The Role of Variation at AβPP, PSEN1, PSEN2, and MAPT in Late Onset Alzheimer's Disease

Rare mutations in AßPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AßPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.

Genome-wide association study of Alzheimer's disease with psychotic symptoms

Psychotic symptoms occur in ~40% of subjects with Alzheimer's disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWASs) to identify loci that (1) increase susceptibility to an AD and subsequent psychotic symptoms; or (2) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. In all, 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls were drawn from Genetic and Environmental Risk in AD Consortium 1 (GERAD1), the National Institute on Aging Late-Onset Alzheimer's Disease (NIA-LOAD) family study and the University of Pittsburgh Alzheimer Disease Research Center (ADRC) GWASs. Unobserved genotypes were imputed to provide data on >1.8 million single-nucleotide polymorphisms (SNPs). Analyses in each data set were completed comparing (1) AD+P to AD-P cases, and (2) AD+P cases with controls (GERAD1, ADRC only). Aside from the apolipoprotein E (APOE) locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; 'AD+PvAD-P' P=2.85 × 10(-7); 'AD+PvControls' P=1.11 × 10(-4)). SNPs upstream of SLC2A9 (rs6834555, P=3.0 × 10(-7)) and within VSNL1 (rs4038131, P=5.9 × 10(-7)) showed strongest evidence for association with AD+P when compared with controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterized.Molecular Psychiatry advance online publication, 18 October 2011; doi:10.1038/mp.2011.125.

Merula

Merula is a thirty-minute work for bass flute and electronics, commissioned by Icelandic flautist Kolbeinn Bjarnason. The premiere took place in the Belfast Festival at Queen’s in November 2012. A recording will be made in 2014. Further performances in Iceland, Norway and Poland are anticipated in 2014-15. I have given a research seminar on this work at Queen’s and will deliver it again at the University of Oxford during 2013-14.

Research Goals
1) To develop an effective means of notating live electronics in a manner that would sustain the work's performance history beyond the current generation of software
2) To apply the techniques of transcription and spectralism used in my composition, Perseid, using birdsongs as source material
3) To explore the problem of sustaining large-scale form in music that is primarily fast
4) To facilitate the emergence of the solo bass flute as an important solo instrument through the completion of a new large-scale work

Methodology
• Methodologies employed in this project included sound recording, sound analysis and transcription, extensive precompositional sketching, electroacoustic techniques of sound manipulation, designing complex live processes of sound transformation and spatialisation
• A considerable part of this work was collaboration with the flautist, both in SARC and Iceland. Mr. Bjarnason was involved all stages of the work, frequently recording source materials and helping to ensure the idiomatic nature of the flute writing.
• Developing a means of notating the live electronics. Building on a model suggested by Pierre Boulez in Anthemes 2 (1998), the score of this work includes a technical manual that describes electronic processes in a manner that can be reprogrammed in subsequent generations of software. Combined with a system of notations employed in the full score, the technical manual will enable this composition to be performed by a wide range of performers and technical teams, with appropriately identical results.

Biomonitoring aquatic environmental quality in a marine protected area: A biomarker approach

The main aims of the present study, conducted in the framework of the MONIQUA-Egadi Scientific Project, were twofold: first, to make the first step in the development and validation of an ecotoxicological approach for the assessment of marine pollution in coastal environments on the basis of a set of biomarker responses in new sentinel species; and second, to obtain preliminary information on environmental quality in an Italian marine protected area, the Egadi Islands (Sicily). Several cytochrome P450-dependent mixed-function oxidase activities were measured in the following sentinel species: rainbow wrasse Coris julis, gastropod limpet Patella caerulea, and sea urchin Paracentrotus lividus. The results suggest that specimens from the Favignana Harbor may be exposed to P450 inducers, whereas most of the other sites seem to share similar environmental quality. The proposed approach has potential for assessment of environmental quality in marine protected areas.

Dark Mission

Composition for bass clarinet and computer

Effects of oscillatory flow on fertilization in the green sea urchin Strongylocentrotus droebachiensis

Broadcast spawning invertebrates that live in shallow, high-energy coastal habitats are subjected to oscillatory water motion that creates unsteady flow fields above the surface of animals. The frequency of the oscillatory fluctuations is driven by the wave period, which will influence the stability of local flow structures and may affect fertilization processes. Using an oscillatory water tunnel, we quantified the percentage of eggs fertilized on or near spawning green sea urchins, Strongylocentrotus droebachiensis. Eggs were sampled in the water column, wake eddy, substratum and aboral surface under a range of different periods (T = 4.5 – 12.7 s) and velocities of oscillatory flow. The root-mean-square wave velocity (rms(uw)) was a good predictor of fertilization in oscillatory flow, although the root-mean-square of total velocity (rms(u)), which incorporates all the components of flow (current, wave and turbulence), also provided significant predictions. The percentage of eggs fertilized varied between 50 – 85% at low flows (rms(uw) < 0.02 m s-1), depending on the location sampled, but declined to below 10% for most locations at higher rms(uw). The water column was an important location for fertilization with a relative contribution greater than that of the aboral surface, especially at medium and high rms(uw) categories. We conclude that gametes can be successfully fertilized on or near the parent under a range of oscillatory flow conditions.

Existing and emerging high impact invasive species are characterized by higher functional responses than natives

Predicting ecological impacts of invasive species and identifying potentially damaging future invaders are research priorities. Since damage by invaders is characterized by their depletion of resources, comparisons of the ‘functional response’ (FR; resource uptake rate as a function of resource density) of invaders and natives might predict invader impact. We tested this by comparing FRs of the ecologically damaging ‘world's worst’ invasive fish, the largemouth bass (Micropterus salmoides), with a native equivalent, the Cape kurper (Sandelia capensis), and an emerging invader, the sharptooth catfish (Clarias gariepinus), with the native river goby (Glossogobius callidus), in South Africa, a global invasion hotspot. Using tadpoles (Hyperolius marmoratus) as prey, we found that the invaders consumed significantly more than natives. Attack rates at low prey densities within invader/native comparisons reflected similarities in predatory strategies; however, both invasive species displayed significantly higher Type II FRs than the native comparators. This was driven by significantly lower prey handling times by invaders, resulting in significantly higher maximum feeding rates. The higher FRs of these invaders are thus congruent with, and can predict, their impacts on native communities. Comparative FRs may be a rapid and reliable method for predicting ecological impacts of emerging and future invasive species.

Relative Effects of Gamete Compatibility and Hydrodynamics on Fertilization in the Green Sea Urchin Strongylocentrotus droebachiensis

Intraspecific variation in gamete compatibility among male/female pairs causes variation in the concentration of sperm required to achieve equivalent fertilization levels. Gamete compatibility is therefore potentially an important factor controlling mating success. Many broadcast-spawning marine invertebrates, however, also live in a dynamic environment where hydrodynamic conditions can affect the concentration of sperm reaching eggs during spawning. Thus flow conditions may moderate the effects of gamete compatibility on fertilization. Using the green sea urchin Strongylocentrotus droebachiensis as a model system, we assessed the relative effects of gamete compatibility (the concentration of sperm required to fertilize 50% of the eggs in specific male/female pairs; F50) and the root-mean-square of total velocity (urms; 0.01-0.11 m s(-1)) on fertilization in four locations near a spawning female (water column, wake eddy, substratum, and aboral surface) in both unidirectional and oscillatory flows. Percent fertilization decreased significantly with increasing urms at all locations and both flow regimes. However, although gamete compatibility varied by almost 1.5 orders of magnitude, it was not a significant predictor of fertilization for most combinations of position and flow. The notable exception was a significant effect of gamete compatibility on fertilization on the aboral surface under unidirectional flow. Our results suggest that selection on variation in gamete compatibility may be strongest in eggs fertilized on the aboral surface of sea urchins and that hydrodynamic conditions may add environmental noise to selection outcomes.

Habitat simplification increases the impact of a freshwater invasive fish

Biodiversity continues to decline at a range of spatial scales and there is an urgent requirement to understand how multiple drivers interact in causing such declines. Further, we require methodologies that can facilitate predictions of the effects of such drivers in the future. Habitat degradation and biological invasions are two of the most important threats to biodiversity and here we investigate their combined effects, both in terms of understanding and predicting impacts on native species. The predatory largemouth bass Micropterus salmoides is one of the World’s Worst Invaders, causing declines in native prey species, and its introduction often coincides with habitat simplification. We investigated the predatory functional response, as a measure of ecological impact, of juvenile largemouth bass in artificial vegetation over a range of habitat complexities (high, intermediate, low and zero). Prey, the female guppy Poecilia reticulata, were representative of native fish. As habitats became less complex, significantly more prey were consumed, since, even although attack rates declined, reduced handling times resulted in higher maximum feeding rates by bass. At all levels of habitat complexity, bass exhibited potentially population destabilising Type II functional responses, with no emergence of more stabilising Type III functional responses as often occurs in predator-prey relationships in complex habitats. Thus, habitat degradation and simplification potentially exacerbate the impact of this invasive species, but even highly complex habitats may ultimately not protect native species. The utilisation of functional responses under varying environmental contexts provides a method for the understanding and prediction of invasive species impacts.

Belfast Soundwalks: Experiences in Sound and Place through Locative Media

This article outlines the ongoing development of a locative smartphone app for iPhone and Android phones entitled The Belfast Soundwalks Project. Drawing upon a method known as soundwalking, the aim of this app is to engage the public in sonic art through the creation of up to ten soundwalks within the city of Belfast. This paper discusses the use of GPS enabled mobile devices in the creation of soundwalks in other cities. The authors identify various strategies for articulating an experience of listening in place as mediated by mobile technologies. The project aims to provide a platform for multiple artists to develop site-specific sound works which highlight the relationship between sound, place and community. The development of the app and the app interface are discussed, as are the methods employed to test and evaluate the project.

Fictions

Work in three movements for chamber ensemble of flute (d piccolo, alto flute), clarinet (d bass clarinet), violin, cello, piano written for Stony Brook Contemporary Music Players, Stony Brook University NY USA

Belfast Soundwalks

The Belfast Soundwalks project, led by Professor Pedro Rebelo and co-ordinated by Dr Sarah Bass (Sonic Arts Research Centre) in collaboration with Belfast City Council (BCC), aims to use sonic art to engage the public through the development of a locative mobile phone app. Targeting both tourists and citizens of the city, this project aims to sonically enhance the experience of a number of areas of the city, including destinations that may not traditionally be accessed as attractions by visitors and/or disregarded or undervalued by local residents. The project will bring together a number of sonic artists/composers who will create approximately ten soundwalks around the city, while liaising with BCC to distribute the resulting app to the public in line with their tourism and cultural strategy. The project is centred on the development of smart phone apps which provide unique listening experiences associated with key places in the city. The user’s location in the city is tracked through GPS which triggers sound materials ranging from speech to environmental sound and abstract imagined sound worlds. Additionally, local community groups will be consulted in order to evaluate and reflect upon the effectiveness of the soundwalks.

The project builds on the success of the Literary Belfast app and aims to further strengthen links between Queen’s University Belfast and Belfast City Council through facilitating the dissemination of an art form not widely experienced by the general public. Through the newly created Institute for Collaborative Research in the Humanities, directed by Professor John Thompson we are articulating this project with Queen’s consortium partners, Newcastle University and Durham University.

“The Arts and Humanities Research Council (AHRC) funds world-class, independent researchers in a wide range of subjects: ancient history, modern dance, archaeology, digital content, philosophy, English literature, design, the creative and performing arts, and much more. This financial year the AHRC will spend approximately £98m to fund research and postgraduate training in collaboration with a number of partners. The quality and range of research supported by this investment of public funds not only provides social and cultural benefits but also contributes to the economic success of the UK. For further information on the AHRC, please go to: www.ahrc.ac.uk”.

Methodologic rigor of clinical trials on surgical management of eyes with coexisting cataract and glaucoma.

OBJECTIVE:

To assess the methodologic quality of published studies of the surgical management of coexisting cataract and glaucoma.

DESIGN:

Literature review and analysis.

METHOD:

We performed a systematic search of the literature to identify all English language articles pertaining to the surgical management of coexisting cataract and glaucoma in adults. Quality assessment was performed on all randomized controlled trials, nonrandomized controlled trials, and cohort studies. Overall quality scores and scores for individual methodologic domains were based on the evaluations of two experienced investigators who independently reviewed articles using an objective quality assessment form.

MAIN OUTCOME MEASURES:

Quality in each of five domains (representativeness, bias and confounding, intervention description, outcomes and follow-up, and statistical quality and interpretation) measured as the percentage of methodologic criteria met by each study.

RESULTS:

Thirty-six randomized controlled trials and 45 other studies were evaluated. The mean quality score for the randomized, controlled clinical trials was 63% (range, 11%-88%), and for the other studies the score was 45% (range, 3%-83%). The mean domain scores were 65% for description of therapy (range, 0%-100%), 62% for statistical analysis (range, 0%-100%), 58% for representativeness (range, 0%-94%), 49% for outcomes assessment (range, 0%-83%), and 30% for bias and confounding (range, 0%-83%). Twenty-five of the studies (31%) received a score of 0% in the bias and confounding domain for not randomizing patients, not masking the observers to treatment group, and not having equivalent groups at baseline.

CONCLUSIONS:

Greater methodologic rigor and more detailed reporting of study results, particularly in the area of bias and confounding, could improve the quality of published clinical studies assessing the surgical management of coexisting cataract and glaucoma.

Surgical strategies for coexisting glaucoma and cataract: an evidence-based update.

OBJECTIVE:

To assess short- and long-term control of intraocular pressure (IOP) with different surgical treatment strategies for coexisting cataract and glaucoma.

DESIGN:

Systematic literature review and analysis.

METHOD:

We performed a search of the published literature to identify all eligible articles pertaining to the surgical management of coexisting cataract and glaucoma in adults. One investigator abstracted the content of each article onto a custom-designed form. A second investigator corroborated the findings. The evidence supporting different approaches was graded by consensus as good, fair, weak, or insufficient.

MAIN OUTCOME MEASURES:

Short-term (24 hours or fewer) and long-term (more than 24 hours) IOP control.

RESULTS:

The evidence was good that long-term IOP is lowered more by combined glaucoma and cataract operations than by cataract operations alone. On average, the IOP was 3 to 4 mmHg lower in the combined groups with fewer medications required. The evidence was weak that extracapsular cataract extraction (ECCE) alone results in short-term increase in IOP and was insufficient to determine the short-term impact of phacoemulsification cataract extraction (PECE) on IOP in glaucoma patients. The evidence was weak that short-term IOP control was better with ECCE or PECE combined with an incisional glaucoma procedure compared with ECCE or PECE alone. The evidence was also weak (but consistent) that long-term IOP is lowered by 2 to 4 mmHg after ECCE or PECE. Finally, there was weak evidence that combined PECE and trabeculectomy produces slightly worse long-term IOP control than trabeculectomy alone, and there was fair evidence that the same is true for ECCE combined with trabeculectomy.

CONCLUSIONS:

There is strong evidence for better long-term control of IOP with combined glaucoma and cataract operations compared with cataract surgery alone. For other issues regarding surgical treatment strategies for cataract and glaucoma, the available evidence is limited or conflicting.