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     

MANAGING DISTRIBUTED COMPUTING Five Practices for Success

Management of distributed environments requires corporate IS managers to shift from being operators of a central utility to facilitators who can recognize the synergy among loosely related groups of users. Success depends on the development of new ways of visualizing and measuring the service delivery process.     

Simulation of magnetic component models in electric circuitsincluding dynamic thermal effects

It is essential in the simulation of power electronics applications to model magnetic components accurately. In addition to modeling the nonlinear hysteresis behavior, eddy currents and winding losses must be included to provide a realistic model. In practice the losses in magnetic components give rise to significant temperature increases which can lead to major changes in the component behavior. In this paper a model of magnetic components is presented which integrates a nonlinear model of hysteresis, electro-magnetic windings and thermal behavior in a single model for use in circuit simulation of power electronics systems. Measurements and simulations are presented which demonstrate the accuracy of the approach for the electrical, magnetic and thermal domains across a variety of operating conditions, including static thermal conditions and dynamic self heating     

What We Mean by Future-Proofing

Perhaps the most powerful claim that advocates of fiber can make,on top of the massive bandwidthfiber makes possible today, is that fiber is future-proof. That is, the fiber that is laid today can be upgraded so that the same strands of glass can carry massively more bandwidth in the future.     

Functional topography of cat primary auditory cortex: response latencies

Minimum onset latency (Lmin) of single- and multiple-unit responses were mapped in the primary auditory cortex (AI) of barbiturate-anesthetized cats. Contralateral Lmin for multiple units was non-homogeneously distributed along the dorso-ventral/isofrequency axis of the AI. Responses with shorter latencies were more often located in the central, more sharply tuned region while longer latencies were more frequently encountered in the dorsal and ventral portions of the AI. For single units, a large scatter of Lmin values was found throughout the extent of the AI including cortical depth. The relationship between Lmin and previously reported spectral, intensity and temporal parameters was analyzed and revealed statistically significant correlations between minimum onset latency and the following response properties in some but not all studied animals: sharpness of tuning of a frequency response area 10 dB above threshold, broadband transient response, strongest response level, monotonicity of rate/level functions, dynamic range, and preferred frequency modulation sweep direction. This analysis suggests that Lmin is determined by several independent factors and that the prediction of Lmin based on relationships with other spectral and temporal response properties is inherently weak. The spatial distribution and the functional relationship between these response parameters may provide an important aspect of the time-based cortical representation of specific features in the animal's natural environment.     

Coronary arteries: retrospective cardiac gating technique to reduce cardiac motion artifact at spiral CT

Coronary artery calcification is a marker of atherosclerosis. Detection and quantification has previously been accomplished with electron-beam computed tomography (CT). Use of spiral CT for this application has been limited by cardiac motion. The authors evaluated a retrospective cardiac-gated postprocessing technique that necessitates no modification of scanner hardware or software. At spiral CT in 26 patients, motion artifact was reduced, coronary arteries were consistently visualized, and quantification of calcification could be performed in those patients with prominent deposits. Coronary artery calcification screening can therefore be offered in sites that have access to only spiral CT.     

Identification of the blood-borne somatotroph-differentiating factor during chicken embryonic development

Somatotrophs become a significant population by day 16 of chicken embryonic development. We have previously demonstrated that an earlier induction of GH cell differentiation is possible with the addition of day 16 embryonic serum to cultures of day 12 pituitary cells, an age when somatotrophs are rare. The present study was designed to identify the blood-borne signal(s) responsible for the serum activity, using reverse hemolytic plaque assays to identify individual GH-secreting cells. The activity was found to be a heat-stable, ether-soluble compound(s) that is bound or inhibited by a trypsin-sensitive protein. The extent of GH cell differentiation was greater (P < 0.05; n = 3) in response to the ether phases of heated day 16 (14.1 +/- 0.4% of all cells) and day 12 sera (9.3 +/- 0.4%) than with untreated serum from days 16 and 12 (6.1 +/- 0.4% and 0.82 +/- 0.4%, respectively). Furthermore, ether-extracted day 16 serum was more effective than ether-extracted day 12 serum, which was also different from basal (0.85 +/- 0.4%; P < 0.05). Based on this biochemical profile, the abilities of various steroids to stimulate differentiation were tested. Three steroids were found to stimulate somatotroph differentiation in vitro: 17beta-estradiol, corticosterone, and progesterone. However, the estradiol receptor antagonist, tamoxifen, while abolishing the effect of estradiol, had no effect on the induction of differentiation by day 16 serum. In contrast, RU486, a specific glucocorticoid receptor antagonist in chickens, blocked the stimulatory effects of corticosterone, progesterone, and day 16 serum on somatotroph differentiation. We next tested whether the active compound in day 16 embryonic serum was corticosterone, the predominant glucocorticoid in chickens. Incubation of day 16 serum with corticosterone antiserum, but not control antiserum, suppressed day 16 serum-induced GH cell differentiation. Therefore, we conclude that corticosterone is the blood-borne signal capable of stimulating somatotroph differentiation in vitro. The present findings together with previous reports indicate that somatotroph differentiation during embryonic development may result from an increase in circulating glucocorticoid concentrations.     

High-resolution HLA typing for the DQB1 gene by sequence-based typing

BACKGROUND: Monocytic tissue factor (TF), initiating the extrinsic blood coagulation pathway, is often upregulated under septic or inflammatory conditions. The complex activating mechanism remains largely unclear and no effective strategy has been firmly established. In this study, we used a model monocytic cell line (human leukemic THP-1 promonocytes) to address (1) the nature of TF activation in response to bacterial endotoxin and (2) the application of anti-inflammatory cytokines in relieving monocytic hypercoagulation. RESULTS: TF in THP-1 cells was substantially activated by exposure to bacterial endotoxin (LPS; 5 micrograms/ml) for 6 h. Human recombinant IL-4 (500 ng/ml) and IL-10 (500 ng/ml) inhibited TF activation induced by LPS. To determine if these cytokines depressed LPS recognition resulting in such inhibition, we employed an anti-CD14 mAb (UCHM-1; Sigma Chemical) to address the role of CD14 in LPS transmembrane signaling. LPS-induced TF activation was depressed by 35% upon inclusion of the anti-CD14 mAb (1:10 dilution). This antibody alone mimicked TF activation which accounted for 35% of the LPS-induced TF activation, suggesting the activating role of CD14 ligation. In addition, the anti-CD14 mAb elicited the production of nitric oxide (NO) which was found to be independent of TF activation. NO production could serve as an independent index for monitoring LPS recognition. IL-4 depressed the anti-CD14 mAb-induced TF activation as well as NO elicitation, indicating the blockade of CD14 ligation. In contrast, IL-10 showed differential inhibitory activities. TF activation induced by either LPS or anti-CD14 mAb was inhibited by IL-10 which did not show any inhibition on NO elicitation under these conditions. In a separate approach, neither IL-4 nor IL-10 inhibited phorbol ester-induced NO elicitation. More direct evidence came from an epifluorescent demonstration showing that IL-4 blocked binding of FITC-conjugated LPS and anti-CD14 mAb to THP-1 cells. CONCLUSIONS: Taken together, the results suggest that LPS action in relation to TF activation consists of CD14-independent and -dependent signaling including CD14 ligation. We also showed that anti-inflammatory cytokines (IL-4 and -10) significantly depressed TF activation. IL-4 antagonized CD14-dependent LPS recognition leading to the depression in TF activation.