Digital transcriptome profiling of normal and glioblastoma-derived neural stem cells identifies genes associated with patient survival.

Background: Glioblastoma multiforme, the most common type of primary brain tumor in adults, is driven by cells with neural stem (NS) cell characteristics. Using derivation methods developed for NS cells, it is possible to expand tumorigenic stem cells continuously in vitro. Although these glioblastoma-derived neural stem (GNS) cells are highly similar to normal NS cells, they harbor mutations typical of gliomas and initiate authentic tumors following orthotopic xenotransplantation.

Calcium input frequency, duration and amplitude differentially modulate the relative activation of calcineurin and CaMKII.

NMDA receptor dependent long-term potentiation (LTP) and long-term depression (LTD) are two prominent forms of synaptic plasticity, both of which are triggered by post-synaptic calcium elevation. To understand how calcium selectively stimulates two opposing processes, we developed a detailed computational model and performed simulations with different calcium input frequencies, amplitudes, and durations. We show that with a total amount of calcium ions kept constant, high frequencies of calcium pulses stimulate calmodulin more efficiently.

Transcriptional data: a new gateway to drug repositioning?

Recent advances in computational biology suggest that any perturbation to the transcriptional programme of the cell can be summarised by a proper 'signature': a set of genes combined with a pattern of expression. Therefore, it should be possible to generate proxies of clinicopathological phenotypes and drug effects through signatures acquired via DNA microarray technology. Gene expression signatures have recently been assembled and compared through genome-wide metrics, unveiling unexpected drug-disease and drug-drug 'connections' by matching corresponding signatures.

m:Explorer: multinomial regression models reveal positive and negative regulators of longevity in yeast quiescence.

We developed m:Explorer for identifying process-specific transcription factors (TFs) from multiple genome-wide sources, including transcriptome, DNA-binding and chromatin data. m:Explorer robustly outperforms similar techniques in finding cell cycle TFs in Saccharomyces cerevisiae. We predicted and experimentally tested regulators of quiescence (G0), a model of ageing, over a six-week time-course.

Large-scale analysis of microRNA evolution.

Background: In animals, microRNAs (miRNA) are important genetic regulators. Animal miRNAs appear to have expanded in conjunction with an escalation in complexity during early bilaterian evolution. Their small size and high-degree of similarity makes them challenging for phylogenetic approaches.

Software support for SBGN maps: SBGN-ML and LibSBGN.

Motivation: LibSBGN is a software library for reading, writing and manipulating Systems Biology Graphical Notation (SBGN) maps stored using the recently developed SBGN-ML file format. The library (available in C++ and Java) makes it easy for developers to add SBGN support to their tools, whereas the file format facilitates the exchange of maps between compatible software applications. The library also supports validation of maps, which simplifies the task of ensuring compliance with the detailed SBGN specifications.

PSI-Search: iterative HOE-reduced profile SSEARCH searching.

Unlabelled: Iterative similarity searches with PSI-BLAST position-specific score matrices (PSSMs) find many more homologs than single searches, but PSSMs can be contaminated when homologous alignments are extended into unrelated protein domains-homologous over-extension (HOE). PSI-Search combines an optimal Smith-Waterman local alignment sequence search, using SSEARCH, with the PSI-BLAST profile construction strategy. An optional sequence boundary-masking procedure, which prevents alignments from being extended after they are initially included, can reduce HOE errors in the PSSM profile.

jmzReader: A Java parser library to process and visualize multiple text and XML-based mass spectrometry data formats.

We here present the jmzReader library: a collection of Java application programming interfaces (APIs) to parse the most commonly used peak list and XML-based mass spectrometry (MS) data formats: DTA, MS2, MGF, PKL, mzXML, mzData, and mzML (based on the already existing API jmzML). The library is optimized to be used in conjunction with mzIdentML, the recently released standard data format for reporting protein and peptide identifications, developed by the HUPO proteomics standards initiative (PSI). mzIdentML files do not contain spectra data but contain references to different kinds of external MS data files.

jmzIdentML API: A Java interface to the mzIdentML standard for peptide and protein identification data.

We present a Java application programming interface (API), jmzIdentML, for the Human Proteome Organisation (HUPO) Proteomics Standards Initiative (PSI) mzIdentML standard for peptide and protein identification data. The API combines the power of Java Architecture of XML Binding (JAXB) and an XPath-based random-access indexer to allow a fast and efficient mapping of extensible markup language (XML) elements to Java objects. The internal references in the mzIdentML files are resolved in an on-demand manner, where the whole file is accessed as a random-access swap file, and only the relevant piece of XMLis selected for mapping to its corresponding Java object.

Accurate extension of multiple sequence alignments using a phylogeny-aware graph algorithm.

Motivation: Accurate alignment of large numbers of sequences is demanding and the computational burden is further increased by downstream analyses depending on these alignments. With the abundance of sequence data, an integrative approach of adding new sequences to existing alignments without their full re-computation and maintaining the relative matching of existing sequences is an attractive option. Another current challenge is the extension of reference alignments with fragmented sequences, as those coming from next-generation metagenomics, that contain relatively little information.

Evidence of non-random mutation rates suggests an evolutionary risk management strategy.

A central tenet in evolutionary theory is that mutations occur randomly with respect to their value to an organism; selection then governs whether they are fixed in a population. This principle has been challenged by long-standing theoretical models predicting that selection could modulate the rate of mutation itself. However, our understanding of how the mutation rate varies between different sites within a genome has been hindered by technical difficulties in measuring it.

Structural analysis and stochastic modelling suggest a mechanism for calmodulin trapping by CaMKII.

Activation of CaMKII by calmodulin and the subsequent maintenance of constitutive activity through autophosphorylation at threonine residue 286 (Thr286) are thought to play a major role in synaptic plasticity. One of the effects of autophosphorylation at Thr286 is to increase the apparent affinity of CaMKII for calmodulin, a phenomenon known as "calmodulin trapping". It has previously been suggested that two binding sites for calmodulin exist on CaMKII, with high and low affinities, respectively.

The impact of focused Gene Ontology curation of specific mammalian systems.

Unlabelled: The Gene Ontology (GO) resource provides dynamic controlled vocabularies to provide an information-rich resource to aid in the consistent description of the functional attributes and subcellular locations of gene products from all taxonomic groups (www.geneontology.org).

SpeCond: a method to detect condition-specific gene expression.

Transcriptomic studies routinely measure expression levels across numerous conditions. These datasets allow identification of genes that are specifically expressed in a small number of conditions. However, there are currently no statistically robust methods for identifying such genes.

ChEMBL: a large-scale bioactivity database for drug discovery.

ChEMBL is an Open Data database containing binding, functional and ADMET information for a large number of drug-like bioactive compounds. These data are manually abstracted from the primary published literature on a regular basis, then further curated and standardized to maximize their quality and utility across a wide range of chemical biology and drug-discovery research problems. Currently, the database contains 5.

How do you find transcription factors? Computational approaches to compile and annotate repertoires of regulators for any genome.

Transcription factors (TFs) play an important role in regulating gene expression. The availability of complete genome sequences and associated functional genomic data offer excellent opportunities to understand the transcriptional regulatory system of an entire organism. To do so, however, it is essential to compile a reliable dataset of regulatory components.

Consequences of the discontinuation of the International Protein Index (IPI) database and its substitution by the UniProtKB "complete proteome" sets.

The International Protein Index (IPI) database has been one of the most widely used protein databases in MS proteomics approaches. Recently, the closure of IPI in September 2011 was announced. Its recommended replacement is the new UniProt Knowledgebase (UniProtKB) "complete proteome" sets, launched in May 2011.

A genomic model of condition-specific nucleosome behavior explains transcriptional activity in yeast.

Nucleosomes play an important role in gene regulation. Molecular studies observed that nucleosome binding in promoters tends to be repressive. In contrast, genomic studies have delivered conflicting results: An analysis of yeast grown on diverse carbon sources reported that nucleosome occupancies remain largely unchanged between conditions, whereas a study of the heat-shock response suggested that nucleosomes get evicted at promoters of genes with increased expression.

Comparative genomics suggests differential deployment of linear and branched signaling across bacteria.

A major mode of signal transduction in bacteria is the two-component system, which involves phosphorylation of an output-generating receiver protein by a signal-sensing histidine kinase. This differs from the more common one-component system--where both signal sensing and output generation are performed by the same protein--in the spatial separation of the two activities and the obligate need for post-translational modification (phosphorylation). Many described two-component systems involve a linear structure where a single kinase phosphorylates a cognate receiver.

Minimum information about a bioactive entity (MIABE).

Bioactive molecules such as drugs, pesticides and food additives are produced in large numbers by many commercial and academic groups around the world. Enormous quantities of data are generated on the biological properties and quality of these molecules. Access to such data - both on licensed and commercially available compounds, and also on those that fail during development - is crucial for understanding how improved molecules could be developed.

Extracting quantitative genetic interaction phenotypes from matrix combinatorial RNAi.

Background: Systematic measurement of genetic interactions by combinatorial RNAi (co-RNAi) is a powerful tool for mapping functional modules and discovering components. It also provides insights into the role of epistasis on the way from genotype to phenotype. The interpretation of co-RNAi data requires computational and statistical analysis in order to detect interactions reliably and sensitively.

The InterPro BioMart: federated query and web service access to the InterPro Resource.

The InterPro BioMart provides users with query-optimized access to predictions of family classification, protein domains and functional sites, based on a broad spectrum of integrated computational models ('signatures') that are generated by the InterPro member databases: Gene3D, HAMAP, PANTHER, Pfam, PIRSF, PRINTS, ProDom, PROSITE, SMART, SUPERFAMILY and TIGRFAMs. These predictions are provided for all protein sequences from both the UniProt Knowledge Base and the UniParc protein sequence archive. The InterPro BioMart is supplementary to the primary InterPro web interface (http://www.

Published and perished? The influence of the searched protein database on the long-term storage of proteomics data.

In proteomics, protein identifications are reported and stored using an unstable reference system: protein identifiers. These proprietary identifiers are created individually by every protein database and can change or may even be deleted over time. To estimate the effect of the searched protein sequence database on the long-term storage of proteomics data we analyzed the changes of reported protein identifiers from all public experiments in the Proteomics Identifications (PRIDE) database by November 2010.

Large-scale nuclear architecture and transcriptional control.

Transcriptional regulation is one the most basic mechanisms for controlling gene expression. Over the past few years, much research has been devoted to understanding the interplay between transcription factors, histone modifications and associated enzymes required to achieve this control. However, it is becoming increasingly apparent that the three-dimensional conformation of chromatin in the interphase nucleus also plays a critical role in regulating transcription.

An overview of prokaryotic transcription factors : a summary of function and occurrence in bacterial genomes.

Transcriptional initiation is arguably the most important control point for gene expression. It is regulated by a combination of factors, including DNA sequence and its three-dimensional topology, proteins and small molecules. In this chapter, we focus on the trans-acting factors of bacterial regulation.