CiteULike: Author Hubbard

Markers of lymphocyte homing distinguish CD4 T cell subsets that turn over in response to HIV-1 infection in humans.

RL Hengel — 2008-07-26T01:25:45-00:00

Journal of immunology (Baltimore, Md. : 1950), Vol. 163, No. 6. (15 September 1999), pp. 3539-3548.

In HIV-1 infection, the abrupt rise in CD4 T cells after effective antiretroviral therapy has been viewed as a measure of HIV-1-related CD4 T cell turnover in the steady state. The early (2-4 wk) response is reportedly dominated by CD4 T cells with a memory (CD45RO) phenotype. It is controversial whether the measurement of steady-state kinetics identifies cells that otherwise would have been recruited into a short-lived, virus-producing pool or reflects lymphoid redistribution/sequestration. We performed detailed phenotypic and kinetic analysis of CD4 T cell subsets in 14 patients. Turnover occurs in memory (CD45RO) as well as naive (CD45RA) cells, if the latter are present at baseline. Most of the turnover occurs in those memory (CD45RO) and naive (CD45RA) cells that are programmed for recirculation through lymphoid organs (CD62L+ and CD44low), whereas very little turnover occurs in memory cells (CD45RO) destined for recirculation from blood to tissue (CD62L- and CD44high). Turnover occurs in both activated (CD25+ and HLA-DR+) and nonactivated populations, although it is restricted to CD38-positive cells, indicating that turnover does not measure cells that are already infected. More likely, turnover occurs in cells that replace infected cells or are on their way to becoming infected. Taken together, markers of lymphocyte trafficking better describe cell turnover related to virus replication than do naive and memory markers per se, and lymph organs, not tissue-destined cells or peripheral blood cells, appear to be the important site of virus replication and CD4 T cell turnover, destruction, and redistribution.

A Bayesian deconvolution strategy for immunoprecipitation-based DNA methylome analysis

Thomas Down — 2008-07-09T06:30:38-00:00

Nature Biotechnology, Vol. 26, No. 7. (08 July 2008), pp. 779-785.

Comprehensive analysis of single-repeat R3 MYB proteins in epidermal cell patterning and their transcriptional regulation in Arabidopsis

Shucai Wang — 2008-07-23T04:05:08-00:00

BMC Plant Biology, Vol. 8 (21 July 2008), 81.

Association of CCR5 [up triangle, open]32 with reduced risk of asthma

Ian Hall — 2008-07-22T10:53:35-00:00

The Lancet, Vol. 354, No. 9186. (9 October 1999), pp. 1264-1265.

Summary We report that individuals carrying the CCR5[up triangle, open]32 mutation, a naturally occurring variant of the C-C chemokine receptor 5 (CCR5), are at reduced risk of developing asthma. These data suggest a possible explanation for the high prevalence of this mutation in the general population.

Glycosaminoglycans Interact Selectively with Chemokines and Modulate Receptor Binding and Cellular Responses

GSV Kuschert — 2008-07-22T09:13:01-00:00

Biochemistry, Vol. 38, No. 39. (28 September 1999), pp. 12959-12968.

Abstract: Chemokines selectively recruit and activate a variety of cells during inflammation. Interactions between cell surface glycosaminoglycans (GAGs) and chemokines drive the formation of haptotactic or immobilized gradients of chemokines at the site of inflammation, directing this recruitment. Chemokines bind to glycosaminoglycans on human umbilical vein endothelial cells (HUVECs) with affinities in the micromolar range: RANTES > MCP-1 > IL-8 > MIP-1. This binding can be competed with by soluble glycosaminoglycans: heparin, heparin sulfate, chondroitin sulfate, and dermatan sulfate. RANTES binding showed the widest discrimination between glycosaminoglycans (700-fold), whereas MIP-1 was the least selective. Almost identical results were obtained in an assay using heparin sulfate beads as the source of immobilized glycosaminoglycan. The binding of chemokines to glycosaminoglycan fragments has a strong length dependence, and optimally requires both N- and O-sulfation. Isothermal titration calorimetry data confirm these results; IL-8 binds heparin fragments with a Kd of 0.39-2.63 M, and requires five saccharide units to bind each monomer of chemokine. In membranes from cells expressing the G-protein-coupled chemokine receptors CXCR1, CXCR2, and CCR1, soluble GAGs inhibit the binding of chemokine ligands to their receptors. Consistent with this, heparin and heparin sulfate could inhibit IL-8-induced neutrophil calcium flux. Chemokines can therefore form complexes with both cell surface and soluble GAGs; these interactions have different functions. Soluble GAG chemokines complexes are unable to bind the receptor, resulting in a block of the biological activity. Previously, we have shown that cell surface GAGs present chemokines to the G-protein-coupled receptors, by increasing the local concentration of protein. A model is presented which brings together all of these data. The selectivity in the chemokine-GAG interaction suggests selective disruption of the haptotactic gradient may be an achievable therapeutic approach in inflammatory disease.

Critical assessment of methods of protein structure prediction-Round VII.

John Moult — 2007-11-16T14:16:26-00:00

Proteins, Vol. 69, No. S8. (5 October 2007), pp. 3-9.

This paper is an introduction to the supplemental issue of the journal PROTEINS, dedicated to the seventh CASP experiment to assess the state of the art in protein structure prediction. The paper describes the conduct of the experiment, the categories of prediction included, and outlines the evaluation and assessment procedures. Highlights are improvements in model accuracy relative to that obtainable from knowledge of a single best template structure; convergence of the accuracy of models produced by automatic servers toward that produced by human modeling teams; the emergence of methods for predicting the quality of models; and rapidly increasing practical applications of the methods. Proteins 2007. (c) 2007 Wiley-Liss, Inc.

Critical assessment of methods of protein structure prediction (CASP)--round 6.

J Moult — 2007-02-05T11:07:03-00:00

Proteins, Vol. 61 Suppl 7 (2005), pp. 3-7.

This article is an introduction to the special issue of the journal Proteins, dedicated to the sixth CASP experiment to assess the state of the art in protein structure prediction. The article describes the conduct of the experiment and the categories of prediction included, and outlines the evaluation and assessment procedures. A brief summary of progress over the decade of CASP experiments is also provided.

Collision Detection for Interactive Graphics Applications

Philip Hubbard — 2007-11-19T09:44:08-00:00

IEEE Transactions on Visualization and Computer Graphics, Vol. 1, No. 3. (1995), pp. 218-230.

Solid objects in the real world do not pass through each other when they collide. Enforcing this property of "solidness" is important in many interactive graphics applications; for example, solidness makes virtual reality more believable, and solidness is essential for the correctness of vehicle simulators. These applications use a collision-detection algorithm to enforce the solidness of objects. Unfortunately, previous collision-detection algorithms do not adequately address the needs of...

Approximating polyhedra with spheres for time-critical collision detection

Philip Hubbard — 2007-07-25T08:27:08-00:00

ACM Transactions on Graphics, Vol. 15, No. 3. (1996), pp. 179-210.

This paper presents a method for approximating polyhedral objects to support a timecritical collision-detection algorithm. The approximations are hierarchies of spheres, and they allow the time-critical algorithm to progressively refine the accuracy of its detection, stopping as needed to maintain the real-time performance essential for interactive applications. The key to this approach is a preprocess that automatically builds tightly fitting hierarchies for rigid and articulated objects. The ...

Prominent use of distal 5' transcription start sites and discovery of a large number of additional exons in ENCODE regions

France Denoeud — 2007-06-14T00:04:11-00:00

Genome Res., Vol. 17, No. 6. (1 June 2007), pp. 746-759.

This report presents systematic empirical annotation of transcript products from 399 annotated protein-coding loci across the 1% of the human genome targeted by the Encyclopedia of DNA elements (ENCODE) pilot project using a combination of 5' rapid amplification of cDNA ends (RACE) and high-density resolution tiling arrays. We identified previously unannotated and often tissue- or cell-line-specific transcribed fragments (RACEfrags), both 5' distal to the annotated 5' terminus and internal to the annotated gene bounds for the vast majority (81.5%) of the tested genes. Half of the distal RACEfrags span large segments of genomic sequences away from the main portion of the coding transcript and often overlap with the upstream-annotated gene(s). Notably, at least 20% of the resultant novel transcripts have changes in their open reading frames (ORFs), most of them fusing ORFs of adjacent transcripts. A significant fraction of distal RACEfrags show expression levels comparable to those of known exons of the same locus, suggesting that they are not part of very minority splice forms. These results have significant implications concerning (1) our current understanding of the architecture of protein-coding genes; (2) our views on locations of regulatory regions in the genome; and (3) the interpretation of sequence polymorphisms mapping to regions hitherto considered to be "noncoding," ultimately relating to the identification of disease-related sequence alterations. 10.1101/gr.5660607

SCOP: a structural classification of proteins database for the investigation of sequences and structures.

AG Murzin — 2005-12-13T11:53:52-00:00

J Mol Biol, Vol. 247, No. 4. (7 April 1995), pp. 536-540.

To facilitate understanding of, and access to, the information available for protein structures, we have constructed the Structural Classification of Proteins (scop) database. This database provides a detailed and comprehensive description of the structural and evolutionary relationships of the proteins of known structure. It also provides for each entry links to co-ordinates, images of the structure, interactive viewers, sequence data and literature references. Two search facilities are available. The homology search permits users to enter a sequence and obtain a list of any structures to which it has significant levels of sequence similarity. The key word search finds, for a word entered by the user, matches from both the text of the scop database and the headers of Brookhaven Protein Databank structure files. The database is freely accessible on World Wide Web (WWW) with an entry point to URL http: parallel scop.mrc-lmb.cam.ac.uk magnitude of scop.

Hydrodynamic friction of arbitrarily shaped Brownian particles

Joseph Hubbard — 2008-06-30T22:26:28-00:00

Physical Review E, Vol. 47, No. 5. (1 May 1993), R2983.

An integrated resource for genome-wide identification and analysis of human tissue-specific differentially methylated regions (tDMRs)

Vardhman Rakyan — 2008-06-25T10:34:37-00:00

Genome Res. (24 June 2008), gr.077479.108.

We report a novel resource (methylation profiles of DNA, mPod) for human genome-wide tissue-specific DNA methylation profiles. mPod consists of three fully integrated parts, genome-wide DNA methylation reference profiles of 13 normal somatic tissues, placenta, sperm and an immortalized cell line, a visualization tool that has been integrated with the Ensembl genome browser and a new algorithm for the analysis of immunoprecipitation-based DNA methylation profiles. We demonstrate the utility of our resource by identifying the first comprehensive genome-wide set of tissue-specific differentially methylated regions (tDMRs) that may play a role in cellular identity and the regulation of tissue-specific genome function. We also discuss the implications of our findings with respect to the regulatory potential of regions with varied CpG density, gene expression, transcription factor motifs, gene ontology and correlation with other epigenetic marks such as histone modifications. 10.1101/gr.077479.108

NestedMICA: sensitive inference of over-represented motifs in nucleic acid sequence

Thomas Down — 2005-04-02T06:50:37-00:00

Nucleic Acids Research, Vol. 33, No. 5. (2005), pp. 1445-1453.

Exploring the use of concept spaces to improve medical information retrieval

Andrea Houston — 2008-06-27T18:55:04-00:00

Decis. Support Syst., Vol. 30, No. 2. (December 2000), pp. 171-186.

This research investigated the application of techniques successfully used in previous information retrieval research, to the more challenging area of medical informatics. It was performed on a biomedical document collection testbed, Ž .CANCERLIT, provided by the National Cancer Institute NCI , which contains information on all types of cancer therapy. The quality or usefulness of terms suggested by three different thesauri, one based on MeSH terms, one based solely on Ž .terms from the document collection, and one based on the Unified Medical Language System UMLS Metathesaurus, was explored with the ultimate goal of improving CANCERLIT information search and retrieval. Researchers affiliated with the University of Arizona Cancer Center evaluated lists of related terms suggested by different thesauri for 12 different directed searches in the CANCERLIT testbed. The preliminary results indicated that among the thesauri, there were no statistically significant differences in either term recall or precision. Surprisingly, there was almost no overlap of relevant terms suggested by the different thesauri for a given search. This suggests that recall could be significantly improved by using a combined thesaurus approach.

Data growth and its impact on the SCOP database: new developments

A Andreeva — 2008-01-31T15:05:36-00:00

Nucleic Acids Research, Vol. 36, No. Database issue. (January 2008), pp. 419-425.

The Structural Classification of Proteins (SCOP) database is a comprehensive ordering of all proteins of known structure, according to their evolutionary and structural relationships. The SCOP hierarchy comprises the following levels: Species, Protein, Family, Superfamily, Fold and Class. While keeping the original classification scheme intact, we have changed the production of SCOP in order to cope with a rapid growth of new structural data and to facilitate the discovery of new protein relationships. We describe ongoing developments and new features implemented in SCOP. A new update protocol supports batch classification of new protein structures by their detected relationships at Family and Superfamily levels in contrast to our previous sequential handling of new structural data by release date. We introduce pre-SCOP, a preview of the SCOP developmental version that enables earlier access to the information on new relationships. We also discuss the impact of worldwide Structural Genomics initiatives, which are producing new protein structures at an increasing rate, on the rates of discovery and growth of protein families and superfamilies. SCOP can be accessed at http://scop.mrc-lmb.cam.ac.uk/scop.

The Arabidopsis Circadian Clock Incorporates a cADPR-Based Feedback Loop

Antony Dodd — 2008-06-24T14:19:13-00:00

Science, Vol. 318, No. 5857. (14 December 2007), pp. 1789-1792.

Transcriptional feedback loops are a feature of circadian clocks in both animals and plants. We show that the plant circadian clock also incorporates the cytosolic signaling molecule cyclic adenosine diphosphate ribose (cADPR). cADPR modulates the circadian oscillator's transcriptional feedback loops and drives circadian oscillations of Ca2+ release. The effects of antagonists of cADPR signaling, manipulation of cADPR synthesis, and mathematical simulation of the interaction of cADPR with the circadian clock indicate that cADPR forms a feedback loop within the plant circadian clock. 10.1126/science.1146757

A census of human cancer genes.

PA Futreal — 2006-09-07T13:26:41-00:00

Nat Rev Cancer, Vol. 4, No. 3. (March 2004), pp. 177-183.

Ensembl 2008.

P Flicek — 2007-11-16T14:27:20-00:00

Nucleic Acids Res (13 November 2007)

The Ensembl project (http://www.ensembl.org) is a comprehensive genome information system featuring an integrated set of genome annotation, databases and other information for chordate and selected model organism and disease vector genomes. As of release 47 (October 2007), Ensembl fully supports 35 species, with preliminary support for six additional species. New species in the past year include platypus and horse. Major additions and improvements to Ensembl since our previous report include extensive support for functional genomics data in the form of a specialized functional genomics database, genome-wide maps of protein-DNA interactions and the Ensembl regulatory build; support for customization of the Ensembl web interface through the addition of user accounts and user groups; and increased support for genome resequencing. We have also introduced new comparative genomics-based data mining options and report on the continued development of our software infrastructure.

Longitudinal profiles of plasma parameters in a laser-ignited capillary discharge and implications for laser wakefield accelerator applications

M Levin — 2008-05-07T17:09:22-00:00

Applied Physics Letters, Vol. 87, No. 26. (2005)

The evolution of longitudinal electron density and temperature profiles in plasma channel produced by a low-current Plexiglas capillary discharge with laser ignition was investigated by spectroscopic methods. The plasma was produced by an electric discharge using a 0.5 mm diameter, 15 mm long Plexiglas capillary. The electron density measured in near-outlet region was found to be lower by 30%. Simulations show that this variation of the plasma density near the entrance of the capillary can pose substantial difficulties for external injection of electrons for laser wakefield accelerator applications.

Toward Verified Biological Models

Avital Sadot — 2008-05-13T01:32:53-00:00

Computational Biology and Bioinformatics, IEEE/ACM Transactions on, Vol. 5, No. 2. (2008), pp. 223-234.

The last several decades have witnessed a vast accumulation of biological data and data analysis. Many of these data sets represent only a small fraction of the system's behavior, making the visualization of full system behavior difficult. A more complete understanding of a biological system is gained when different types of data (and/or conclusions drawn from the data) are integrated into a larger-scale representation or model of the system. Ideally, this type of model is consistent with all available data about the system, and it is then used to generate additional hypotheses to be tested. Computer-based methods intended to formulate models that integrate various events and to test the consistency of these models with respect to the laboratory-based observations on which they are based are potentially very useful. In addition, in contrast to informal models, the consistency of such formal computer-based models with laboratory data can be tested rigorously by methods of formal verification. We combined two formal modeling approaches in computer science that were originally developed for non-biological system design. One is the inter-object approach using the language of live sequence charts (LSCs) with the Play-Engine tool, and the other is the intra-object approach using the language of statecharts and Rhapsody as the tool. Integration is carried out using InterPlay, a simulation engine coordinator. Using these tools, we constructed a combined model comprising three modules. One module represents the early lineage of the somatic gonad of C. elegans in LSCs, while a second more detailed module in statecharts represents an interaction between two cells within this lineage that determine their developmental outcome. Using the advantages of the tools, we created a third module representing a set of key experimental data using LSCs. We tested the combined statechart-LSC model by showing that the simulations were consistent with the set of experimental LSCs. This small- -scale modular example demonstrates the potential for using similar approaches for verification by exhaustive testing of models by LSCs. It also shows the advantages of these approaches for modeling biology.

Priorities for nucleotide trace, sequence and annotation data capture at the Ensembl Trace Archive and the EMBL Nucleotide Sequence Database

Guy Cochrane — 2008-06-08T15:26:12-00:00

Nucl. Acids Res. (26 November 2007), gkm1018.

The Ensembl Trace Archive (http://trace.ensembl.org/) and the EMBL Nucleotide Sequence Database (http://www.ebi.ac.uk/embl/), known together as the European Nucleotide Archive, continue to see growth in data volume and diversity. Selected major developments of 2007 are presented briefly, along with data submission and retrieval information. In the face of increasing requirements for nucleotide trace, sequence and annotation data archiving, data capture priority decisions have been taken at the European Nucleotide Archive. Priorities are discussed in terms of how reliably information can be captured, the long-term benefits of its capture and the ease with which it can be captured. 10.1093/nar/gkm1018

Comparative genome analysis across a kingdom of eukaryotic organisms: Specialization and diversification in the Fungi

Michael Cornell — 2007-11-08T08:46:23-00:00

Genome Res. (5 November 2007), gr.6531807.

The recent proliferation of genome sequencing in diverse fungal species has provided the first opportunity for comparative genome analysis across a eukaryotic kingdom. Here, we report a comparative study of 34 complete fungal genome sequences, representing a broad diversity of Ascomycete, Basidiomycete, and Zygomycete species. We have clustered all predicted protein-encoding gene sequences from these species to provide a means of investigating gene innovations, gene family expansions, protein family diversification, and the conservation of essential gene functionsempirically determined in Saccharomyces cerevisiaeamong the fungi. The results are presented with reference to a phylogeny of the 34 fungal species, based on 29 universally conserved protein-encoding gene sequences. We contrast this phylogeny with one based on gene presence and absence and show that, while the two phylogenies are largely in agreement, there are differences in the positioning of some species. We have investigated levels of gene duplication and demonstrate that this varies greatly between fungal species, although there are instances of coduplication in distantly related fungi. We have also investigated the extent of orthology for protein families and demonstrate unexpectedly high levels of diversity among genes involved in lipid metabolism. These analyses have been collated in the e-Fungi data warehouse, providing an online resource for comparative genomic analysis of the fungi. 10.1101/gr.6531807

Ensembl 2007.

TJ Hubbard — 2007-04-27T17:06:10-00:00

Nucleic Acids Res, Vol. 35, No. Database issue. (January 2007)

The Ensembl (http://www.ensembl.org/) project provides a comprehensive and integrated source of annotation of chordate genome sequences. Over the past year the number of genomes available from Ensembl has increased from 15 to 33, with the addition of sites for the mammalian genomes of elephant, rabbit, armadillo, tenrec, platypus, pig, cat, bush baby, common shrew, microbat and european hedgehog; the fish genomes of stickleback and medaka and the second example of the genomes of the sea squirt (Ciona savignyi) and the mosquito (Aedes aegypti). Some of the major features added during the year include the first complete gene sets for genomes with low-sequence coverage, the introduction of new strain variation data and the introduction of new orthology/paralog annotations based on gene trees.

Comparison of Mascot and X!Tandem Performance for Low and High Accuracy Mass Spectrometry and the Development of an Adjusted Mascot Threshold

Markus Brosch — 2008-06-03T09:30:57-00:00

Mol Cell Proteomics, Vol. 7, No. 5. (1 May 2008), pp. 962-970.

It is a major challenge to develop effective sequence database search algorithms to translate molecular weight and fragment mass information obtained from tandem mass spectrometry into high quality peptide and protein assignments. We investigated the peptide identification performance of Mascot and X!Tandem for mass tolerance settings common for low and high accuracy mass spectrometry. We demonstrated that sensitivity and specificity of peptide identification can vary substantially for different mass tolerance settings, but this effect was more significant for Mascot. We present an adjusted Mascot threshold, which allows the user to freely select the best trade-off between sensitivity and specificity. The adjusted Mascot threshold was compared with the default Mascot and X!Tandem scoring thresholds and shown to be more sensitive at the same false discovery rates for both low and high accuracy mass spectrometry data. 10.1074/mcp.M700293-MCP200

Capture and analysis of quantitative proteomic data

King Lau — 2007-08-04T15:41:21-00:00

PROTEOMICS, Vol. 9999, No. 9999. (2007), NA.

Whilst the array of techniques available for quantitative proteomics continues to grow, the attendant bioinformatic software tools are similarly expanding in number. The data capture and analysis of such quantitative data is obviously crucial to the experiment and the methods used to process it will critically affect the quality of the data obtained. These tools must deal with a variety of issues, including identification of labelled and unlabelled peptide species, location of the corresponding MS scans in the experiment, construction of representative ion chromatograms, location of the true peptide ion chromatogram start and end, elimination of background signal in the mass spectrum and chromatogram and calculation of both peptide and protein ratios/abundances. A variety of tools and approaches are available, in part restricted by the nature of the experiment to be performed and available instrumentation. Currently, although there is no single consensus on precisely how to calculate protein and peptide abundances, many common themes have emerged which identify and reduce many of the key sources of error. These issues will be discussed, along with those relating to deposition of quantitative data. At present, mature data standards for quantitative proteomics are not yet available, although formats are beginning to emerge.

PEDRo: a database for storing, searching and disseminating experimental proteomics data.

K Garwood — 2004-11-22T00:17:30-00:00

BMC Genomics, Vol. 5, No. 1. (17 September 2004)

BACKGROUND: Proteomics is rapidly evolving into a high-throughput technology, in which substantial and systematic studies are conducted on samples from a wide range of physiological, developmental, or pathological conditions. Reference maps from 2D gels are widely circulated. However, there is, as yet, no formally accepted standard representation to support the sharing of proteomics data, and little systematic dissemination of comprehensive proteomic data sets. RESULTS: This paper describes the design, implementation and use of a Proteome Experimental Data Repository (PEDRo), which makes comprehensive proteomics data sets available for browsing, searching and downloading. It is also serves to extend the debate on the level of detail at which proteomics data should be captured, the sorts of facilities that should be provided by proteome data management systems, and the techniques by which such facilities can be made available. CONCLUSIONS: The PEDRo database provides access to a collection of comprehensive descriptions of experimental data sets in proteomics. Not only are these data sets interesting in and of themselves, they also provide a useful early validation of the PEDRo data model, which has served as a starting point for the ongoing standardisation activity through the Proteome Standards Initiative of the Human Proteome Organisation.

Large-Scale Discovery of Promoter Motifs in Drosophila melanogaster

Thomas Down — 2007-01-23T14:07:06-00:00

PLoS Computational Biology, Vol. 3, No. 1. (1 January 2007), e7.

A key step in understanding gene regulation is to identify the repertoire of transcription factor binding motifs (TFBMs) that form the building blocks of promoters and other regulatory elements. Identifying these experimentally is very laborious, and the number of TFBMs discovered remains relatively small, especially when compared with the hundreds of transcription factor genes predicted in metazoan genomes. We have used a recently developed statistical motif discovery approach, NestedMICA, to detect candidate TFBMs from a large set of Drosophila melanogaster promoter regions. Of the 120 motifs inferred in our initial analysis, 25 were statistically significant matches to previously reported motifs, while 87 appeared to be novel. Analysis of sequence conservation and motif positioning suggested that the great majority of these discovered motifs are predictive of functional elements in the genome. Many motifs showed associations with specific patterns of gene expression in the D. melanogaster embryo, and we were able to obtain confident annotation of expression patterns for 25 of our motifs, including eight of the novel motifs. The motifs are available through Tiffin, a new database of DNA sequence motifs. We have discovered many new motifs that are overrepresented in D. melanogaster promoter regions, and offer several independent lines of evidence that these are novel TFBMs. Our motif dictionary provides a solid foundation for further investigation of regulatory elements in Drosophila, and demonstrates techniques that should be applicable in other species. We suggest that further improvements in computational motif discovery should narrow the gap between the set of known motifs and the total number of transcription factors in metazoan genomes.

Initial sequencing and comparative analysis of the mouse genome.

RH Waterston — 2004-11-22T00:17:30-00:00

Nature, Vol. 420, No. 6915. (5 December 2002), pp. 520-562.

The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.

Large-Scale Mutagenesis in p19ARF- and p53-Deficient Mice Identifies Cancer Genes and Their Collaborative Networks

Anthony Uren — 2008-05-16T14:44:15-00:00

Cell, Vol. 133, No. 4. (16 May 2008), pp. 727-741.

Summary p53 and p19ARF are tumor suppressors frequently mutated in human tumors. In a high-throughput screen in mice for mutations collaborating with either p53 or p19ARF deficiency, we identified 10,806 retroviral insertion sites, implicating over 300 loci in tumorigenesis. This dataset reveals 20 genes that are specifically mutated in either p19ARF-deficient, p53-deficient or wild-type mice (including Flt3, mmu-mir-106a-363, Smg6, and Ccnd3), as well as networks of significant collaborative and mutually exclusive interactions between cancer genes. Furthermore, we found candidate tumor suppressor genes, as well as distinct clusters of insertions within genes like Flt3 and Notch1 that induce mutants with different spectra of genetic interactions. Cross species comparative analysis with aCGH data of human cancer cell lines revealed known and candidate oncogenes (Mmp13, Slamf6, and Rreb1) and tumor suppressors (Wwox and Arfrp2). This dataset should prove to be a rich resource for the study of genetic interactions that underlie tumorigenesis.

ISPIDER Central: an integrated database web-server for proteomics.

Jennifer A Siepen — 2008-04-29T13:06:32-00:00

Nucleic acids research (25 April 2008)

Despite the growing volumes of proteomic data, integration of the underlying results remains problematic owing to differences in formats, data captured, protein accessions and services available from the individual repositories. To address this, we present the ISPIDER Central Proteomic Database search (http://www.ispider.manchester.ac.uk/cgi-bin/ProteomicSearch.pl), an integration service offering novel search capabilities over leading, mature, proteomic repositories including PRoteomics IDEntifications database (PRIDE), PepSeeker, PeptideAtlas and the Global Proteome Machine. It enables users to search for proteins and peptides that have been characterised in mass spectrometry-based proteomics experiments from different groups, stored in different databases, and view the collated results with specialist viewers/clients. In order to overcome limitations imposed by the great variability in protein accessions used by individual laboratories, the European Bioinformatics Institute's Protein Identifier Cross-Reference (PICR) service is used to resolve accessions from different sequence repositories. Custom-built clients allow users to view peptide/protein identifications in different contexts from multiple experiments and repositories, as well as integration with the Dasty2 client supporting any annotations available from Distributed Annotation System servers. Further information on the protein hits may also be added via external web services able to take a protein as input. This web server offers the first truly integrated access to proteomics repositories and provides a unique service to biologists interested in mass spectrometry-based proteomics.

Protein tyrosine kinase structure and function.

SR Hubbard — 2007-12-30T12:27:08-00:00

Annu Rev Biochem, Vol. 69 (2000), pp. 373-398.

Tyrosine phosphorylation is one of the key covalent modifications that occurs in multicellular organisms as a result of intercellular communication during embryogenesis and maintenance of adult tissues. The enzymes that carry out this modification are the protein tyrosine kinases (PTKs), which catalyze the transfer of the phosphate of ATP to tyrosine residues on protein substrates. Phosphorylation of tyrosine residues modulates enzymatic activity and creates binding sites for the recruitment of downstream signaling proteins. Two classes of PTKs are present in cells: the transmembrane receptor PTKs and the nonreceptor PTKs. Because PTKs are critical components of cellular signaling pathways, their catalytic activity is strictly regulated. Over the past several years, high-resolution structural studies of PTKs have provided a molecular basis for understanding the mechanisms by which receptor and nonreceptor PTKs are regulated. This review will highlight the important results that have emerged from these structural studies.

Data Access and Integration in the ISPIDER Proteomics Grid

Lucas Zamboulis — 2008-05-14T15:56:33-00:00

Data Integration in the Life Sciences (2006), pp. 3-18.

Grid computing has great potential for supporting the integration of complex, fast changing biological data repositories to enable distributed data analysis. One scenario where Grid computing has such potential is provided by proteomics resources which are rapidly being developed with the emergence of affordable, reliable methods to study the proteome. The protein identifications arising from these methods derive from multiple repositories which need to be integrated to enable uniform access to them. A number of technologies exist which enable these resources to be accessed in a Grid environment, but the independent development of these resources means that significant data integration challenges, such as heterogeneity and schema evolution, have to be met. This paper presents an architecture which supports the combined use of Grid data access (OGSA-DAI), Grid distributed querying (OGSA-DQP) and data integration (AutoMed) software tools to support distributed data analysis. We discuss the application of this architecture for the integration of several autonomous proteomics data resources.

The Functional Genomics Experiment model (FuGE): an extensible framework for standards in functional genomics

Andrew Jones — 2007-10-11T16:03:11-00:00

Nat Biotech, Vol. 25, No. 10. (October 2007), pp. 1127-1133.

e-Fungi: a data resource for comparative analysis of fungal genomes

Cornelia Hedeler — 2007-11-21T10:10:29-00:00

BMC Genomics, Vol. 8 (20 November 2007), 426.

Crystal Structures of Two FGF-FGFR Complexes Reveal the Determinants of Ligand-Receptor Specificity

Alexander Plotnikov — 2008-05-13T16:07:02-00:00

Cell, Vol. 101, No. 4. (12 May 2000), pp. 413-424.

To elucidate the structural determinants governing specificity in fibroblast growth factor (FGF) signaling, we have determined the crystal structures of FGF1 and FGF2 complexed with the ligand binding domains (immunoglobulin-like domains 2 [D2] and 3 [D3]) of FGF receptor 1 (FGFR1) and FGFR2, respectively. Highly conserved FGF-D2 and FGF-linker (between D2-D3) interfaces define a general binding site for all FGF-FGFR complexes. Specificity is achieved through interactions between the N-terminal and central regions of FGFs and two loop regions in D3 that are subject to alternative splicing. These structures provide a molecular basis for FGF1 as a universal FGFR ligand and for modulation of FGF-FGFR specificity through primary sequence variations and alternative splicing.

The Politics of Women's Biology

Ruth Hubbard — 2008-05-08T05:40:08-00:00

(31 March 1990)

Paradoxical Role of Alveolar Macrophage-Derived Granulocyte Macrophage Colony Stimulating Factor in Pulmonary Host Defense post-Bone Marrow Transplantation.

Megan N Ballinger — 2008-05-08T04:39:50-00:00

American journal of physiology. Lung cellular and molecular physiology (2 May 2008)

Impaired host defense post-bone marrow transplant (BMT) is related to overproduction of prostaglandin E2 (PGE2) by alveolar macrophages (AMs). We show AMs post-BMT overproduce granulocyte-macrophage colony stimulating factor (GM-CSF) whereas GM-CSF in lung homogenates is impaired both at baseline and in response to infection post-BMT. Homeostatic regulation of GM-CSF may occur by hematopoietic/structural cell crosstalk. To determine whether AM overproduction of GM-CSF influenced immunosuppression post-BMT, we compared mice which received BMT from wild-type donors (control BMT) or mice that received BMT from GM-CSF-/- donors (GM-CSF-/- BMT) to untransplanted mice. GM-CSF-/- BMT mice were less susceptible to pneumonia with Pseudomonas aeruginosa compared to control BMT mice and showed anti-bacterial responses equal or better than untransplanted mice. GM-CSF-/- BMT AMs displayed normal phagocytosis and a trend towards enhanced bacterial killing. Surprisingly, AMs from GM-CSF-/- BMT mice overproduced PGE2, but expression of the inhibitory EP2 receptor was diminished. As a consequence of decreased EP2 receptor expression, we found diminished accumulation of cyclic adenosine monophosphate (cAMP) in response to PGE2 stimulation in GM-CSF-/-BMT AMs compared to control BMT AMs. In addition, GM-CSF-/- BMT AMs retained cysteinyl leukotriene production and normal tumor necrosis factor (TNF)-alpha response compared to AMs from control BMT mice. GM-CSF-/- BMT neutrophils also showed improved bacterial killing. While genetic ablation of GM-CSF in hematopoietic cells post-BMT improved host defense, transplantation of wild-type BM into GM-CSF-/- recipients demonstrated that parenchymal cell-derived GM-CSF is necessary for effective innate immune responses post-BMT. These results highlight the complex regulation of GM-CSF and innate immunity post-BMT. Key words: P. aeruginosa, eicosanoid, macrophage, neutrophil.

Structural Basis for FGF Receptor Dimerization and Activation

Alexander Plotnikov — 2008-05-01T16:01:33-00:00

Cell, Vol. 98, No. 5. (3 September 1999), pp. 641-650.

The crystal structure of FGF2 bound to a naturally occurring variant of FGF receptor 1 (FGFR1) consisting of immunoglobulin-like domains 2 (D2) and 3 (D3) has been determined at 2.8 Å resolution. Two FGF2:FGFR1 complexes form a 2-fold symmetric dimer. Within each complex, FGF2 interacts extensively with D2 and D3 as well as with the linker between the two domains. The dimer is stabilized by interactions between FGF2 and D2 of the adjoining complex and by a direct interaction between D2 of each receptor. A positively charged canyon formed by a cluster of exposed basic residues likely represents the heparin-binding site. A general model for FGF- and heparin-induced FGFR dimerization is inferred from the crystal structure, unifying a wealth of biochemical data.

Locating interaction sites on proteins: the crystal structure of thermolysin soaked in 2% to 100% isopropanol.

AC English — 2008-04-28T13:26:03-00:00

Proteins, Vol. 37, No. 4. (1 December 1999), pp. 628-640.

Multiple-solvent crystal structure determination (MSCS) allows the position and orientation of bound solvent fragments to be identified by determining the structure of protein crystals soaked in organic solvents. We have extended this technique by the determination of high-resolution crystal structures of thermolysin (TLN), generated from crystals soaked in 2% to 100% isopropanol. The procedure causes only minor changes to the conformation of the protein, and an increasing number of isopropanol interaction sites could be identified as the solvent concentration is increased. Isopropanol occupies all four of the main subsites in the active site, although this was only observed at very high concentrations of isopropanol for three of the four subsites. Analysis of the isopropanol positions shows little correlation with interaction energy computed using a molecular mechanics force field, but the experimentally determined positions of isopropanol are consistent with the structures of known protein-ligand complexes of TLN.

Experimental and computational mapping of the binding surface of a crystalline protein.

AC English — 2008-04-28T13:24:50-00:00

Protein engineering, Vol. 14, No. 1. (January 2001), pp. 47-59.

Multiple Solvent Crystal Structures (MSCS) is a crystallographic technique to identify energetically favorable positions and orientations of small organic molecules on the surface of proteins. We determined the high-resolution crystal structures of thermolysin (TLN), generated from crystals soaked in 50--70% acetone, 50--80% acetonitrile and 50 mM phenol. The structures of the protein in the aqueous-organic mixtures are essentially the same as the native enzyme and a number of solvent interaction sites were identified. The distribution of probe molecules shows clusters in the main specificity pocket of the active site and a buried subsite. Within the active site, we compared the experimentally determined solvent positions with predictions from two computational functional group mapping techniques, GRID and Multiple Copy Simultaneous Search (MCSS). The experimentally determined small molecule positions are consistent with the structures of known protein--ligand complexes of TLN.

Receptor tyrosine kinases: mechanisms of activation and signaling

Stevan Hubbard — 2007-03-15T09:30:25-00:00

Current Opinion in Cell Biology, Vol. 19, No. 2. (April 2007), pp. 117-123.

Receptor tyrosine kinases (RTKs) are essential components of signal transduction pathways that mediate cell-to-cell communication. These single-pass transmembrane receptors, which bind polypeptide ligands -- mainly growth factors -- play key roles in processes such as cellular growth, differentiation, metabolism and motility. Recent progress has been achieved towards an understanding of the precise (and varied) mechanisms by which RTKs are activated by ligand binding and by which signals are propagated from the activated receptors to downstream targets in the cell.

The Ensembl genome database project

T Hubbard — 2007-03-14T18:29:35-00:00

Nucl. Acids Res., Vol. 30, No. 1. (1 January 2002), pp. 38-41.

The Ensembl (http://www.ensembl.org/) database project provides a bioinformatics framework to organise biology around the sequences of large genomes. It is a comprehensive source of stable automatic annotation of the human genome sequence, with confirmed gene predictions that have been integrated with external data sources, and is available as either an interactive web site or as flat files. It is also an open source software engineering project to develop a portable system able to handle very large genomes and associated requirements from sequence analysis to data storage and visualisation. The Ensembl site is one of the leading sources of human genome sequence annotation and provided much of the analysis for publication by the international human genome project of the draft genome. The Ensembl system is being installed around the world in both companies and academic sites on machines ranging from supercomputers to laptops. 10.1093/nar/30.1.38

An overview of Ensembl.

E Birney — 2005-09-22T20:06:34-00:00

Genome Res, Vol. 14, No. 5. (May 2004), pp. 925-928.

Ensembl (http://www.ensembl.org/) is a bioinformatics project to organize biological information around the sequences of large genomes. It is a comprehensive source of stable automatic annotation of individual genomes, and of the synteny and orthology relationships between them. It is also a framework for integration of any biological data that can be mapped onto features derived from the genomic sequence. Ensembl is available as an interactive Web site, a set of flat files, and as a complete, portable open source software system for handling genomes. All data are provided without restriction, and code is freely available. Ensembl's aims are to continue to "widen" this biological integration to include other model organisms relevant to understanding human biology as they become available; to "deepen" this integration to provide an ever more seamless linkage between equivalent components in different species; and to provide further classification of functional elements in the genome that have been previously elusive.

Molecular recognition : Conformational analysis of limited proteolytic sites and serine proteinase protein inhibitors

SJ Hubbard — 2008-04-24T12:35:25-00:00

Journal of Molecular Biology, Vol. 220, No. 2. (20 July 1991), pp. 507-530.

The conformations of known tryptic limited proteolytic sites have been analysed and compared to the structures of the binding regions of serine proteinase inhibitors, as they are found when complexed to a serine proteinase. Conformational parameters studied include main-chain torsion angles, root-mean-square fits, accessibility, mobility and protrusion indices. As observed before, the inhibitors share a common main-chain conformation at the binding loop from P3-P'3 (Schechter, Berger notation), which is maintained throughout all the serine proteinase inhibitor families for which X-ray data is available, despite lack of similarity in the rest of the protein. This canonical structure is not found amongst the limited proteolytic sites (or nicksites), which differ markedly from the inhibitor binding loop conformation, and also amongst themselves. The experimentally determined nicksites are in general both accessible and protruding; as are the inhibitor binding loops, as well as being typically flexible regions of structure, as denoted by elevated temperature factors from crystallographic determinations. For cleavage by serine proteinases these loops must radically alter their local conformations and a large motion of the loop relative to the structure, in some cases, would be required to orientate these sites for cleavage.

Ensembl 2005.

T Hubbard — 2005-05-29T20:36:07-00:00

Nucleic Acids Res, Vol. 33, No. Database issue. (1 January 2005)

The Ensembl (http://www.ensembl.org/) project provides a comprehensive and integrated source of annotation of large genome sequences. Over the last year the number of genomes available from the Ensembl site has increased by 7 to 16, with the addition of the six vertebrate genomes of chimpanzee, dog, cow, chicken, tetraodon and frog and the insect genome of honeybee. The majority have been annotated automatically using the Ensembl gene build system, showing its flexibility to reliably annotate a wide variety of genomes. With the increased number of vertebrate genomes, the comparative analysis provided to users has been greatly improved, with new website interfaces allowing annotation of different genomes to be directly compared. The Ensembl software system is being increasingly widely reused in different projects showing the benefits of a completely open approach to software development and distribution.

Giving speech a hand: Gesture modulates activity in auditory cortex during speech perception.

Amy L Hubbard — 2008-04-22T01:41:52-00:00

Human brain mapping (15 April 2008)

Viewing hand gestures during face-to-face communication affects speech perception and comprehension. Despite the visible role played by gesture in social interactions, relatively little is known about how the brain integrates hand gestures with co-occurring speech. Here we used functional magnetic resonance imaging (fMRI) and an ecologically valid paradigm to investigate how beat gesture-a fundamental type of hand gesture that marks speech prosody-might impact speech perception at the neural level. Subjects underwent fMRI while listening to spontaneously-produced speech accompanied by beat gesture, nonsense hand movement, or a still body; as additional control conditions, subjects also viewed beat gesture, nonsense hand movement, or a still body all presented without speech. Validating behavioral evidence that gesture affects speech perception, bilateral nonprimary auditory cortex showed greater activity when speech was accompanied by beat gesture than when speech was presented alone. Further, the left superior temporal gyrus/sulcus showed stronger activity when speech was accompanied by beat gesture than when speech was accompanied by nonsense hand movement. Finally, the right planum temporale was identified as a putative multisensory integration site for beat gesture and speech (i.e., here activity in response to speech accompanied by beat gesture was greater than the summed responses to speech alone and beat gesture alone), indicating that this area may be pivotally involved in synthesizing the rhythmic aspects of both speech and gesture. Taken together, these findings suggest a common neural substrate for processing speech and gesture, likely reflecting their joint communicative role in social interactions. Hum Brain Mapp, 2008. (c) 2008 Wiley-Liss, Inc.