77,439 research outputs found

    ADENYLYL CYCLASE TYPE 9: REGULATION AND CARDIAC FUNCTION

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    Abnormalities in cardiac stress signaling underlie a number of cardiovascular diseases (e.g. arrhythmias and heart failure). Cardiac stress signaling pathways normally integrate signals from the sympathetic nervous system to promote efficient contraction and relaxation under stress. Sympathetic control through β-adrenergic stimulation is propagated by adenylyl cyclase (AC). AC synthesizes cyclic AMP (cAMP), an important second messenger that initiates signaling pathways to modulate physiological and pathophysiological functions of the heart, including the activation of PKA and subsequent phosphorylation of ion channels, contractile machinery, and stress response proteins that enhance cardiac function. Alterations of cAMP signaling occur in the failing heart and contribute to impaired function. Of the AC isoforms present in adult cardiomyocytes (AC 4, 5, 6, and 9), AC9 is the most divergent in sequence and understudied. The work presented in this dissertation sought to evaluate the direct regulatory properties of AC9 and explores roles for AC9 in heart. To clarify conflicting reports for AC9 regulation, proposed regulators were systematically evaluated, including G-proteins, protein kinases, and forskolin utilizing in vitro and cell based assays. Overall, I conclude that most G-proteins or protein kinases do not directly regulate AC9, except Gαs, in vitro. Although AC9 is forskolin insensitive alone, weak activation by forskolin in the presence of Gαs is possible. AC9 shows significant homodimerization and modest heterodimerization with AC5/6, which may account for the conflicting reports surrounding the regulation of this AC isoform. viii To study the role of AC9 in heart, a mouse model of AC9 genetic deletion was utilized. Although deletion of AC9 reduces less than 3% of total AC activity in heart, Yotiao-associated AC activity is eliminated. AC9-/- mice exhibit no structural abnormalities but show a significant bradycardia and alterations in Doppler echocardiography indicative of grade 1 diastolic dysfunction with preserved ejection fraction. Identification of novel AC9 binding partners, including the small heat shock protein 20 (Hsp20) and Popeye domain containing (Popdc) proteins may contribute to the underlying mechanisms of AC9-/- phenotypes. Collectively, this work suggests that AC9 forms distinct macromolecular complexes that contribute to local cAMP pools important for driving physiological function of the heart

    A well-ordered society with publicly acknowledged principles - a re-interpretation of Rawlsian social contract

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    John Rawls is arguably the most influential political philosopher of the twentieth century. In his most seminal books, A Theory of Justice (1971), Rawls claims that his aim is to ‘present a conception of justice which generalizes and carries to a higher level of abstraction the familiar theory of the social contract as found, say, in Locke, Rousseau, and Kant.’ However, what role does the idea of social contract play in Rawls’ theory is rarely discussed among Rawls scholars. Some scholars contend that Rawlsian social contract is a kind of hypothetical contract which people would make behind the ‘veil of ignorance,’ and this idea is redundant in Rawls’ theory. In this poster, I would like to argue that Rawlsian social contract should rather be understood as a social agreement on political principles which people would make in a well-ordered society. The idea of social contract is necessary because it represents a political ideal in Rawls’ mind

    The Immigration Advocates Network: An Online Collaboration led by Pro Bono Net Provides Immigration - Related Resources

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    This is the story of how coalitions of organizations with a shared goal can collaborate online to provide learning and information resources that alone, they might never be able to offer. Pro Bono Net's Immigration Advocates Network, profiled here, is still a work in progress but one with quantifiable results in the present and great promise for the future

    A GIT Construction of Moduli Spaces of Stable Maps in Positive Characteristic

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    In a previous paper, the author and David Swinarski constructed the moduli spaces of stable maps, \bar M_g,n(P^r,d), via geometric invariant theory (GIT). That paper required the base field to be the complex numbers, a restriction which this paper removes: here the coarse moduli spaces of stable maps are constructed via GIT over a more general base.Comment: 20 pages; the main theorem is now proved over a more general bas

    The Visual Documentation of Antietam: Peaceful Settings, Morbid Curiosity, and a Profitable Business

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    On September 17, 1862, Confederate General Robert E. Lee led the Army of Northern Virginia into Sharpsburg, Maryland to confront Federal General George McClellan and the Army of the Potomac. The battle that followed became the single bloodiest day in American history. There were approximately 25,000 American casualties and battlefields were left in desolation, strewn with corpses needing burial. The Battle of Antietam, or Sharpsburg, is a well-documented and important battle of the Civil War. Endless research has been done regarding its impact on the war, military strategies, and politics. However, there is a unique aspect of Antietam which merits closer attention: its visual documentation. [excerpt

    Family Dynamics and Auditory Verbal Therapy

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    Auditory Verbal Therapy (AVT) is an intervention approach that is structured around caregiver involvement. While this model emphasizes the need for interventions to occur throughout the week within activities of daily living, many families have different dynamics and are drifting away from the “standard” two-parent structure. This study aims to explore the different family structures and dynamics of children who are receiving AVT services. Findings demonstrated that AVT does not seem to interfere with participation in extracurricular activities, it may be beneficial for families to have different people in the family taking the child to therapy and facilitating therapy at home, and extended family living close may be beneficial to the family and their involvement with Auditory Verbal Therapy

    Necessary Intrustion or Criminalising the Innocent? An exploration of Modern Criminal Vetting

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    This article considers the processes of criminal vetting and outlines the legislative framework allowing such disclosures and subsequent judicial interpretation of that framework. The focus is on disclosure of non-conviction (so-called ‘soft’) materials on ‘enhanced’ certificates and subsequent challenges to those disclosures at judicial review. Key cases are analysed, including R (on the application of X) v Chief Constable of West Midlands Police (2004) and R (on the application of L) (FC) (Appellant) v Commissioner of Police of the Metropolis (Respondent) (2009). The proportionality test in R (L) is noted and its subsequent application in the recent decisions of R (on the application of C) v Chief Constable of Greater Manchester; Secretary of State for the Home Department (2011) and R (on the application of B) v Chief Constable of Derbyshire Constabulary (2011) is scrutinised. The article also highlights interference in Article 8 of the European Convention on Human Rights (right to privacy) and questions whether interference can be justified, and whether the present judicial focus on right of representations in such cases is misplaced

    Leopards, Roman Soldiers, and the Historia Augusta

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    Form Follows Function

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    Natural history. Teaching. Writing. All have form, all have function. But just as no architecture is risk-free, no architecture is neutral. In this personal essay, I explore the surprising connections that develop when university students engage with natural history as way of knowing the ground underfoot
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