Murine, but not human, ephrin-B2 can be efficiently cleaved by the serine protease kallikrein-4: Implications for xenograft models of human prostate cancer

Background Ephrin-B2 is the sole physiologically-relevant ligand of the receptor tyrosine kinase EphB4, which is over-expressed in many epithelial cancers, including 66% of prostate cancers, and contributes to cancer cell survival, invasion and migration. Crucially, however, the cancer-promoting EphB4 signalling pathways are independent of interaction with its ligand ephrin-B2, as activation of ligand-dependent signalling causes tumour suppression. Ephrin-B2, however, is often found on the surface of endothelial cells of the tumour vasculature, where it can regulate angiogenesis to support tumour growth. Proteolytic cleavage of endothelial cell ephrin-B2 has previously been suggested as one mechanism whereby the interaction between tumour cell-expressed EphB4 and endothelial cell ephrin-B2 is regulated to support both cancer promotion and angiogenesis. Methods An in silico approach was used to search accessible surfaces of 3D protein models for cleavage sites for the key prostate cancer serine protease, KLK4, and this identified murine ephrin-B2 as a potential KLK4 substrate. Mouse ephrin-B2 was then confirmed as a KLK4 substrate by in vitro incubation of recombinant mouse ephrin-B2 with active recombinant human KLK4. Cleavage products were visualised by SDS-PAGE, silver staining and Western blot and confirmed by N-terminal sequencing. Results At low molar ratios, KLK4 cleaved murine ephrin-B2 but other prostate-specific KLK family members (KLK2 and KLK3/PSA) were less efficient, suggesting cleavage was KLK4-selective. The primary KLK4 cleavage site in murine ephrin-B2 was verified and shown to correspond to one of the in silico predicted sites between extracellular domain residues arginine 178 and asparagine 179. Surprisingly, the highly homologous human ephrin-B2 was poorly cleaved by KLK4 at these low molar ratios, likely due to the 3 amino acid differences at this primary cleavage site. Conclusion These data suggest that in in vivo mouse xenograft models, endogenous mouse ephrin-B2, but not human tumour ephrin-B2, may be a downstream target of cancer cell secreted human KLK4. This is a critical consideration when interpreting data from murine explants of human EphB4+/KLK4+ cancer cells, such as prostate cancer cells, where differential effects may be seen in mouse models as opposed to human clinical situations.

A Web-based system enabling the integration, analysis, and 3D sub-surface visualization of groundwater monitoring data and geological models

The 3D Water Chemistry Atlas is an intuitive, open source, Web-based system that enables the three-dimensional (3D) sub-surface visualization of ground water monitoring data, overlaid on the local geological model (formation and aquifer strata). This paper firstly describes the results of evaluating existing virtual globe technologies, which led to the decision to use the Cesium open source WebGL Virtual Globe and Map Engine as the underlying platform. Next it describes the backend database and search, filtering, browse and analysis tools that were developed to enable users to interactively explore the groundwater monitoring data and interpret it spatially and temporally relative to the local geological formations and aquifers via the Cesium interface. The result is an integrated 3D visualization system that enables environmental managers and regulators to assess groundwater conditions, identify inconsistencies in the data, manage impacts and risks and make more informed decisions about coal seam gas extraction, waste water extraction, and water reuse.

Electrochemical phase formation (ECPF): Nucleation growth vis-a-vis adsorption models

The nucleataon growth model of electrochemical phase formation is analysed for the hnear potential sweep input Apart from deducing diagnostic criteria and method~ of estimating model parameters, the predictions of the nucleation growth model are compared and contrasted with those of a sample adsorption model A dastlnCtlOn is made possible between adsorption and phase transition, which seems useful for understanding the nature of ECPF phenomena, especially underpotentlal deposition (UPD).

Adsorption isotherms for neutral organic compounds - A hierarchy in modelling: Part V. Models for the inner layer potential difference in the presence of dipolar adsorption

The relations for the inner layer potential &fference (E) in the presence of adsorbed orgamc molecules are derived for three hterarchlcal models, m terms of molecular constants like permanent &pole moments, polarlzablhtles, etc It is shown how the experimentally observed patterns of the E vs 0 plots (hnear m all ranges of $\sigma^M$, non-linear in one or both regions of o M, etc ) can be understood in a serm-quantltatlve manner from the simplest model in our hierarchy, viz the two-state site panty version Two-state multi-site and three-state (sxte panty) models are also analysed and the slope (3E/80),,M tabulated for these also The results for the Esm-Markov effect are denved for all the models and compared with the earlier result of Parsons. A comparison with the GSL phenomenologlcal equation is presented and its molecular basis, as well as the hmltatlons, is analysed. In partxcular, two-state multa-slte and three-state (site panty) models yield E-o M relations that are more general than the "umfied" GSL equation The posslblhty of vaewlng the compact layer as a "composite medium" with an "effective dlelectnc constant" and obtaimng novel phenomenological descnptions IS also indicated.

Analysis of an internally mountable accelerometer balance system for use with non-isotropic models in shock tunnels

Knowledge of drag force is an important design parameter in aerodynamics. Measurement of aerodynamic forces at hypersonic speed is a challenge and usually ground test facilities like shock tunnels are used to carry out such tests. Accelerometer based force balances are commonly employed for measuring aerodynamic drag around bodies in hypersonic shock tunnels. In this study, we present an analysis of the effect of model material on the performance of an accelerometer balance used for measurement of drag in impulse facilities. From the experimental studies performed on models constructed out of Bakelite HYLEM and Aluminum, it is clear that the rigid body assumption does not hold good during the short testing duration available in shock tunnels. This is notwithstanding the fact that the rubber bush used for supporting the model allows unconstrained motion of the model during the short testing time available in the shock tunnel. The vibrations induced in the model on impact loading in the shock tunnel are damped out in metallic model, resulting in a smooth acceleration signal, while the signal become noisy and non-linear when we use non-isotropic materials like Bakelite HYLEM. This also implies that careful analysis and proper data reduction methodologies are necessary for measuring aerodynamic drag for non-metallic models in shock tunnels. The results from the drag measurements carried out using a 60 degrees half angle blunt cone is given in the present analysis.

An analysis of theories of search and search behavior

Theories of search and search behavior can be used to glean insights and generate hypotheses about how people interact with retrieval systems. This paper examines three such theories, the long standing Information Foraging Theory, along with the more recently proposed Search Economic Theory and the Interactive Probability Ranking Principle. Our goal is to develop a model for ad-hoc topic retrieval using each approach, all within a common framework, in order to (1) determine what predictions each approach makes about search behavior, and (2) show the relationships, equivalences and differences between the approaches. While each approach takes a different perspective on modeling searcher interactions, we show that under certain assumptions, they lead to similar hypotheses regarding search behavior. Moreover, we show that the models are complementary to each other, but operate at different levels (i.e., sessions, patches and situations). We further show how the differences between the approaches lead to new insights into the theories and new models. This contribution will not only lead to further theoretical developments, but also enables practitioners to employ one of the three equivalent models depending on the data available.

Electrochemical phase formation (ECPF) and macrogrowth Part I. Hemispherical models

The phenomenological theory of hemispherical growth is generalised to time-dependent nucleation and growth-rates. Special cases, which include models with diffusion-controlled rates, are analysed. Expressions are obtained for small and large time behaviour and peak characteristics of potentiostatic transients, and their use in model parameter estimation is discussed. Two earlier equations are corrected. Numerically calculated transients which are presented exhibit some interesting features such as a maximum preceding the steady state, oscillations and shoulder.

Electrochemical phase formation (ECPF) and macrogrowth Part II. Two-rate models

A general theory is evolved for a class of macrogrowth models which possess two independent growth-rates. Relations connecting growth-rates to growth geometry are established and some new growth forms are shown to result for models with passivation or diffusion-controlled rates. The corresponding potentiostatic responses, their small and large time behaviours and peak characteristics are obtained. Numerical transients are also presented. An empirical equation is derived as a special case and an earlier equation is corrected. An interesting stochastic result pertaining to nucleation events in the successive layers is proved.

Derivation of the decoupling relations for composite models from anomaly constraints and n-independence

It is shown, in the composite fermion models studied by 't Hooft and others, that the requirements of Adler-Bell-Jackiw anomaly matching and n-independence are sufficient to fix the indices of composite representations. The third requirement, namely that of decoupling relations, follows from these two constraints in such models and hence is inessential.

Solubilities of solids in supercritical fluids using dimensionally consistent modified solvate complex models

New dimensionally consistent modified solvate complex models are derived to correlate solubilities of solids in supercritical fluids both in the presence and absence of entrainers (cosolvents). These models are compared against the standard solvate complex models [J.Chrastil, J. Phys. Chem. 86 (1982) 3016-3021; J.C. Gonzalez, M.R.Vieytes, A.M. Botana, J.M. Vieites, L.M. Botana, J. Chromatogr. A 910 (2001) 119-125; Y. Adachi, B.C.Y. Lu, Fluid Phase Equilb. 14 (1983) 47-156; J.M. del Valle, J.M. Aguilera, Ind. Eng. Chem. Res. 27 (1988) 1551-1553] by correlating the solubilities of 13 binary and 12 ternary systems. Though the newly derived models are not significantly better than the standard models in predicting the solubilities, they are dimensionally consistent. (C) 2009 Elsevier B.V. All rights reserved.

Queuing Models for Estimating Aircraft Fleet Availability

The availability of a small fleet of aircraft in a flying-base, repair-depot combination is modeled and studied. First, a deterministic flow model relates parameters of interest and represents the state-of-the art in the planning of such systems. Second, a cyclic queue model shows the effect of the principal uncertainties in operation and repair and shows the consequent decrease in the availability of aircraft at the flying-base. Several options such as increasing fleet size, investments in additional repair facilities, or building reliability and maintainability into the individual aircraft during its life-cycle are open for increasing the availability. A life-cycle cost criterion brings out some of these features. Numerical results confirm Rose's prediction that there exists a minimal cost combination of end products and repair-depot capability to achieve a prescribed operational availability.

An Optimal Mechanism for Sponsored Search Auctions on the Web and Comparison With Other Mechanisms

In this paper, we first describe a framework to model the sponsored search auction on the web as a mechanism design problem. Using this framework, we describe two well-known mechanisms for sponsored search auction-Generalized Second Price (GSP) and Vickrey-Clarke-Groves (VCG). We then derive a new mechanism for sponsored search auction which we call optimal (OPT) mechanism. The OPT mechanism maximizes the search engine's expected revenue, while achieving Bayesian incentive compatibility and individual rationality of the advertisers. We then undertake a detailed comparative study of the mechanisms GSP, VCG, and OPT. We compute and compare the expected revenue earned by the search engine under the three mechanisms when the advertisers are symmetric and some special conditions are satisfied. We also compare the three mechanisms in terms of incentive compatibility, individual rationality, and computational complexity. Note to Practitioners-The advertiser-supported web site is one of the successful business models in the emerging web landscape. When an Internet user enters a keyword (i.e., a search phrase) into a search engine, the user gets back a page with results, containing the links most relevant to the query and also sponsored links, (also called paid advertisement links). When a sponsored link is clicked, the user is directed to the corresponding advertiser's web page. The advertiser pays the search engine in some appropriate manner for sending the user to its web page. Against every search performed by any user on any keyword, the search engine faces the problem of matching a set of advertisers to the sponsored slots. In addition, the search engine also needs to decide on a price to be charged to each advertiser. Due to increasing demands for Internet advertising space, most search engines currently use auction mechanisms for this purpose. These are called sponsored search auctions. A significant percentage of the revenue of Internet giants such as Google, Yahoo!, MSN, etc., comes from sponsored search auctions. In this paper, we study two auction mechanisms, GSP and VCG, which are quite popular in the sponsored auction context, and pursue the objective of designing a mechanism that is superior to these two mechanisms. In particular, we propose a new mechanism which we call the OPT mechanism. This mechanism maximizes the search engine's expected revenue subject to achieving Bayesian incentive compatibility and individual rationality. Bayesian incentive compatibility guarantees that it is optimal for each advertiser to bid his/her true value provided that all other agents also bid their respective true values. Individual rationality ensures that the agents participate voluntarily in the auction since they are assured of gaining a non-negative payoff by doing so.

Negotiation schemes for multi-agent cooperative search

Because of limited sensor and communication ranges, designing efficient mechanisms for cooperative tasks is difficult. In this article, several negotiation schemes for multiple agents performing a cooperative task are presented. The negotiation schemes provide suboptimal solutions, but have attractive features of fast decision-making, and scalability to large number of agents without increasing the complexity of the algorithm. A software agent architecture of the decision-making process is also presented. The effect of the magnitude of information flow during the negotiation process is studied by using different models of the negotiation scheme. The performance of the various negotiation schemes, using different information structures, is studied based on the uncertainty reduction achieved for a specified number of search steps. The negotiation schemes perform comparable to that of optimal strategy in terms of uncertainty reduction and also require very low computational time, similar to 7 per cent to that of optimal strategy. Finally, analysis on computational and communication requirement for the negotiation schemes is carried out.

On the DC Conductivity of HV DC Cable Insulation - Cautions in using the Empirical Models

The electrical conduction in insulating materials is a complex process and several theories have been suggested in the literature. Many phenomenological empirical models are in use in the DC cable literature. However, the impact of using different models for cable insulation has not been investigated until now, but for the claims of relative accuracy. The steady state electric field in the DC cable insulation is known to be a strong function of DC conductivity. The DC conductivity, in turn, is a complex function of electric field and temperature. As a result, under certain conditions, the stress at cable screen is higher than that at the conductor boundary. The paper presents detailed investigations on using different empirical conductivity models suggested in the literature for HV DC cable applications. It has been expressly shown that certain models give rise to erroneous results in electric field and temperature computations. It is pointed out that the use of these models in the design or evaluation of cables will lead to errors.

Microarchitecture sensitive empirical models for compiler optimizations.

This paper proposes the use of empirical modeling techniques for building microarchitecture sensitive models for compiler optimizations. The models we build relate program performance to settings of compiler optimization flags, associated heuristics and key microarchitectural parameters. Unlike traditional analytical modeling methods, this relationship is learned entirely from data obtained by measuring performance at a small number of carefully selected compiler/microarchitecture configurations. We evaluate three different learning techniques in this context viz. linear regression, adaptive regression splines and radial basis function networks. We use the generated models to a) predict program performance at arbitrary compiler/microarchitecture configurations, b) quantify the significance of complex interactions between optimizations and the microarchitecture, and c) efficiently search for'optimal' settings of optimization flags and heuristics for any given microarchitectural configuration. Our evaluation using benchmarks from the SPEC CPU2000 suits suggests that accurate models (< 5% average error in prediction) can be generated using a reasonable number of simulations. We also find that using compiler settings prescribed by a model-based search can improve program performance by as much as 19% (with an average of 9.5%) over highly optimized binaries.