Coexpression of cyclooxygenase-2 and vascular endothelial growth factor in gastrointestinal stromal tumor: possible relations to pathological parameters and clinical behavior.

Background/aims: Currently, the clinicopathological significance of coexpression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in gastrointestinal stromal tumors (GISTs) has not been fully described.

Methodology: The present study was designed to investigate the co-expression of the two markers and its significance in 54 patients with GIST by means of immunohistochemistry.

Results: We demonstrated that the expressions of COX-2 and VEGF were significantly higher in malignant GIST than those in benign and potentially malignant GIST (p<0.

GADEM: a genetic algorithm guided formation of spaced dyads coupled with an EM algorithm for motif discovery.

Genome-wide analyses of protein binding sites generate large amounts of data; a ChIP dataset might contain 10,000 sites. Unbiased motif discovery in such datasets is not generally feasible using current methods that employ probabilistic models. We propose an efficient method, GADEM, which combines spaced dyads and an expectation-maximization (EM) algorithm.

The effects of GPX-1 knockout on membrane transport and intracellular homeostasis in the lens.

Glutathione peroxidase-1 (GPX-1) is an enzyme that protects the lens against H2O2-mediated oxidative damage. The purpose of the present study was to determine the effects of GPX-1 knockout (KO) on lens transport and intracellular homeostasis. To investigate these lenses we used (1) whole lens impedance studies to measure membrane conductance, resting voltage and fiber cell gap junction coupling conductance; (2) osmotic swelling of fiber cell membrane vesicles to determine water permeability; and (3) injection of Fura2 and Na+-binding benzofuran isophthalate (SBFI) into fiber cells to measure [Ca2+]i and [Na+]i, respectively, in intact lenses.

Gene set enrichment analysis for non-monotone association and multiple experimental categories.

Background: Recently, microarray data analyses using functional pathway information, e.g., gene set enrichment analysis (GSEA) and significance analysis of function and expression (SAFE), have gained recognition as a way to identify biological pathways/processes associated with a phenotypic endpoint.

Oct4/Sox2-regulated miR-302 targets cyclin D1 in human embryonic stem cells.

Oct4 and Sox2 are transcription factors required for pluripotency during early embryogenesis and for the maintenance of embryonic stem cell (ESC) identity. Functional mechanisms contributing to pluripotency are expected to be associated with genes transcriptionally activated by these factors. Here, we show that Oct4 and Sox2 bind to a conserved promoter region of miR-302, a cluster of eight microRNAs expressed specifically in ESCs and pluripotent cells.

NELF-mediated stalling of Pol II can enhance gene expression by blocking promoter-proximal nucleosome assembly.

The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. To determine the full spectrum of NELF target genes in Drosophila, we performed a microarray analysis of S2 cells depleted of NELF and discovered that NELF RNAi affects many rapidly inducible genes involved in cellular responses to stimuli. Surprisingly, only one-third of NELF target genes were, like Hsp70, up-regulated by NELF-depletion, whereas the majority of target genes showed decreased expression levels upon NELF RNAi.

fdrMotif: identifying cis-elements by an EM algorithm coupled with false discovery rate control.

Motivation: Most de novo motif identification methods optimize the motif model first and then separately test the statistical significance of the motif score. In the first stage, a motif abundance parameter needs to be specified or modeled. In the second stage, a Z-score or P-value is used as the test statistic.

Optimal lens epithelial cell proliferation is dependent on the connexin isoform providing gap junctional coupling.

Purpose: Gap junctions between epithelial cells are essential for normal lens growth. In mice, knockout of Cx50 or targeted replacement of Cx50 with Cx46 (knockin) caused smaller lenses because of decreased epithelial cell proliferation. However, it remains unclear whether Cx50 functionally contributes to lens epithelial coupling during maximal proliferation on postnatal day 2 (P2) and P3.

Stereoselective synthesis of a MCHr1 antagonist.

Melanin-concentrating hormone (MCH) is implicated in the feeding behavior in mammals affording a potential target to control overeating in people. Compound 1 (AMG 076) has been identified as a potent MCHr1 antagonist for the treatment of obesity. A synthesis suitable for the large-scale preparation of this lead candidate was developed to support preclinical studies.

Significance analysis and multiple pharmacophore models for differentiating P-glycoprotein substrates.

P-glycoprotein (Pgp) mediated drug efflux affects the absorption, distribution, and clearance of a broad structural variety of drugs. Early assessment of the potential of compounds to interact with Pgp can aid in the selection and optimization of drug candidates. To differentiate nonsubstrates from substrates of Pgp, a robust predictive pharmacophore model was targeted in a supervised analysis of three-dimensional (3D) pharmacophores from 163 published compounds.

Measurement of retinal nerve fiber layer in primary acute angle closure glaucoma by optical coherence tomography.

Purpose: To detect the objective structure changes of the retinal nerve fiber layer (RNFL) in primary acute angle closure glaucoma (PAACG) and to evaluate the efficacy of quantitative assessment of RNFL thickness with optical coherence tomography (OCT).

Patients And Methods: Forty patients who had unilateral PAACG attack in the first 4 months after remission and 40 single eyes from 40 normal controls were enrolled in this cross-sectional study. For all cases, PAACG had resolved after treatment.

GAPWM: a genetic algorithm method for optimizing a position weight matrix.

Motivation: Position weight matrices (PMWs) are simple models commonly used in motif-finding algorithms to identify short functional elements, such as cis-regulatory motifs, on genes. When few experimentally verified motifs are available, estimation of the PWM may be poor. The resultant PWM may not reliably discriminate a true motif from a false one.

Identification and functional characterization of polymorphisms in human cyclooxygenase-1 (PTGS1).

Objective: Cyclooxygenase-1 (COX-1, PTGS1) catalyzes the conversion of arachidonic acid to prostaglandin H2, which is subsequently metabolized to various biologically active prostaglandins. We sought to identify and characterize the functional relevance of genetic polymorphisms in PTGS1.

Methods: Sequence variations in human PTGS1 were identified by resequencing 92 healthy individuals (24 African, 24 Asian, 24 European/Caucasian, and 20 anonymous).

Identification of potential target genes for RFX4_v3, a transcription factor critical for brain development.

Regulatory factor X4 variant transcript 3 (Rfx4_v3) gene disruption in mice demonstrated that interruption of a single allele (heterozygous, +/-) prevented formation of the subcommissural organ, resulting in congenital hydrocephalus, while interruption of two alleles (homozygous, -/-) caused fatal failure of dorsal midline brain structure formation. To identify potential target genes for RFX4_v3, we used microarray analysis to identify differentially expressed genes in Rfx4_v3-deficient mouse brains at embryonic day 10.5, before gross structural changes were apparent.

Optimized mixed Markov models for motif identification.

Background: Identifying functional elements, such as transcriptional factor binding sites, is a fundamental step in reconstructing gene regulatory networks and remains a challenging issue, largely due to limited availability of training samples.

Results: We introduce a novel and flexible model, the Optimized Mixture Markov model (OMiMa), and related methods to allow adjustment of model complexity for different motifs. In comparison with other leading methods, OMiMa can incorporate more than the NNSplice's pairwise dependencies; OMiMa avoids model over-fitting better than the Permuted Variable Length Markov Model (PVLMM); and OMiMa requires smaller training samples than the Maximum Entropy Model (MEM).

Phase analysis of circadian-related genes in two tissues.

Background: Recent circadian clock studies using gene expression microarray in two different tissues of mouse have revealed not all circadian-related genes are synchronized in phase or peak expression times across tissues in vivo. Instead, some circadian-related genes may be delayed by 4-8 hrs in peak expression in one tissue relative to the other. These interesting biological observations prompt a statistical question regarding how to distinguish the synchronized genes from genes that are systematically lagged in phase/peak expression time across two tissues.

Discovery and optimization of a novel series of liver X receptor-alpha agonists.

A novel series of hexafluorocarbinols were discovered as potent activators of the liver X receptor-alpha using a fluorescence polarization assay. Structure-activity relationship study led to the identification of compounds that are more potent agonists than the endogenous ligand, 24(S), 25-epoxycholesterol, with similar efficacy. Several compounds, including T0901317, were shown to have desirable pharmacokinetic profiles suitable for in vivo studies.

Accurate anchoring alignment of divergent sequences.

Motivation: Obtaining high quality alignments of divergent homologous sequences for cross-species sequence comparison remains a challenge.

Results: We propose a novel pairwise sequence alignment algorithm, ACANA (ACcurate ANchoring Alignment), for aligning biological sequences at both local and global levels. Like many fast heuristic methods, ACANA uses an anchoring strategy.

[The development of a polarized vernier optometer for tonic accommodation measurement].

A vernier optometer, based on the Scheiner principle, that makes use of polarized light, is designed and developed. It is specialized in measurement of tonic accommodation, accommodation and accommodation response. The vernier optometer has been proved by chinical testing results, to be a reliable and effective instrument with fine stabilily, good repeatability and sensitivity for short sight study relating to oculogyral parameters.

Deuterium and its role in the machinery of evolution.

An argument is presented that the spontaneous mutation rate, the core of evolution theory, may be dictated by the deuterium/hydrogen (D/H) abundance ratio. This argument is supported by quantum mechanical calculations of the zero-point energy reduction for DNA base pairs upon deuterium substitution for hydrogen and recent experiments that show that the rate of catalytic dsDNA unwinding is dependent on the stability of the dsDNA.

Connexin50 is essential for normal postnatal lens cell proliferation.

Purpose: Connexin50 (Cx50) is absolutely essential for normal postnatal lens growth. Deletion of Cx50 or replacement with Cx46 by knockin resulted in smaller lenses containing fewer cells. To determine why Cx50-deficient lenses fail to grow normally, cell proliferation was assayed during the period of growth failure.

A random-periods model for expression of cell-cycle genes.

We propose a nonlinear regression model for quantitatively analyzing periodic gene expression in studies of experimentally synchronized cells. Our model accounts for the observed attenuation in cycle amplitude by a simple and biologically plausible mechanism. We represent the expression level for each gene as an average across a large number of cells.

Gene expression profiling of rat livers reveals indicators of potential adverse effects.

This study tested the hypothesis that gene expression profiling can reveal indicators of subtle injury to the liver induced by a low dose of a substance that does not cause overt toxicity as defined by conventional criteria of toxicology (e.g., abnormal clinical chemistry and histopathology).

Application of the GA/KNN method to SELDI proteomics data.

Summary: Proteomics technology has shown promise in identifying biomarkers for disease, toxicant exposure and stress. We show by example that the genetic algorithm/k-nearest neighbors method, developed for mining high-dimensional microarray gene expression data, is also capable of mining surface enhanced laser desorption/ionization-time-of-flight proteomics data.

Availability: The source code of the program and documentation on how to use it are freely available to non-commercial users at http://dir.

Novel consensus DNA-binding sequence for BRCA1 protein complexes.

Increasing evidence continues to emerge supporting the early hypothesis that BRCA1 might be involved in transcriptional processes. BRCA1 physically associates with more than 15 different proteins involved in transcription and is paradoxically involved in both transcriptional activation and repression. However, the underlying mechanism by which BRCA1 affects the gene expression of various genes remains speculative.