"Grant us eyes, grant us eyes! Plant eyes on our brains, to cleanse our beastly idiocy!": FromSoftware's Bloodborne, and the New Frontier of the Gothic

This article will consider the ways that Bloodborne (FromSoftware, 2015) plays on a broad range of Gothic themes and conventions, utilising unusual narrative techniques and gameplay mechanics which offer the player a means by which they might experience a Gothic narrative in ways that the traditional novel format does not allow for. It will argue that Bloodborne showcases the genre's potential new frontier: converting conventions into interesting new gameplay mechanics, and letting the player experience the genre through player-led narrative and agency

Structural and functional characterisation of neuronal Gq protein coupled receptors.

Both G protein coupled receptor 10 (GPR10) and the muscarinic IVh receptor are members of family A of the G protein coupled receptor superfamily. GPR10 is the human orthologue of a former orphan receptor for which prolactin releasing peptides (PrRP) have been identified as the cognate ligands. In contrast, the N/h receptor represents a well-established receptor for which up until the discovery of AC-42 (4-(4-butyl-1-piperidinyl)-1-(2-methylphenyl)-1-butanone) it has been difficult to identify a selective agonist. Little is known of the pharmacology of PrRPs and AC-42 at GPR10 and the human Mi (hMi) receptor, respectively. Similarly, the molecular nature of their respective binding sites is as yet unknown. In the studies in this thesis, the interaction of PrRPs with GPR10 and of AC-42 (and other ectopic agonists) with the hMi receptor have been extensively characterised using a range of pharmacological techniques in both recombinant cell lines stably and transiently expressing the receptor(s) of interest and native tissue preparations. Furthermore, the molecular interactions between ligand and receptor have been probed using homology modelling, site-directed mutagenesis (SDM) and pharmacological evaluation. The results generated reveal that PrRPs are high affinity, potent agonists at GPR10 that cause the receptor to activate effector systems that are known to couple to Gq/n proteins. Radioligand binding studies suggest both high and low affinity sites for binding. In addition, homology modelling and SDM have been used to reveal key interactions of the C-terminal region of PrRP with transmembrane domain (TM) 6 (D302) and TM7 (Q317) and extracellular loop (ECL) 2 (E213). Selective activation of the Mi receptor can be achieved using AC-42 and other novel ligands. Using functional calcium mobilisation assays, inositol phosphate assays and radioligand binding studies it has been possible to demonstrate that this class of compounds interacts with the receptor in an allosteric manner. SDM studies also suggest that residues distinct from the orthosteric binding site form part of the binding site for AC-42 and related compounds. These studies provide the first extensive pharmacological analysis characterising the interaction of PrRP and GPR10 and identify the signal transduction cascade activated by this former orphan receptor. Furthermore, SDM studies have partly elucidated the molecular nature of the PrRP binding site. Both pharmacological and SDM based examination of the muscarinic Mi receptor have revealed a unique allosteric method of activation by AC-42 and a novel class of allosteric agonists

ALGORITHMS AND HIGH PERFORMANCE COMPUTING APPROACHES FOR SEQUENCING-BASED COMPARATIVE GENOMICS

As cost and throughput of second-generation sequencers continue to improve, even modestly resourced research laboratories can now perform DNA sequencing experiments that generate hundreds of billions of nucleotides of data, enough to cover the human genome dozens of times over, in about a week for a few thousand dollars. Such data are now being generated rapidly by research groups across the world, and large-scale analyses of these data appear often in high-profile publications such as Nature, Science, and The New England Journal of Medicine. But with these advances comes a serious problem: growth in per-sequencer throughput (currently about 4x per year) is drastically outpacing growth in computer speed (about 2x every 2 years). As the throughput gap widens over time, sequence analysis software is becoming a performance bottleneck, and the costs associated with building and maintaining the needed computing resources is burdensome for research laboratories. This thesis proposes two methods and describes four open source software tools that help to address these issues using novel algorithms and high-performance computing techniques. The proposed approaches build primarily on two insights. First, that the Burrows-Wheeler Transform and the FM Index, previously used for data compression and exact string matching, can be extended to facilitate fast and memory-efficient alignment of DNA sequences to long reference genomes such as the human genome. Second, that these algorithmic advances can be combined with MapReduce and cloud computing to solve comparative genomics problems in a manner that is scalable, fault tolerant, and usable even by small research groups

Sustainable Heritage: Retrofitting Historic Buildings for Improved Environmental Performance

Building materials outlive people. What we build is left for the next generation as a resource and as an artifact of our own time. This thesis explores how we can alter our existing building stock to become more environmentally sustainable. By examining the common ground between the conservation of the built world and the conservation of the natural world, we can redefine stewardship for the present age. Let our built legacy express that we value history, culture, and consideration for the prosperity of future generations. As a case study, the practice of sustainable retrofitting will be implemented at an abandoned building campus in Silver Spring, Maryland. Designed in 1927 for the National Association of Dyers and Cleaners, these buildings retain their dignity despite years of poor stewardship. The site has the potential to exemplify how historic buildings can become a sustainable resource for the future of an expanding, diverse community

Task-driven programming pedagogy in the digital humanities

In this chapter, we advocate for a task-driven approach to teaching computer programming to students of the digital humanities (DH). Our perspective is grounded first in Birnbaum's (2014) plenary address to the University of Pittsburgh Faculty Senate (Birnbaum 2014), in which he argued that coding, like writing, should be taught across the liberal arts curriculum in domain-appropriate ways. This position argued that (1) coding is not an esoteric specialization to be taught solely by computer scientists, and that (2) coding might be taught most effectively in the context of different disciplines. Here, we present a method for embedding Digital Humanities education, and more specifically programming pedagogy, within the long-standing traditions of the Humanities and argue that this approach works most effectively when new learners have access to context-specific mentorship. Our second point of reference lies with oral-proficiency-oriented (OP) foreign language pedagogy. Within an OP model, the ability to communicate in a foreign language is a skill, and the primary goal for learners who seek to acquire that skill is not an academic understanding of the grammar of a language, but, instead, the ability to function successfully within realistic contextualized human interactions. Seen from this perspective, computer-programming curricula organized around the features of the programming language might be compared to older grammar-and-translation foreign-language pedagogies. What we advocate instead is that the ability to use a programming language (programming proficiency) is best acquired in the context of performing contextualized, discipline-conscious tasks that are meaningful to humanists, an approach that has parallels to OP language learning

Coral community dynamics and disturbances : a modelling approach for Caribbean coral reefs

The capacity of reefs to recover after disturbance is fundamental to prediction of their stability. This is particularly relevant now, following the global decline of reefs during the last decades. A discrete, spatially explicit model (probabilistic cellular automaton) was developed to simulate a Caribbean coral community. Community complexity was generated from behaviour of fundamental units of corals, the polyps. Regarding background disturbance, area disturbed and patch size were investigated; both were equally important in driving coral community structure and diversity. A powerlaw model was developed to predict natural disturbances, and implemented in later testing of system dynamics. Corals were assigned differential susceptibilities to background disturbances. Results assessed against field data showed that most modelled species had realistic colony size frequency distributions (though 20% had insufficient comparison data). Following model development, recovery from single impacts (simulated warming events) was tested. Model responses indicate importance of local setting to community resilience. Individual susceptibility of species was mediated by life history strategy investment. Application of a warming sequence of predicted anomalies for this century was then introduced. Community composition changed betwee1 0-40 years from predominantly persistent, large, slow growing species to small, fecund, fast growing species. After 40 years a phase shift occurred in which algae dominated the community. It is concluded that the future may herald declines in the main Caribbean reef-building species, in ways that match several previous but largely untested speculations. This model indicates that there will be serious implications to reefs, including their numerous commercially important species. The model includes all known major life history attributes of the corals, based on real data. Structural properties of the model were tested for stability and computational efficiency. Disturbances of several types were investigated; natural background disturbance, and warming events, both as single and repeated incidents to assess recovery dynamics in the light of ongoing, intensifying climate-mediated global changes