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Biomedical subjects

Lawrence Hunter

Publications and source records attributed to Lawrence Hunter.

17 recordsLinked to original sources
PubMed2006

A critical review of PASBio's argument structures for biomedical verbs.

BACKGROUND: Propositional representations of biomedical knowledge are a critical component of most aspects of semantic mining in biomedicine. However, the proper set of propositions has yet to be determined. Recently, the PASBio project proposed a set of propositions and argument structures for biomedical verbs. This initial set of representations presents an opportunity for evaluating the suitability of predicate-argument structures as a scheme for representing verbal semantics in the biomedical domain. Here, we quantitatively evaluate several dimensions of the initial PASBio propositional structure repository. RESULTS: We propose a number of metrics and heuristics related to arity, role labelling, argument realization, and corpus coverage for evaluating large-scale predicate-argument structure proposals. We evaluate the metrics and heuristics by applying them to PASBio 1.0. CONCLUSION: PASBio demonstrates the suitability of predicate-argument structures for representing aspects of the semantics of biomedical verbs. Metrics related to theta-criterion violations and to the distribution of arguments are able to detect flaws in semantic representations, given a set of predicate-argument structures and a relatively small corpus annotated with them.

Abstracting and Indexing↗
PubMed2006

Identification of genes controlled by the pregnane X receptor by microarray analysis of mRNAs from pregnenolone 16alpha-carbonitrile-treated rats.

Mammalian liver contains a pregnane X receptor (PXR, NR1I2), which binds drugs and other xenobiotics, and stimulates (or suppresses) expression of numerous genes involved in the metabolic elimination of foreign compounds and some toxic endogenous substances. In the present study, we used microarray analysis to identify genes whose expression in rat liver was significantly altered by pregnenolone 16alpha-carbonitrile (PCN) treatment. PCN is a synthetic steroid that induces cytochrome P4503A expression and is hepatoprotective by increasing resistance to subsequent stressful insults. Significant induction was seen for 138 genes while expression of 82 genes was significantly repressed. We found induction of genes known to be induced by PCN, such as enzymes involved in drug metabolism and transport. In addition, many genes were differentially expressed whose functions concerned intracellular metabolism, transport of essential small molecules, cell cycle, and redox balance. Our results support the idea that the domain of PXR-controlled gene networks may be even more extensive than currently thought and may extend to functions apart from xenobiotic metabolism.

Animals↗
PubMed2006

Enrichment of OBO ontologies.

This paper describes a frame-based integration of the three GO subontologies, the Chemical Entities of Biological Interest ontology, and the Cell Type Ontology in which relationships are modeled in a way that better captures the semantics between biological concepts represented by the terms, rather than between the terms themselves, than previous frame-based efforts. We also describe a methodology for creating suggested enriching assertions by identifying patterns in GO terms, mapping these patterns to new, specific relationships, and matching term substrings to concepts. Using this methodology, a predicted assertion was made for 62% of GO terms that matched one of 31 patterns, and 97% of these predicted assertions were assessed to be valid, resulting in an initial set of over 4000 assertions. Furthermore, this methodology programmatically integrates assertions into an ontology such that each assertion is fully consistent with respect to higher (i.e., more general) relevant class and slot levels.

Computational Biology↗
PubMed2006

Serial gene expression profiling in the intact human heart.

BACKGROUND: In chronic heart failure due to a dilated cardiomyopathy phenotype, the molecular bases for contractile dysfunction and chamber remodeling remain largely unidentified. METHODS: To investigate the feasibility of measuring global gene expression serially in the intact failing human heart, we performed repeated messenger RNA (mRNA) expression profiling using RNA extracted from endomyocardial biopsy specimens and gene chip methodology in 8 subjects with idiopathic dilated cardiomyopathy. In patients treated with beta-blocking agents or placebo, myocardial gene expression was measured in endomyocardial biopsy material and radionuclide ejection fraction was measured at baseline and after 4 to 12 months of treatment. Gene expression was measured for 12,625 gene sequences by using Affymetrix U95 gene chips and commercially available software. For 6 mRNAs, gene chip results were compared with measurements made by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: In an unfiltered composite analysis of changes in expression detected in the patients with high-signal intensity chips, 241 genes showed an increase and 331 genes a decrease in mRNA abundance. There was good agreement between changes measured by quantitative RT-PCR and those determined by gene chips. There was less variance between differences in phenotype in patients sampled serially as compared between subjects with similar phenotypes sampled at baseline. CONCLUSIONS: Serial gene expression profiling with association to phenotypic change is feasible in the intact human heart and may offer advantages to cross-sectional expression profiling. This study suggests that the intact failing remodeled human heart is in an activated state of gene expression, with a large net reduction in gene expression occurring as phenotypic improvement occurs.

Adolescent↗
PubMed2006

Evaluation of lexical methods for detecting relationships between concepts from multiple ontologies.

We used exact term matching, stemming, and inclusion of synonyms, implemented via the Lucene information retrieval library, to discover relationships between the Gene Ontology and three other OBO ontologies: ChEBI, Cell Type, and BRENDA Tissue. Proposed relationships were evaluated by domain experts. We discovered 91,385 relationships between the ontologies. Various methods had a wide range of correctness. Based on these results, we recommend careful evaluation of all matching strategies before use, including exact string matching. The full set of relationships is available at compbio.uchsc.edu/dependencies.

Computational Biology↗
PubMed2006

Finding GeneRIFs via gene ontology annotations.

A Gene Reference Into Function (GeneRIF) is a concise phrase describing a function of a gene in the Entrez Gene database. Applying techniques from the area of natural language processing known as automatic summarization, it is possible to link the Entrez Gene database, the Gene Ontology, and the biomedical literature. A system was implemented that automatically suggests a sentence from a PubMed/MEDLINE abstract as a candidate GeneRIF by exploiting a gene's GO annotations along with location features and cue words. Results suggest that the method can significantly increase the number of GeneRIF annotations in Entrez Gene, and that it produces qualitatively more useful GeneRIFs than other methods.

Algorithms↗
PubMed2005

BioCreAtIvE task1A: entity identification with a stochastic tagger.

BACKGROUND: Our approach to Task 1A was inspired by Tanabe and Wilbur's ABGene system. Like Tanabe and Wilbur, we approached the problem as one of part-of-speech tagging, adding a GENE tag to the standard tag set. Where their system uses the Brill tagger, we used TnT, the Trigrams 'n' Tags HMM-based part-of-speech tagger. Based on careful error analysis, we implemented a set of post-processing rules to correct both false positives and false negatives. We participated in both the open and the closed divisions; for the open division, we made use of data from NCBI. RESULTS: Our base system without post-processing achieved a precision and recall of 68.0% and 77.2%, respectively, giving an F-measure of 72.3%. The full system with post-processing achieved a precision and recall of 80.3% and 80.5% giving an F-measure of 80.4%. We achieved a slight improvement (F-measure = 80.9%) by employing a dictionary-based post-processing step for the open division. We placed third in both the open and the closed division. CONCLUSION: Our results show that a part-of-speech tagger can be augmented with post-processing rules resulting in an entity identification system that competes well with other approaches.

Databases, Genetic↗
PubMed2005

Proteomic exploration of pancreatic islets in mice null for the alpha2A adrenergic receptor.

The present studies extend recent findings that mice null for the alpha(2A) adrenergic receptor (alpha(2A) AR KO mice) lack suppression of exogenous secretagogue-stimulated insulin secretion in response to alpha(2) AR agonists by evaluating the endogenous secretagogue, glucose, ex vivo, and providing in vivo data that baseline insulin levels are elevated and baseline glucose levels are decreased in alpha(2A) AR KO mice. These latter findings reveal that the alpha(2A) AR subtype regulates glucose-stimulated insulin release in response to endogenous catecholamines in vivo. The changes in alpha(2A) AR responsiveness and resultant changes in insulin/glucose homeostasis encouraged us to utilize proteomics strategies to identify possible alpha(2A) AR downstream signaling molecules or other resultant changes due to perturbation of alpha(2A) AR expression. Although agonist stimulation of islets from wild type (WT) mice did not significantly alter islet protein profiles, several proteins were enriched in islets from alpha(2A) AR KO mice when compared with those from WT mice, including an enzyme participating in insulin protein processing. The present studies document the important role of the alpha(2A) AR subtype in tonic suppression of insulin release in response to endogenous catecholamines as well as exogenous alpha(2) agonists and provide insights into pleiotropic changes that result from loss of alpha(2A) AR expression and tonic suppression of insulin release.

Adrenergic alpha-2 Receptor Agonists↗
PubMed2005

Implications of compositionality in the gene ontology for its curation and usage.

In this paper we argue that a richer underlying representational model for the Gene Ontology that captures the implicit compositional structure of GO terms could have a positive impact on two activities crucial to the success of GO: ontology curation and database annotation. We show that many of the new terms added to GO in a one-year span appear to be compositional variations of other terms. We found that 90.2% of the 3,652 new terms added between July 2003 and July 2004 exhibited characteristics of compositionality. We also examine annotations available from the GO Consortium website that are either manually curated or automatically generated. We found that 74.5% and 63.2% of GO terms are seldom, if ever, used in manual and automatic annotations, respectively. We show that there are features that tend to distinguish terms that are used from those that are not. In order to characterize the effect of compositionality on the combinatorial properties of GO, we employ finite state automata that represent sets of GO terms. This representational tool demonstrates how ontologies can grow very fast, and also shows that small conceptual changes can directly result in a large number of changes to the terminology. We argue that the curation and annotation findings we report are influenced by the combinatorial properties that present themselves in an ontology that does not have a model that properly captures the compositional structure of its terms.

Computational Biology↗
PubMed2005

Empirical data on corpus design and usage in biomedical natural language processing.

This paper describes the design of six publicly available biomedical corpora. We then present usage data for the six corpora. We show that corpora that are carefully annotated with respect to structural and linguistic characteristics and that are distributed in standard formats are more widely used than corpora that are not. These findings have implications for the design of the next generation of biomedical corpora.

Computational Biology↗
PubMed2003

Innate differences in protein expression in the nucleus accumbens and hippocampus of inbred alcohol-preferring and -nonpreferring rats.

Two-dimensional gel electrophoresis (2-DE) was used to separate protein samples solubilized from the nucleus accumbens and hippocampus of alcohol-naïve, adult, male inbred alcohol-preferring (iP) and alcohol-nonpreferring (iNP) rats. Several protein spots were excised from the gel, destained, digested with trypsin, and analyzed by mass spectrometry. In the hippocampus, 1629 protein spots were matched to the reference pattern, and in the nucleus accumbens, 1390 protein spots were matched. Approximately 70 proteins were identified in both regions. In the hippocampus, only 8 of the 1629 matched protein spots differed in abundance between the iP and iNP rats. In the nucleus accumbens, 32 of the 1390 matched protein spots differed in abundance between the iP and iNP rats. In the hippocampus, the abundances of all 8 proteins were higher in the iNP than iP rat. In the nucleus accumbens, the abundances of 31 of 32 proteins were higher in the iNP than iP rat. In the hippocampus, only 2 of the 8 proteins that differed could be identified, whereas in the nucleus accumbens 21 of the 32 proteins that differed were identified. Higher abundances of cellular retinoic acid-binding protein 1 and a calmodulin-dependent protein kinase (both of which are involved in cellular signaling pathways) were found in both regions of the iNP than iP rat. In the nucleus accumbens, additional differences in the abundances of proteins involved in (i) metabolism (e.g., calpain, parkin, glucokinase, apolipoprotein E, sorbitol dehydrogenase), (ii) cyto-skeletal and intracellular protein transport (e.g., beta-actin), (iii) molecular chaperoning (e.g., grp 78, hsc70, hsc 60, grp75, prohibitin), (iv) cellular signaling pathways (e.g., protein kinase C-binding protein), (v) synaptic function (e.g., complexin I, gamma-enolase, syndapin IIbb), (vi) reduction of oxidative stress (thioredoxin peroxidase), and (vii) growth and differentiation (hippocampal cholinergic neurostimulating peptide) were found. The results of this study indicate that selective breeding for disparate alcohol drinking behaviors produced innate alterations in the expression of several proteins that could influence neuronal function within the nucleus accumbens and hippocampus.

Alcohol Drinking↗
PubMed2003

Differential gene expression in human cerebrovascular malformations.

OBJECTIVE: We sought to identify genes with differential expression in cerebral cavernous malformations (CCMs), arteriovenous malformations (AVMs), and control superficial temporal arteries (STAs) and to confirm differential expression of genes previously implicated in the pathobiology of these lesions. METHODS: Total ribonucleic acid was isolated from four CCM, four AVM, and three STA surgical specimens and used to quantify lesion-specific messenger ribonucleic acid expression levels on human gene arrays. Data were analyzed with the use of two separate methodologies: gene discovery and confirmation analysis. RESULTS: The gene discovery method identified 42 genes that were significantly up-regulated and 36 genes that were significantly down-regulated in CCMs as compared with AVMs and STAs (P = 0.006). Similarly, 48 genes were significantly up-regulated and 59 genes were significantly down-regulated in AVMs as compared with CCMs and STAs (P = 0.006). The confirmation analysis showed significant differential expression (P < 0.05) in 11 of 15 genes (angiogenesis factors, receptors, and structural proteins) that previously had been reported to be expressed differentially in CCMs and AVMs in immunohistochemical analysis. CONCLUSION: We identify numerous genes that are differentially expressed in CCMs and AVMs and correlate expression with the immunohistochemistry of genes implicated in cerebrovascular malformations. In future efforts, we will aim to confirm candidate genes specifically related to the pathobiology of cerebrovascular malformations and determine their biological systems and mechanistic relevance.

Adolescent↗
PubMed2002

A bioinformatics tool to select sequences for microarray studies of mouse models of oncogenesis.

UNLABELLED: One of the challenges to the effective utilization of cDNA microarray analysis in mouse models of oncogenesis is the choice of a critical set of probes that are informative for human disease. Given the thousands of genes with a potential role in human oncogenesis and the hundreds of thousands of mouse sequences available for use as probes, selection of an informative set of mouse probes can be an overwhelming task. We have developed a web based sequence mining tool using DataBase Independent (DBI) Perl to annotate publicly available sequences. The Mouse Oncochip Design Tool uses the Mouse Genome Database (MGD) developed and maintained by the Jackson Laboratories for mouse DNA sequences. There are over 380 000 sequences in their database. The output list has been ordered to present the genes more likely to be informative in a mouse model of human cancer using a candidate set of oncogenes to order the list. Mouse sequences that represent genes that are homologous with a member of a human oncogene set are listed first. In addition it provides a set of links for information on clone source gene function. CONTACT: http://nciarray.nci.nih.gov/cgi-bin/me/mouse_design.cgi

Animals↗