Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements

Retinitis pigmentosa (RP) is a devastating form of retinal degeneration, with significant social and professional consequences. Molecular genetic information is invaluable for an accurate clinical diagnosis of RP due to its high genetic and clinical heterogeneity. Using a gene capture panel that covers 163 of the currently known retinal disease genes, including 48 RP genes, we performed a comprehensive molecular screening in a collection of 123 RP unsettled probands from a wide variety of ethnic backgrounds, including 113 unrelated simplex and 10 autosomal recessive RP (arRP) cases. As a result, 61 mutations were identified in 45 probands, including 38 novel pathogenic alleles. Interestingly, we observed that phenotype and genotype were not in full agreement in 21 probands. Among them, eight probands were clinically reassessed, resulting in refinement of clinical diagnoses for six of these patients. Finally, recessive mutations in CLN3 were identified in five retinal degeneration patients, including four RP probands and one cone-rod dystrophy patient, suggesting that CLN3 is a novel non-syndromic retinal disease gene. Collectively, our results underscore that, due to the high molecular and clinical heterogeneity of RP, comprehensive screening of all retinal disease genes is effective in identifying novel pathogenic mutations and provides an opportunity to discover new genotype-phenotype correlations. Information gained from this genetic screening will directly aid in patient diagnosis, prognosis, and treatment, as well as allowing appropriate family planning and counseling.

Race, space and politics in Mid-Victorian Ireland: the ethnologies of Abraham Hume and John McElheran

There has been much scholarly debate about the significance and influence of racialist thinking in the political and cultural history of nineteenth-century Ireland. With reference to that ongoing historiographical discussion, this paper considers the racial geographies and opposing political motivations of two Irish ethnologists, Abraham Hume and John McElheran, using their racialist regimes to query some of the common assumptions that have informed disagreements over the role and reach of racial typecasting in mid-nineteenth-century Ireland. As well as examining in detail the racial imaginaries promulgated by Hume and McElheran, the paper also argues for the importance of situating racialist discourse in the spaces in which it was communicated and contested. Further, in highlighting the ways in which Hume and McElheran collapsed together race, class and religion, the paper troubles the utility of a crisp analytical distinction between those disputed categories.

The Pan-STARRS Moving Object Processing System

We describe the Pan-STARRS Moving Object Processing System (MOPS), a modern software package that produces automatic asteroid discoveries and identifications from catalogs of transient detections from next-generation astronomical survey telescopes. MOPS achieves >99.5% efficiency in producing orbits from a synthetic but realistic population of asteroids whose measurements were simulated for a Pan-STARRS4-class telescope. Additionally, using a nonphysical grid population, we demonstrate that MOPS can detect populations of currently unknown objects such as interstellar asteroids. MOPS has been adapted successfully to the prototype Pan-STARRS1 telescope despite differences in expected false detection rates, fill-factor loss, and relatively sparse observing cadence compared to a hypothetical Pan-STARRS4 telescope and survey. MOPS remains highly efficient at detecting objects but drops to 80% efficiency at producing orbits. This loss is primarily due to configurable MOPS processing limits that are not yet tuned for the Pan-STARRS1 mission. The core MOPS software package is the product of more than 15 person-years of software development and incorporates countless additional years of effort in third-party software to perform lower-level functions such as spatial searching or orbit determination. We describe the high-level design of MOPS and essential subcomponents, the suitability of MOPS for other survey programs, and suggest a road map for future MOPS development.

Report of the workshop for life detection in samples from Mars

The question of whether there is or was life on Mars has been one of the most pivotal since Schiaparellis' telescopic observations of the red planet. With the advent of the space age, this question can be addressed directly by exploring the surface of Mars and by bringing samples to Earth for analysis. The latter, however, is not free of problems. Life can be found virtually everywhere on Earth. Hence the potential for contaminating the Mars samples and compromising their scientific integrity is not negligible. Conversely, if life is present in samples from Mars, this may represent a potential source of extraterrestrial biological contamination for Earth. A range of measures and policies, collectively termed ‘planetary protection’, are employed to minimise risks and thereby prevent undesirable consequences for the terrestrial biosphere. This report documents discussions and conclusions from a workshop held in 2012, which followed a public conference focused on current capabilities for performing life-detection studies on Mars samples. The workshop focused on the evaluation of Mars samples that would maximise scientific productivity and inform decision making in the context of planetary protection. Workshop participants developed a strong consensus that the same measurements could be employed to effectively inform both science and planetary protection, when applied in the context of two competing hypotheses: 1) that there is no detectable life in the samples; or 2) that there is martian life in the samples. Participants then outlined a sequence for sample processing and defined analytical methods that would test these hypotheses. They also identified critical developments to enable the analysis of samples from Mars.

Banished to the Barn - John Doherty and 'Bonnie Kate'

John Doherty (1900-1980) was one of the most influential Irish musicians of the twentieth century. His music has had a lasting impact on Irish traditional music making around the globe. This paper traces the development of his setting of the canonical reel 'Bonnie Kate'. Using transcription historical investigation Doherty's style is examined in comparison to his contemporaries.

The Vertical Distribution and Evolution of Slam Pressure on an Oscillating Wave Surge Converter

The accurate definition of the extreme wave loads which act on offshore structures represents a significant challenge for design engineers and even with decades of empirical data to base designs upon there are still failures attributed to wave loading. The environmental conditions which cause these loads are infrequent and highly non-linear which means that they are not well understood or simple to describe. If the structure is large enough to affect the incident wave significantly further non-linear effects can influence the loading. Moreover if the structure is floating and excited by the wave field then its responses, which are also likely to be highly non-linear, must be included in the analysis. This makes the description of the loading on such a structure difficult to determine and the design codes will often suggest employing various tools including small scale experiments, numerical and analytical methods, as well as empirical data if available.
Wave Energy Converters (WECs) are a new class of offshore structure which pose new design challenges, lacking the design codes and empirical data found in other industries. These machines are located in highly exposed and energetic sites, designed to be excited by the waves and will be expected to withstand extreme conditions over their 25 year design life. One such WEC is being developed by Aquamarine Power Ltd and is called Oyster. Oyster is a buoyant flap which is hinged close to the seabed, in water depths of 10 to 15m, piercing the water surface. The flap is driven back and forth by the action of the waves and this mechanical energy is then converted to electricity.
It has been identified in previous experiments that Oyster is not only subject to wave impacts but it occasionally slams into the water surface with high angular velocity. This slamming effect has been identified as an extreme load case and work is ongoing to describe it in terms of the pressure exerted on the outer skin and the transfer of this short duration impulsive load through various parts of the structure.
This paper describes a series of 40th scale experiments undertaken to investigate the pressure on the face of the flap during the slamming event. A vertical array of pressure sensors are used to measure the pressure exerted on the flap. Characteristics of the slam pressure such as the rise time, magnitude, spatial distribution and temporal evolution are revealed. Similarities are drawn between this slamming phenomenon and the classical water entry problems, such as ship hull slamming. With this similitude identified, common analytical tools are used to predict the slam pressure which is compared to that measured in the experiment.

Defining the role of common variation in the genomic and biological architecture of adult human height

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated 1/42,000, 1/43,700 and 1/49,500 SNPs explained 1/421%, 1/424% and 1/429% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/I 2-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.