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Genome-wide transcription factor binding site/promoter databases for the analysis of gene sets and co-occurrence of transcription factor binding motifs

<p>Abstract</p> <p>Background</p> <p>The use of global gene expression profiling is a well established approach to understand biological processes. One of the major goals of these investigations is to identify sets of genes with similar expression patterns. Such gene signatures may be very informative and reveal new aspects of particular biological processes. A logical and systematic next step is to reduce the identified gene signatures to the regulatory components that induce the relevant gene expression changes. A central issue in this context is to identify transcription factors, or transcription factor binding sites (TFBS), likely to be of importance for the expression of the gene signatures.</p> <p>Results</p> <p>We develop a strategy that efficiently produces TFBS/promoter databases based on user-defined criteria. The resulting databases constitute all genes in the Santa Cruz database and the positions for all TFBS provided by the user as position weight matrices. These databases are then used for two purposes, to identify significant TFBS in the promoters in sets of genes and to identify clusters of co-occurring TFBS. We use two criteria for significance, significantly enriched TFBS in terms of total number of binding sites for the promoters, and significantly present TFBS in terms of the fraction of promoters with binding sites. Significant TFBS are identified by a re-sampling procedure in which the query gene set is compared with typically 10⁵gene lists of similar size randomly drawn from the TFBS/promoter database. We apply this strategy to a large number of published ChIP-Chip data sets and show that the proposed approach faithfully reproduces ChIP-Chip results. The strategy also identifies relevant TFBS when analyzing gene signatures obtained from the MSigDB database. In addition, we show that several TFBS are highly correlated and that co-occurring TFBS define functionally related sets of genes.</p> <p>Conclusions</p> <p>The presented approach of promoter analysis faithfully reproduces the results from several ChIP-Chip and MigDB derived gene sets and hence may prove to be an important method in the analysis of gene signatures obtained through ChIP-Chip or global gene expression experiments. We show that TFBS are organized in clusters of co-occurring TFBS that together define highly coherent sets of genes.</p

Control Of Small Wind Turbines In High Wind Speed Areas

The strategy developed also addresses a system start-up problem that prevents the generator from accelerating to an uncontrollable operating point in high wind speed conditions. This is accomplished with voltage and current sensors only, and does not require direct measurements of wind speed or generator. The proposed method is applied to a small wind turbine system consisting of a permanent magnet synchronous generator (PMSG) and a simple transducer topology. Experimental and simulation results are included to demonstrate the performance of the proposed method. The document also shows the limitations of using stator driving force to estimate rotor speed in a PMSG connected to a rectifier, due to large d-axis current at high load

Independent component analysis reveals new and biologically significant structures in micro array data

BACKGROUND: An alternative to standard approaches to uncover biologically meaningful structures in micro array data is to treat the data as a blind source separation (BSS) problem. BSS attempts to separate a mixture of signals into their different sources and refers to the problem of recovering signals from several observed linear mixtures. In the context of micro array data, "sources" may correspond to specific cellular responses or to co-regulated genes. RESULTS: We applied independent component analysis (ICA) to three different microarray data sets; two tumor data sets and one time series experiment. To obtain reliable components we used iterated ICA to estimate component centrotypes. We found that many of the low ranking components indeed may show a strong biological coherence and hence be of biological significance. Generally ICA achieved a higher resolution when compared with results based on correlated expression and a larger number of gene clusters with significantly enriched for gene ontology (GO) categories. In addition, components characteristic for molecular subtypes and for tumors with specific chromosomal translocations were identified. ICA also identified more than one gene clusters significant for the same GO categories and hence disclosed a higher level of biological heterogeneity, even within coherent groups of genes. CONCLUSION: Although the ICA approach primarily detects hidden variables, these surfaced as highly correlated genes in time series data and in one instance in the tumor data. This further strengthens the biological relevance of latent variables detected by ICA

Tiling resolution array CGH and high density expression profiling of urothelial carcinomas delineate genomic amplicons and candidate target genes specific for advanced tumors.

ABSTRACT: BACKGROUND: Urothelial carcinoma (UC) is characterized by nonrandom chromosomal aberrations, varying from one or a few changes in early-stage and low-grade tumors, to highly rearranged karyotypes in muscle-invasive lesions. Recent array-CGH analyses have shed further light on the genomic changes underlying the neoplastic development of UC, and have facilitated the molecular delineation amplified and deleted regions to the level of specific candidate genes. In the present investigation we combine detailed genomic information with expression information to identify putative target genes for genomic amplifications. METHODS: We analyzed 38 urothelial carcinomas by whole-genome tiling resolution array-CGH and high density expression profiling to identify putative target genes in common genomic amplifications. When necessary expression profiling was complemented with Q-PCR of individual genes. RESULTS: Three genomic segments were frequently and exclusively amplified in high grade tumors; 1q23, 6p22 and 8q22, respectively. Detailed mapping of the 1q23 segment showed a heterogeneous amplification pattern and no obvious commonly amplified region. The 6p22 amplicon was defined by a 1.8 Mb core region present in all amplifications, flanked both distally and proximally by segments amplified to a lesser extent. By combining genomic profiles with expression profiles we could show that amplification of E2F3, CDKAL1, SOX4, and MBOAT1 as well as NUP153, AOF1, FAM8A1 and DEK in 6p22 was associated with increased gene expression. Amplification of the 8q22 segment was primarily associated with YWHAZ (14-3-3-zeta) and POLR2K over expression. The possible importance of the YWHA genes in the development of urothelial carcinomas was supported by another recurrent amplicon paralogous to 8q22, in 2p25, where increased copy numbers lead to enhanced expression of YWHAQ (14-3-3-theta). Homozygous deletions were identified at 10 different genomic locations, most frequently affecting CDKN2A/CDKN2B in 9p21 (32%). Notably, the latter occurred mutually exclusive with 6p22 amplifications. CONCLUSION: The presented data indicates 6p22 as a composite amplicon with more than one possible target gene. The data also suggests that amplification of 6p22 and homozygous deletions of 9p21 may have complementary roles. Furthermore, the analysis of paralogous regions that showed genomic amplification indicated altered expression of YWHA (14-3-3) genes as important events in the development of UC

Histopathology Slide Indexing and Search: Are We There Yet?

The search and retrieval of digital histopathology slides is an important task that has yet to be solved. In this case study, we investigate the clinical readiness of three state-of-the-art histopathology slide search engines, Yottixel, SISH, and RetCCL, on three patients with solid tumors. We provide a qualitative assessment of each model's performance in providing retrieval results that are reliable and useful to pathologists. We found that all three image search engines fail to produce consistently reliable results and have difficulties in capturing granular and subtle features of malignancy, limiting their diagnostic accuracy. Based on our findings, we also propose a minimal set of requirements to further advance the development of accurate and reliable histopathology image search engines for successful clinical adoption

A Molecular Taxonomy for Urothelial Carcinoma.

PURPOSE: Even though urothelial cancer is the fourth most common tumor type among males, progress in treatment has been scarce. A problem in day-to-day clinical practice is that precise assessment of individual tumors is still fairly uncertain; consequently efforts have been undertaken to complement tumor evaluation with molecular biomarkers. An extension of this approach would be to base tumor classification primarily on molecular features. Here, we present a molecular taxonomy for urothelial carcinoma based on integrated genomics. EXPERIMENTAL DESIGN: We use gene expression profiles from 308 tumor cases to define five major urothelial carcinoma subtypes: urobasal A, genomically unstable, urobasal B, squamous cell carcinoma like, and an infiltrated class of tumors. Tumor subtypes were validated in three independent publically available data sets. The expression of 11 key genes was validated at the protein level by immunohistochemistry. RESULTS: The subtypes show distinct clinical outcomes and differ with respect to expression of cell-cycle genes, receptor tyrosine kinases particularly FGFR3, ERBB2, and EGFR, cytokeratins, and cell adhesion genes, as well as with respect to FGFR3, PIK3CA, and TP53 mutation frequency. The molecular subtypes cut across pathologic classification, and class-defining gene signatures show coordinated expression irrespective of pathologic stage and grade, suggesting the molecular phenotypes as intrinsic properties of the tumors. Available data indicate that susceptibility to specific drugs is more likely to be associated with the molecular stratification than with pathologic classification. CONCLUSIONS: We anticipate that the molecular taxonomy will be useful in future clinical investigations. Clin Cancer Res; 1-10. ©2012 AACR

Influence of sonication on the physicochemical and biological characteristics of selenium-substituted hydroxyapatites

Although the material hydroxyapatite (HAP) has excellent porous, biocompatible, and biodegradable properties, its mechanical strength and microbial inhibition rate are not adequate for its direct use in bone tissue engineering or in constructing artificial teeth. To overcome some of its limitations, in the present study, we have formed an organic-inorganic composite with an altered internal structureviadoping selenium (Se) cations into the lattice of HAP. We have synthesized Se-substituted HAP (Se-HAP) composites with different Se/P ratios (0.01, 0.05, and 0.1 M)viaa wet chemical route in which two different sets of samples were collected (1) after only precipitation (referred to as the precipitation method) and (2) after precipitation followed by sonication (referred to as the sonochemical method). FTIR and Raman spectroscopic analyses confirmed the successful doping of Se into the HAP matrices, while powder XRD studies indicated their highly crystalline nature, which was significantly influenced by Se doping. The XRD data also showed that the Se-HAP particles formed by the precipitation method have a size of 56 nm and those formed by the sonochemical method have a size of 29 nm. Morphological analysis by means of SEM and TEM indicated that the sonochemical method produces well-defined rod-shaped particles, while the precipitation method produces particles with agglomerated structures. Hemolytic studies confirmed that the Se-HAP particles are biocompatible, and that the hemolytic ratio increases with the Se content. In addition, antibacterial studies indicated that Se-HAP responds quite well against a Gram-positive strain (S. aureus), on a par with the response to a Gram-negative strain (P. aeruginosa). Finally,in vitrocell viability and proliferation studies indicated an increase in the proliferation capacity of non-cancer cells (NIH-3T3 fibroblasts) and a considerable reduction in the viability of cancer cells (MG-63 osteosarcoma). Based on the overall analysis, the Se-HAP samples formed by the sonochemical approach could have potential for biomedical applications in bone cell repair, growth, and regeneration