The impact of high density receptor clusters on VEGF signaling

Vascular endothelial growth factor (VEGF) signaling is involved in the process of blood vessel development and maintenance. Signaling is initiated by binding of the bivalent VEGF ligand to the membrane-bound receptors (VEGFR), which in turn stimulates receptor dimerization. Herein, we discuss experimental evidence that VEGF receptors localize in caveloae and other regions of the plasma membrane, and for other receptors, it has been shown that receptor clustering has an impact on dimerization and thus also on signaling. Overall, receptor clustering is part of a complex ecosystem of interactions and how receptor clustering impacts dimerization is not well understood. To address these questions, we have formulated the simplest possible model. We have postulated the existence of a single high affinity region in the cell membrane, which acts as a transient trap for receptors. We have defined an ODE model by introducing high- and low-density receptor variables and introduce the corresponding reactions from a realistic model of VEGF signal initiation. Finally, we use the model to investigate the relation between the degree of VEGFR concentration, ligand availability, and signaling. In conclusion, our simulation results provide a deeper understanding of the role of receptor clustering in cell signaling.Comment: In Proceedings HSB 2013, arXiv:1308.572

Contract enforcement, institutions and social capital: the Maghribi traders reappraised

Economists draw important lessons for modern development from the medieval Maghribi traders who, according to Greif, enforced contracts multilaterally through a closed, private-order coalition'. We show that this view is untenable. The Maghribis used formal legal mechanisms and entered business associations with non-Maghribis. Not a single empirical example adduced by Greif shows that any coalition' actually existed. The Maghribis cannot be used to argue that the social capital of exclusive networks will facilitate exchange in developing economies. Nor do they provide any support for the cultural theories of economic development and institutional change for which they have been mobilised

How weak is the weakest-link principle? : On the measurement of firm owners' control rights

The paper argues that the weakest link principle, which has been widely used as a measure of ultimate owners? control rights, has a number of serious problems. A theoretically more satisfactory method of measuring control rights, based on voting power indices, is proposed, and the different measures are compared using a sample of large listed German firms. The different measures produce very different results. But, whichever measure is used, taking account of pyramid ownership structures has little effect on the values of control and cashflow rights. The results also show that neither first-tier nor ultimate control rights measures are adequate on their own, suggesting that further work on ownership structure and pyramids is required to obtain satisfactory measures of large owners? control rights

Metabolic flux balance analysis and the in silico analysis of Escherichia coli K-12 gene deletions

BACKGROUND: Genome sequencing and bioinformatics are producing detailed lists of the molecular components contained in many prokaryotic organisms. From this 'parts catalogue' of a microbial cell, in silico representations of integrated metabolic functions can be constructed and analyzed using flux balance analysis (FBA). FBA is particularly well-suited to study metabolic networks based on genomic, biochemical, and strain specific information. RESULTS: Herein, we have utilized FBA to interpret and analyze the metabolic capabilities of Escherichia coli. We have computationally mapped the metabolic capabilities of E. coli using FBA and examined the optimal utilization of the E. coli metabolic pathways as a function of environmental variables. We have used an in silico analysis to identify seven gene products of central metabolism (glycolysis, pentose phosphate pathway, TCA cycle, electron transport system) essential for aerobic growth of E. coli on glucose minimal media, and 15 gene products essential for anaerobic growth on glucose minimal media. The in silico tpi(-), zwf, and pta(-) mutant strains were examined in more detail by mapping the capabilities of these in silico isogenic strains. CONCLUSIONS: We found that computational models of E. coli metabolism based on physicochemical constraints can be used to interpret mutant behavior. These in silica results lead to a further understanding of the complex genotype-phenotype relation. Supplementary information

The measurement of firm ownership and its effect on managerial pay

This paper uses German evidence to address two questions about corporate governance. The effects of ownership on corporate governance have received much recent attention, but very little of this has been devoted to the appropriate way to measure firm ownership. The results of this paper show that the conclusions reached about the effects of ownership on corporate governance can depend critically on the particular ownership measure used, and that the widely-used weakest-link principle is wholly unsatisfactory as a means of dealing with the issues raised by pyramid ownership structures. The paper also shows that greater ownership concentration typically weakens the link between managerial pay and firm profitability. This is inconsistent with the hypothesis, emphasised in the recent literature on the USA, that large owners are a complement to, rather than a substitute for, such a link

MAPK Cascade Possesses Decoupled Controllability of Signal Amplification and Duration

AbstractThe three important characteristics of the output signal of mitogen activated protein kinase (MAPK) cascade are time delay between stimulus and response, amplitude gain, and duration of the output signal. In this study, we performed a sensitivity analysis on the computational model of epidermal growth factor receptor (EGFR) activated MAPK cascade developed by Schoeberl and co-workers (1) to identify the sensitive steps of the pathway affecting these characteristics. We show that the signaling network is sensitive in a decoupled manner, which provides the ability to control its output amplitude and duration one at a time. Signal duration is found sensitive only to the phosphatase reactions at the MEK level. In contrast, signal amplitude is found most sensitive to the phosphatase reactions at the ERK level. Time delay is found to be a robust characteristic of the system

Heterogeneities in EGF receptor density at the cell surface can lead to concave up scatchard plot of EGF binding

AbstractThe mechanism responsible for the concave up nature of the Scatchard plot of epidermal growth factor (EGF) binding on EGF receptor (EGFR) has been a controversial issue for more than a decade. Past efforts to mechanistically simulate the concave up nature of the Scatchard plot of EGF binding have shown that negative cooperativity in EGF binding on an EGFR dimer or inclusion of some external site or binding event can describe this behavior. However, herein we show that heterogeneity in the density of EGFR due to localization in certain regions of the plasma membrane, which has been experimentally reported, can also lead to concave up shape of the Scatchard plot of the EGF binding on EGFR

Computational modeling reveals molecular details of epidermal growth factor binding

BACKGROUND: The ErbB family of receptors are dysregulated in a number of cancers, and the signaling pathway of this receptor family is a critical target for several anti-cancer drugs. Therefore a detailed understanding of the mechanisms of receptor activation is critical. However, despite a plethora of biochemical studies and recent single particle tracking experiments, the early molecular mechanisms involving epidermal growth factor (EGF) binding and EGF receptor (EGFR) dimerization are not as well understood. Herein, we describe a spatially distributed Monte Carlo based simulation framework to enable the simulation of in vivo receptor diffusion and dimerization. RESULTS: Our simulation results are in agreement with the data from single particle tracking and biochemical experiments on EGFR. Furthermore, the simulations reveal that the sequence of receptor-receptor and ligand-receptor reaction events depends on the ligand concentration, receptor density and receptor mobility. CONCLUSION: Our computer simulations reveal the mechanism of EGF binding on EGFR. Overall, we show that spatial simulation of receptor dynamics can be used to gain a mechanistic understanding of receptor activation which may in turn enable improved cancer treatments in the future

Control Rights, Pyramids, and the Measurement of Ownership Concentration

The recent corporate governance literature has emphasised the distinction between control and cash-flow rights but has disregarded measurement issues. Control rights may be measured by immediate shareholder votes, the voting rights as traced through ownership chains, or voting power indices that may or may not trace ownership through chains. We compare the ability of various measures to identify the effects of ownership concentration on share valuation using a German panel data set. The widely-used weakest link principle does not perform well in this comparison. Furthermore, measures that trace control through ownership chains do not outperform those that rely on immediate ownership, thus questioning the role of pyramids in the separation of control and cash-flow rights. The paper emphasises that there is a distinction between these two aspects of ownership even without pyramids or preferred stock, identification of which requires measures that, like the Shapley-Shubik index, do not simply equate control rights with voting rights

Control Rights, Pyramids, and the Measurement of Ownership Concentration

The recent corporate governance literature has emphasised the distinction between control and cash-flow rights but has disregarded measurement issues. Control rights may be measured by immediate shareholder votes, the voting rights as traced through ownership chains, or voting power indices that may or may not trace ownership through chains. We compare the ability of various measures to identify the effects of ownership concentration on share valuation using a German panel data set. The widely-used weakest link principle does not perform well in this comparison. Furthermore, measures that trace control through ownership chains do not outperform those that rely on immediate ownership, thus questioning the role of pyramids in the separation of control and cash-flow rights. The paper emphasises that there is a distinction between these two aspects of ownership even without pyramids or preferred stock, identification of which requires measures that, like the Shapley-Shubik index, do not simply equate control rights with voting rights