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.     

Training in firearm safety counseling in family practice residency programs

We have studied the function of partial orthotopic liver transplantation in the rat by evaluating prothrombin time (PT), liver blood flow, basal and glucose-stimulated insulin secretion and glucose tolerance, and the reticuloendothelial function (RES) in hepatectomized rats subjected to partial liver transplantation. A graft corresponding to 68% of a normal liver was transplanted to totally hepatectomized rats. Comparison was made between control rats and rats subjected to 32% liver resection. PT was not significantly different in the transplanted group compared with liver-resected and control rats. Laser Doppler flowmetry showed that at 28 days after surgery, blood flow had increased in the transplanted livers. Furthermore, on the third day after transplantation, basal plasma insulin was increased and the plasma insulin response to glucose was exaggerated, suggesting reduced insulin action and impaired insulin degradation. Finally, uptake of radioactive-labeled E. coli bacteria, as a measure of RES function, was not compromised in transplanted animals. Based on these results, we conclude that reduced-size liver transplant in out-bred rats results in fast normalization of liver function after surgery although, immediately after surgery, glucose intolerance is seen.     

Relation between sexual abuse in childhood and adult depression: case-control study

OBJECTIVE: To examine the association between sexual abuse in childhood and adult depression in women. DESIGN: Two stage, case detection and case identification design, using the 30-item general health questionnaire and the Beck depression inventory for screening and the affective items relating to current functioning on the schizophrenia and affective disorders schedule to identify depressed cases. Details of sexual abuse in childhood were elicited retrospectively by semistructured interview, and social problems by the social problems questionnaire. SETTING: Three general practices, in middle class suburban, deprived inner city, and rural areas. SUBJECTS: 1189 women were screened and 237 subsequently interviewed; 132 were depressed. RESULTS: 49 (37%) of the depressed interviews and 24 (23%) of the non-depressed interviews reported experience of sexual abuse when they were aged under 16 years. A positive association existed between the more severe abuse and depression--all those who had experienced penetration were depressed as adults. A relation was also found between sexual abuse in childhood and sexual problems, housing problems, and problems with their children at school. CONCLUSION: A positive association between child sexual abuse and depression was confirmed, but this was confined to more severe abuse (penetration or attempted penetration).     

Changes in medical stability upon admission to a rehabilitation unit

The implementation of Medicare's prospective payment system in acute care has coincided with a steady increase in medically unstable admissions to our freestanding rehabilitation facility. We investigated the consequences of these admissions by collecting medical information regarding transfers beginning in 1983. Patients requiring transfer back to the acute setting within 1 day of admission were considered medically unstable and their charts were reviewed. The number of patients requiring transfer back within 1 day increased from 1.5% of all first admissions to 3.1% in 1988 (Mantel - Haenszel chi 2 = 8.03, (df = 1), p < .01), but the increase among Medicare patients alone was not significant. This progressive increase was most pronounced in the cerebrovascular accident and spinal cord injury populations. Beginning in 1988, an intensified preadmission evaluation program was implemented, resulting in a significant decline in unstable patient transfers from hospitals where our consultants were on staff. Physiatric consultations at referral institutions decreased the number of unstable patients at admission.     

Family practice physicians' firearm safety counseling beliefs and behaviors

The purpose of this study was to identify family physicians' firearm safety counseling beliefs and behaviors. A survey was mailed to a random sample of 600 members of the American Academy of Family Physicians. A three wave mailing technique was used to maximize the response rate and yielded 271 usable surveys (55% response rate). Outcome measures included training experience in firearm safety counseling, the prevalence of firearm safety counseling by family physicians, and their perceptions regarding such counseling. The majority (78%) of family physicians lacked formal training on how to counsel patients about firearm safety and 49% believed more time should be spent in residency programs on firearm safety counseling. The majority (84%) of respondents never or rarely counseled patients on firearm safety and 50% believed firearm safety counseling should be a low priority in their delivery of primary care. The majority of respondents did not regularly counsel patients about firearm safety, did not believe firearm safety counseling should be a priority, and did not believe firearm safety counseling would be effective in reducing firearm-related trauma.     

Running programs backwards: The logical inversion of imperative computation

Imperative programs can be inverted directly from their forward-directed program code with the use of logical inference. The relational semantics of imperative computations treats programs as logical relations over the observable state of the environment, which is taken to be the state of the variables in memory. Program relations denote both forward and backward computations, and the direction of the computation depends upon the instantiation pattern of arguments in the relation. This view of inversion has practical applications when the relational semantics is treated as a logic program. Depending on the logic programming inference scheme used, execution of this relational program can compute the inverse of the imperative program. A number of nontrivial imperative computations can be inverted with minimal logic programming tools.