state CVs and for the weakness of the Balmer absorption edge (relative to simple models of optically thick accretion disks). We find that a standard disk wind model that is successful in reproducing the UV spectra of CVs also leaves a noticeable imprint on the optical spectrum, particularly for systems viewed at high inclination. The strongest optical wind-formed recombination lines are H$\alpha$ and He II $\lambda4686$. We demonstrate that a higher-density outflow model produces all the expected H and He lines and produces a recombination continuum that can fill in the Balmer jump at high inclinations. This model displays reasonable verisimilitude with the optical spectrum of RW Trianguli. No single-peaked emission is seen, although we observe a narrowing of the double-peaked emission lines from the base of the wind. Finally, we show that even denser models can produce a single-peaked H$\alpha$ line. On the basis of our results, we suggest that winds can modify, and perhaps even dominate, the line and continuum emission from CVs.Comment: 15 pages, 13 figures. Accepted to MNRA

Line-driven Disk Winds in Active Galactic Nuclei: The Critical Importance of Ionization and Radiative Transfer

Accretion disk winds are thought to produce many of the characteristic features seen in the spectra of active galactic nuclei (AGN) and quasi-stellar objects (QSOs). These outflows also represent a natural form of feedback between the central supermassive black hole and its host galaxy. The mechanism for driving this mass loss remains unknown, although radiation pressure mediated by spectral lines is a leading candidate. Here, we calculate the ionization state of, and emergent spectra for, the hydrodynamic simulation of a line-driven disk wind previously presented by Proga & Kallman (2004). To achieve this, we carry out a comprehensive Monte Carlo simulation of the radiative transfer through, and energy exchange within, the predicted outflow. We find that the wind is much more ionized than originally estimated. This is in part because it is much more difficult to shield any wind regions effectively when the outflow itself is allowed to reprocess and redirect ionizing photons. As a result, the calculated spectrum that would be observed from this particular outflow solution would not contain the ultraviolet spectral lines that are observed in many AGN/QSOs. Furthermore, the wind is so highly ionized that line-driving would not actually be efficient. This does not necessarily mean that line-driven winds are not viable. However, our work does illustrate that in order to arrive at a self-consistent model of line-driven disk winds in AGN/QSO, it will be critical to include a more detailed treatment of radiative transfer and ionization in the next generation of hydrodynamic simulations.Comment: 13 pages, 10 figures - Accepted for publication in Ap

The reverberation signatures of rotating disc winds in active galactic nuclei

The broad emission lines (BELs) in active galactic nuclei (AGN) respond to ionizing continuum variations. The time and velocity dependence of their response depends on the structure of the broad-line region: its geometry, kinematics and ionization state. Here, we predict the reverberation signatures of BELs formed in rotating accretion disc winds. We use a Monte Carlo radiative transfer and ionization code to predict velocity-delay maps for representative high- (C$~IV$) and low-ionization (H$\alpha$) emission lines in both high- and moderate-luminosity AGN. Self-shielding, multiple scattering and the ionization structure of the outflows are all self-consistently taken into account, while small-scale structure in the outflow is modelled in the micro-clumping approximation. Our main findings are: (1) The velocity-delay maps of smooth/micro-clumped outflows often contain significant negative responses. (2)~The reverberation signatures of disc wind models tend to be rotation dominated and can even resemble the classic "red-leads-blue" inflow signature. (3) Traditional "blue-leads-red" outflow signatures can usually only be observed in the long-delay limit. (4) Our models predict lag-luminosity relationships similar to those inferred from observations, but systematically underpredict the observed centroid delays. (5) The ratio between "virial product" and black hole mass predicted by our models depends on viewing angle. Our results imply that considerable care needs to be taken in interpreting data obtained by observational reverberation mapping campaigns. In particular, basic signatures such as "red-leads-blue", "blue-leads-red" and "blue and red vary jointly" are not always reliable indicators of inflow, outflow or rotation. This may help to explain the perplexing diversity of such signatures seen in observational campaigns to date.Comment: 15 pages, 17 figures, 2 tables. Accepted by MNRAS 20/7/201

Patient and public involvement and engagement in a doctoral research project exploring self-harm in older adults

Background: The contribution of involving patients and public in health research is widely reported, particularly within mental health research. Less is written about such contributions to doctoral research. The research focus of this doctoral research, self-harm in older adults, was put forward by a Patient Public Involvement Engagement (PPIE) group, who contributed to its development. Aims: Critically reflect on the process, potential impact and identify challenges and opportunities in involving robust PPIE in a doctoral study. Methods: Three PPIE members contributed to a systematic review (SR) and a qualitative study through a series of four workshops to meet the aims of the study. PPIE contributed to developing the SR review questions, protocol, data analysis and dissemination of findings. For the qualitative study, they helped develop research questions, protocol, public-facing documentation, recruitment strategies and data analysis. Involvement followed the GRIPP2-SF reporting checklist. Results: PPIE enhanced methodological rigour, data analysis, interpretation and dissemination of findings. Challenges included lack of ethical guidance, time-related pressures and ensuring support for PPIE members. These were successfully managed through ongoing dialogue and regular communication. Conclusions: PPIE can enhance the quality and depth of doctoral research, as lived experiences shared by PPIE members add to research's components. Exposing early-career researchers to PPIE can build research cultures sensitive to PPIE's potential contribution and develop the expertise needed to avoid tokenistic involvement. Capturing lay perspectives is essential in mental health research to ensure research findings are accessible and that findings inform clinical practice. However, clear guidance on the ethical dimensions to PPIE is needed

High-resolution wetness index mapping: A useful tool for regional scale wetland management

Wetland ecosystems are key habitats for carbon sequestration, biodiversity and ecosystem services, yet in many they localities have been subject to modification or damage. In recent years, there has been increasing focus on effective management and, where possible, restoration of wetlands. Whilst this is highly laudable, practical implementation is limited by the high costs and unpredictable rates of success. Accordingly, there is a need for spatial information to guide restoration, ideally at the regional scale that land managers operate. In this study, we use high-resolution Light Detection and Ranging (LiDAR)-derived elevation, in conjunction with regional soil and land cover maps, to model the wetness potential of an area of conservation importance in north-west England. We use the Compound Topographic Index (CTI) as a measure for the site-specific wetness and potential to be receptive to wetland restoration. The resulting model is in agreement with the regional-scale distribution of wetlands and is clearly influenced by the topographic and soil parameters. An assessment of three representative case studies highlights the small scale features that determine the potential wetness of an area. For each site, the model results conform to the expected patterns of wetness, highlighting restoration and management activity. Furthermore, areas showing high potential wetness that may be suitable for wetland habitat creation, are highlighted. The increasing availability of LiDAR data at regional and national scales will allow studies of this nature to be undertaken at previously unobtainable resolutions. Simple models, such as implemented here, benefit from explainability and relatability and have clear potential for use by managers and conservation agencies involved in wetland restoration

Contributions of Non-consumptive Wildlife Tourism to Conservation

Wildlife tourism has the potential to contribute to conservation through a variety of mechanisms. This chapter presents a preliminary assessment of the extent to which this potential is currently being realised, comparing tourism based on viewing of animals in captive settings (with a focus on federated zoos) with that in free-ranging situations (wildlife watching). The key mechanisms involved are: direct wildlife management and research; use of income derived from wildlife tourism to fund conservation; education of visitors to behave in a more conservation-friendly manner; political lobbying in support of conservation; and provision of a socio-economic incentive for conservation. All of these occur in at least some zoos and wildlife-watching situations, and collectively the contribution of non-consumptive wildlife tourism to conservation is significant, though impossible to quantify. The key strengths of the zoo sector in this regard are its inputs into captive breeding and its potential to educate large numbers of people. in contrast, wildlife watching provides significant socio-economic incentives for conservation of natural habitats. There seem to be significant opportunities for expanding the role of non-consumptive wildlife tourism in conservation