The Balance Between Prostaglandin E2 Ep3 And Ep4 Receptors Determines Severity Of Cardiac Damage In Myocardial Infarction And An Angiotensin Ii-Induced Model Of Hypertension

According to the center for disease control about 610,000 people die every year in the United States from heart disease, of which, coronary heart disease is the most common form. One major risk factor for heart attack is hypertension, which affects nearly half of all Americans [472, 473]. PGE2 plays an important role in regulating cardiovascular function and mediating inflammation, both of which contribute to the development of hypertension and/or heart disease. Prostaglandin E2 can act as a vasodilator or vasoconstrictor depending on which of its receptor subtypes are activated. In general, activation of the EP1 and EP3 receptors is vasoconstrictive while EP2/EP4 activation promotes vasodilation [13]. Treatment with an EP4 agonist has been shown to protect the heart during reperfusion after ischemia, while antagonizing EP4 reduced cardiac function and exacerbated cardiac remodeling [267, 394]. We have published that mice lacking the EP4 receptor in cardiomyocytes develop heart failure and have worsened cardiac function after MI [73, 268]. With regard to the EP3 receptor, we have published that its activation reduces contractility in isolated cardiomyocyte preparations and in the ex-vivo Langedorff system [219]. In this dissertation, we have been the first to show in both the MI and the Ang II hypertension model, that EP3 expression increases significantly, whereby the expression of EP4 does not change or increases slightly. Thus, we hypothesize that the deleterious effects of PGE2 are via the EP3 receptor. Furthermore, we have presented here that overexpression of the EP4 receptor in the cardiomyocytes is protective in a mouse model of MI by improving cardiac function, and reducing fibrosis and inflammation [218]. We postulated that the mechanism of reduced inflammation may be mediated by the cardiac fibroblasts. We therefore show in isolated adult mouse cardiac fibroblasts, that PGE2 and an EP4 receptor agonist reduce LPS-stimulated MCP-5 production. Lastly, we report that activation of the EP3 receptor is deleterious in Ang II hypertension and that systemic administration of an EP3 antagonist can reduce blood pressure after Ang II infusion

A Self-Tuning WEC Controller for Changing Sea States

A self-tuning proportional-integral control law prescribing motor torques was tested in experiment on a three degree-of-freedom wave energy converter. The control objective was to maximize electrical power. The control law relied upon an identified model of device intrinsic impedance to generate a frequency-domain estimate of the wave-induced excitation force and measurements of device velocities. The control law was tested in irregular sea-states that evolved over hours (a rapid, but realistic time-scale) and that changed instantly (an unrealistic scenario to evaluate controller response). For both cases, the controller converges to gains that closely approximate the postcalculated optimal gains for all degrees of freedom in a sufficiently short-time for realistic sea states. In addition, electrical power was found to be relatively insensitive to gain tuning over a broad range of gains, implying that an imperfectly tuned controller does not result in a large penalty to electrical power capture. Because the controller relies on an identified model of device intrinsic impedance, the sensitivity of power capture was evaluated with respect to uncertainty in the constituent terms of intrinsic impedance. Power capture is found to be relatively insensitive to uncertainty of 20% in constituent terms of the identified intrinsic impedance model. An extension of this control law that allows for adaptation to a changing device impedance model over time is proposed for long-term deployments, as well as an approach to explicitly handle constraints within this architecture

Neoliberal governing through social enterprise: Exploring the neglected roles of deviance and ignorance in public value creation

This article makes a case for paying greater attention to how informal relationships between government officials and civil society practitioners impact processes of public value creation. Drawing on data from a five‐year qualitative longitudinal study, we illuminate how civil society practitioners deviate from the formal objectives of social enterprise policies in order to create what they see as having public value. Through a process of theory elaboration, we demonstrate how government officials’ wilful ignorance of, or informal collaboration in, such deviance, precipitates forms of public value that are consistent with wider political objectives. Our analysis adds nuance and granularity to the debate on public value by drawing attention to the arcane ways it may be informally negotiated and created outside of the public sphere. This opens up new empirical and theoretical opportunities for understanding how deviance and ignorance might be symbiotically related in processes of public value creation.

The integration of human resource and operation management practices and its link with performance: A longitudinal latent class study

This paper reviews the literature on the association between lean production and performance. From this, propositions on the integration and evolution of operation and human resource management practices associated with the lean production concept are developed. Using 24 years of data on the use of seven core OM and HRM practices in British manufacturing firms, the potential link between integration in the use of practices and productivity is tested. In each year, three latent clusters are identified via ordered restricted latent class models; the cluster that consistently makes a more integrated use of practices outperforms the others. Furthermore, the longitudinal nature of the data permits modeling the growth curves of each practice in the sample, recognizing any similarity in growth and investigating whether or not an early integration in adoption of practices is associated with higher final productivity. The results show that pioneers are more productive, thus suggesting that the head start in integrating core OM and HRM practices associated with the lean production concept has paid off. © 2010 Elsevier B.V. All rights reserved

Positive Selection Differs between Protein Secondary Structure Elements in Drosophila

Different protein secondary structure elements have different physicochemical properties and roles in the protein, which may determine their evolutionary flexibility. However, it is not clear to what extent protein structure affects the way Darwinian selection acts at the amino acid level. Using phylogeny-based likelihood tests for positive selection, we have examined the relationship between protein secondary structure and selection across six species of Drosophila. We find that amino acids that form disordered regions, such as random coils, are far more likely to be under positive selection than expected from their proportion in the proteins, and residues in helices and β-structures are subject to less positive selection than predicted. In addition, it appears that sites undergoing positive selection are more likely than expected to occur close to one another in the protein sequence. Finally, on a genome-wide scale, we have determined that positively selected sites are found more frequently toward the gene ends. Our results demonstrate that protein structures with a greater degree of organization and strong hydrophobicity, represented here as helices and β-structures, are less tolerant to molecular adaptation than disordered, hydrophilic regions, across a diverse set of proteins