Posttranslational modification of the AU-rich element binding protein HuR by protein kinase Cdelta elicits angiotensin II-induced stabilization and nuclear export of cyclooxygenase 2 mRNA

The mRNA stabilizing factor HuR is involved in the posttranscriptional regulation of many genes, including that coding for cyclooxygenase 2 (COX-2). Employing RNA interference technology and actinomycin D experiments, we demonstrate that in human mesangial cells (hMC) the amplification of cytokine-induced COX-2 by angiotensin II (AngII) occurs via a HuR-mediated increase of mRNA stability. Using COX-2 promoter constructs with different portions of the 3' untranslated region of COX-2, we found that the increase in COX-2 mRNA stability is attributable to a distal class III type of AU-rich element (ARE). Likewise, the RNA immunoprecipitation assay showed AngII-induced binding of HuR to this ARE. Using the RNA pulldown assay, we demonstrate that the AngII-caused HuR assembly with COX-2 mRNA is found in free and cytoskeleton-bound polysomes indicative of an active RNP complex. Mechanistically, the increased HuR binding to COX-2-ARE by AngII is accompanied by increased nucleocytoplasmic HuR shuttling and depends on protein kinase Cdelta (PKCdelta), which physically interacts with nuclear HuR, thereby promoting its phosphorylation. Mapping of phosphorylation sites identified serines 221 and 318 as critical target sites for PKCdelta-triggered HuR phosphorylation and AngII-induced HuR export to the cytoplasm. Posttranslational modification of HuR by PKCdelta represents an important novel mode of HuR activation implied in renal COX-2 regulation.

INTEGRATED ASSESSMENT OF ANTHROPOGENIC, CLIMATE, AND POLICY INDUCED CHANGES OF PHOSPHORUS EXPORT IN THE UNITED STATES LAURENTIAN GREAT LAKES WATERSHEDS

Anthropogenic activities have increased phosphorus (P) loading in tributaries to the Laurentian Great Lakes resulting in eutrophication in small bays to most notably, Lake Erie. Changes to surface water quality from P loading have resulted in billions of dollars in damage and threaten the health of the world’s largest freshwater resource. To understand the factors affecting P delivery with projected increasing urban lands and biofuels expansion, two spatially explicit models were coupled. The coupled models predict that the majority of the basin will experience a significant increase in urban area P sources while the agriculture intensity and forest sources of P will decrease. Changes in P loading across the basin will be highly variable spatially. Additionally, the impacts of climate change on high precipitation events across the Great Lakes were examined. Using historical regression relationships on phosphorus concentrations, key Great Lakes tributaries were found to have future changes including decreasing total loads and increases to high-flow loading events. The urbanized Cuyahoga watersheds exhibits the most vulnerability to these climate-induced changes with increases in total loading and storm loading , while the forested Au Sable watershed exhibits greater resilience. Finally, the monitoring network currently in place for sampling the amount of phosphorus entering the U.S. Great Lakes was examined with a focus on the challenges to monitoring. Based on these interviews, the research identified three issues that policy makers interested in maintaining an effective phosphorus monitoring network in the Great Lakes should consider: first, that the policy objectives driving different monitoring programs vary, which results in different patterns of sampling design and frequency; second, that these differences complicate efforts to encourage collaboration; and third, that methods of funding sampling programs vary from agency to agency, further complicating efforts to generate sufficient long-term data to improve our understanding of phosphorus into the Great Lakes. The dissertation combines these three areas of research to present the potential future impacts of P loading in the Great Lakes as anthropogenic activities, climate and monitoring changes. These manuscripts report new experimental data for future sources, loading and climate impacts on phosphorus.

ON THE DIGITAL-POLITICAL TOPOGRAPHY OF MUSIC

The persuasive power of music is often relegated to the dimension of pathos: that which moves us emotionally. Yet, the music commodity is now situated in and around the liminal spaces of digitality. To think about how music functions, how it argues across media, and how it moves us, we must examine its material and immaterial realities as they present themselves to us and as we so create them. This dissertation rethinks the relationship between rhetoric and music by examining the creation, performance, and distribution of music in its material and immaterial forms to demonstrate its persuasive power. While both Plato and Aristotle understood music as a means to move men toward virtue, Aristotle tells us in his Laws, through the Athenian Stranger, that the very best kinds of music can help guide us to truth. From this starting point, I assess the historical problem of understanding the rhetorical potential of music as merely that which directs or imitates the emotions: that which “Soothes the savage breast,” as William Congreve writes. By furthering work by Vickers and Farnsworth, who suggest that the Baroque fascination with applying rhetorical figures to musical figures is an insufficient framework for assessing the rhetorical potential of music, I demonstrate the gravity of musical persuasion in its political weight, in its violence—the subjective violence of musical torture at Guantanamo and the objective, ideological violence of music—and in what Jacques Attali calls the prophetic nature of music. I argue that music has a significant function, and as a non-discursive form of argumentation, works on us beyond affect. Moreover, with the emergence of digital music distribution and domestic digital recording technologies, the digital music commodity in its material and immaterial forms allows for ruptures in the former methods of musical composition, production, and distribution and in the political potential of music which Jacques Attali describes as being able to foresee new political realities. I thus suggest a new theoretical framework for thinking about rhetoric and music by expanding on Lloyd Bitzer’s rhetorical situation, by offering the idea of “openings” to the existing exigence, audience, and constraints. The prophetic and rhetorical power of music in the aleatoric moment can help provide openings from which new exigencies can be conceived. We must, therefore, reconsider the role of rhetorical-musical composition for the citizen, not merely as a tool for entertainment or emotional persuasion, but as an arena for engaging with the political.

Comparison of music perception in bilateral and unilateral cochlear implant users and normal-hearing subjects

Music plays an important role in the daily life of cochlear implant (CI) users, but electrical hearing and speech processing pose challenges for enjoying music. Studies of unilateral CI (UCI) users' music perception have found that these subjects have little difficulty recognizing tempo and rhythm but great difficulty with pitch, interval and melody. The present study is an initial step towards understanding music perception in bilateral CI (BCI) users. The Munich Music Questionnaire was used to investigate music listening habits and enjoyment in 23 BCI users compared to 2 control groups: 23 UCI users and 23 normal-hearing (NH) listeners. Bilateral users appeared to have a number of advantages over unilateral users, though their enjoyment of music did not reach the level of NH listeners.