Hyper-contractility and impaired cGMP signaling in the BKCa channel deletion model of erectile dysfunction

Matthias E. Werner is with the Division of Cardiovascular and Endocrine Science, School of Medicine, University of Manchester, Manchester M13 9NT, UK -- Andrea L. Meredith is with the Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA -- Richard W. Aldrich is with the Section of Neurobiology, 1 University Station C7000, The University of Texas at Austin, Austin, TX 78712, USA -- Mark T. Nelson is with the Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405, USAErectile dysfunction (ED) is frequently elicited by a multiplicity of pathogenic factors, predominantly by impaired formation of and responsiveness to nitric oxide (NO) and the downstream effectors soluble guanylate cyclase (sGC) and cGMP-dependent protein kinase I (PKGI). In smooth muscle, one important target of PKGI is the large conductance, calcium-sensitive potassium (BKCa) channel, which upon activation hyperpolarizes the smooth muscle cell membrane, causing relaxation. In our earlier report [1], we demonstrated that ablation of the gene, encoding for the pore-forming α subunit of the BKCa channel in mice (Slo-/-) induced an increase of corpus cavernosum smooth muscle (CCSM) force oscillations, led to reduced nerve-evoked relaxations and ED. In our current work, we used this ED model to explore the role of the BKCa channel in the NO/cGMP pathway. Electrical field stimulation (EFS)-induced contractions of CCSM strips from Slo-/- mice demonstrated a 53% increase that could be reduced by sildenafil similar to levels observed in strips from wild-type (Slo+/+) mice. In Slo-/- strips precontracted with phenylephrine (PE), SNP and sildenafil induced relaxations, which were diminished by 10% and 7% over Slo+/+, respectively. Neither SNP nor sildenafil was able to reduce the enhanced force oscillations, which were induced by the loss of BKCa channel function. Yet, these oscillations could be completely eliminated by blocking L-type voltage-dependent calcium channels (VDCCs). The latter results indicate that loss of BKCa channel leads to ED and hyper-contractility likely due to instability of membrane potential which activates VDCCs. Moreover, since the relaxing effects of SNP and sildenafil were reduced in Slo-/-, the ED phenotype in our BKCa channel deletion model could also be the consequence of an impaired NO/cGMP signaling [email protected]

Proceedings, Pot Chrysanthemum School, 1971

Space management / Robert W. Langhans -- Soils / D. C. Kiplinger -- Nutrition / George L. Staby -- Temperature and photoperiod / Joseph W. Love -- Automated short day control -- R. A. Aldrich -- Growth regulators / James B. Shanks -- Programming for insect-free pot mums / Richard K. Lindquist -- Programming for disease-free pot mums / Lester P. Nichols and Paul E. Nelson -- Where you go wrong / Harry K. Tayam

Untangling the Conceptual Isssues Raised in Reydon and Scholz’s Critique of Organizational Ecology and Darwinian Populations

Reydon and Scholz raise doubts about the Darwinian status of organizational ecology by arguing that Darwinian principles are not applicable to organizational populations. Although their critique of organizational ecology’s typological essentialism is correct, they go on to reject the Darwinian status of organizational populations. This paper claims that the distinction between replicators and interactors, raised in modern philosophy of biology but not discussed by Reydon and Scholz, points the way forward for organizational ecologists. It is possible to conceptualise evolving Darwinian populations providing the inheritance mechanism is appropriately specified. By this approach, adaptation and selection are no longer dichotomised, and the evolutionary significance of knowledge transmission is highlightedPeer reviewe

Re-imagining the growth process: (co)-evolving metaphorical representations of entrepreneurial growth

We investigate the role and influence of the biological metaphor ‘growth’ in studies of organizations, specifically in entrepreneurial settings. We argue that we need to reconsider metaphorical expressions of growth processes in entrepreneurship studies in order to better understand growth in the light of contemporary challenges, such as environmental concerns. Our argument is developed in two stages: first, we review the role of metaphor in organization and entrepreneurship studies. Second, we reflect critically on three conceptualizations of growth that have drawn on biological metaphors: the growing organism, natural selection and co-evolution. We find the metaphor of co-evolution heuristically valuable but under-used and in need of further refinement. We propose three characteristics of the co-evolutionary metaphor that might enrich our understanding of entrepreneurial growth: relational epistemology; collectivity; and multidimensionality. Through this we provide a conceptual means of reconciling an economic impetus for entrepreneurial growth with an environmental imperative for sustainability

Learning From Early Attempts to Generalize Darwinian Principles to Social Evolution

Copyright University of Hertfordshire & author.Evolutionary psychology places the human psyche in the context of evolution, and addresses the Darwinian processes involved, particularly at the level of genetic evolution. A logically separate and potentially complementary argument is to consider the application of Darwinian principles not only to genes but also to social entities and processes. This idea of extending Darwinian principles was suggested by Darwin himself. Attempts to do this appeared as early as the 1870s and proliferated until the early twentieth century. But such ideas remained dormant in the social sciences from the 1920s until after the Second World War. Some lessons can be learned from this earlier period, particularly concerning the problem of specifying the social units of selection or replication

Contemplating an evolutionary approach to entrepreneurship

This paper explores that application of evolutionary approaches to the study of entrepreneurship. It is argued an evolutionary theory of entrepreneurship must give as much concern to the foundations of evolutionary thought as it does the nature entrepreneurship. The central point being that we must move beyond a debate or preference of the natural selection and adaptationist viewpoints. Only then can the interrelationships between individuals, firms, populations and the environments within which they interact be better appreciated

Lysine-Rich Extracellular Rings Formed by hβ2 Subunits Confer the Outward Rectification of BK Channels

The auxiliary β subunits of large-conductance Ca2+-activated K+ (BK) channels greatly contribute to the diversity of BK (mSlo1 α) channels, which is fundamental to the adequate function in many tissues. Here we describe a functional element of the extracellular segment of hβ2 auxiliary subunits that acts as the positively charged rings to modify the BK channel conductance. Four consecutive lysines of the hβ2 extracellular loop, which reside sufficiently close to the extracellular entryway of the pore, constitute three positively charged rings. These rings can decrease the extracellular K+ concentration and prevent the Charybdotoxin (ChTX) from approaching the extracellular entrance of channels through electrostatic mechanism, leading to the reduction of K+ inflow or the outward rectification of BK channels. Our results demonstrate that the lysine rings formed by the hβ2 auxiliary subunits influences the inward current of BK channels, providing a mechanism by which current can be rapidly diminished during cellular repolarization. Furthermore, this study will be helpful to understand the functional diversity of BK channels contributed by different auxiliary β subunits

Maintenance of cross-sector partnerships: the role of frames in sustained collaboration

We examine the framing mechanisms used to maintain a cross-sector partnership (XSP) that was created to address a complex long-term social issue. We study the first eight years of existence of an XSP that aims to create a market for recycled phosphorus, a nutrient that is critical to crop growth but whose natural reserves have dwindled significantly. Drawing on 27 interviews and over 3,000 internal documents, we study the evolution of different frames used by diverse actors in an XSP. We demonstrate the role of framing in helping actors to avoid some of the common pitfalls for an XSP, such as debilitating conflict, and in creating sufficient common ground to sustain collaboration. As opposed to a commonly held assumption in the XSP literature, we find that collaboration in a partnership does not have to result in a unanimous agreement around a single or convergent frame regarding a contentious issue. Rather, successful collaboration between diverse partners can also be achieved by maintaining a productive tension between different frames through ‘optimal’ frame plurality – not excessive frame variety that may prevent agreements from emerging, but the retention of a select few frames and the deletion of others towards achieving a narrowing frame bandwidth. One managerial implication is that resources need not be focussed on reaching a unanimous agreement among all partners on a single mega-frame vis-à-vis a contentious issue, but can instead be used to kindle a sense of unity in diversity that allows sufficient common ground to emerge, despite the variety of actors and their positions