VictorJuiz/thesis huggingface dataset:
The Role Of Homeodomain Transcription Factor Irx5 In Cardiac Contractility and Hypertrophic Response

Irx5 is a homeodomain transcription factor that negatively regulates cardiac fast transient outward K+ currents (Ito,f) via the KV4.2 gene and is thereby a major determinant of the transmural repolarization gradient. While Ito,f is invariably reduced in heart disease and changes in Ito,f can modulate both cardiac contractility and hypertrophy, less is known about a functional role of Irx5, and its relationship with Ito,f, in the normal and diseased heart. Here I show that Irx5 plays crucial roles in the regulation of cardiac contractility and proper adaptive hypertrophy. Specifically, Irx5-deficient (Irx5-/-) hearts had reduced cardiac contractility and lacked the normal regional difference in excitation-contraction with decreased action potential duration, Ca2+ transients and myocyte shortening in sub-endocardial, but not sub-epicardial, myocytes. In addition, Irx5-/- mice showed less cardiac hypertrophy, but increased interstitial fibrosis and greater contractility impairment following pressure overload. A defect in hypertrophic responses in Irx5-/- myocardium was confirmed in cultured neonatal mouse ventricular myocytes, exposed to norepinephrine while being restored with Irx5 replacement. Interestingly, studies using mice virtually lacking Ito,f (i.e. KV4.2-deficient) showed that reduced contractility in Irx5-/- mice was completely restored by loss of KV4.2, whereas hypertrophic responses to pressure-overload in hearts remained impaired when both Irx5 and Ito,f were absent. These findings suggest that Irx5 regulates cardiac contractility in an Ito,f-dependent manner while affecting hypertrophy independent of Ito,f. On the other hand, Irx5-ablation attenuated calcineurin (Cn)-induced hypertrophy in hearts and cultured cardiomyocytes, suggesting that the effect of Irx5 on hypertrophy involves the Cn-NFAT signalling cascade. Biochemical assessments further revealed that Irx5 can positively mediate Cn-NFAT activities as well as Nfatc3 and Gata4 expression, and interacts with Nfatc3 and Gata4, suggesting the formation of a transcription complex for hypertrophic gene regulation. Taken together, these studies have identified Irx5 as a vital cardiac transcription factor, important for contractile function of the heart by regulating Ito,f, and compensatory hypertrophic response to biomechanical stress in the heart by affecting the Cn-NFAT (and Gata4) signaling pathway.

Keywords: Transcription factor
Irx5
Contractility
Hypertrophy
Heart
Advisor: Backx, Peter
Critical Investigation of the Sierra Leone Conlfict: A Moral Practical Reconstruction of Crisis and Colonization in the Evolution of Society

This Sierra Leone Conflict arose from the society’s failure to institutionalize the requisite post-conventional organizing principle for collective will formation and for conflict resolution. In this post-traditional society - one artificially constructed from diverse political and cultural groups, without a shared ethos – only mutual (communicative) understanding can resolve differences and ensure solidarity. A lack of mutual understanding overburdens the adaptive capacity of the society, creating crises tendencies. Repression only intensified these tendencies, ensuring their eventual catastrophic explosion, 11 years civil conflict. State hindrances to social (communicative) interaction rendered the society incapable of realizing the requisite post conventional moral learning i.e. the social intelligence or problem-solving equipment required to resolve conflict, decolonize itself, neutralize normative power, shed dogmatic consciousness, change oppressive conventions, and influential customs. Thus, the study promotes civic virtues of post conventional morality (justice, truthfulness, moral rightness) as the key for liberating the society from its crisis-inducing colonial organizing principle. As the basis of sociology, the discipline the remains focused on society-wide problems, the theory of social evolution is adopted here to reconstruct the crisis in Sierra Leone’s constitutional democratic development. The study uses the rational reconstructive method to explicate problematic validity claims of norms, policy decisions, or the social order. The social order was rendered crisis-ridden because the reasons - the axis around which mutual understanding revolve - adduced for it cannot admit of consensus. The emerging social disintegration exemplifies use of deficient logic in social interaction, one below the requisite categorical moral cognitive consciousness. For this research, colonization is not necessarily externally induced, but forms of understanding in the political, legal, social, and educational interactions. The key point of the study is this: today Sierra Leone achieves solidarity, and decolonize from its conventional organizing principle, only if the state, economy, and civil society can find their limit in the socio-cultural domain.

Keywords: critical social theory
contemporary social theory
critical pedagogy
discourse theory of law and democracy
procedural paradigm of law
political philosophy of justice
postmetaphysical thought
reconstruction of historical materialism
rational reconstruction
theory of social evolution
African crisis and conflict
critical African studies
politics of decolonization
The Sierra Leone conflict
Advisor: Dei, George Jerry Sefa
Competition in Visual Working Memory

The processing of information within the visual system is limited by several cognitive and neural bottlenecks. One critical bottleneck occurs in visual working memory (VWM), as the amount of information that can be maintained on-line is limited to three to four items. While numerous theories have addressed this limited capacity of VWM, it is unclear how processing bottlenecks in the initial selection and perception of visual information affect the number or precision of representations that can be maintained in VWM. The purpose of this dissertation was to examine whether early competition for resources within the visual system limits the number or precision of representation that can be maintained in VWM. To establish whether competitive interactions affect VWM, Chapters 1 – 4 tested whether performance on VWM tasks was related to the distance between memory items. The results of these experiments reveal that when objects are presented close together in space, VWM performance is impaired relative to when those same objects are presented further apart. Using a three-component model of continuous responses in a recall task, Chapters 3 – 4 demonstrated that the distance between objects primarily affects the precision of responses, and increases the number of non-target errors. Chapter 5 extended these findings to distractors, demonstrating that multiple distractors affect the precision and accuracy of VWM responses. Chapters 6 – 7 tested how attentional selection can bias memory representations, revealing that objects that are given high attentional priority were reported with greater precision. Finally, Chapters 8 and 9 examined bias-signals as a potential source of individual differences in VWM performance, revealing that high-performers have more precise representations of sub-capacity representations than low-performers. Together, these results reveal that VWM performance is limited by competition for representation within the visual system, and that attention plays a critical role in resolving competition and consequently, determining the contents of VWM.

Keywords: Visual Working Memory
Biased Competition
Cognitive Neuroscience
Advisor: Ferber, Susanne
Re(art)iculating Empowerment: Cooperative Explorations with Community Development Workers in Pakistan

Situated in the postcolonial modernizing discourse of development, many empowerment narratives tend to pre-identify, pre-construct and categorize community development workers/ mobilizers as empowered bodies, catalysts, and change agents. These bodies are expected to and are assumed will facilitate a transformation in oppressed peoples’ self image and belief’s about their rights and capabilities. Although feminist academics/activists have been critical of imperialist, neo-liberal and politico-religious co-optations of understandings of empowerment, limited attention seems to have been paid to the material effects of empowerment narratives on the lives of these community development workers. Nor does there appear to be sufficient analysis into how local community development workers/mobilizers who find themselves in precarious positions of employment, engage with these narratives. Provided with guidelines based on project objectives and lists of targets, many development workers/mobilizers in Pakistan tend to live with expectations of how best to ‘translate/transform’ empowerment from the abstract into the concrete while restricted in their space to critically reflect on theoretical notions that drive their practice. This thesis provides insight into the economy of empowerment narratives and the potential they have to mediate ‘encounters’ shaping ‘subject’ and ‘other’ by critically exploring how bodies of community development workers are put to work and are made to work. Drawing on feminists poststructuralist and postcolonial theory my work explores how these community workers/mobilizers located in the urban metropolis of Karachi, embedded in a web of multiple intersecting structures of oppression and power relations ‘encounter’, theorize, strategize and act upon understanding of empowerment and community development through an arts informed cooperative inquiry. Through the use of prose, creative writing, short stories, photo narratives, artwork and interactive discussions my participants and I begin to complicate these narratives. As a result empowerment narratives begin to appear as colliding discourses, multi-layered complex constructs, which may form unpredictable, messy and contradictory assemblages; as opposed to linear, universal, inevitable and easily understood outcomes and processes. I conclude that the insistence to complicate and situate such messy understandings in specific contexts is important for women’s movements if empowerment is to retain its strategic meaning and value in feminist theorizing.

Keywords: Empowerment
Community Development
Development Workers
Pakistan
Advisor: Kiran, Mirchandani
The Clathrin Adaptor AP-1 and Type II Phosphatidylinositol 4-Kinase are Required for Glue Granule Biogenesis in Drosophila

Regulated secretion of hormones, digestive enzymes and other biologically active molecules requires formation of secretory granules. However, the molecular machinery required for secretory granule biogenesis is incompletely understood. I used powerful genetic approaches available in the fruit fly Drosophila melanogaster to investigate the factors required for biogenesis of mucin-containing ‘glue granules,’ which form within epithelial cells of the third-instar larval salivary gland. I discovered that clathrin and the clathrin adaptor protein complex (AP-1), as well the enzyme type II phosphatidylinositol 4-kinase (PI4KII), are indispensable for glue granule biogenesis. Clathrin and AP-1 are necessary for maturation of exocrine, endocrine and neuroendocrine secretory granules in mammalian cells. I found that Drosophila clathrin and AP-1 colocalize at the TGN and that clathrin recruitment requires AP-1. I further showed that clathrin and AP-1 colocalize with secretory cargo at the TGN and on glue granules. Finally, I demonstrated that loss of clathrin or AP-1 leads to a profound block in secretory granule biogenesis. These findings establish a novel role for AP-1/clathrin-dependent trafficking in the formation of mucin-containing secretory granules. Type II phosphatidylinositol 4-kinase (PI4KII) generates the membrane lipid phosphatidylinositol 4-phosphate (PI4P) at the trans-Golgi network and is required to recruit cargo to endosomes in mammalian cells. I generated null mutations in the sole Drosophila PI4KII and demonstrated a role for PI4KII in both glue granule and pigment granule biogenesis. PI4KII mutant salivary gland cells exhibit small glue granules and mislocalize glue protein to abnormally large late endosomes. Additionally, PI4KII mutants exhibit altered distribution of the granule specific SNARE, SNAP-24. These data point to a crucial role for PI4KII in sorting of regulated secretory products during granule biogenesis. Together, my results indicate that the larval salivary gland is a valuable system for investigating molecular mechanisms involved in secretory granule biogenesis, and provide a framework for future studies using this system.

Keywords: Drosophila
adaptor protein complex
clathrin
phosphatidylinositol 4-kinase
trafficking
glue granule
mucin
AP-1
Advisor: Brill, Julie
The Versio Dionysii of John Scottus Eriugena. A Study of the Manuscript Tradition and Influence of Eriugena's Translation of the Corpus Areopagiticum From the 9th through the 12th century.

Abstract The research presented in this dissertation is an examination of the manuscript tradition of John Scottus Eriugena’s Latin translation (the Versio Dionysii) of the Greek works of Dionysius the pseudo-Areopagite. The goal of this project is fourfold: first, to establish the relationship between the extant families of the manuscripts; second, to re-examine the state of Greek studies in the 9th century based on the relationship between the manuscript families; third, to trace the continued use of these recensions through the 12th century; and, finally, to examine Eriugena’s interpretation of the writings of the pseudo-Areopagite based on the Irishman’s translations of certain philosophic ideas. The First chapter establishes the existence of three distinct recensions, rather than two, as previously thought. Two of these recensions represent attempted corrections of the third. All three recensions (together with their corrections) are attributable to Eriugena (whether directly or indirectly). The second chapter examines the level of Eriugena’s understanding of Greek, especially within the context of the state of Greek studies in the 9th century. Special attention is given to the corrections of the later recensions, which suggest an improvement in Eriugena’s Hellenism. The third chapter examines the continued use of the Versio’s during the Middle Ages through the 12th century, with special care to clarify which recensions were known to which readers. The fourth and final chapter presents the originality of Eriugena’s interpretation of the pseudo-Areopagite’s thought. This originality stems in part from his understanding of the Greek text, and in part from his attempts to harmonize his sources.

Keywords: Eriugena
Dionysius Areopagita
Versio Dionysii
Advisor: Magee, John
Shakespeare's Openings in Action: A Study of Four Plays from the Period 1591-c.1602

Regardless of genre, Shakespeare’s plays open in many different ways on the stage. Some openings come in the form of a prologue and extend from it; others in the form of a framing dialogue; some may begin in medias res; and there is also a single case of an induction in The Taming of the Shrew. My dissertation, “Shakespeare’s Openings in Action: A Study of Four Plays from the Period 1591- c.1602,” subsequently referred to as “Shakespeare’s Openings in Action,” attempts to define the construction of openings in the context of Shakespeare’s dramaturgy and to understand texts which were written in the first place to be performed on a platform stage by actors experienced in theatrical practice. By analysing the playwright’s organization of the dramatic material, as reflected in the play-texts, I attempt to gauge how an opening set out to engage original audiences in the play, an essential function of theatrical composition, and to determine to what extent the play-text may be considered as an extended stage direction for early modern actors.1 What is the present state of scholarship in the subject? Although sparse, critical interest in the openings of Shakespeare’s plays can be found as early as 1935 in the work of A. C. Sprague, Shakespeare and the Audience. In more recent years, other studies have appeared, for instance, Robert F. Willson, Jr., Shakespeare’s Opening Scenes (1977), and a number of articles included in Entering the Maze: Shakespeare’s Art of Beginning, edited by F. Willson Jr. (1995). Existing scholarship provides a good general framework for further research into the openings of Shakespeare’s plays. In addition to the studies presented above, I shall draw on analytical approaches to play-text analysis which involve theatre practice, for example in the work of André Helbo, Approaching Theatre (1991), Anne Ubersfeld, Reading Theatre (1996), and John Russell Brown, Shakespeare’s Plays in Performance (1993); John Barton, Playing Shakespeare (1984), and Cicely Berry, Text in Action. London (2001). These works provide revealing insights into the theatrical possibilities of dramatic language and actor technique. 1The analytical method presented in this dissertation supplements studies made of the complex textual histories of Shakespeare’s plays by considering the staging and characterisation information they contain. In the case of multiple-text plays, it takes account of editorial scholarship and explains the reasons for choosing to analyse the material contained in one version over the other(s).

Keywords: Early Modern Drama, Shakespeare, Theory of Early Modern Drama
Openings
Beginnings
Openings in Shakespearean Dramaturgy
Advisor: Levenson, Jill L.
The Nature of Working Memory: Separate, Flexible Resources for Location- vs. Feature-based Representations in Visual Short-term Memory

Working memory, or the ability to maintain and manipulate information in mind when it is no longer physically present, is a pervasive yet severely capacity-limited component of cognition. Visual working memory, also known as visual short-term memory (VSTM), is limited to three or four items on average, with individual differences that range from roughly two to up to six items. Despite agreement that capacity is functionally limited, the current literature is split with respect to the nature of VSTM representations on two key questions: (1) What information is maintained in VSTM? (2) How is information stored in VSTM? The studies presented here address these questions using an event-related potential (ERP) task and a series of behavioural experiments that incorporate attentional selection via retrospective cueing (retro-cues). Experiment 1 manipulated both the number of features and the number of locations to be remembered in a lateralized change-detection task, with differences in the amplitude and topography of the resulting contralateral delay activity (CDA) indicating separate stores for features and locations. Experiments 2a-c established the basic effects of retro-cues on change-detection tasks, showing that attentional selection operated on one system at a time, with overall shorter response times and increased capacity estimates once baseline capacity was exceeded. Experiments 3a-b demonstrated that retro-cues biased VSTM resources to the cued item at the expense of representational strength of the other, non-cued items, showing flexible reallocation of resources. Experiments 4a-b presented multiple retro-cues to further examine the flexible reallocation of resources in VSTM, showing that capacity benefits depended on spatial specificity of retro-cues and that VSTM weights could be reallocated multiple times before probe comparison. Experiment 5 discounted the potential role of a general alerting mechanism in boosting capacity estimates, showing again that the retro-cue benefit required specificity of the cue. Experiment 6 showed that flexible reallocation of resources within one system did not change the online maintenance of representations within the other system. Thus, the studies collectively address the questions of (1) what and (2) how information is stored by supporting a two-system model of VSTM in which (1) locations and features are stored (2) independently via flexibly allocated resources.

Keywords: visual short-term memory
attention
Advisor: Ferber, Susanne
Characterization of an IL-12-driven Anticancer Response, and the CD4+ CTL Population Incited, in a Murine Model of Leukaemia

For the treatment of cancer, immunotherapy has some inherent advantages over other treatment modalities: disseminated disease can be eradicated due to the systemic nature of immunity, the immune system is effective against a wide range of targets, long-term memory can offer added protection against disease relapse, immunotherapy should be relatively non-toxic, and it can be synergistically combined with other treatment platforms such as radiation and chemotherapy. Type 1 immune responses are thought to be superior for the treatment of cancer and, as the quintessential Th1 polarizing cytokine, interleukin-12 (IL-12) holds much promise; however, optimal therapeutic protocols have yet to be developed and clinical results have fallen short of this promise. The in vivo IL-12 experiments described here highlight a characteristic of cellular therapy that has not previously been appreciated. That is, the effect of cell-mediated cytokine delivery on the immediate microenvironment and how that affects the immune response initiated. This observation has implications for the clinical application of IL-12 therapy but may also prove to be an important consideration when studying other immunostimulants. I have herein developed a novel in vitro assay system that I have used to dissect the cellular responses to IL-12 and to identify the signals that are required for activation of a cluster of differentiation 4 (CD4)+ effector population that affects leukaemia cell clearance both in vitro and in vivo. This work, and the future studies proposed, will expand our understanding of the potential of IL-12 immunotherapy and enhance our ability to manipulate therapeutic conditions to favour the desired response. Moreover, the in vitro assay system offers a method for further characterization of CD4+ effector cells and the development of protocols to initiate their potent anticancer activity.

Keywords: IL-12
immunotherapy
mouse
cytotoxic
Advisor: Paige, Christopher J.