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     

A shell for cooperating expert systems

Abstract: This paper describes a shell for cooperating expert systems that has been developed at the University of Porto. The main goal of this shell is two-fold: to generate a community of cooperative knowledge-based systems and to develop several special reasoning techniques which can be used under a distributed and cooperative paradigm. UPShell is able to convert a set of generated intelligent systems (ISs) into a community of cooperative ISs. In this first version it is already possible to generate different intelligent systems which are able to run 'simultaneously' as separate Unix processes and, using a message-passing mechanism, to communicate among themselves. They can be set to pursue an overall goal in a cooperative way. Moreover, several tasks can be given to each IS to be solved simultaneously, and the IS can switch from task to task according to dynamic priorities reflecting the urgency attached to the specific sub-tasks that emerge. The shell described here may also be used to test, within a distributed environment, some time-bounded reasoning techniques that are presently being developed. The paper has three main parts: a general overview of the UPShell (Section 1); a tutorial explaining, by means of examples, how to use the package (Section 2); and, finally, some considerations on the reasoning techniques used and future improvements (Sections 3–5).     

Organic matter release in low temperature thermal treatment of biological sludge for reduction of excess sludge production.

Thermal treatment applied in association with a biological system allows for a significant reduction in excess sludge production (approximately 50%). In general, heat treatment is described as a sludge disintegration technique. This paper offers a thorough study on the impact of heat treatment, at temperatures below 100 degrees C, on the solubilisation of the sludge COD and its biodegradability. Discontinuous heating experiments were performed on activated and digested sludge. At all temperatures tested the released COD for digested sludge was systematically higher than that for activated sludge (15 and 40%, respectively, at 95 degrees C for 40 min of contact time). For the first 30 min, a 1st order kinetic, with respect to the residual COD, was systematically found. In the range of 40-95 degrees C, digested sludge had a lower activation energy than activated sludge (26 kcal/mol compared to 70-160 kcal/mol). COD solubilisation is thus more positively influenced by temperature in the case of activated sludge. This may be due to the significant difference in the ratio of protein/carbohydrate in digested and activated sludge (1-5 and 0.2-0.7, respectively). The increase in the COD/TKN ratio in the solubilised fraction after thermal treatment of activated sludge suggests a preferential solubilisation of proteins over carbohydrates. Respirometric tests performed on the solubilised COD showed that whatever the sludge origin, only 40-50% of released COD is biodegradable at a conventional hydraulic retention time (i.e., 24 h). Hence, heat treatment would act more through organic matter solubilisation rather than by a biodegradability increase.     

Moral value transfer from regulatory fit: What feels right is right and what feels wrong is wrong.

People experience regulatory fit (E. T. Higgins, 2000) when the strategic manner of their goal pursuit suits their regulatory orientation, and this regulatory fit feels right. Fit violation feels wrong. Four studies tested the proposal that experiences of fit can transfer to moral evaluations. The authors examined transfer of feeling wrong from fit violation by having participants in a promotion or prevention focus recall transgressions of commission or omission (Studies 1 and 2). Both studies found that when the type of transgression was a fit violation, participants expressed more guilt. Studies 3 and 4 examined transfer of feeling right from regulatory fit. Participants evaluated conflict resolutions (Study 3) and public policies (Study 4) as more right when the means pursued had fit. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Synthesis,characterization and properties of functionalized styrene–maleimide copolymers

New functionalized styrene–maleimide copolymers were prepared by free radical copolymerization of styrene (St) and N‐4‐carboxybutylmaleimide (NBMI) in chloroform, using 2,2′‐azobisisobutyronitrile (AIBN) as initiator. Monomer and copolymer characterization was carried out by ¹H‐ and ¹³C‐NMR. Copolymer composition was determined by elemental analysis and Fourier‐transform infrared (FTIR) spectroscopy. The glass transition temperature (from DSC) and the thermogravimetric analysis (TGA) of the copolymers were consistent with the thermal behavior and stability observed for alternating St–maleimide copolymers. St–NBMI copolymers crosslinked with divinylbenzene (DVB) were also synthesized and their cation exchange properties evaluated in order to assess the capacity of the new copolymers to bind metallic ions. Copyright © 2005 Society of Chemical Industry     

Longitudinal bone mineral density changes in early rheumatoid arthritis

A prospective longitudinal study of patients with early RA was performed to examine the influence of disease duration, disease activity and physical activity on bone loss. Sixty-seven patients with non-steroid treated RA of less than 5 yr duration, including 16 patients with disease duration less than 6 months, had BMD measurements of the femoral neck and the lumbar spine over a 12-month period using dual energy X-ray absorptiometry. The BMD changes were compared with values from 72 control patients and were also correlated with serial measurements of disease activity (measured by the Stoke Index) and disability [measured by the Health Assessment Questionnaire (HAQ) score], at 3-monthly intervals over the 12-month period. No significant differences in BMD changes were found between RA patients and controls overall. Patients with disease duration of less than 6 months had significantly greater loss of BMD at the femoral neck (-3.9%, S.E.M. 1.5) than the remainder of the cohort (-0.2%, S.E.M. 0.7) (P = 0.02) and controls (-0.8%, S.E.M. 0.6). Lumbar spine BMD changes correlated with the initial Stoke Index (Rs-0.373, P = 0.01) but not mean Stoke Indices. There was no correlation of BMD changes with age or HAQ scores. These findings suggest that significant bone loss occurs within the first few months of disease in patients with RA.     

A multidistrict audit on the management of Chlamydia trachomatis in genitourinary medicine clinics in Yorkshire

Although there have been recent molecular biological studies for evidence of possible changes in trypanosome biochemistry, such studies are not yet complemented by parallel clinical studies to determine the possible implications to the sleeping sickness patient. The study of the duration of symptoms and the case fatality of T. b. rhodesiense showed that the disease progressed to the stage of central nervous system involvement between three weeks to two months of infection. Most (> 80%) deaths occurred within six months of illness. The case fatality rate of treated sleeping sickness patients was 6% of which the rate in the late-stage of sleeping sickness was more than two and a half times that in the early stage. The incidence of melarsoprol encephalopathy was 2.5% and case fatality due to this condition was 1.0% and similar to previous findings. Thus it appears the virulence of T. b. rhodesiense circulating in south east Uganda has not changed during the past decades.     

Effects of pramipexole on contraversive rotation and functional motor impairments in 1-methyl-4-phenyl1,2,3, 6-tetrahydropyridine-induced chronic hemiparkinsonian monkeys

Rotational and functional motor behavioral changes were studied in five MPTP lesioned chronic hemiparkinsonian Macaca nemestrina monkeys after i.m. pramipexole, a predominant D2 subfamily agonist. Pramipexole induced contraversive rotations in a dose-dependent manner with an optimal dose of 56 microg/kg for approximately 2 to 4 hr after injection. Three different rating scales were used to determine drug-induced functional improvement. They included a monkey parkinsonism rating scale, volitional responses to fruit presentations, and number of hand movements that appeared volitional. A dose of 56 microg/kg of pramipexole produced functional improvements on hand disability, and on a parkinsonian rating scale for monkeys in a dose-dependent manner from 32 to 100 microg/kg. These doses produced an increase in significant hand movements in the affected (contralateral) as well as in the normal (ipsilateral) hand to the side of the brain lesion compared with 5% dextrose in water vehicle control. With a dose of 100 microg/kg, the therapeutic effects of pramipexole on hand movements were less than with 56 microg/kg, due to side effects such as scratching.     

Biology of chronic radiation effect on tissues and wound healing

Radiation therapy exerts both acute and chronic effects on normal tissue included within treatment fields. The physics of radiation therapy and treatment techniques to minimize deleterious effects of radiation are presented. Management of radiation-damaged skin is discussed. Radiation effect on tissue, wound healing, and tumorigenesis also are reviewed.