Distribution channel activities account for a large share of economic activity, and innovation in distribution is recurrently shown to hold great potential for efficiency-improvement and restructuring. In recent years, there has been a resurgence of interest in innovations and their role in economic change. A growing body of work uses an evolutionary economic approach to these questions. Empirically, this research has primarily been directed towards innovation in product design or production processes, while innovation in distribution channels has remained a relatively unexplored area of study within evolutionary economics.This study was inspired by the possibility to use the emerging evolutionary economic theory to improve our understanding of innovation in distribution channels. The evolutionary framework is combined with theory on distribution channels, and the adapted framework applied to two cases of innovation in Swedish grocery trade. These two innovations, the introduction of the self-service format and the development of a vertically and horizontally coordinated, channel organisation, the so-called all-channel, have both been important in shaping distribution channel structures.In addition to providing some new insights into these historical developments, the study makes a contribution to the theory of distribution channels with regard to innovations. The role of the environment in shaping the characteristics of the innovation is an addition to conventional views of innovation in channel theory. The interdependent nature of actors and processes in distribution channel is acknowledged, and the possibilities for modularising the system is advanced as an important strategic tool in facilitating the adoptability of distribution innovations. However, the success or failure of an innovation is found to depend on the adopting actors’ ability to mobilise system-wide effects. / Diss. Stockholm : Handelshögskolan, 1998

We present a serially concatenated coding scheme for partial response channels. The encoder consists of an outer irregular LDPC code and an inner matched spectrum trellis code. These codes are shown to offer considerable improvement over the i.i.d. capacity (> 1 dB) of the channel for low rates (approximately 0.1 bits per channel use). We also present a qualitative argument on the optimality of these codes for low rates. We also formulate a performance index for such codes to predict their performance for low rates. The results have been verified via simulations for the (1-D)/sqrt(2) and the (1-D+0.8D^2)/sqrt(2.64) channels. The structure of the encoding/decoding scheme is considerably simpler than the existing scheme to maximize the information rate of encoders over partial response channels.

My PhD project investigated the regulation of human cardiac transient outward potassium current (Ito) by protein tyrosine kinases (PTKs) and the functional expression of transient receptor potential (TRP) channels in human atrial myocytes to make an advanced understanding of human cardiac electrophysiology and pathophysiology. The modulation of human cardiac Itoby PTKs was studied in human atrial myocytes and HEK 293 cells expressing hKv4.3 (coding human cardiac Ito). We found that the broad-spectrum PTK inhibitor genistein, the selective EGFR kinase inhibitor AG556, and the Src-family kinases inhibitor PP2 inhibited human atrial Itoand the inhibitory effect was countered by the protein tyrosine phosphatase (PTP) inhibitor orthovanadate. Similar results were observed in hKv4.3-HEK cells. Interestingly, tyrosine phosphorylation of hKv4.3channels was reduced by genistein, AG556, and PP2,and the reduction was antagonized by orthovanadate. The mutant Y136F of hKv4.3 lost the inhibitory response to AG556, whileY108F lost the response to PP2.The double mutant Y108F-Y136F hKv4.3 failed to respond to both AG556 and PP2, and exhibited a dramatic reduction of tyrosine phosphorylation. These results indicate that native cardiac Itois regulated by both EGFR and Src family kinases. In the second part, we studied whether TRPC channels would mediate the nonselective cation current described previously in human atrial myocytes. It was found that TRPC1 channel activator thapsigargin activated the current, and the effect was suppressed by La3+or prevented by intracellular anti-TRPC1 antibody. Endothelin-1 and angiotensin II stimulated the current, andthe effect was inhibited by La3+and/or 2-APB. RT-PCR and Western blot analysis revealed that in addition to the TRPC1 channels mediating the nonselective cation current, the components of store-operated Ca2+channels (SOCs), STIM1 and Orai1 were abundantly expressed in human atria. The interaction of TRPC1, STIM1, and Orai1 was confirmed by co-immunoprecipitation. Interestingly, we found that protein expression of TRPC1 and STIM1, but not Orai1, was up-regulated in human atria with atrial fibrillation. The third part of the project determined whether TRPM7 channels were expressed in human atrial myocytes, since this channel was reported in human atrial fibroblasts, conferring atrial fibrosis in human atria with atrial fibrillation. We found a TRPM7 -like current which was potentiated by acidic pH, and inhibited by La3+and 2-APB, and a Ca2+-activated TRPM4 current. RT-PCR and Western blot analysis confirmed the expression of TRPM7 and TRPM4 channels in human atria. Moreover, we found TRPM7 protein, but not TRPM4 protein was significantly up-regulated in human atria with atrial fibrillation, suggesting the potential participation of TRPM7 channels in atrial remodeling of human atria with atrial fibrillation. Collectively, this PhD thesis project has demonstrated for the first time that human cardiac Itois modulated by EGFR kinase and Src kinases via phosphorylating Y136and Y108, respectively. TRPC1 channels mediate the nonselective cation current and SOCs.TRPM7 channels are expressed in human atrial myocytes. The up-regulation of TRPC1, STIM1, and TRPM7 channels in human atria with atrial fibrillation suggest that they are likely involved in atrial electrical and/or structure remodeling in patients with atrial fibrillation. / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

In embryonic neurons, the intracellular chloride concentration is elevated, making GABA and glycine depolarizing. Later in development, coincident with neuronal maturation, the extruding potassium-chloride co-transporter KCC2 is expressed. It reverses the chloride gradient, rendering it hyperpolarizing. Early depolarization is assumed to play trophic roles during nervous system development. I thus decided to investigate the effects of the depolarizing chloride gradient on development in vivo in the zebrafish embryo. I first determined the temporal pattern of KCC2 expression in zebrafish and found it was absent in the embryo. I then over-expressed wild-type, gain-of-function and loss-of-function variants of human KCC2, using GFP-tagged constructs for detection purposes. Over-expression of functional hKCC2 perturbed the morphology and motor behaviours of the embryos. At the cellular level, KCC2 impaired axonal growth and affected the neuronal populations in the brain, hindbrain and spinal cord. This suggests the depolarizing effects of glycine are critical for neurogenesis.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Thesis (M.S.)--State University of New York at Binghamton, Geological Sciences & Environmental Studies Department, 2007. / Includes bibliographical references.

Thesis (M.S.)--Oregon State University, 1997. / Typescript (photocopy). Includes bibliographical references (leaves 62-67). Also available on the World Wide Web.

Thesis (Ph. D.)--University of Missouri--Columbia, 1998. / "December 1998" Typescript. Vita. Includes bibliographical references (l. 152-155). Also available on the Internet.

Thesis (M.B.A.)--University of Hong Kong, 1993.

Background potassium currents play an important role in the regulation of the resting membrane potential and excitability of mammalian neurons. Recently cloned two- pore domain potassium channels (K2p) are believed to underlie these currents. The roles of K2P channels in general anesthesia and neuroprotection have been proposed recently. In view of this, we investigated the ability of trichloroethanol (an active metabolite of the non-volatile general anesthetic cldoral hydrate, widely used as a pediatric sedative) to modulate the activity of human TREK-1 and TRAAK channels. We found that trichloroethanol potently activates both hTREK-1 and hTRAAK channels at pharmacologically relevant concentrations. The parent compound chloral hydrate was also found to augtnent the activity of both the channels reversibly. Studies with carboxy- terminal deletion mutants (hTREK-1A89, hTREK-1 A100 and hTREK-1 A1 19), suggested that C-terminal tail is not essential for the activation of TREK-1 by trichloroethanol. Our findings identify TREK-1 and TRCL4K channels as molecular targets for trichloroethanol and we propose that activation of both these channels might contribute to the CNS depressant effects of chloral hydrate. Another channel TASK-2, which is essentially absent in the human brain was also found to be potently activated by both trichloroethanol and chloral hydrate. In another series of experiments, we studied the effects of methyl xanthines caffeine and theophylline on hTREK-1 channels. Caffeine and theophylline are used for therapeutic purposes and frequently cause life-threatening convulsive seizures due to systemic toxicity. The mechanisms for the epileptogenicity of caffeine and theophylline are not clear. Recent experiments using knockout mice provided direct evidence for a role for TREK-1 in the control of epileptogenesis. We hypothesized that the epileptogenicity of caffeine and theophylline may be related to the inhibition of TREK-1 channels. We investigated this possibility and observed massive inhibition of TREK-1 channels at toxicologically relevant concentrations. Experiments with the mutant TREK-1 channel (S348A mutant) suggested the involvement of cANP/PKA pathway in the inhibition of TREK-1 channels by caffeine and theophylline. We suggest that inhibition of TREK-1 channels may contribute to the convulsive seizures induced by toxic levels of caffeine and theophylline. Local anesthetics exhibit their clinical effects not only by binding to voltage-gated sodium channels, but also by interacting with other ion channels such as potassium channels. Because of the physiological significance of TREK-1 channels and their abundant expression in peripheral sensory neurons, we investigated the effects of lidocaine to see whether its interaction with 'REK-1 channels contribute to the conduction blockade. Lidocaine caused dose-dependent inhibition of TREK-1channels and the inhibition was voltage-independent. Cytoplasmic C-terminal tail is critically required for lidocaine action. Inhibition of TREK-1 channels is achieved at concentrations for iiz vivo action and this effect may have implications for the clinically observed drug action of lidocaine.