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1.  InterProScan 5: genome-scale protein function classification 
Bioinformatics  2014;30(9):1236-1240.
Motivation: Robust large-scale sequence analysis is a major challenge in modern genomic science, where biologists are frequently trying to characterize many millions of sequences. Here, we describe a new Java-based architecture for the widely used protein function prediction software package InterProScan. Developments include improvements and additions to the outputs of the software and the complete reimplementation of the software framework, resulting in a flexible and stable system that is able to use both multiprocessor machines and/or conventional clusters to achieve scalable distributed data analysis. InterProScan is freely available for download from the EMBl-EBI FTP site and the open source code is hosted at Google Code.
Availability and implementation: InterProScan is distributed via FTP at ftp://ftp.ebi.ac.uk/pub/software/unix/iprscan/5/ and the source code is available from http://code.google.com/p/interproscan/.
Contact: http://www.ebi.ac.uk/support or interhelp@ebi.ac.uk or mitchell@ebi.ac.uk
doi:10.1093/bioinformatics/btu031
PMCID: PMC3998142  PMID: 24451626
2.  In Vivo Measurement of Hippocampal GABAA/cBZR Density with [18F]-Flumazenil PET for the Study of Disease Progression in an Animal Model of Temporal Lobe Epilepsy 
PLoS ONE  2014;9(1):e86722.
Purpose
Imbalance of inhibitory GABAergic neurotransmission has been proposed to play a role in the pathogenesis of temporal lobe epilepsy (TLE). This study aimed to investigate whether [18F]-flumazenil ([18F]-FMZ) PET could be used to non-invasively characterise GABAA/central benzodiazepine receptor (GABAA/cBZR) density and affinity in vivo in the post-kainic acid status epilepticus (SE) model of TLE.
Methods
Dynamic [18F]-FMZ -PET scans using a multi-injection protocol were acquired in four male wistar rats for validation of the partial saturation model (PSM). SE was induced in eight male Wistar rats (10 weeks of age) by i.p. injection of kainic acid (7.5–25 mg/kg), while control rats (n = 7) received saline injections. Five weeks post-SE, an anatomic MRI scan was acquired and the following week an [18F]-FMZ PET scan (3.6–4.6 nmol). The PET data was co-registered to the MRI and regions of interest drawn on the MRI for selected structures. A PSM was used to derive receptor density and apparent affinity from the [18F]-FMZ PET data.
Key Findings
The PSM was found to adequately model [18F]-FMZ binding in vivo. There was a significant decrease in hippocampal receptor density in the SE group (p<0.01), accompanied by an increase in apparent affinity (p<0.05) compared to controls. No change in cortical receptor binding was observed. Hippocampal volume reduction and cell loss was only seen in a subset of animals. Histological assessment of hippocampal cell loss was significantly correlated with hippocampal volume measured by MRI (p<0.05), but did not correlate with [18F]-FMZ binding.
Significance
Alterations to hippocampal GABAA/cBZR density and affinity in the post-kainic acid SE model of TLE are detectable in vivo with [18F]-FMZ PET and a PSM. These changes are independent from hippocampal cell and volume loss. [18F]-FMZ PET is useful for investigating the role that changes GABAA/cBZR density and binding affinity play in the pathogenesis of TLE.
doi:10.1371/journal.pone.0086722
PMCID: PMC3897736  PMID: 24466212
4.  InterPro in 2011: new developments in the family and domain prediction database 
Nucleic Acids Research  2011;40(Database issue):D306-D312.
InterPro (http://www.ebi.ac.uk/interpro/) is a database that integrates diverse information about protein families, domains and functional sites, and makes it freely available to the public via Web-based interfaces and services. Central to the database are diagnostic models, known as signatures, against which protein sequences can be searched to determine their potential function. InterPro has utility in the large-scale analysis of whole genomes and meta-genomes, as well as in characterizing individual protein sequences. Herein we give an overview of new developments in the database and its associated software since 2009, including updates to database content, curation processes and Web and programmatic interfaces.
doi:10.1093/nar/gkr948
PMCID: PMC3245097  PMID: 22096229
5.  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.ebi.ac.uk/interpro), providing a web service and the ability to build complex, custom queries that can efficiently return thousands of rows of data in a variety of formats. This article describes the information available from the InterPro BioMart and illustrates its utility with examples of how to build queries that return useful biological information.
Database URL: http://www.ebi.ac.uk/interpro/biomart/martview.
doi:10.1093/database/bar033
PMCID: PMC3170169  PMID: 21785143
6.  QuickGO: a user tutorial for the web-based Gene Ontology browser 
The Gene Ontology (GO) has proven to be a valuable resource for functional annotation of gene products. At well over 27 000 terms, the descriptiveness of GO has increased rapidly in line with the biological data it represents. Therefore, it is vital to be able to easily and quickly mine the functional information that has been made available through these GO terms being associated with gene products. QuickGO is a fast, web-based tool for browsing the GO and all associated GO annotations provided by the GOA group. After undergoing a redevelopment, QuickGO is now able to offer many more features beyond simple browsing. Users have responded well to the new tool and given very positive feedback about its usefulness. This tutorial will demonstrate how some of these features could be useful to the researcher wanting to discover more about their dataset, particular areas of biology or to find new ways of directing their research.
Database URL: http://www.ebi.ac.uk/QuickGO
doi:10.1093/database/bap010
PMCID: PMC2794795  PMID: 20157483
7.  QuickGO: a web-based tool for Gene Ontology searching 
Bioinformatics  2009;25(22):3045-3046.
Summary: QuickGO is a web-based tool that allows easy browsing of the Gene Ontology (GO) and all associated electronic and manual GO annotations provided by the GO Consortium annotation groups QuickGO has been a popular GO browser for many years, but after a recent redevelopment it is now able to offer a greater range of facilities including bulk downloads of GO annotation data which can be extensively filtered by a range of different parameters and GO slim set generation.
Availability and Implementation: QuickGO has implemented in JavaScript, Ajax and HTML, with all major browsers supported. It can be queried online at http://www.ebi.ac.uk/QuickGO. The software for QuickGO is freely available under the Apache 2 licence and can be downloaded from http://www.ebi.ac.uk/QuickGO/installation.html
Contact: goa@ebi.ac.uk; dbinns@ebi.ac.uk
doi:10.1093/bioinformatics/btp536
PMCID: PMC2773257  PMID: 19744993
8.  The GOA database in 2009—an integrated Gene Ontology Annotation resource 
Nucleic Acids Research  2008;37(Database issue):D396-D403.
The Gene Ontology Annotation (GOA) project at the EBI (http://www.ebi.ac.uk/goa) provides high-quality electronic and manual associations (annotations) of Gene Ontology (GO) terms to UniProt Knowledgebase (UniProtKB) entries. Annotations created by the project are collated with annotations from external databases to provide an extensive, publicly available GO annotation resource. Currently covering over 160 000 taxa, with greater than 32 million annotations, GOA remains the largest and most comprehensive open-source contributor to the GO Consortium (GOC) project. Over the last five years, the group has augmented the number and coverage of their electronic pipelines and a number of new manual annotation projects and collaborations now further enhance this resource. A range of files facilitate the download of annotations for particular species, and GO term information and associated annotations can also be viewed and downloaded from the newly developed GOA QuickGO tool (http://www.ebi.ac.uk/QuickGO), which allows users to precisely tailor their annotation set.
doi:10.1093/nar/gkn803
PMCID: PMC2686469  PMID: 18957448
9.  InterPro: the integrative protein signature database 
Nucleic Acids Research  2008;37(Database issue):D211-D215.
The InterPro database (http://www.ebi.ac.uk/interpro/) integrates together predictive models or ‘signatures’ representing protein domains, families and functional sites from multiple, diverse source databases: Gene3D, PANTHER, Pfam, PIRSF, PRINTS, ProDom, PROSITE, SMART, SUPERFAMILY and TIGRFAMs. Integration is performed manually and approximately half of the total ∼58 000 signatures available in the source databases belong to an InterPro entry. Recently, we have started to also display the remaining un-integrated signatures via our web interface. Other developments include the provision of non-signature data, such as structural data, in new XML files on our FTP site, as well as the inclusion of matchless UniProtKB proteins in the existing match XML files. The web interface has been extended and now links out to the ADAN predicted protein–protein interaction database and the SPICE and Dasty viewers. The latest public release (v18.0) covers 79.8% of UniProtKB (v14.1) and consists of 16 549 entries. InterPro data may be accessed either via the web address above, via web services, by downloading files by anonymous FTP or by using the InterProScan search software (http://www.ebi.ac.uk/Tools/InterProScan/).
doi:10.1093/nar/gkn785
PMCID: PMC2686546  PMID: 18940856
10.  New developments in the InterPro database 
Nucleic Acids Research  2007;35(Database issue):D224-D228.
InterPro is an integrated resource for protein families, domains and functional sites, which integrates the following protein signature databases: PROSITE, PRINTS, ProDom, Pfam, SMART, TIGRFAMs, PIRSF, SUPERFAMILY, Gene3D and PANTHER. The latter two new member databases have been integrated since the last publication in this journal. There have been several new developments in InterPro, including an additional reading field, new database links, extensions to the web interface and additional match XML files. InterPro has always provided matches to UniProtKB proteins on the website and in the match XML file on the FTP site. Additional matches to proteins in UniParc (UniProt archive) are now available for download in the new match XML files only. The latest InterPro release (13.0) contains more than 13 000 entries, covering over 78% of all proteins in UniProtKB. The database is available for text- and sequence-based searches via a webserver (), and for download by anonymous FTP (). The InterProScan search tool is now also available via a web service at .
doi:10.1093/nar/gkl841
PMCID: PMC1899100  PMID: 17202162
11.  An evaluation of GO annotation retrieval for BioCreAtIvE and GOA 
BMC Bioinformatics  2005;6(Suppl 1):S17.
Background
The Gene Ontology Annotation (GOA) database aims to provide high-quality supplementary GO annotation to proteins in the UniProt Knowledgebase. Like many other biological databases, GOA gathers much of its content from the careful manual curation of literature. However, as both the volume of literature and of proteins requiring characterization increases, the manual processing capability can become overloaded.
Consequently, semi-automated aids are often employed to expedite the curation process. Traditionally, electronic techniques in GOA depend largely on exploiting the knowledge in existing resources such as InterPro. However, in recent years, text mining has been hailed as a potentially useful tool to aid the curation process.
To encourage the development of such tools, the GOA team at EBI agreed to take part in the functional annotation task of the BioCreAtIvE (Critical Assessment of Information Extraction systems in Biology) challenge.
BioCreAtIvE task 2 was an experiment to test if automatically derived classification using information retrieval and extraction could assist expert biologists in the annotation of the GO vocabulary to the proteins in the UniProt Knowledgebase.
GOA provided the training corpus of over 9000 manual GO annotations extracted from the literature. For the test set, we provided a corpus of 200 new Journal of Biological Chemistry articles used to annotate 286 human proteins with GO terms. A team of experts manually evaluated the results of 9 participating groups, each of which provided highlighted sentences to support their GO and protein annotation predictions. Here, we give a biological perspective on the evaluation, explain how we annotate GO using literature and offer some suggestions to improve the precision of future text-retrieval and extraction techniques. Finally, we provide the results of the first inter-annotator agreement study for manual GO curation, as well as an assessment of our current electronic GO annotation strategies.
Results
The GOA database currently extracts GO annotation from the literature with 91 to 100% precision, and at least 72% recall. This creates a particularly high threshold for text mining systems which in BioCreAtIvE task 2 (GO annotation extraction and retrieval) initial results precisely predicted GO terms only 10 to 20% of the time.
Conclusion
Improvements in the performance and accuracy of text mining for GO terms should be expected in the next BioCreAtIvE challenge. In the meantime the manual and electronic GO annotation strategies already employed by GOA will provide high quality annotations.
doi:10.1186/1471-2105-6-S1-S17
PMCID: PMC1869009  PMID: 15960829
12.  The Gene Ontology Annotation (GOA) Database: sharing knowledge in Uniprot with Gene Ontology 
Nucleic Acids Research  2004;32(Database issue):D262-D266.
The Gene Ontology Annotation (GOA) database (http://www.ebi.ac.uk/GOA) aims to provide high-quality electronic and manual annotations to the UniProt Knowledgebase (Swiss-Prot, TrEMBL and PIR-PSD) using the standardized vocabulary of the Gene Ontology (GO). As a supplementary archive of GO annotation, GOA promotes a high level of integration of the knowledge represented in UniProt with other databases. This is achieved by converting UniProt annotation into a recognized computational format. GOA provides annotated entries for nearly 60 000 species (GOA-SPTr) and is the largest and most comprehensive open-source contributor of annotations to the GO Consortium annotation effort. By integrating GO annotations from other model organism groups, GOA consolidates specialized knowledge and expertise to ensure the data remain a key reference for up-to-date biological information. Furthermore, the GOA database fully endorses the Human Proteomics Initiative by prioritizing the annotation of proteins likely to benefit human health and disease. In addition to a non-redundant set of annotations to the human proteome (GOA-Human) and monthly releases of its GO annotation for all species (GOA-SPTr), a series of GO mapping files and specific cross-references in other databases are also regularly distributed. GOA can be queried through a simple user-friendly web interface or downloaded in a parsable format via the EBI and GO FTP websites. The GOA data set can be used to enhance the annotation of particular model organism or gene expression data sets, although increasingly it has been used to evaluate GO predictions generated from text mining or protein interaction experiments. In 2004, the GOA team will build on its success and will continue to supplement the functional annotation of UniProt and work towards enhancing the ability of scientists to access all available biological information. Researchers wishing to query or contribute to the GOA project are encouraged to email: goa@ebi.ac.uk.
doi:10.1093/nar/gkh021
PMCID: PMC308756  PMID: 14681408
13.  The InterPro Database, 2003 brings increased coverage and new features 
Nucleic Acids Research  2003;31(1):315-318.
InterPro, an integrated documentation resource of protein families, domains and functional sites, was created in 1999 as a means of amalgamating the major protein signature databases into one comprehensive resource. PROSITE, Pfam, PRINTS, ProDom, SMART and TIGRFAMs have been manually integrated and curated and are available in InterPro for text- and sequence-based searching. The results are provided in a single format that rationalises the results that would be obtained by searching the member databases individually. The latest release of InterPro contains 5629 entries describing 4280 families, 1239 domains, 95 repeats and 15 post-translational modifications. Currently, the combined signatures in InterPro cover more than 74% of all proteins in SWISS-PROT and TrEMBL, an increase of nearly 15% since the inception of InterPro. New features of the database include improved searching capabilities and enhanced graphical user interfaces for visualisation of the data. The database is available via a webserver (http://www.ebi.ac.uk/interpro) and anonymous FTP (ftp://ftp.ebi.ac.uk/pub/databases/interpro).
PMCID: PMC165493  PMID: 12520011
14.  Absence of a Relationship between Tumor 18F-fluorodeoxyglucose Standardized Uptake Value and Survival in Patients Treated with Definitive Radiotherapy for Non–Small-Cell Lung Cancer 
Journal of Thoracic Oncology  2014;9(3):377-382.
Introduction:
A recent meta-analysis suggested that patients with non–small-cell lung cancer (NSCLC) whose primary tumors have a higher standardized uptake value (SUV) derived from 18F-fluorodeoxyglucose positron emission tomography (PET) have a worse prognosis in comparison with those with tumors with lower values. However, previous analyses have had methodological weaknesses. Furthermore, the prognostic significance over the full range of SUV values in patients treated nonsurgically remains unclear. The aim of this retrospective study was to investigate the relationship between survival and maximum SUV (SUVmax) analyzed as a continuous variable, in patients with NSCLC, staged using PET/computed tomography (CT) and treated with radiotherapy with or without chemotherapy.
Methods:
Eligible patients had a histological diagnosis of NSCLC, were treated with radical radiotherapy with or without chemotherapy as their primary treatment, and had pretreatment PET/CT scans. SUVmax, defined as the maximum pixel SUV value retrieved from the primary tumor, was analyzed primarily as a continuous variable for overall survival.
Results:
Eighty-eight patients met eligibility criteria: stage I, 19; stage II, 10; and stage III, 59. Median SUVmax was 15.0 (range, 2.5–56). Higher stage was associated with higher SUVmax values (p = 0.048). In univariate analysis, there was no evidence of a prognostic effect of SUVmax (hazard ratio per doubling = 0.83; 95% confidence interval, 0.62–1.11; p = 0.22). Analyzing SUVmax as a dichotomous variable (median cut point = 15.0), the hazard ratio (high: low) for risk of death was 0.71, with p = 0.18 (95% confidence interval, 0.44–1.15).
Conclusions:
In this cohort of patients, increasing SUVmax derived from 18F-fluorodeoxyglucose–PET/CT was associated with increasing tumor, node, metastasis (TNM) stage. We found no evidence of an association of increasing SUVmax with a shorter survival. Previous reports of an association between prognosis and SUVmax may partly be the result of methodological differences between this study and previous reports and an association between stage and SUVmax.
doi:10.1097/JTO.0000000000000096
PMCID: PMC4132041  PMID: 24518089
Non–small-cell lung cancer; Positron emission tomography; Standardized uptake value; Prognosis

Results 1-14 (14)