Dampening Spontaneous Activity Improves the Light Sensitivity and Spatial Acuity of Optogenetic Retinal Prosthetic Responses

Retinitis pigmentosa is a progressive retinal dystrophy that causes irreversible visual impairment and blindness. Retinal prostheses currently represent the only clinically available vision-restoring treatment, but the quality of vision returned remains poor. Recently, it has been suggested that the pathological spontaneous hyperactivity present in dystrophic retinas may contribute to the poor quality of vision returned by retinal prosthetics by reducing the signal-to-noise ratio of prosthetic responses. Here, we investigated to what extent blocking this hyperactivity can improve optogenetic retinal prosthetic responses. We recorded activity from channelrhodopsin-expressing retinal ganglion cells in retinal wholemounts in a mouse model of retinitis pigmentosa. Sophisticated stimuli, inspired by those used in clinical visual assessment, were used to assess light sensitivity, contrast sensitivity and spatial acuity of optogenetic responses; in all cases these were improved after blocking spontaneous hyperactivity using meclofenamic acid, a gap junction blocker. Our results suggest that this approach significantly improves the quality of vision returned by retinal prosthetics, paving the way to novel clinical applications. Moreover, the improvements in sensitivity achieved by blocking spontaneous hyperactivity may extend the dynamic range of optogenetic retinal prostheses, allowing them to be used at lower light intensities such as those encountered in everyday life

A note on area variables in Regge calculus

We consider the possibility of setting up a new version of Regge calculus in four dimensions with areas of triangles as the basic variables rather than the edge-lengths. The difficulties and restrictions of this approach are discussed.Comment: 4 pages, amstex. Revision has minor changes and more precise conclusion

Information transmission in normal vision and optogenetically resensitised dystrophic retinas

Phd ThesisThe retina is a sophisticated image processing machine, transforming the visual scene as detected by the photoreceptors into a pattern of action potentials that is sent to the brain by the retinal ganglion cells (RGCs), where it is further processed to help us understand and navigate the world. Understanding this encoding process is important on a number of levels. First, it informs the study of upstream visual processing by elucidating the signals higher visual areas receive as input and how they relate to the outside world. Second, it is important for the development of treatments for retinal blindness, such as retinal prosthetics. In this thesis, I present work using multielectrode array (MEA) recordings of RGC populations from ex-vivo retinal wholemounts to study various aspects of retinal information processing. My results fall into two main themes. In the rst part, in collaboration with Dr Geo rey Portelli and Dr Pierre Kornprobst of INRIA, I use ashed gratings of varying spatial frequency and phase to compare di erent coding strategies that the retina might use. These results show that information is encoded synergistically by pairs of neurons and that, of the codes tested, a Rank Order Code based on the relative order of ring of the rst spikes of a population of neurons following a stimulus provides information about the stimulus faster and more e ciently than other codes. In the later parts, I use optogenetic stimulation of RGCs in congenitally blind retinas to study how visual information is corrupted by the spontaneous hyperactivity that arises as a result of photoreceptor degeneration. I show that by dampening this activity with the gap junction blocker meclofenamic acid, I can improve the signal-to-noise ratio, spatial acuity and contrast sensitivity of prosthetically evoked responses. Taken together, this work provides important insights for the future development of retinal prostheses

Bodies, Representations, Situations, Practices: qualitative research on affect, emotion and feeling

We introduce this special issue of Qualitative Research in Psychology by discussing four themes which, in our view, characterise the collective significance of the papers in this special issue. Even in highlighting these thematic similarities, however, we point to important differences in their manifestation across different papers. In discussing bodies, we highlight an underexplored distinction between the body as ground of experience and the body as the enabler of experience. We also draw attention to three issues relating to (linguistic) representations of feelings, emotions and affect: the problem of ineffability; the role of naming feeling; and how to methodologically and analytically account for differences in the ways that feelings are talked about and named. Regarding situatedness in space and time, we note at least four analytical positions, which frame and reveal different aspects of affective phenomena. Finally, with respect to affective practices we identify two quite different approaches that, whilst sharing some characteristics, are different enough to warrant further specification when researchers deploy this term. Whilst welcoming the apparent trend away from purely language-based methods, we also offer some suggestions for how researchers can move further down this path. Nonetheless qualitative research on feeling, affect and emotion is in fine fettle. As the contributions attest, the time is ripe for this special issue of Qualitative Research in Psychology

Association of FCGR2A and FCGR2A-FCGR3A haplotypes with susceptibility to giant cell arteritis

The Fc gamma receptors have been shown to play important roles in the initiation and regulation of many immunological and inflammatory processes and to amplify and refine the immune response to an infection. We have investigated the hypothesis that polymorphism within the FCGR genetic locus is associated with giant cell arteritis (GCA). Biallelic polymorphisms in FCGR2A, FCGR3A, FCGR3B and FCGR2B were examined for association with biopsy-proven GCA (n = 85) and healthy ethnically matched controls (n = 132) in a well-characterised cohort from Lugo, Spain. Haplotype frequencies and linkage disequilibrium (D') were estimated across the FCGR locus and a model-free analysis performed to determine association with GCA. There was a significant association between FCGR2A-131RR homozygosity (odds ratio (OR) 2.10, 95% confidence interval (CI) 1.12 to 3.77, P = 0.02, compared with all others) and carriage of FCGR3A-158F (OR 3.09, 95% CI 1.10 to 8.64, P = 0.03, compared with non-carriers) with susceptibility to GCA. FCGR haplotypes were examined to refine the extent of the association. The haplotype showing the strongest association with GCA susceptibility was the FCGR2A-FCGR3A 131R-158F haplotype (OR 2.84, P = 0.01 for homozygotes compared with all others). There was evidence of a multiplicative joint effect between homozygosity for FCGR2A-131R and HLA-DRB1*04 positivity, consistent with both of these two genetic factors contributing to the risk of disease. The risk of GCA in HLA-DRB1*04 positive individuals homozygous for the FCGR2A-131R allele is increased almost six-fold compared with those with other FCGR2A genotypes who are HLA-DRB1*04 negative. We have demonstrated that FCGR2A may contribute to the 'susceptibility' of GCA in this Spanish population. The increased association observed with a FCGR2A-FCGR3A haplotype suggests the presence of additional genetic polymorphisms in linkage disequilibrium with this haplotype that may contribute to disease susceptibility. These findings may ultimately provide new insights into disease pathogenesis

Reversible Resistance Induced by FLT3 Inhibition: A Novel Resistance Mechanism in Mutant FLT3-Expressing Cells

Clinical responses achieved with FLT3 kinase inhibitors in acute myeloid leukemia (AML) are typically transient and partial. Thus, there is a need for identification of molecular mechanisms of clinical resistance to these drugs. In response, we characterized MOLM13 AML cell lines made resistant to two structurally-independent FLT3 inhibitors.MOLM13 cells were made drug resistant via prolonged exposure to midostaurin and HG-7-85-01, respectively. Cell proliferation was determined by Trypan blue exclusion. Protein expression was assessed by immunoblotting, immunoprecipitation, and flow cytometry. Cycloheximide was used to determine protein half-life. RT-PCR was performed to determine FLT3 mRNA levels, and FISH analysis was performed to determine FLT3 gene expression.We found that MOLM13 cells readily developed cross-resistance when exposed to either midostaurin or HG-7-85-01. Resistance in both lines was associated with dramatically elevated levels of cell surface FLT3 and elevated levels of phosphor-MAPK, but not phospho-STAT5. The increase in FLT3-ITD expression was at least in part due to reduced turnover of the receptor, with prolonged half-life. Importantly, the drug-resistant phenotype could be rapidly reversed upon withdrawal of either inhibitor. Consistent with this phenotype, no significant evidence of FLT3 gene amplification, kinase domain mutations, or elevated levels of mRNA was observed, suggesting that protein turnover may be part of an auto-regulatory pathway initiated by FLT3 kinase activity. Interestingly, FLT3 inhibitor resistance also correlated with resistance to cytosine arabinoside. Over-expression of FLT3 protein in response to kinase inhibitors may be part of a novel mechanism that could contribute to clinical resistance

Kassiopeia: A Modern, Extensible C++ Particle Tracking Package

The Kassiopeia particle tracking framework is an object-oriented software package using modern C++ techniques, written originally to meet the needs of the KATRIN collaboration. Kassiopeia features a new algorithmic paradigm for particle tracking simulations which targets experiments containing complex geometries and electromagnetic fields, with high priority put on calculation efficiency, customizability, extensibility, and ease of use for novice programmers. To solve Kassiopeia's target physics problem the software is capable of simulating particle trajectories governed by arbitrarily complex differential equations of motion, continuous physics processes that may in part be modeled as terms perturbing that equation of motion, stochastic processes that occur in flight such as bulk scattering and decay, and stochastic surface processes occuring at interfaces, including transmission and reflection effects. This entire set of computations takes place against the backdrop of a rich geometry package which serves a variety of roles, including initialization of electromagnetic field simulations and the support of state-dependent algorithm-swapping and behavioral changes as a particle's state evolves. Thanks to the very general approach taken by Kassiopeia it can be used by other experiments facing similar challenges when calculating particle trajectories in electromagnetic fields. It is publicly available at https://github.com/KATRIN-Experiment/Kassiopei

In their own voice: the role of the Shape of the Australian Curriculum: The Arts paper writers in ensuring equitable access to quality Arts education in Australia

This paper examines the personal and professional experiences of the five arts leaders who co-wrote the foundation document for Australia’s first national curriculum in the Arts. Their personal and professional backgrounds, which were explored during in depth interviews, drove the complex collaborative process that informed the first iteration of the Australian Curriculum: The Arts. Though each couched their responses in the context of their background and arts discipline, they shared an awareness of the important role of the Arts in providing the analytical tools for children and young people to identify and subsequently challenge social injustice. The findings, which are presented as a group narrative using a Narrative Inquiry approach, reveal how the five arts leaders’ individual lived experience, disciplinary experience and expertise, and commitment to collaborative leadership informed their approach. It was one driven by their shared belief that all Australian students, regardless of their background, are entitled to a quality arts education

V344 Lyrae: A Touchstone SU UMa Cataclysmic Variable in the Kepler Field

We report on the analysis of the Kepler short-cadence (SC) light curve of V344 Lyr obtained during 2009 June 20 through 2010 Mar 19 (Q2--Q4). The system is an SU UMa star showing dwarf nova outbursts and superoutbursts, and promises to be a touchstone for CV studies for the foreseeable future. The system displays both positive and negative superhumps with periods of 2.20 and 2.06-hr, respectively, and we identify an orbital period of 2.11-hr. The positive superhumps have a maximum amplitude of ~0.25-mag, the negative superhumps a maximum amplitude of ~0.8 mag, and the orbital period at quiescence has an amplitude of ~0.025 mag. The quality of the Kepler data is such that we can test vigorously the models for accretion disk dynamics that have been emerging in the past several years. The SC data for V344 Lyr are consistent with the model that two physical sources yield positive superhumps: early in the superoutburst, the superhump signal is generated by viscous dissipation within the periodically flexing disk, but late in the superoutburst, the signal is generated as the accretion stream bright spot sweeps around the rim of the non-axisymmetric disk. The disk superhumps are roughly anti-phased with the stream/late superhumps. The V344 Lyr data also reveal negative superhumps arising from accretion onto a tilted disk precessing in the retrograde direction, and suggest that negative superhumps may appear during the decline of DN outbursts. The period of negative superhumps has a positive dP/dt in between outbursts.Comment: ApJ, In Press (20 pages, 27 figures) A version with full-resolution figures is available at http://www.astro.fit.edu/wood/WoodV344.pd

Sheep Updates 2007 - part 3

This session covers seven papers from different authors: PROFITABILITY 1. Benchmarking demonstrates both the potential and realised productivity gains in the sheep and wool industry, Andrew Ritchie, Edward Riggall and James Hall, ICON Agriculture, Darkan 2. Improving sheep genetics will increase farm profitability, Gus Rose, Johan Greeff Department of Agriculture and Food Western Australia, John Young Farming Systems Analysis Service, WA 3. Meat, Merinos and making money in WA Pastoral Zone, M. Alchin, M. Young and T. Johnson, Department of Agriculture and Food Western Australia, GRAZING 4. Nitrogen - farmers\u27 friend or foe? John Lucy and Martin Staines, Department of Agriculture and Food Western Australia 5. Drought proofing grazing systems - a case study from Binnu 2006/7, Tim Wiley & Rob Grima, Department of Agriculture & Food Western Australia 6. Minimising \u27Esperance Storm\u27 livestock losses, Sandra Prosser and Matt Ryan, Department of Agriculture and Food Western Australia 7. Sub-tropical grasses in WA - what is their potential? Geoff Moore, Tony Albertsen, Department of Agriculture & Food Western Australia, Phil Barrett-Lennard, Evergreen Farming, George Woolston, John Titterington, Department of Agriculture and Food Western Australia, Sarah Knight, Irwin-Mingenew Group, Brianna Peake, Liebe Group, Buntine, W