Computational Approaches for the Analysis of Chromosome Conformation Capture Data and Their Application to Study Long-Range Gene Regulation: A Dissertation

Over the last decade, development and application of a set of molecular genomic approaches based on the chromosome conformation capture method (3C), combined with increasingly powerful imaging approaches have enabled high resolution and genome-wide analysis of the spatial organization of chromosomes. The aim of this thesis is two-fold; 1), to provide guidelines for analyzing and interpreting data obtained from genome-wide 3C methods such as Hi-C and 3C-seq and 2), to leverage the 3C technology to solve genome function, structure, assembly, development and dosage problems across a broad range of organisms and disease models. First, through the introduction of cWorld, a toolkit for manipulating genome structure data, I accelerate the pace at which *C experiments can be performed, analyzed and biological insights inferred. Next I discuss a set of practical guidelines one should consider while planning an experiment to study the structure of the genome, a simple workflow for data processing unique to *C data and a set of considerations one should be aware of while attempting to gain insights from the data. Next, I apply these guidelines and leverage the cWorld toolkit in the context of two dosage compensation systems. The first is a worm condensin mutant which shows a reduction in dosage compensation in the hermaphrodite X chromosomes. The second is an allele-specific study consisting of genome wide Hi-C, RNA-Seq and ATAC-Seq which can measure the state of the active (Xa) and inactive (Xi) X chromosome. Finally I turn to studying specific gene – enhancer looping interactions across a panel of ENCODE cell-lines. These studies, when taken together, further our understanding of how genome structure relates to genome function

A Framework for Dynamic Terrain with Application in Off-road Ground Vehicle Simulations

The dissertation develops a framework for the visualization of dynamic terrains for use in interactive real-time 3D systems. Terrain visualization techniques may be classified as either static or dynamic. Static terrain solutions simulate rigid surface types exclusively; whereas dynamic solutions can also represent non-rigid surfaces. Systems that employ a static terrain approach lack realism due to their rigid nature. Disregarding the accurate representation of terrain surface interaction is rationalized because of the inherent difficulties associated with providing runtime dynamism. Nonetheless, dynamic terrain systems are a more correct solution because they allow the terrain database to be modified at run-time for the purpose of deforming the surface. Many established techniques in terrain visualization rely on invalid assumptions and weak computational models that hinder the use of dynamic terrain. Moreover, many existing techniques do not exploit the capabilities offered by current computer hardware. In this research, we present a component framework for terrain visualization that is useful in research, entertainment, and simulation systems. In addition, we present a novel method for deforming the terrain that can be used in real-time, interactive systems. The development of a component framework unifies disparate works under a single architecture. The high-level nature of the framework makes it flexible and adaptable for developing a variety of systems, independent of the static or dynamic nature of the solution. Currently, there are only a handful of documented deformation techniques and, in particular, none make explicit use of graphics hardware. The approach developed by this research offloads extra work to the graphics processing unit; in an effort to alleviate the overhead associated with deforming the terrain. Off-road ground vehicle simulation is used as an application domain to demonstrate the practical nature of the framework and the deformation technique. In order to realistically simulate terrain surface interactivity with the vehicle, the solution balances visual fidelity and speed. Accurately depicting terrain surface interactivity in off-road ground vehicle simulations improves visual realism; thereby, increasing the significance and worth of the application. Systems in academia, government, and commercial institutes can make use of the research findings to achieve the real-time display of interactive terrain surfaces

Development and implementation of in silico molecule fragmentation algorithms for the cheminformatics analysis of natural product spaces

Computational methodologies extracting specific substructures like functional groups or molecular scaffolds from input molecules can be grouped under the term “in silico molecule fragmentation”. They can be used to investigate what specifically characterises a heterogeneous compound class, like pharmaceuticals or Natural Products (NP) and in which aspects they are similar or dissimilar. The aim is to determine what specifically characterises NP structures to transfer patterns favourable for bioactivity to drug development. As part of this thesis, the first algorithmic approach to in silico deglycosylation, the removal of glycosidic moieties for the study of aglycones, was developed with the Sugar Removal Utility (SRU) (Publication A). The SRU has also proven useful for investigating NP glycoside space. It was applied to one of the largest open NP databases, COCONUT (COlleCtion of Open Natural prodUcTs), for this purpose (Publication B). A contribution was made to the Chemistry Development Kit (CDK) by developing the open Scaffold Generator Java library (Publication C). Scaffold Generator can extract different scaffold types and dissect them into smaller parent scaffolds following the scaffold tree or scaffold network approach. Publication D describes the OngLai algorithm, the first automated method to identify homologous series in input datasets, group the member structures of each group, and extract their common core. To support the development of new fragmentation algorithms, the open Java rich client graphical user interface application MORTAR (MOlecule fRagmenTAtion fRamework) was developed as part of this thesis (Publication E). MORTAR allows users to quickly execute the steps of importing a structural dataset, applying a fragmentation algorithm, and visually inspecting the results in different ways. All software developed as part of this thesis is freely and openly available (see https://github.com/JonasSchaub)

ScaleTrotter: Illustrative Visual Travels Across Negative Scales

We present ScaleTrotter, a conceptual framework for an interactive, multi-scale visualization of biological mesoscale data and, specifically, genome data. ScaleTrotter allows viewers to smoothly transition from the nucleus of a cell to the atomistic composition of the DNA, while bridging several orders of magnitude in scale. The challenges in creating an interactive visualization of genome data are fundamentally different in several ways from those in other domains like astronomy that require a multi-scale representation as well. First, genome data has intertwined scale levels---the DNA is an extremely long, connected molecule that manifests itself at all scale levels. Second, elements of the DNA do not disappear as one zooms out---instead the scale levels at which they are observed group these elements differently. Third, we have detailed information and thus geometry for the entire dataset and for all scale levels, posing a challenge for interactive visual exploration. Finally, the conceptual scale levels for genome data are close in scale space, requiring us to find ways to visually embed a smaller scale into a coarser one. We address these challenges by creating a new multi-scale visualization concept. We use a scale-dependent camera model that controls the visual embedding of the scales into their respective parents, the rendering of a subset of the scale hierarchy, and the location, size, and scope of the view. In traversing the scales, ScaleTrotter is roaming between 2D and 3D visual representations that are depicted in integrated visuals. We discuss, specifically, how this form of multi-scale visualization follows from the specific characteristics of the genome data and describe its implementation. Finally, we discuss the implications of our work to the general illustrative depiction of multi-scale data

Research genres and multiliteracies: channelling the audience's gaze in powerpoint presentations

Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Comunicação e Expressão. Programa de Pós-Graduação em Letras/Inglês e Literatura Correspondente.PowerPoint-supported presentations have become an important event for creating and sharing scientific knowledge within and across disciplines (LaPorte et al., 2002; Kunkel, 2004; Tardy, 2005; Adams, 2006). Yet little is known about the ways semiotic resources enabled by PowerPoint technology of slide editing and management (e.g. slide dimensions, layout, colour) are combined with conventional resources of "research talks" (Swales, 2005[2004]) and contribute to building presentations that are valued in specific contexts. In order to inform our understanding of how research meanings are multimodally made under the influence of the software, in this thesis I investigate a set of fourteen PowerPoint Research Presentations (PPRPs) from Applied Linguistics. Two planes of cohesion are explored: (1) along the slideshows; and (2) between the slideshows and the performance. Regarding the first plane, the analysis of "periodicity" (Martin and Rose, 2007[2003]) revealed that applied linguists foreground the software's 'modularised logic', construing 'serial expansion' (Martin and Rose (2007[2003]). Others however customise slideshows so as to build 'Design Hierarchies', in which particular slides are assigned higher discursive statuses. These presenters construed a path for their audiences gaze by a configuration of semiotic resources of the display mode - e.g. slide position, background, layout, typography. As for the second plane of cohesion, I propose that slides and performance relate by 'synchronicity'. The tool recontextualizes the system of taxis (Halliday, 2009c; Halliday and Matthiessen, 2004) to account for the semantic interdependency between the displayed discourse and the performative discourse at a given point in PPRPs. In each of the cohesive planes, I set out to identify the software resources that play a role in construing cohesive ties, and evaluate both their "functional specialization" (cf. Halliday, 2009e[1975]; Kress, 2008[2003]; Jewitt and Kress, 2008[2003]) and the demands they impose on presenters and on audiences in terms of genre, discipline, software and multimodal literacies. By indicating some of the ways in which the software influences the "process of semiotic production" (Kress and van Leeuwen, 2001) of such practice, I intend to move beyond prescriptive (e. g. Costa, 2001; Cyphert, 2004; DuFrene and Lehman, 2004; Grant, 2010) as well as technically-focused (e.g. Downing and Garmon, 2002; Jones, 2003) accounts of PowerPoint. As a conclusion, I suggest that descriptions of the meaning potential in PPRPs and its conditions of access should be incorporated in pedagogies of academic multiliteracies (New London Group, 1996; Kope and Kalantizs, 2000).Apresentações de pesquisa com uso de PowerPoint desempenham um papel importante na criação e negociação de conhecimento científico em diferentes disciplinas (LaPorte et al., 2002; Kunkel, 2004; Tardy, 2005; Adams, 2006). Entretanto, pouco sabemos sobre os modos como os recursos semióticos potencializados pela tecnologia PowerPoint para edição e gerenciamento de slides (e.g. dimensões do slide, arranjo, cor) são combinados com recursos convencionais dos "relatos de pesquisa" (Swales, 2005[2004]) e contribuem para construir apresentações valorizadas em contextos específicos. No intuito de informar nosso entendimento sobre como significados de pesquisa são multimodalmente construídos sob a influência do software, nesta tese, investigo um conjunto de quatorze apresentações de pesquisa em PowerPoint (APPP) em Linguística Aplicada. Dois planos coesivos são explorados: (1) ao longo do texto em slides; e (2) entre os slides e a performance. No tocante ao primeiro plano, a análise da "periodicidade" (Martin e Rose, 2007[2003]) da informação revelou que os linguistas aplicados tendem a aderir à 'lógica modularizada' do software, realizando "expansão em série" (Martin e Rose (2007[2003]) do discurso. Outros, porém, 'personalizam' o texto em slides de modo a construir 'Hieraquias de Desenho', as quais atribuem valor de informação superordinada à determinados slides. Esses apresentadores direcionam o olhar de sua audiência por meio de uma configuração de recursos semióticos particulares do modo de exibição (e.g. sequência, fundo, arranjo, tipografia). Quanto ao segundo plano coesivo, proponho que slides e performance se relacionam por 'sincronicidade'. Essa erramenta recontextualiza o sistema de taxe (Halliday, 2009c; Halliday e Matthiessen, 2004) para explicar a interdependência semântica entre o discurso exibido e o discurso performado em um determinado ponto da APPP. Em cada um dos planos coesivos, busco identificar os recursos do software que desempenham função coesiva e avaliar tanto a sua "especialização funcional" (cf. Halliday, 2009e[1975]; Kress, 2008[2003]; Jewitt e Kress, 2008[2003]) quanto as demandas de letramento que impõem nos apresentadores e na audiência no que tange a gênero, disciplina, software e multimodalidade. Ao apontar alguns dos modos pelos quais o software influencia o "processo de produção semiótica" (Kress e van Leeuwen, 2001) dessa prática, pretendo ir além de orientações prescritivas (e. g. Costa, 2001; Cyphert, 2004; DuFrene e Lehman, 2004; Grant, 2010) e focadas em aspectos técnicos (e.g. Downing and Garmon, 2002; Jones, 2003). Sugiro, por fim, que a descrição dos significados potenciais em APPP e suas condições de acesso sejam incorporadas em pedagogias de multiletramentos acadêmicos (New London Group, 1996; Kope e Kalantizs, 2000)

Identity Crisis: “Intersectionality,” “Multidimensionality,” and the Development of an Adequate Theory of Subordination

While essentialism remains a prominent feature of progressive social movements, critical scholars have offered persuasive arguments against traditional, single-issue politics and have proposed reforms in a variety of doctrinal and policy contexts. The feminist of color critiques of feminism and antiracism provided the earliest framework for analyzing oppression in complex terms. Feminists of color and other critical scholars have examined racism and patriarchy as “intersecting” phenomena, rather than as separate and mutually exclusive systems of domination. Their work on the intersectionality of subordination has encouraged some judges and progressive scholars to discard the “separate spheres” analysis of race and gender. The powerful intersectionality model has also inspired many other avenues of critical engagement. Lesbian-feminist theorists, for example, have challenged the patriarchy and heterosexism of law and sexuality and feminist theorists, respectively, and, recently, a growing intellectual movement has emerged that responds to racism within gay and lesbian circles and heterosexism within antiracist activism. These “post-intersectionality” scholars are collectively pushing jurists and progressive theorists to examine forms of subordination as interrelated, rather than conflicting, phenomena. This Article arises out of the intersectionality and post-intersectionality literature and makes a case against the essentialist considerations that informed the Human Rights Campaign\u27s endorsement of then-United States Senator Alfonse D\u27Amato, a Republican from New York. Part I discusses the pitfalls that occur when scholars and activists engage in essentialist politics and treat identities and forms of subordination as conflicting forces. Part II examines how essentialism negatively affects legal theory in the equality context. Part III considers the historical motivation for and the efficacy of the “intersectionality” response to the problem of essentialism. Part III also extensively analyzes the “multidimensional” critiques of essentialism offered by the most recent school of thought in this area--the race-sexuality critics of law and sexuality and critical race theory. Finally, Part III examines the conceptual and substantive distinctions between multidimensionality (and other post-intersectionality theories) and intersectionality and offers suggestions for future theorizing in anti-subordination jurisprudence

Identity Crisis: Intersectionality, Multidimensionality, and the Development of an Adequate Theory of Subordination

This Article arises out of the intersectionality and post-intersectionality literature and makes a case against the essentialist considerations that informed the Human Rights Campaign\u27s endorsement of United States Senator Alfonse D\u27Amato. Part I discusses the pitfalls that occur when scholars and activists engage in essentialist politics and treat identities and forms of subordination as conflicting forces. Part II examines how essentialism negatively affects legal theory in the equality context. Part III considers the historical motivation for and the efficacy of the intersectionality response to the problem of essentialism. Part III also extensively analyzes the multidimensional critiques of essentialism offered by the most recent school of thought in this area-the race-sexuality critics of law and sexuality and critical race theory. Finally, Part III examines the conceptual and substantive distinctions between multidimensionality (and other post-intersectionality theories) and intersectionality and offers suggestions for future theorizing in anti-subordination jurisprudence