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     

Effect of shigella enterotoxin 1 (ShET1) on rabbit intestine in vitro and in vivo

The purpose of this study was to identify the optimal knot construction for interrupted dermal sutures. A synthetic braided absorbable suture, sizes 3-0 and 5-0, was selected for this evaluation. With reproducible mechanical performance tests, we determined that the construction of secure knots without ears required one additional throw as compared with secure knots with 3-mm ears. The direction of applied tension did not alter knot security, with the exception of granny knots, which required an extra throw when tension was applied parallel to the suture loop. Because interrupted dermal knot construction is accomplished without knot ears and with an applied tension parallel to the wound, one additional throw must be added to the knot to ensure knot security.     

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.     

Cell-mediated immunological responses in cervical and vaginal cancer patients immunized with a lipidated epitope of human papillomavirus type 16 E7

Human papillomavirus (HPV) infection has been causally associated with cervical cancer. We tested the effectiveness of an HLA-A*0201-restricted, HPV-16 E7 lipopeptide vaccine in eliciting cellular immune responses in vivo in women with refractory cervical cancer. In a nonrandomized Phase I clinical trial, 12 women expressing the HLA-A2 allele with refractory cervical or vaginal cancer were vaccinated with four E786-93 lipopeptide inoculations at 3-week intervals. HLA-A2 subtyping was also performed, and HPV typing was assessed on tumor specimens. Induction of epitope-specific CD8+ T-lymphocyte (CTL) responses was analyzed using peripheral blood leukapheresis specimens obtained before and after vaccination. CTL specificity was measured by IFN-gamma release assay using HLA-A*0201 matched target cells. Clinical responses were assessed by physical examination and radiographic images. All HLA-A*0201 patients were able to mount a cellular immune response to a control peptide. E786-93-specific CTLs were elicited in 4 of 10 evaluable HLA-A*0201 subjects before vaccination, 5 of 7 evaluable HLA-A*0201 patients after two vaccinations, and 2 of 3 evaluable HLA-A*0201 cultures after all four inoculations. Two of three evaluable patients' CTLs converted from unreactive to reactive after administration of all four inoculations. There were no clinical responses or treatment toxicities. The ability to generate specific cellular immune responses is retained in patients with advanced cervical cancer. Vaccination with a lipidated HPV peptide epitope appears capable of safely augmenting CTL reactivity. Although enhancements of cellular immune responses are needed to achieve therapeutic utility in advanced cervical cancer, this approach might prove useful in treating preinvasive disease.     

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.     

Analysis of the roles of antilipopolysaccharide and anti-cholera toxin immunoglobulin A (IgA) antibodies in protection against Vibrio cholerae and cholera toxin by use of monoclonal IgA antibodies in vivo

Secretory immunoglobulin A (IgA) antibodies (sIgA) directed against cholera toxin (CT) and surface components of Vibrio cholerae are associated with protection against cholera, but the relative importance of specific sIgAs in protection is unknown. A monoclonal IgA directed against the V. cholerae lipopolysaccharide (LPS), secreted into the intestines of neonatal mice bearing hybridoma tumors, was previously shown to provide protection against a lethal oral dose of 10(7) V. cholerae cells. We show here that a single oral dose of 5 to 50 micrograms of the monoclonal anti-LPS IgA, given within 2 h before V. cholerae challenge, protected neonatal mice against challenge. In contrast, an oral dose of 80 micrograms of monoclonal IgA directed against CT B subunit (CTB) failed to protect against V. cholerae challenge. A total of 80 micrograms of monoclonal anti-CTB IgA given orally protected neonatal mice from a lethal (5-micrograms) oral dose of CT. Secretion of the same anti-CTB IgA antibodies into the intestines of mice bearing IgA hybridoma backpack tumors, however, failed to protect against lethal oral doses of either CT (5 micrograms) or V. cholerae (10(7) cells). Furthermore, monoclonal anti-CTB IgA, either delivered orally or secreted onto mucosal surfaces in mice bearing hybridoma tumors, did not significantly enhance protection over that provided by oral anti-LPS IgA alone. These results demonstrate that anti-LPS sIgA is much more effective than anti-CT IgA in prevention of V. cholerae-induced diarrheal disease.