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Harold R Garner

Publications and source records attributed to Harold R Garner.

At least 19 recordsLinked to original sources
PubMed2006

Detection of length-dependent effects of tandem repeat alleles by 3-D geometric decomposition of craniofacial variation.

Topologically conservative morphological transformations typify the succession of species in the fossil record and also typify more subtle morphological variation within species. Isolation and quantification of morphological variation along its various intermingled modes becomes increasingly difficult as the structures under consideration increase in complexity. Here, we describe a comparative morphometric and genomic study in dogs in which complex three-dimensional craniofacial variation is mathematically distilled into simpler geometric components to test the hypothesis that incremental mutations at developmental loci result in simple geometric deformations of morphology. Combinations of candidate transforms are computationally evaluated for their ability to accurately transform a reference three-dimensional skull model into those of distinct breeds. A set of five simple basis functions are found to be sufficient to describe most craniofacial variation among dogs. Allele lengths of amino acid repeat length variants in developmental regulator genes, which frequently have quantitative effects on phenotype, were compared to geometric terms using Pearson correlation and regression. The coordinated quantitative representation of both phenotype and genotype improves the statistical power for the detection of causative genotype-phenotype relationships and enabled the characterization of the influence of Runx-2 coding repeat length on craniofacial variation among domestic dogs.

Animals↗
PubMed2006

Text similarity: an alternative way to search MEDLINE.

MOTIVATION: The most widely used literature search techniques, such as those offered by NCBI's PubMed system, require significant effort on the part of the searcher, and inexperienced searchers do not use these systems as effectively as experienced users. Improved literature search engines can save researchers time and effort by making it easier to locate the most important and relevant literature. RESULTS: We have created and optimized a new, hybrid search system for Medline that takes natural text as input and then delivers results with high precision and recall. The combination of a fast, low-sensitivity weighted keyword-based first pass algorithm to cast a wide net to gather an initial set of literature, followed by a unique sentence-alignment based similarity algorithm to rank order those results was developed that is sensitive, fast and easy to use. Several text similarity search algorithms, both standard and novel, were implemented and tested in order to determine which obtained the best results in information retrieval exercises. AVAILABILITY: Literature searching algorithms are implemented in a system called eTBLAST, freely accessible over the web at http://invention.swmed.edu. A variety of other derivative systems and visualization tools provides the user with an enhanced experience and additional capabilities. CONTACT: Harold.Garner@UTSouthwestern.edu.

Abstracting and Indexing↗
PubMed2006

Murine macrophage transcriptional and functional responses to Bacillus anthracis edema toxin.

Edema toxin (EdTx), which is a combination of edema factor and a binding moiety (protective antigen), is produced by Bacillus anthracis, the etiological agent of anthrax. EdTx is an adenylyl cyclase enzyme that converts adenosine triphosphate to adenosine-3',5'-monophosphate, resulting in interstitial edema seen in anthrax patients. We used GeneChip analysis to examine global transcriptional profiles of EdTx-treated RAW 264.7 murine macrophage-like cells and identified 71 and 259 genes whose expression was significantly altered by the toxin at 3 and 6h, respectively. Alteration in the expression levels of selected genes was confirmed by real time-reverse transcriptase polymerase chain reaction. The genes with up-regulated expression in macrophages in response to EdTx-treatment were known to be involved in inflammatory responses, regulation of apoptosis, adhesion, immune cell activation, and transcription regulation. Additionally, GeneChip analysis results implied that EdTx-induced activation of activator protein-1 (AP-1) and CAAAT/enhancer-binding protein-beta (C/EBP-beta). Gel shift assays were therefore performed, and an increase in the activities of both of these transcription factors was observed within 30 min. EdTx also inhibited tumor necrosis factor alpha production and crippled the phagocytic ability of the macrophages. This is the first report detailing the host cell global transcriptional responses to EdTx.

Animals↗
PubMed2005

Selective identification of secreted and transmembrane breast cancer markers using Escherichia coli ampicillin secretion trap.

Secreted and cell surface proteins play important roles in cancer and are potential drug targets and tumor markers. Here, we describe a large-scale analysis of the genes encoding secreted and cell surface proteins in breast cancer. To identify these genes, we developed a novel signal sequence trap method called Escherichia coli ampicillin secretion trap (CAST). For CAST, we constructed a plasmid in which the signal sequence of beta-lactamase was deleted such that it does not confer ampicillin resistance. Eukaryotic cDNA libraries cloned into pCAST produced tens of thousands of ampicillin-resistant clones, 80% of which contained cDNA fragments encoding secreted and membrane spanning proteins. We identified 2,708 unique sequences from cDNA libraries made from surgical breast cancer specimens. We analyzed the expression of 1,287 of the 2,708 genes and found that 166 were overexpressed in breast cancers relative to normal breast tissues. Eighty-five percent of these genes had not been previously identified as markers of breast cancer. Twenty-three of the 166 genes (14%) were relatively tissue restricted, suggesting use as cancer-specific targets. We also identified several new markers of ovarian cancer. Our results indicate that CAST is a robust, rapid, and low cost method to identify cell surface and secreted proteins and is applicable to a variety of relevant biological questions.

Ampicillin Resistance↗
PubMed2005

Rapid hologram updates for real-time volumetric information displays.

We have demonstrated that holograms incorporating changes in three-dimensional (3D) scenes can be recalculated in real time to present dynamic updates on information displays. This approach displays 3D information in a compatible format for fast and reliable interpretation of changes in the 3D scenes. The rapid-update algorithm has been demonstrated by real-time computation and transcription of the holograms to our digital micromirror device hologram projection system for visual validation of the reconstruction. The reported algorithm enables full parallax 1024 x 768 pixel holograms of 3D scenes to be updated at a rate of 0.8 s with a 1.8 GHz personal computer. Volumetric information displays that can enhance reliable data assimilation and decrease reaction times for applications such as air-traffic control, cockpit heads-up displays, mission crew stations, and undersea navigation can benefit from this research.

Algorithms↗
PubMed2005

Data-mining analysis suggests an epigenetic pathogenesis for type 2 diabetes.

The etiological origin of type 2 diabetes mellitus (T2DM) has long been controversial. The body of literature related to T2DM is vast and varied in focus, making a broad epidemiological perspective difficult, if not impossible. A data-mining approach was used to analyze all electronically available scientific literature, over 12 million Medline records, for "objects" such as genes, diseases, phenotypes, and chemical compounds linked to other objects within the T2DM literature but were not themselves within the T2DM literature. The goal of this analysis was to conduct a comprehensive survey to identify novel factors implicated in the pathology of T2DM by statistically evaluating mutually shared associations. Surprisingly, epigenetic factors were among the highest statistical scores in this analysis, strongly implicating epigenetic changes within the body as causal factors in the pathogenesis of T2DM. Further analysis implicates adipocytes as the potential tissue of origin, and cytokines or cytokine-like genes as the dysregulated factor(s) responsible for the T2DM phenotype. The analysis provides a wealth of literature supporting this hypothesis, which-if true-represents an important paradigm shift for researchers studying the pathogenesis of T2DM.

Journal Article↗
PubMed2005

Evidence for the regulation of alternative splicing via complementary DNA sequence repeats.

MOTIVATION: While the mechanism for regulating alternative splicing is poorly understood, secondary structure has been shown to be integral to this process. Due to their propensity for forming complementary hairpin loops and their elevated mutation rates, tandem repeated sequences have the potential to influence splicing regulation. RESULTS: An analysis of human intronic sequences reveals a strong correlation between alternative splicing and the prevalence of mono- through hexanucleotide tandem repeats that may engage in complementary pairing in introns that flank alternatively spliced exons. While only 44% of the 18 173 genes in the Human Alternative Splicing Database are known to be alternatively spliced, they contain 84% of the 694 237 intronic complementary repeat pairs. Significantly, the normalized frequency and distribution of repeat sequences, independent of their potential for pairing, are indistinguishable between alternatively spliced and non-alternatively spliced genes. Thus, the increased prevalence of repeats with pairing potential in alternatively spliced genes is not merely a consequence of more repeats or repeat composition bias. These results suggest that complementary repeats may play a role in the regulation of alternative splicing. CONTACT: harold.garner@utsouthwestern.edu.

Alternative Splicing↗
PubMed2005

Biomedical term mapping databases.

Longer words and phrases are frequently mapped onto a shorter form such as abbreviations or acronyms for efficiency of communication. These abbreviations are pervasive in all aspects of biology and medicine and as the amount of biomedical literature grows, so does the number of abbreviations and the average number of definitions per abbreviation. Even more confusing, different authors will often abbreviate the same word/phrase differently. This ambiguity impedes our ability to retrieve information, integrate databases and mine textual databases for content. Efforts to standardize nomenclature, especially those doing so retrospectively, need to be aware of different abbreviatory mappings and spelling variations. To address this problem, there have been several efforts to develop computer algorithms to identify the mapping of terms between short and long form within a large body of literature. To date, four such algorithms have been applied to create online databases that comprehensively map biomedical terms and abbreviations within MEDLINE: ARGH (http://lethargy.swmed.edu/ARGH/argh.asp), the Stanford Biomedical Abbreviation Server (http://bionlp.stanford.edu/abbreviation/), AcroMed (http://medstract.med.tufts.edu/acro1.1/index.htm) and SaRAD (http://www.hpl.hp.com/research/idl/projects/abbrev.html). In addition to serving as useful computational tools, these databases serve as valuable references that help biologists keep up with an ever-expanding vocabulary of terms.

Abbreviations as Topic↗
PubMed2005

Differential activation profiles of multiple transcription factors during dendritic cell maturation.

Immature dendritic cells (DC) at the environmental interfaces, such as the skin, constantly survey the tissue for the emergence of microbial products and pro-inflammatory mediators. Upon recognition of such "danger" signals, they undergo dynamic reprogramming of gene expression and functions, the process known as DC maturation, which plays critical roles in both innate and adaptive immune responses. Although DC have been shown to discriminate different maturation stimuli by expressing stimulus-specific signature genes and unique phenotypic and functional properties, underlying mechanisms for this extraordinary plasticity remain relatively unclear. We hypothesized that DC might activate unique sets of transcription factors (TF) upon sensing different stimuli. To test this hypothesis, we transduced a mouse epidermal-derived DC line XS106 to express the luciferase reporter gene under the control of each of 15 different cis-enhancer elements. The resulting DC panels were then exposed to 14 different microbial, endogenous, environmental, and pharmacological agents that produced unique maturational changes. This approach allowed systematic determination of TF activation profiles in DC. Our results revealed striking diversity, with different classes of stimuli triggering preferential activation of distinct sets of TF. We propose that differential TF usage represents a previously unrecognized mechanism regulating the direction of DC maturation.

Animals↗
PubMed2004

Molecular origins of rapid and continuous morphological evolution.

Mutations in cis-regulatory sequences have been implicated as being the predominant source of variation in morphological evolution. We offer a hypothesis that gene-associated tandem repeat expansions and contractions are a major source of phenotypic variation in evolution. Here, we describe a comparative genomic study of repetitive elements in developmental genes of 92 breeds of dogs. We find evidence for selection for divergence at coding repeat loci in the form of both elevated purity and extensive length polymorphism among different breeds. Variations in the number of repeats in the coding regions of the Alx-4 (aristaless-like 4) and Runx-2 (runt-related transcription factor 2) genes were quantitatively associated with significant differences in limb and skull morphology. We identified similar repeat length variation in the coding repeats of Runx-2, Twist, and Dlx-2 in several other species. The high frequency and incremental effects of repeat length mutations provide molecular explanations for swift, yet topologically conservative morphological evolution.

Alleles↗
PubMed2004

Protein-coated poly(L-lactic acid) fibers provide a substrate for differentiation of human skeletal muscle cells.

Tissue engineering represents a potential method for repairing damaged skeletal muscle tissue. Extracellular matrix (ECM) proteins were evaluated for their ability to aid in cell attachment, whereas a poly(L-lactic acid) (PLLA) fiber scaffold was tested as a substrate for the differentiation of human skeletal muscle cells. In comparison to uncoated or gelatin-coated PLLA films, cell attachment increased significantly (p < 0.001) on PLLA films coated with ECM gel, fibronectin, or laminin. Myoblasts differentiated into multinucleated myofibers on ECM gel-coated PLLA fibers, and expressed muscle markers such as myosin and alpha-actinin. Oligonucleotide microarray analysis showed similar gene expression profiles for human skeletal muscle cells on ECM gel-coated PLLA fibers as to that observed for myofibers on tissue culture plates. Therefore, PLLA fibers coated with ECM proteins provide a scaffold for the development of skeletal muscle tissue for tissue engineering and cell transplantation applications.

Animals↗
PubMed2004

ELXR: a resource for rapid exon-directed sequence analysis.

ELXR (Exon Locator and Extractor for Resequencing) streamlines the process of determining exon/intron boundaries and designing PCR and sequencing primers for high-throughput resequencing of exons. We have pre-computed ELXR primer sets for all exons identified from the human, mouse, and rat mRNA reference sequence (RefSeq) public databases curated by the National Center for Biotechnology Information. The resulting exon-flanking PCR primer pairs have been compiled into a system called ELXRdb, which may be searched by keyword, gene name or RefSeq accession number.

Algorithms↗
PubMed2004

Photolithographic synthesis of peptoids.

We describe a novel photolithographic approach to the synthesis of peptoids (oligo-N-substituted glycines). This strategy enables the construction of a spatially addressable peptoid microarray, thus providing a potentially powerful tool for the discovery of protein ligands.

Journal Article↗
PubMed2004

Patterning adhesion of mammalian cells with visible light, tris(bipyridyl)ruthenium(II) chloride, and a digital micromirror array.

Patterns of cellular adhesion were created on a surface using novel photochemistry that is stimulated with visible light. A glass surface coated with polyethylene glycol is nonadhesive to a variety of adherent mammalian cell types. Treatment of that surface with a mixture of tris(bipyridyl)ruthenium(II) chloride, ammonium persulfate, and a tryptophan derivative or tryptophan-bearing peptide in conjunction with irradiation with visible light (447 nm) made the surface adhesive to several cell types including mouse fibroblasts, human myoblasts, and human lung tumor cells. Immunostaining data suggest that tryptophan-containing peptides are crosslinked intact to the surface by this chemistry, which enables patterning of peptides containing only naturally occurring amino acids. Microscopic patterns of cellular adhesion were created with this chemistry by projecting microscopic patterns of visible light with a digital micromirror array. Using this method, regions of cellular adhesion were patterned with single-cell resolution.

Animals↗
PubMed2004

Shared relationship analysis: ranking set cohesion and commonalities within a literature-derived relationship network.

MOTIVATION: There is a general scientific need to be able to identify and evaluate what any given set of 'objects' (e.g. genes, phenotypes, chemicals, diseases) has in common. Whether it is to classify, expand upon or identify commonalities and functional groupings, informational needs can be diverse and the best source to identify relationships among a potentially heterogeneous set of objects is the scientific literature. RESULTS: We first establish a network of related objects by their co-occurrence within MEDLINE records. A set of objects within this network can then be queried to identify shared relationships, and a method is presented to score their statistical relevance by comparing observed frequencies with what would be expected in a random network model. Using Gene Ontology (GO) categories, we demonstrate that this method enables a quantitative ranking of the 'cohesiveness' of a set of objects and, importantly, allows other objects related to this set to be identified and evaluated for their 'cohesion' to it. Supplemental information: A list of ranked genes related to each GO category analyzed can be found at http://innovation.swmed.edu/IRIDESCENT/GO_relationships.htm

Abstracting and Indexing↗
PubMed2004

Knowledge discovery by automated identification and ranking of implicit relationships.

MOTIVATION: New relationships are often implicit from existing information, but the amount and growth of published literature limits the scope of analysis an individual can accomplish. Our goal was to develop and test a computational method to identify relationships within scientific reports, such that large sets of relationships between unrelated items could be sought out and statistically ranked for their potential relevance as a set. RESULTS: We first construct a network of tentative relationships between 'objects' of biomedical research interest (e.g. genes, diseases, phenotypes, chemicals) by identifying their co-occurrences within all electronically available MEDLINE records. Relationships shared by two unrelated objects are then ranked against a random network model to estimate the statistical significance of any given grouping. When compared against known relationships, we find that this ranking correlates with both the probability and frequency of object co-occurrence, demonstrating the method is well suited to discover novel relationships based upon existing shared relationships. To test this, we identified compounds whose shared relationships predicted they might affect the development and/or progression of cardiac hypertrophy. When laboratory tests were performed in a rodent model, chlorpromazine was found to reduce the progression of cardiac hypertrophy.

Abstracting and Indexing↗
PubMed2004

Association of extensive polymorphisms in the SLAM/CD2 gene cluster with murine lupus.

Susceptibility to autoimmunity in B6.Sle1b mice is associated with extensive polymorphisms between two divergent haplotypes of the SLAM/CD2 family of genes. The B6.Sle1b-derived SLAM/CD2 family haplotype is found in many other laboratory mouse strains but only causes autoimmunity in the context of the C57Bl/6 (B6) genome. Phenotypic analyses have revealed variations in the structure and expression of several members of the SLAM/CD2 family in T and B lymphocytes from B6.Sle1b mice. T lymphocytes from B6.Sle1b mice have modified signaling responses to stimulation at 4-6 weeks of age. While autoimmunity may be mediated by a combination of genes in the SLAM/CD2 family cluster, the strongest candidate is Ly108, a specific isoform of which is constitutively upregulated in B6.Sle1b lymphocytes.

Alleles↗