False positive reduction in protein-protein interaction predictions using gene ontology annotations

<p>Abstract</p> <p>Background</p> <p>Many crucial cellular operations such as metabolism, signalling, and regulations are based on protein-protein interactions. However, the lack of robust protein-protein interaction information is a challenge. One reason for the lack of solid protein-protein interaction information is poor agreement between experimental findings and computational sets that, in turn, comes from huge false positive predictions in computational approaches. Reduction of false positive predictions and enhancing true positive fraction of computationally predicted protein-protein interaction datasets based on highly confident experimental results has not been adequately investigated.</p> <p>Results</p> <p>Gene Ontology (GO) annotations were used to reduce false positive protein-protein interactions (PPI) pairs resulting from computational predictions. Using experimentally obtained PPI pairs as a training dataset, eight top-ranking keywords were extracted from GO molecular function annotations. The sensitivity of these keywords is 64.21% in the yeast experimental dataset and 80.83% in the worm experimental dataset. The specificities, a measure of recovery power, of these keywords applied to four predicted PPI datasets for each studied organisms, are 48.32% and 46.49% (by average of four datasets) in yeast and worm, respectively. Based on eight top-ranking keywords and co-localization of interacting proteins a set of two knowledge rules were deduced and applied to remove false positive protein pairs. The '<it>strength</it>', a measure of improvement provided by the rules was defined based on the signal-to-noise ratio and implemented to measure the applicability of knowledge rules applying to the predicted PPI datasets. Depending on the employed PPI-predicting methods, the <it>strength </it>varies between two and ten-fold of randomly removing protein pairs from the datasets.</p> <p>Conclusion</p> <p>Gene Ontology annotations along with the deduced knowledge rules could be implemented to partially remove false predicted PPI pairs. Removal of false positives from predicted datasets increases the true positive fractions of the datasets and improves the robustness of predicted pairs as compared to random protein pairing, and eventually results in better overlap with experimental results.</p

Effects of EpCAM overexpression on human breast cancer cell lines

<p>Abstract</p> <p>Background</p> <p>Recently, EpCAM has attracted major interest as a target for antibody- and vaccine-based cancer immunotherapies. In breast cancer, the EpCAM antigen is overexpressed in 30-40% of all cases and this increased expression correlates with poor prognosis. The use of EpCAM-specific monoclonal antibodies is a promising treatment approach in these patients.</p> <p>Methods</p> <p>In order to explore molecular changes following EpCAM overexpression, we investigated changes of the transcriptome upon EpCAM gene expression in commercially available human breast cancer cells lines Hs578T and MDA-MB-231. To assess cell proliferation, a tetrazolium salt based assay was performed. A TCF/LEF Reporter Kit was used to measure the transcriptional activity of the Wnt/β-catenin pathway. To evaluate the accumulation of β-catenin in the nucleus, a subcellular fractionation assay was performed.</p> <p>Results</p> <p>For the first time we could show that expression profiling data of EpCAM transfected cell lines Hs578T^EpCAMand MDA-MB-231^EpCAMindicate an association of EpCAM overexpression with the downregulation of the Wnt signaling inhibitors SFRP1 and TCF7L2. Confirmation of increased Wnt signaling was provided by a TCF/LEF reporter kit and by the finding of the nuclear accumulation of ß-catenin for MDA-MB-231^EpCAMbut not Hs578T^EpCAMcells. In Hs578T cells, an increase of proliferation and chemosensitivity to Docetaxel was associated with EpCAM overexpression.</p> <p>Conclusions</p> <p>These data show a cell type dependent modification of Wnt signaling components after EpCAM overexpression in breast cancer cell lines, which results in marginal functional changes. Further investigations on the interaction of EpCAM with SFRP1 and TCF7L2 and on additional factors, which may be causal for changes upon EpCAM overexpression, will help to characterize unique molecular properties of EpCAM-positive breast cancer cells.</p

Systematic identification of functional modules and cis-regulatory elements in Arabidopsis thaliana

<p>Abstract</p> <p>Background</p> <p>Several large-scale gene co-expression networks have been constructed successfully for predicting gene functional modules and cis-regulatory elements in Arabidopsis (<it>Arabidopsis thaliana</it>)<it>.</it> However, these networks are usually constructed and analyzed in an <it>ad hoc</it> manner. In this study, we propose a completely parameter-free and systematic method for constructing gene co-expression networks and predicting functional modules as well as cis-regulatory elements.</p> <p>Results</p> <p>Our novel method consists of an automated network construction algorithm, a parameter-free procedure to predict functional modules, and a strategy for finding known cis-regulatory elements that is suitable for consensus scanning without prior knowledge of the allowed extent of degeneracy of the motif. We apply the method to study a large collection of gene expression microarray data in Arabidopsis. We estimate that our co-expression network has ~94% of accuracy, and has topological properties similar to other biological networks, such as being scale-free and having a high clustering coefficient. Remarkably, among the ~300 predicted modules whose sizes are at least 20, 88% have at least one significantly enriched functions, including a few extremely significant ones (ribosome, <it>p</it> < 1E-300, photosynthetic membrane, <it>p</it> < 1.3E-137, proteasome complex, <it>p</it> < 5.9E-126). In addition, we are able to predict cis-regulatory elements for 66.7% of the modules, and the association between the enriched cis-regulatory elements and the enriched functional terms can often be confirmed by the literature. Overall, our results are much more significant than those reported by several previous studies on similar data sets. Finally, we utilize the co-expression network to dissect the promoters of 19 Arabidopsis genes involved in the metabolism and signaling of the important plant hormone gibberellin, and achieved promising results that reveal interesting insight into the biosynthesis and signaling of gibberellin.</p> <p>Conclusions</p> <p>The results show that our method is highly effective in finding functional modules from real microarray data. Our application on Arabidopsis leads to the discovery of the largest number of annotated Arabidopsis functional modules in the literature. Given the high statistical significance of functional enrichment and the agreement between cis-regulatory and functional annotations, we believe our Arabidopsis gene modules can be used to predict the functions of unknown genes in Arabidopsis, and to understand the regulatory mechanisms of many genes.</p

A general co-expression network-based approach to gene expression analysis: comparison and applications

<p>Abstract</p> <p>Background</p> <p>Co-expression network-based approaches have become popular in analyzing microarray data, such as for detecting functional gene modules. However, co-expression networks are often constructed by ad hoc methods, and network-based analyses have not been shown to outperform the conventional cluster analyses, partially due to the lack of an unbiased evaluation metric.</p> <p>Results</p> <p>Here, we develop a general co-expression network-based approach for analyzing both genes and samples in microarray data. Our approach consists of a simple but robust rank-based network construction method, a parameter-free module discovery algorithm and a novel reference network-based metric for module evaluation. We report some interesting topological properties of rank-based co-expression networks that are very different from that of value-based networks in the literature. Using a large set of synthetic and real microarray data, we demonstrate the superior performance of our approach over several popular existing algorithms. Applications of our approach to yeast, Arabidopsis and human cancer microarray data reveal many interesting modules, including a fatal subtype of lymphoma and a gene module regulating yeast telomere integrity, which were missed by the existing methods.</p> <p>Conclusions</p> <p>We demonstrated that our novel approach is very effective in discovering the modular structures in microarray data, both for genes and for samples. As the method is essentially parameter-free, it may be applied to large data sets where the number of clusters is difficult to estimate. The method is also very general and can be applied to other types of data. A MATLAB implementation of our algorithm can be downloaded from <url>http://cs.utsa.edu/~jruan/Software.html</url>.</p

Phylogeny and evolution of life-history strategies in the Sycophaginae non-pollinating fig wasps (Hymenoptera, Chalcidoidea)

<p>Abstract</p> <p>Background</p> <p>Non-pollinating Sycophaginae (Hymenoptera, Chalcidoidea) form small communities within <it>Urostigma </it>and <it>Sycomorus </it>fig trees. The species show differences in galling habits and exhibit apterous, winged or dimorphic males. The large gall inducers oviposit early in syconium development and lay few eggs; the small gall inducers lay more eggs soon after pollination; the ostiolar gall-inducers enter the syconium to oviposit and the cleptoparasites oviposit in galls induced by other fig wasps. The systematics of the group remains unclear and only one phylogeny based on limited sampling has been published to date. Here we present an expanded phylogeny for sycophagine fig wasps including about 1.5 times the number of described species. We sequenced mitochondrial and nuclear markers (4.2 kb) on 73 species and 145 individuals and conducted maximum likelihood and Bayesian phylogenetic analyses. We then used this phylogeny to reconstruct the evolution of Sycophaginae life-history strategies and test if the presence of winged males and small brood size may be correlated.</p> <p>Results</p> <p>The resulting trees are well resolved and strongly supported. With the exception of <it>Apocrytophagus</it>, which is paraphyletic with respect to <it>Sycophaga</it>, all genera are monophyletic. The Sycophaginae are divided into three clades: (i) <it>Eukoebelea</it>; (ii) <it>Pseudidarnes</it>, <it>Anidarnes </it>and <it>Conidarnes </it>and (iii) <it>Apocryptophagus</it>, <it>Sycophaga </it>and <it>Idarnes</it>. The ancestral states for galling habits and male morphology remain ambiguous and our reconstructions show that the two traits are evolutionary labile.</p> <p>Conclusions</p> <p>The three main clades could be considered as tribes and we list some morphological characters that define them. The same biologies re-evolved several times independently, which make Sycophaginae an interesting model to test predictions on what factors will canalize the evolution of a particular biology. The ostiolar gall-inducers are the only monophyletic group. In 15 Myr, they evolved several morphological adaptations to enter the syconia that make them strongly divergent from their sister taxa. Sycophaginae appears to be another example where sexual selection on male mating opportunities favored winged males in species with small broods and wingless males in species with large broods. However, some species are exceptional in that they lay few eggs but exhibit apterous males, which we hypothesize could be due to other selective pressures selecting against the re-appearance of winged morphs.</p

The European Solar Telescope

The European Solar Telescope (EST) is a project aimed at studying the magnetic connectivity of the solar atmosphere, from the deep photosphere to the upper chromosphere. Its design combines the knowledge and expertise gathered by the European solar physics community during the construction and operation of state-of-the-art solar telescopes operating in visible and near-infrared wavelengths: the Swedish 1m Solar Telescope, the German Vacuum Tower Telescope and GREGOR, the French Télescope Héliographique pour l’Étude du Magnétisme et des Instabilités Solaires, and the Dutch Open Telescope. With its 4.2 m primary mirror and an open configuration, EST will become the most powerful European ground-based facility to study the Sun in the coming decades in the visible and near-infrared bands. EST uses the most innovative technological advances: the first adaptive secondary mirror ever used in a solar telescope, a complex multi-conjugate adaptive optics with deformable mirrors that form part of the optical design in a natural way, a polarimetrically compensated telescope design that eliminates the complex temporal variation and wavelength dependence of the telescope Mueller matrix, and an instrument suite containing several (etalon-based) tunable imaging spectropolarimeters and several integral field unit spectropolarimeters. This publication summarises some fundamental science questions that can be addressed with the telescope, together with a complete description of its major subsystems

Gender reassignment surgery - a 13 year review of surgical outcomes

PURPOSE: The aim of this study is to thoroughly report on surgical outcomes from 332 patients who underwent male to female gender reassignment surgery (GRS). MATERIAL AND METHODS: Records from 332 patients who underwent GRS from 1995 to 2008 were reviewed. All patients were submitted to penile inversion vaginoplasty with glans-derived sensate clitoroplasty. Mean age was 36.7 years (range 19-68 years). Surgical complications were stratified in 6 main groups: genital region, urinary tract, gastrointestinal events, wound healing disorders and unspecific events. RESULTS: Progressive obstructive voiding disorder due to meatal stenosis was the main complication observed in 40% of the patients, feasibly corrected during the second setting. Stricture recurrence was found in 15%. Stricture of vaginal introitus was observed in 15% of the cases followed by 12% and 8% of vaginal stenosis and lost of vaginal depth, respectively. Rectal injury was seen in 3% and minor wound healing disorders in 33% of the subjects. CONCLUSION: Regarding male to female GRS, a review of the current literature demonstrated scarce description of complications and their treatment options. These findings motivated a review of our surgical outcomes. Results showed a great number of adverse events, although functionality preserved. Comparision of our outcomes with recent publications additionally showed that treatment options provide satisfying results. Moreover, outcomes reaffirm penile inversion vaginoplasty in combination with glans-derived sensate clitoroplasty as a safe technique. Nevertheless, discussing and improving surgical techniques in order to reduce complications and their influence on patient's quality of life is still strongly necessary and theme of our future reports