Use of automatic relevance determination in QSAR studies using Bayesian neural networks.

We describe the use of Bayesian regularized artificial neural networks (BRANNs) coupled with automatic relevance determination (ARD) in the development of quantitative structure-activity relationship (QSAR) models. These BRANN-ARD networks have the potential to solve a number of problems which arise in QSAR modeling such as the following: choice of model; robustness of model; choice of validation set; size of validation effort; and optimization of network architecture. The ARD method ensures that irrelevant or highly correlated indices used in the modeling are neglected as well as showing which are the most important variables in modeling the activity data.

Molecular characterization of 11q deletions points to a pathogenic role of the ATM gene in mantle cell lymphoma.

Deletions involving the long arm of chromosome 11 (11q) have been recently found as recurrent chromosome aberrations in mantle cell lymphoma (MCL). In the current study, the incidence and molecular extent of 11q deletions were analyzed in a series of 81 MCL by fluorescence in situ hybridization with probes from a contiguous set of yeast artificial chromosomes (YACs). Loss of chromosome 11 material was observed in 37 of 81 cases (46%).

Spot synthesis: observations and optimizations.

Positionally addressable syntheses of peptides on continuous cellulose membranes (spot synthesis) have often been reported in detail, but important questions dealing with synthesis quality, reproducibility and subsequent binding assays have largely been under-emphasized. In this report we have investigated some of these problems. The most important results were: (i) the signal intensity of ligate binding to cellulose-bound peptides and the affinity of the corresponding soluble peptides show good correlation, illustrated by three different ligate binding assays; (ii) reducing peptide density on the cellulose avoids the 'ring spot' effect, i.

Spinal markers: A new method for increasing accuracy in spinal navigation.

Spinal navigation opens up a completely new dimension in the planning and realization of neurosurgical and orthopedic procedures, and offers the possibility of simulating the operation preoperatively. There is currently only limited experience with spinal navigation, and despite the development of advanced software, intraoperative difficulties include identification of characteristic and reproducible anatomical landmarks, localization of these points in the surgical field, referencing, and intraoperative control. We report the use of a new kind of implantable fiducial marker in a case of a 58-year-old female patient with spondylolisthesis.

Robust QSAR models using Bayesian regularized neural networks.

We describe the use of Bayesian regularized artificial neural networks (BRANNs) in the development of QSAR models. These networks have the potential to solve a number of problems which arise in QSAR modeling such as: choice of model; robustness of model; choice of validation set; size of validation effort; and optimization of network architecture. The application of the methods to QSAR of compounds active at the benzodiazepine and muscarinic receptors is illustrated.

The protective effect of lipoxygenase inhibitor FLM 5011 on mitochondria ultrastructure of ischemic and reperfused cardiomyocytes.

Lipoxygenase inhibitor FLM 5011 was used in experimental ischemia and reperfusion with dogs to investigate its ultrastructure-preserving effects on the mitochondria of myocardium. Ischemic and non-ischemic areas of the heart were ultrastructural-morphometric analysed, which revealed that FLM 5011 was able to diminish ischemic damage especially of mitochondria. The protective effects on mitochondria consisted mainly in reduction of defective intramitochondrial areas and in excellent protection of the structural integrity of cristae and matrix.

A comparison of cytochrome b and DNA hybridization data bearing on the phylogeny of swallows (Aves: Hirundinidae).

Cytochrome b sequence data from 17 species representing 16 genera of swallows (Aves: Hirundinidae) were compared with DNA-DNA hybridization data from the same species in a taxonomic congruence assessment of swallow phylogeny. In the process, subsets (partitions) of the cytochrome b sequence data were examined in light of the DNA hybridization distances to assess their potential phylogenetic informativeness. When the sequence data were weighted-with or without reference to the DNA hybridization data-they produced parsimony and maximum likelihood (but not distance) trees that were largely congruent with the DNA hybridization tree.

The protective effect of iloprost, a PGL2 analogue, on ultratructure of ischemic and reperfused myocardial myocytes.

Iloprost was used in experiments with dogs to investigate its ultrastructure-preserving effects on the myocardium during ischemia and reperfusion, focussed especially on the mitochondria. Ischemia was performed by ligation of the left anterior descending coronary artery (LAD) for 90 min followed by reperfusion of 180 min. Samples were taken from the ischemic and non-ischemic area before ligation of LAD, immediately after ischemia and reperfusion.

Enkephalin analogs containing 4,4-difluoro-2-aminobutyric acid: synthesis and fluorine effect on the biological activity.

Analogs of Met-enkephalin and [D-Pen2, D-Pen5]enkephalin (DPDPE) containing the partially fluorinated amino acid 4,4-difluoro-2-aminobutyric acid (DFAB) in the 2- or 3-position of the peptide sequence were synthesized and their opioid activities and receptor selectivities were determined in vitro. The linear fluorinated [D-DFAB2, Met5-NH2]enkephalin showed mu and delta agonist potencies comparable to those of natural [Leu5]enkephalin. The partially fluorinated DPDPE analogs behaved differently as compared with their non-fluorinated correlates.

Identification of residues in the cysteine-rich domain of Raf-1 that control Ras binding and Raf-1 activity.

We have identified mutations in Raf-1 that increase binding to Ras. The mutations were identified making use of three mutant forms of Ras that have reduced Raf-1 binding (Winkler, D. G.

Identification and characterization of mutations in Ha-Ras that selectively decrease binding to cRaf-1.

The oncoprotein Ras transforms cells by binding to one or more effector proteins. Effector proteins have been identified by their ability to bind to Ras in the GTP but not GDP form, and by their requirement for the Ras effector domain for binding. The best understood Ras effectors are serine/threonine kinases of the Raf family, but other candidate Ras effectors, including a Ral guanine nucleotide dissociation stimulator and phosphatidylinositol 3-kinase (PI3 kinase) have also been identified.

Molecular modeling studies of "flap up" mannosyl cation mimics.

The importance of inhibitors of glycosidases as therapeutic agents for viral, proliferative, and metabolic diseases is being increasingly recognised. Several years ago we reported that the activities of mannosidase inhibitors may be explained in terms of their similarity to the mannosyl cation intermediate postulated to form during the enzyme-catalyzed processing of oligosaccharide substrates. Recently, the validity of this model has been called in to question by some authors.

Stereoconservative and stereoselective syntheses of rare and non-naturalα-amino acids from (S)-aspartic acid and (S)-malic acid.

A new strategy for stereoconservative and stereoselective syntheses of several types of amino acids starting fromα-functional carboxylic acids employing hexafluoroacetone as protecting and activating reagent is described. Outstanding features of this new method are the mild reaction conditions and the high yields for introduction and cleavage of the protective group allowing sensitive functional groups in the side chain to survive. Furthermore, the new concept results in saving of synthetic steps.

Modification of Ser59 in the unique N-terminal region of tyrosine kinase p56lck regulates specificity of its Src homology 2 domain.

During T-cell activation, Ser59 in the unique N-terminal region of p56lck is phosphorylated. Mutation of Ser59 to Glu59 mimics Ser59 phosphorylation, and upon CD4 crosslinking, this mutant p56lck induces tyrosine phosphorylation of intracellular proteins distinct from those induced by wild-type p56lck. Mutant and wild-type p56lck have similar affinities for CD4 and similar kinase activities.

High expression of NK-1.1 antigen is induced by infection with murine AIDS virus.

Spleen cells from mice infected with LP-BM5 MuLV, a causative agent of murine acquired immunodeficiency syndrome (MAIDS), were tested for frequency of NK-1.1+ cells and natural killer (NK) activity. During the first 3 weeks following infection, NK activity was well conserved, but by 9-12 weeks post-infection (p.

Evolution of nest construction in swallows (Hirundinidae): a molecular phylogenetic perspective.

Nest construction is more diverse in the Hirundinidae than in any other family of oscine birds. To explore the evolution of this diversity, we superimposed nest data on a DNA-hybridization phylogeny of 17 swallow species. Nest construction is tightly linked to the inferred evolutionary history.