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In recent years, considerable advances have been made in the characterization of protein-coding alterations involved in the pathogenesis of melanoma. However, despite their growing implication in cancer, little is known about the role of long noncoding RNAs in melanoma progression. We hypothesized that copy number alterations (CNAs) of intergenic nonprotein-coding domains could help identify long intergenic noncoding RNAs (lincRNAs) associated with metastatic cutaneous melanoma. Among several candidates, our approach uncovered the chromosome 6p22.3 CASC15 (cancer susceptibility candidate 15) lincRNA locus as a frequently gained genomic segment in metastatic melanoma tumors and cell lines. The locus was actively transcribed in metastatic melanoma cells, and upregulation of CASC15 expression was associated with metastatic progression to brain metastasis in a mouse xenograft model. In clinical specimens, CASC15 levels increased during melanoma progression and were independent predictors of disease recurrence in a cohort of 141 patients with AJCC (American Joint Committee on Cancer) stage III lymph node metastasis. Moreover, small interfering RNA (siRNA) knockdown experiments revealed that CASC15 regulates melanoma cell phenotype switching between proliferative and invasive states. Accordingly, CASC15 levels correlated with known gene signatures corresponding to melanoma proliferative and invasive phenotypes. These findings support a key role for CASC15 in metastatic melanoma.

Patients with triple-negative breast cancer (TNBC) have a high incidence of early relapse and metastasis; however, the molecular basis for recurrence in these individuals remains poorly understood. Here, we demonstrate that RASAL2, which encodes a RAS-GTPase-activating protein (RAS-GAP), is a functional target of anti-invasive microRNA-203 and is overexpressed in a subset of triple-negative or estrogen receptor-negative (ER-negative) breast tumors. As opposed to luminal B ER-positive breast cancers, in which RASAL2 has been shown to act as a RAS-GAP tumor suppressor, we found that RASAL2 is oncogenic in TNBC and drives mesenchymal invasion and metastasis. Moreover, high RASAL2 expression was predictive of poor disease outcomes in patients with TNBC. RASAL2 acted independently of its RAS-GAP catalytic activity in TNBC; however, RASAL2 promoted small GTPase RAC1 signaling, which promotes mesenchymal invasion, through binding and antagonizing the RAC1-GAP protein ARHGAP24. Together, these results indicate that activation of a RASAL2/ARHGAP24/RAC1 module contributes to TNBC tumorigenesis and identify a context-dependent role of RASAL2 in breast cancer.

In recent years, considerable advances have been made in the characterization of protein-coding alterations involved in the pathogenesis of melanoma. However, despite their growing implication in cancer, little is known about the role of long non-coding RNAs in melanoma progression. We hypothesized that copy number alterations of intergenic non-protein coding domains could help identify long intergenic non-coding RNAs (lincRNAs) associated with metastatic cutaneous melanoma. Among several candidates, our approach uncovered the chromosome 6p22.3 CASC15 lincRNA locus as a frequently gained genomic segment in metastatic melanoma tumors and cell lines. The locus was actively transcribed in metastatic melanoma cells, and up-regulation of CASC15 expression was associated with metastatic progression to brain metastasis in a mouse xenograft model. In clinical specimens, CASC15 levels increased during melanoma progression and were independent predictors of disease recurrence in a cohort of 141 patients with AJCC stage III lymph node metastasis. Moreover, siRNA knockdown experiments revealed that CASC15 regulates melanoma cell phenotype switching between proliferative and invasive states. Accordingly, CASC15 levels correlated with known gene signatures corresponding to melanoma proliferative and invasive phenotypes. These findings support a key role for CASC15 in metastatic melanoma.

This thesis investigates the entwined relationship between the creative process of composition and the development of technological frameworks, specifically software development, as parallel practices in digital-interactive contexts. Drawing on the tenets of intermediality, notably the writing of Elleström, Nelson, Bay-Cheng, and Kattenbelt, this work aims to explore and analyse the resonances and possibilities for renegotiating our perceptions of temporality, authorship and the construction of experience. This interrogation of digital-intermedial composition consists of three practical research projects and a threechapter written thesis that addresses the theoretical and practical concerns of a creative process exploring the notion of ‘composing experience.’ The reflexive relationship between composition and digital technologies the focus of this research yet further theoretical concepts arise from the central inquiry later in the thesis. A key methodology in my research has been the finding the balance between writing, analysis and practical engagement with the work. This is a Practice-as-Research PhD and as such a complex interaction between theoretical and practical elements define my inquiry, something reflected in the writing of this thesis. Chapter One seeks to locate the core aspects and processes of my own work within the field of contemporary practice looking notably at the work of artists involved in digital interactive work and composing with sound and image. The chapter looks specifically at the validity of creating interactive works from single data stream input devices – such as gaming controllers and the notion of how these interfaces should be ‘mapped’ (Elleström) to effective points of interaction in the context of the audiences experience. Chapter Two charts the linear journey of my practical projects beginning with Comrade Coffee (Donovan 2010) and my exploration of interdisciplinarity. My second research project, Inter-activity (Donovan 2011), details the shift in my research focus from interdisciplinarity to intermedial process in constructing work in digital-interactive contexts. The basis of my final work, Digital Spaces (Donovan 2012), is set up, for its exploration in Chapter Three, through analysing the system’s early development and the exploration of different methodological approaches including gamification. Chapter Three is split into four sections and focuses on the conceptual development and analysis of my research primarily through Digital Spaces and the theoretical issues emerging from these contexts. The thesis concludes by exploring the validity and functionality of a meta-compositional process and the composition of experience as being methodological and ideological focuses for creative arts practice in digital-interactive contexts.

In the limnetic zones of small, highly productive reservoirs, young-of-year (YOY) gizzard shad (Dorosoma cepedianum) or threadfin shad (D. petenense) (henceforth, shad) often attain high densities during spring. Environmental factors facilitating early growth and survival of shad plus potential interspecific competition for zooplankton may reduce growth and survival of YOY bluegill (Lepomis macrochirus), another common species in reservoirs. We hypothesized that fewer YOY bluegill moving from the limnetic zone to the littoral zone in late spring probably slows or prevents the ontogenetic switch to piscivory by YOY largemouth bass (Micropterus salmoides), reducing their oversummer growth, overwinter survival, and hence recruitment to their second year. To determine whether shad and bluegill abundances indeed vary inversely in reservoirs, we quantified densities of YOY shad and bluegill in four reservoirs across several years (1987-1994; N = 22 reservoir-years). To assess how YOY bluegill abundance influenced the ontogenetic dietary switch to fish by largemouth bass, we conducted experiments with differing levels of realism and control (4-m2littoral cages, 4.5-m2outdoor pools, and 0.33-m2laboratory aquaria). In reservoirs, peak YOY bluegill density declined weakly in the limnetic zone but strongly in the littoral zone when peak limnetic YOY Dorosoma spp. exceeded 10 individuals/m3. In pools and aquaria, largemouth bass grew more rapidly at ≥3 than at zero bluegill per largemouth bass. Using known temperatures and largemouth bass growth in a bioenergetics model, we discovered that YOY largemouth bass in pools and aquaria ate ≤65% of their maximum daily consumption potential (in grams of wet mass) at ≥6 bluegill per largemouth bass. In cages, largemouth bass consumed only 40% of their maximum and grew less at bluegill abundances similar to those in pools and aquaria, probably because dense vegetation and depletion of bluegill inhibited predatory success. In reservoirs with abundant shad, reduced littoral bluegill density likely compromises first-year growth and recruitment of largemouth bass. However, variable abiotic and biotic factors may modify YOY bluegill abundance and hence invalidate our predictions for largemouth bass recruitment success. To better predict fish community structure and develop management actions for reservoir ecosystems, multi-scale experimentation should be combined with whole-system manipulations (e.g., via adaptive management) to bound these variable interactions.

Though young-of-year (YOY) saugeyes (Stizostedion vitreum x S. canadense) are routinely stocked in spring to create and maintain percid fisheries, their growth and survival to fall vary greatly among Ohio reservoirs, as well as among years within a reservoir. To understand the relative importance of size-dependent and size-independent mechanisms during ontogeny that underlie variable stocking success of saugeye, we quantified the role of stocking date and prey density (zooplankton and ichthyoplankton, i.e., larval gizzard shad [Dorosoma cepedianum]) in field enclosure, pond, and reservoir experiments. In 1-m3enclosures, ichthyoplankton density (0, 5, 10, or 20 larval gizzard shad/m3) did not influence time to switch to piscivory by saugeye (all switched in <12 h); saugeye in enclosures with ichthyoplankton, regardless of density, grew faster than those without ichthyoplankton. In 0.4-ha ponds, saugeye growth and survival did not differ between ponds with zooplankton plus macrobenthic prey and ponds with those prey plus small ichthyoplankton (<10 mm). In reservoir experiments, we evaluated how time in reservoirs, zooplankton density, and peak density (as well as date) of ichthyoplankton influenced saugeye growth and survival during 1991-1994 (N = 31 reservoir-years). In 1993, we attempted to bracket the ichthyoplankton peak in five Ohio reservoirs by stocking two genetically identifiable cohorts of saugeye 2 wk apart in spring. For all reservoirs, those saugeye stocked before the ichthyoplankton peak grew larger than those stocked after the ichthyoplankton peak by 1 October. In 1994, we hypothesized that saugeye might overexploit local populations of ichthyoplankton when stocked at a single site. We paired 10 reservoirs (N = 5 pairs) with one reservoir of each pair scatter-stocked (i.e., saugeye numbers equally divided among five sites) and the second point stocked (i.e., at a single site). Stocking method did not influence saugeye survival; late gizzard shad spawning, coupled with low larval densities, yielded poor saugeye survival in 1994. However, YOY saugeye were considerably larger in fall 1994 than in fall 1993, when gizzard shad appeared earlier and produced more larvae. Zooplankton density at stocking influenced neither growth nor survival. Increased time in reservoirs increased fall size but did not influence survival. Although saugeye growth and survival during their first year were unrelated, both measures of stocking success critically depended on gizzard shad availability. Across all years, saugeyes stocked before ichthyoplankton peaks were large (as a result of their ability to consume fast-growing gizzard shad through summer), but survived poorly to fall (perhaps owing to early, high predatory mortality). Conversely, saugeyes stocked after ichthyoplankton peaks were small in fall (for they were unable to exploit large gizzard shad) but survived better (perhaps because gizzard shad provided a predatory buffer). By manipulating stock date relative to ichthyoplankton peaks, fisheries managers can either increase saugeye size or survival to fall, but not both.

Structure property relationships of noble metal nanoparticles (NPs) can be drastically different than bulk properties of the same metals. This research study used state-of-the-art analytical electron microscopy and scanned probe microscopy to determine material properties on the nanoscale of bio-related Au and Pd NPs. Recently, it has been demonstrated the self-assembly of Au NPs on functionalized silica surfaces creates a conductive surface. Determination of the aggregate morphology responsible for electron conduction was studied by atomic force microscopy (AFM) and scanning electron microscopy (SEM). In addition, changes in the electrical properties of the substrates after low temperature (<350°C) annealing was also studied. It was found that coalescence and densification of the Au NP aggregates disrupted the interconnected network which subsequently created a loss of conductivity. Investigation of bio-related Au/SiO2 core-shell NPs determined why published experimental results showed the sol-gel silica shell improved, by almost an order of magnitude, the detection efficiency of a DNA detection assay. Novel 360° rotation scanning TEM (STEM) imaging allowed study of individual NP surface morphology and internal structure. Electron energy loss spectroscopy (EELS) spectrum imaging determined optoelectronic properties and chemical composition of the silica shell used to encapsulate Au NPs. Results indicated the sol-gel deposited SiO2 had a band gap energy of ∼8.9eV, bulk plasmon-peak energy of ∼25.5eV and chemical composition of stoichiometric SiO2. Lastly, an attempt to elicit structure property relationships of novel RNA mediated Pd hexagon NPs was performed. Selected area electron diffraction (SAD), low voltage scanning transmission electron microscopy (LV-STEM), electron energy loss spectroscopy (EELS) and energy dispersive spectroscopy (EDS) were chosen for characterization of atomic ordering, chemical composition and optoelectronic properties of the novel nanostructures. Data from control experiments found the hexagons could be made without RNA and confirmed the presence of nanocrystalline Pd metal NPs in unpurified Pd2(DBA)3 reagent powder. Furthermore, the study determined the hexagon platelets to have a chemical composition of ∼90at% carbon and ∼10at% Pd and a lattice parameter corresponding to molecular crystals of Pd2(DBA)3 precursor, not Pd metal.* *This dissertation is a compound document (contains both a paper copy and a CD as part of the dissertation). The CD requires the following system requirements: Windows MediaPlayer or RealPlayer.