Quantitative pharmacophore models with inductive logic programming

Three-dimensional models, or pharmacophores, describing Euclidean constraints on the location on small molecules of functional groups (like hydrophobic groups, hydrogen acceptors and donors, etc.), are often used in drug design to describe the medicinal activity of potential drugs (or ‘ligands’). This medicinal activity is produced by interaction of the functional groups on the ligand with a binding site on a target protein. In identifying structure-activity relations of this kind there are three principal issues: (1) It is often difficult to “align” the ligands in order to identify common structural properties that may be responsible for activity; (2) Ligands in solution can adopt different shapes (or `conformations’) arising from torsional rotations about bonds. The 3-D molecular substructure is typically sought on one or more low-energy conformers; and (3) Pharmacophore models must, ideally, predict medicinal activity on some quantitative scale. It has been shown that the logical representation adopted by Inductive Logic Programming (ILP) naturally resolves many of the difficulties associated with the alignment and multi-conformation issues. However, the predictions of models constructed by ILP have hitherto only been nominal, predicting medicinal activity to be present or absent. In this paper, we investigate the construction of two kinds of quantitative pharmacophoric models with ILP: (a) Models that predict the probability that a ligand is “active”; and (b) Models that predict the actual medicinal activity of a ligand. Quantitative predictions are obtained by the utilising the following statistical procedures as background knowledge: logistic regression and naive Bayes, for probability prediction; linear and kernel regression, for activity prediction. The multi-conformation issue and, more generally, the relational representation used by ILP results in some special difficulties in the use of any statistical procedure. We present the principal issues and some solutions. Specifically, using data on the inhibition of the protease Thermolysin, we demonstrate that it is possible for an ILP program to construct good quantitative structure-activity models. We also comment on the relationship of this work to other recent developments in statistical relational learning. Editors: Tamás Horváth and Akihiro Yamamoto     

Parameter Uncertainty and Policy Intensity: Some Extensions and Suggestions for Further Work

The effects of parameter uncertainty on optimal policy have been a matter of interest for academics, and even for some policymakers, for a long time. Two lines of literature have developed analytical results on this matter. The first line uses static models and the second dynamic models. In this dynamic line most of the results are confined to models with a single state and a single control variable. In this paper we want to encourage the analysis of more general dynamic cases. To do so, the results in the dynamic line are extended from one-state and one-control finite horizon models to models with a pair of control variables. We then discuss some of the hurdles which must be surmounted for the results to be made more general and suggests some lines for further research. JEL classification: C61; E61     

The effects of nonlocal impact ionization on the speed of avalanche photodiodes

The nonlocal enhancement in the velocities of charge carriers to ionization is shown to outweigh the opposing effects of dead space, increasing the avalanche speed of short avalanche photodiodes (APDs) over the predictions of a conventional local model which ignores both of these effects. The trends in the measured gain-bandwidth product of two short InAlAs APDs reported in the literature support this result. Relatively large speed benefits are predicted to result from further small reductions in the lengths of short multiplication regions.     

Start-up and steady-state results of a full-scale UASB reactor treating malting wastewater.

An Imhoff tank was reconstructed into a 250 m3 UASB reactor in order to treat a malting plant wastewater. The UASB was inoculated with sludge from an anaerobic lagoon used for slaughterhouse wastewater treatment. After two months of operation the reactor achieved full load with an HRT of 17 h, a COD removal higher than 80% and a biogas production of 300 m3/day (77% average methane content), with an organic loading rate of 3.6 kgCOD/m3.d (0.24 kgCOD/kgVSS.d). A yield coefficient of 0.09 gVSS/gCODrem was found from a mass balance. The fat present in the inoculated sludge (48 mg/gSSV) did not affect the start up performance. Sludge from the inoculum with high content of fat (270 mg/gSSV), was separated by flotation in the first week of operation. The COD removal efficiency was scarcely influenced by the reactor operation temperature (17-25 degrees C).     

Effect of pulse time gate on CsI(T1) light output

The mass and charge identification of secondary particles with Z < 4 by a large CsI(T1) scintillation detector is performed using pulse shape analysis and time-of-flight methods. The dependence of the light output on E, A and Z is studied in the energy range of 1–20 MeV/A and special attention is paid to the integration time of the photomultiplier anode signal. It is found that the behaviour of the calibration curves strongly depends on the choice of the integration time interval.     

Morphological changes induced by colchicine in the chick optic cup in early stages of development. A stereological study

In this study chick embryo optic cups at HH stage 13 of development were analyzed under normal conditions and after inoculation with colchicine for 1, 2, 4, and 8 h. Several changes were seen after these periods of treatment: 1) modifications of the structure, with thicker regions in the cup and a general decrease in the total volume according to the duration of exposure to the drug (about 4 times less than normal, 5,035 x 10(3) microns 3 vs 1,334 x 10(3) microns 3 after 8 h of treatment); 2) enlargement of the ventricular cavity and its closure, due to failure of approximation of retinal and pigmentary layers; 3) failure of lens development, with delay and impairment of pit formation and deformation of all structures; lens volume was less than normal (about 4 times less, 2,148 x 10(3) microns 3 vs 658 x 10(3) microns 3 after 8 h of treatment); 4) a general segregation of the cells making up the structure, principally in the more active proliferating zones. The local alterations found are described.