ADENYLYL CYCLASE TYPE 9: REGULATION AND CARDIAC FUNCTION

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

How Much Do You Love Grey’s Anatomy?

Does the prominence of medical Television Shows impact people’s decision to pursue a medical career? We are constantly told that the things we see in media and entertainment influences how we think about things, but not much research has been done regarding its ability to impact major life choices such as career choice. This paper investigates this by examining the causal relationship between television and interest in the pursuit of a medical career. An ordinary least squares model, created using time series data over the last 24 years, tested specifically the effect of the number and quality of medical television shows both on the rate of change in medical school applications for men and women and the proportion of female applicants. This study found that while medical tv shows don’t have a statistically significant impact on application rates for men or women, female-driven shows cause a larger proportion of the applicant pool to be female

Family Dynamics and Auditory Verbal Therapy

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

Demographic Data for Development: Overview Report

Presents findings from case studies in Ethiopia, Ghana, Senegal, and Uganda of the demand for and utilization of data by policy makers and the factors behind their underutilization. Explores ways to improve access to data needed to develop sound policies

Form Follows Function

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

Leopards, Roman Soldiers, and the Historia Augusta

published or submitted for publicatio

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

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

Contact monoids and Stein cobordisms

Suppose S is a compact surface with boundary, and let g be a diffeomorphism of S which fixes the boundary pointwise. We denote by (M_{S,g},\xi_{S,g})$ the contact 3-manifold compatible with the open book (S,g). In this article, we construct a Stein cobordism from the contact connected sum (M_{S,h},\xi_{S,h}) # (M_{S,g},\xi_{S,g}) to (M_{S,hg},\xi_{S,hg}), for any two boundary-fixing diffeomorphisms h and g. This cobordism accounts for the comultiplication map on Heegaard Floer homology discovered in an earlier paper by the author, and it illuminates several geometrically interesting monoids in the mapping class group of S. We derive some consequences for the fillability of contact manifolds obtained as cyclic branched covers of transverse knots.Comment: 12 pages, 5 figure