Ontology-assisted database integration to support natural language processing and biomedical data-mining

Successful biomedical data mining and information extraction require a complete picture of biological phenomena such as genes, biological processes, and diseases; as these exist on different levels of granularity. To realize this goal, several freely available heterogeneous databases as well as proprietary structured datasets have to be integrated into a single global customizable scheme. We will present a tool to integrate different biological data sources by mapping them to a proprietary biomedical ontology that has been developed for the purposes of making computers understand medical natural language

Ontology-Assisted Database Integration to Support Natural Language Processing and Biomedical Data-mining

Successful biomedical data mining and information extraction require a complete picture of biological phenomena such as genes, biological processes, and diseases; as these exist on different levels of granularity. To realize this goal, several freely available heterogeneous databases as well as proprietary structured datasets have to be integrated into a single global customizable scheme. We will present a tool to integrate different biological data sources by mapping them to a proprietary biomedical ontology that has been developed for the purposes of making computers understand medical natural language

The competitive interaction of actin and PIP2 with actophorin is based on overlapping target sites : design of a gain-of-function mutant

We studied the effect of mutations in an alpha-helical region of actophorin (residues 91-108) on F-actin and PIP2 binding. As in cofilin, residues in the NH2-terminal half of this region are involved in F-actin binding. We show here also that basic residues in the COOH-terminal half of the region participate in this interaction whereby we extend the previously defined actin binding interface [Lappalainen, P., et al. (1997) EMBO J. 16, 5520-5530]. In addition, we demonstrate that some of the lysines in this alpha-helical region in actophorin are implicated in PIP2 binding. This indicates that the binding sites of F-actin and PIP2 on actophorin overlap, explaining the mutually exclusive binding of these ligands. The Ca2+-dependent F-actin binding of a number of actophorin mutants (carrying a lysine to glutamic acid substitution at the COOH-terminal positions of the actin binding helical region) may mimic the behavior of members of the gelsolin family. In addition, we show that PIP2 binding, but not actin binding, of actophorin is strongly enhanced by a point mutation that leads to a reinforcement of the positive electrostatic potential of the studied alpha-helical region

Analogous F-actin binding by cofilin and gelsolin segment 2 substantiates their structural relationship

Cofilin is representative for a family of low molecular weight actin filament binding and depolymerizing proteins. Recently the three-dimensional structure of yeast cofilin and of the cofilin homologs destrin and actophorin were resolved, and a striking similarity to segments of gelsolin and related proteins was observed (Hatanaka, H., Ogura, K., Moriyama, K., Ichikawa, S., Yahara, I., and Inagaka, F. (1996) Cell 85, 1047-1055; Fedorov, A. A., Lappalainen, P., Fedorov, E. V., Drubin, D. G., and Almo, S. C. (1997) Not. Struct. Biol. 4, 366-369; Leonard, S. A., Gittis, A. G., Petrella, E. C., Pollard, T. D., and Lattman, E. E. (1997) Not. Struct. Biol. 4, 369-373). Using peptide mimetics, we show that the actin binding site stretches over the entire cofilin alpha-helix 112-128. In addition, we demonstrate that cofilin and its actin binding peptide compete with gelsolin segments 2-3 for binding to actin filaments. Based on these competition data, we propose that cofilin and segment 2 of gelsolin use a common structural topology to bind to actin and probably share a similar target site on the filament. This adds a functional dimension to their reported structural homology, and this F-actin binding mode provides a basis to further enlighten the effect of members of the cofilin family on actin filament dynamics

Effects of natural mutations in lecithin:cholesterol acyltransferase on the enzyme structure and activity

A molecular model was built for human lecithin:cholesterol acyltransferase (LCAT) based upon the structural homology between this enzyme and lipases (Peelman et al, 1998, Prot. Sci, 7: 585-597), We proposed that LCAT belongs to the alpha/beta hydrolase fold family, and that the central domain of LCAT consists of a mixed seven-stranded beta-pleated sheet with four alpha-helices and loops linking the beta-strands, The catalytic triad of LCAT was identified as Asp345 and His377, as well as Ser181, This model is used here for the interpretation of the structural defects linked to the point mutations identified in LCAT which cause either familial LCAT deficiency (FLD) or fish-eye disease (FED). We show that these mutations occur in separate domains of the 3D structure of the enzyme. Most mutations causing familial LCAT deficiency are either clustered in the vicinity of the catalytic triad or affect conserved structural elements in LCAT. Most mutations causing fish-eye disease are localized on the outer hydrophilic surface of the amphipathic helical segments, These mutations affect only minimally the overall structure of the enzyme, but are Likely to impair the interaction of the enzyme with its co-factor and/ or substrate

A Coreference Corpus and Resolution System for Dutch

We present the main outcomes of the COREA project: a corpus annotated with coreferential relations and a coreference resolution system for Dutch. We discuss the annotation of the corpus: the type of annotated relations, the guidelines, the annotation tool and interannotator agreement. We also show a visualization of the annotated relations. The standard approach to evaluate a coreference resolution system is to compare the predictions of the system to a hand-annotated gold standard test set (cross-validation). A more practically oriented evaluation is to test the usefulness of coreference relation information in an NLP application. We present results of both types of evalutation. We run experiments with an Information Extraction module for the medical domain, and measure the performance of this module with and without coreference relation information. In a separate experiment we also evaluate the effect of coreference information produced by a simple rule-based coreference module in a Question Answering application. 1

Effect of mutations of N- and C-terminal charged residues on the activity of LCAT.

A