Simulating current global river runoff with a global hydrological model: model revisions, validation, and sensitivity analysis

Global hydrological models (GHMs) model the land surface hydrologic dynamics of continental-scale river basins. Here we describe one such GHM, the Macro-scale - Probability-Distributed Moisture model.09 (Mac-PDM.09). The model has undergone a number of revisions since it was last applied in the hydrological literature. This paper serves to provide a detailed description of the latest version of the model. The main revisions include the following: (1) the ability for the model to be run for n repetitions, which provides more robust estimates of extreme hydrological behaviour, (2) the ability of the model to use a gridded field of coefficient of variation (CV) of daily rainfall for the stochastic disaggregation of monthly precipitation to daily precipitation, and (3) the model can now be forced with daily input climate data as well as monthly input climate data. We demonstrate the effects that each of these three revisions has on simulated runoff relative to before the revisions were applied. Importantly, we show that when Mac-PDM.09 is forced with monthly input data, it results in a negative runoff bias relative to when daily forcings are applied, for regions of the globe where the day-to-day variability in relative humidity is high. The runoff bias can be up to - 80% for a small selection of catchments but the absolute magnitude of the bias may be small. As such, we recommend future applications of Mac-PDM.09 that use monthly climate forcings acknowledge the bias as a limitation of the model. The performance of Mac-PDM.09 is evaluated by validating simulated runoff against observed runoff for 50 catchments. We also present a sensitivity analysis that demonstrates that simulated runoff is considerably more sensitive to method of PE calculation than to perturbations in soil moisture and field capacity parameters.

A Bayesian approach for dose-escalation in a phase I clinical trial incorporating pharmacodynamic endpoints

Bayesian decision procedures have already been proposed for and implemented in Phase I dose-escalation studies in healthy volunteers. The procedures have been based on pharmacokinetic responses reflecting the concentration of the drug in blood plasma and are conducted to learn about the dose-response relationship while avoiding excessive concentrations. However, in many dose-escalation studies, pharmacodynamic endpoints such as heart rate or blood pressure are observed, and it is these that should be used to control dose-escalation. These endpoints introduce additional complexity into the modeling of the problem relative to pharmacokinetic responses. Firstly, there are responses available following placebo administrations. Secondly, the pharmacodynamic responses are related directly to measurable plasma concentrations, which in turn are related to dose. Motivated by experience of data from a real study conducted in a conventional manner, this paper presents and evaluates a Bayesian procedure devised for the simultaneous monitoring of pharmacodynamic and pharmacokinetic responses. Account is also taken of the incidence of adverse events. Following logarithmic transformations, a linear model is used to relate dose to the pharmacokinetic endpoint and a quadratic model to relate the latter to the pharmacodynamic endpoint. A logistic model is used to relate the pharmacokinetic endpoint to the risk of an adverse event.

Analysis of molecular determinants of affinity and relative efficacy of a series of R- and S-2-(dipropylamino)tetralins at the 5-HT1A serotonin receptor

1 Factors influencing agonist affinity and relative efficacy have been studied for the 5-HT1A serotonin receptor using membranes of CHO cells expressing the human form of the receptor and a series of R-and S-2-(dipropylamino)tetralins (nonhydroxylated and monohydroxylated (5-OH, 6-OH, 7-OH, 8-OH) species). 2 Ligand binding studies were used to determine dissociation constants for agonist binding to the 5HT(1A) receptor: (a) K-i values for agonists were determined in competition versus the binding of the agonist [H-3]-8-OH DPAT. Competition data were all fitted best by a one-binding site model. (b) K-i values for agonists were also determined in competition versus the binding of the antagonist [H-3]-NAD-199. Competition data were all fitted best by a two-binding site model, and agonist affinities for the higher (K-h) and lower affinity (K-1) sites were determined. 3 The ability of the agonists to activate the 5-HT1A receptor was determined using stimulation of [S-35]-GTPgammaS binding. Maximal effects of agonists (E-max) and their potencies (EC50) were determined from concentration/response curves for stimulation of [S-35]-GTPgammaS binding. 4 K-1/K-h determined from ligand binding assays correlated with the relative efficacy (relative Em) of agonists determined in [S-35]-GTPgammaS binding assays. There was also a correlation between K-1/K-h and K-1/EC50 for agonists determined from ligand binding and [S-35]-GTPgammaS binding assays. 5 Simulations of agonist binding and effect data were performed using the Ternary Complex Model in order to assess the use of K-1/K-h for predicting the relative efficacy of agonists. British Journal of Pharmacology (2003) 138, 1129-1139. doi: 10. 1038/sj.bjp.705085.

Toxic phorbol esters from Chinese Tallow (Sapium sebiferum L.Roxb.)

Toxic phorbol esters from Chinese tallow stimulate protein kinase C. Toxicon25, 1129 – 1233, 1987. — Phorbol esters were isolated from the seeds of Chinese tallow (Sapium sebiferum L. Roxb.). These compounds were based on the tigliane nuclei, 4-deoxyphorbol, 12-deoxyphorbol and 4,20-dideoxy-5-hydroxyphorbol. The pro-inflammatory activity (id50) of the pure compounds was between 0.042 and 2.6 nmoles per ear. Protein kinase C activation assays were carried out on samples of enzyme purified from mammalian brain and the activities (Ka) were in the range 76 – 176 nM. The 4,20-dideoxy-5-hydroxy analogue was inactive in both tests. Chinese tallow, which is used as a substitute for linseed oil, may represent an industrial toxic hazard in terms of both pro-inflammatory and tumour-promoting effects.

Biomimetic triblock copolymer membranes: from aqueous solutions to solid supports

In the present paper, we studied the preparation of biomimetic triblock copolymer (ABA) membranes in aqueous solution and their deposition into solid supports. The self-assembly structures of the ABA in aqueous solution was investigated by using optical microscopy, dynamic light scattering, electron microscopy (EM) and SAXS. Spherical and tubular polymersomes were found at the highest concentrations investigated. The mechanism of deposition on solid supports (mica and glass) was elucidated by using atomic force microscopy (AFM). The deposition results in the formation of a uniform defect-free membrane at suitable polymer concentrations.

Representing geometrical knowledge

This paper introduces perspex algebra which is being developed as a common representation of geometrical knowledge. A perspex can currently be interpreted in one of four ways. First, the algebraic perspex is a generalization of matrices, it provides the most general representation for all of the interpretations of a perspex. The algebraic perspex can be used to describe arbitrary sets of coordinates. The remaining three interpretations of the perspex are all related to square matrices and operate in a Euclidean model of projective space-time, called perspex space. Perspex space differs from the usual Euclidean model of projective space in that it contains the point at nullity. It is argued that the point at nullity is necessary for a consistent account of perspective in top-down vision. Second, the geometric perspex is a simplex in perspex space. It can be used as a primitive building block for shapes, or as a way of recording landmarks on shapes. Third, the transformational perspex describes linear transformations in perspex space that provide the affine and perspective transformations in space-time. It can be used to match a prototype shape to an image, even in so called 'accidental' views where the depth of an object disappears from view, or an object stays in the same place across time. Fourth, the parametric perspex describes the geometric and transformational perspexes in terms of parameters that are related to everyday English descriptions. The parametric perspex can be used to obtain both continuous and categorical perception of objects. The paper ends with a discussion of issues related to using a perspex to describe logic.

Ownership, occupation and risk: a view of the City of London office market

Office returns in the City of London are more volatile than in other UK markets. This volatility may reflect fluctuations in capital flows associated with changing patterns of ownership and the growing linkage between real estate and financial markets in the City. Using current and historical data, patterns of ownership in the City are investigated. They reveal that overseas ownership has grown markedly since 1985, that owners are predominantly FIRE-sector firms and that there are strong links between ownership and occupation. This raises concerns about future volatility and systemic risk in a market strongly influenced by the cyclical behaviour and shocks of the international financial system.

Robust pole assignment in linear state feedback

Numerical methods are described for determining robust, or well-conditioned, solutions to the problem of pole assignment by state feedback. The solutions obtained are such that the sensitivity of the assigned poles to perturbations in the system and gain matrices is minimized. It is shown that for these solutions, upper bounds on the norm of the feedback matrix and on the transient response are also minimized and a lower bound on the stability margin is maximized. A measure is derived which indicates the optimal conditioning that may be expected for a particular system with a given set of closed-loop poles, and hence the suitability of the given poles for assignment.

Structural spoilers or structural supports? Unionism and the strategic integration of HR functions

The strategic integration of the human resource (HR) function is regarded as crucial in the literature on (strategic) human resource management ((S)HRM). Evidence on the contextual or structural influences on this integration is, however, limited. The structural implications of unionism are particularly intriguing given the evolution of study of the employment relationship. Pluralism is typically seen as antithetical to SHRM, and unions as an impediment to the strategic integration of HR functions, but there are also suggestions in the literature that unionism might facilitate the strategic integration of HR. This paper deploys large-scale international survey evidence to examine the organization-level influence of unionism on this strategic integration, allowing for other established and plausible influences. The analysis reveals that exceptionally, where the organization-level role of unions is particularly contested, unionism does impede the strategic integration of HR. However, it is the predominance of the facilitation of the strategic integration of HR by unionism which is most remarkable.

Padé approximants for the acoustical characteristics of rigid frame porous media

In this paper it is shown that a number of theoretical models of the acoustical properties of rigid frame porous media, especially those involving ratios of Bessel functions of complex argument, can be accurately approximated and greatly simplified by the use of Padé approximation techniques. In the case of the model of Attenborough [J. Acoust. Soc. Am. 81, 93–102 (1987)] rational approximations are produced for the characteristic impedance, propagation constant, dynamic compressibility, and dynamic density, as a function of frequency and the material parameters. The model proposed by Stinson and Champoux