Recognition of the blood group H type 2 trisaccharide epitope by 28 monoclonal antibodies and three lectins

The patterns of cross-reaction of 30 monoclonal antibodies and three lectins were determined by ELISA with 21 ABH, Ii or Lewis related synthetic oligosaccharides coupled to bovine serum albumin. At least seven main groups of cross-reactive patterns were identified among the antibodies, plus several intermediate patterns between two of the main antibody groups. The three lectins had different cross-reaction patterns,Galactia tenuiflora was different from all the antibodies,Ulex europaeus lectin 1 andLotus tetragonolobus were similar, but not identical to groups III and V of antibodies respectively. The anti-H antibodies cross-reacting with A type 2 gave similar agglutination scores with all the normal ABO erythrocytes, while the anti-H antibodies not cross-reacting with A type 2 reacted with different scores: O>A₂>A₂B>B>A₁>A₁B>O_h, suggesting that these antibodies react better with the free H epitopes and do not recognize the H in A or B epitopes. Based on the ELISA and agglutination results and the lowest energy conformations of each oligosaccharide obtained by computer modelling, the most probable oligosaccharide surface areas recognized by each antibody main group are illustrated.     

Model-based analysis of non-specific binding for background correction of high-density oligonucleotide microarrays

Motivation: High-density DNA microarrays provide us with usefultools for analyzing DNA and RNA comprehensively. However, thebackground signal caused by the non-specific binding (NSB) betweenprobe and target makes it difficult to obtain accurate measurements.To remove the background signal, there is a set of backgroundprobes on Affymetrix Exon arrays to represent the amount ofnon-specific signals, and an accurate estimation of non-specificsignals using these background probes is desirable for improvementof microarray analyses. Results: We developed a thermodynamic model of NSB on shortnucleotide microarrays in which the NSBs are modeled by duplexformation of probes and multiple hypothetical targets. We fittedthe observed signal intensities of the background probes withthose expected by the model to obtain the model parameters.As a result, we found that the presented model can improve theaccuracy of prediction of non-specific signals in comparisonwith previously proposed methods. This result will provide auseful method to correct for the background signal in oligonucleotidemicroarray analysis. Availability: The software is implemented in the R languageand can be downloaded from our website (http://www-shimizu.ist.osaka-u.ac.jp/shimizu_lab/MSNS/). Contact: furusawa{at}ist.osaka-u.ac.jp Supplementary information: Supplementary data are availableat Bioinformatics online. The authors wish it to be known that, in their opinion, thefirst two authors should be regarded as joint First Authors. Associate Editor: Trey Ideker     

In defence of the Cell Quota model of micro-algal growth

When proper statistical procedures were employed, the empiricalCell Quota model of Droop (J. Mar. Biol. Assoc. UK, 48, 689–733,1968; J. Phycol., 9, 264–272, 1973) proved a better fitto 20 out of 21 data sets (of conserved nutrients) than didthe power law-based Chemical Reaction model of Baird (J. PlanktonRes., 21, 85–126, 1999).     

MMG: a probabilistic tool to identify submodules of metabolic pathways

Motivation: A fundamental task in systems biology is the identificationof groups of genes that are involved in the cellular responseto particular signals. At its simplest level, this often reducesto identifying biological quantities (mRNA abundance, enzymeconcentrations, etc.) which are differentially expressed intwo different conditions. Popular approaches involve using t-teststatistics, based on modelling the data as arising from a mixturedistribution. A common assumption of these approaches is thatthe data are independent and identically distributed; however,biological quantities are usually related through a complex(weighted) network of interactions, and often the more pertinentquestion is which subnetworks are differentially expressed,rather than which genes. Furthermore, in many interesting cases(such as high-throughput proteomics and metabolomics), onlyvery partial observations are available, resulting in the needfor efficient imputation techniques. Results: We introduce Mixture Model on Graphs (MMG), a novelprobabilistic model to identify differentially expressed submodulesof biological networks and pathways. The method can easily incorporateinformation about weights in the network, is robust againstmissing data and can be easily generalized to directed networks.We propose an efficient sampling strategy to infer posteriorprobabilities of differential expression, as well as posteriorprobabilities over the model parameters. We assess our methodon artificial data demonstrating significant improvements overstandard mixture model clustering. Analysis of our model resultson quantitative high-throughput proteomic data leads to theidentification of biologically significant subnetworks, as wellas the prediction of the expression level of a number of enzymes,some of which are then verified experimentally. Availability: MATLAB code is available from http://www.dcs.shef.ac.uk/~guido/software.html Contact: guido{at}dcs.shef.ac.uk Supplementary information: Supplementary data are availableat Bioinformatics online. Associate Editor: Jonathan Wren     

How frugal is Mother Nature with haplotypes?

Motivation: Inference of haplotypes from genotype data is crucialand challenging for many vitally important studies. The first,and most critical step, is the ascertainment of a biologicallysound model to be optimized. Many models that have been proposedrely partially or entirely on reducing the number of uniquehaplotypes in the solution. Results: This article examines the parsimony of haplotypes usingknown haplotypes as well as genotypes from the HapMap project.Our study reveals that there are relatively few unique haplotypes,but not always the least possible, for the datasets with knownsolutions. Furthermore, we show that there are frequently verylarge numbers of parsimonious solutions, and the number increasesexponentially with increasing cardinality. Moreover, these solutionsare quite varied, most of which are not consistent with thetrue solutions. These results quantify the limitations of thePure Parsimony model and demonstrate the imperative need toconsider additional properties for haplotype inference models.At a higher level, and with broad applicability, this articleillustrates the power of combinatorial methods to tease outimperfections in a given biological model. Contact: weixiong.zhang{at}wustl.edu Associate Editor: Alex Bateman     

Identification of genes expressed in vascular tissues using NPA-induced vascular overgrowth in Arabidopsis

The genetic basis of vascular differentiation and function isrelatively poorly understood, partly due to the difficulty ofscreening for mutants defective in internal vascular tissues.Here we present an approach based on a predicted increase invascular-related gene expression in response to an auxin transportinhibitor-induced vascular overgrowth. We used microarray analysesto identify 336 genes that were up-regulated 2-fold in shoottissues of Arabidopsis thaliana showing vascular overgrowth.Promoter–marker gene fusions revealed that 38 out of 40genes with 4-fold up-regulation in vascular overgrowth tissueshad vascular-related expression in transgenic Arabidopsis plants.Obtained expression patterns included cambial tissues and differentiatingxylem, phloem and fibers. A total of 15 genes were found tohave vascular-specific expression patterns in the leaves and/orinflorescence stems. This study provides empirical evidenceof the efficiency of the approach and describes for the firsttime the in situ expression patterns of the majority of theassessed genes.     

Co-nutrient limitation of diatom growth under nitrogen or silicon limitation. A reply to the paper of Flynn and Martin-Jezequel

Flynn and Martin-Jézéquel (J. Plankton Res., 22,447–472, 2000) derived a mechanistic model for nitrogenand silicon physiology of diatoms. During their analysis, theycompared the output of this model with that of the co-nutrientmodel of Davidson and Gurney (J. Plankton Res., 21, 839–858,1999). They highlighted some discrepancies between the predictionsof the two models, which occurred subsequent to exhaustion ofthe yield-limiting nutrient, and suggested that the co-nutrientmodel contained technical inaccuracies in its output. Here itis shown that by simply modifying the numerical values of twoof the parameters of the co-nutrient model, while retainingexactly the same model structure, it is possible to producesimilar dynamics to those exhibited by the model of Flynn andMartin-Jézéquel.     

TOPALi v2: a rich graphical interface for evolutionary analyses of multiple alignments on HPC clusters and multi-core desktops

Summary: TOPALi v2 simplifies and automates the use of severalmethods for the evolutionary analysis of multiple sequence alignments.Jobs are submitted from a Java graphical user interface as TOPALiweb services to either run remotely on high-performance computingclusters or locally (with multiple cores supported). Methodsavailable include model selection and phylogenetic tree estimationusing the Bayesian inference and maximum likelihood (ML) approaches,in addition to recombination detection methods. The optimalsubstitution model can be selected for protein or nucleic acid(standard, or protein-coding using a codon position model) datausing accurate statistical criteria derived from ML co-estimationof the tree and the substitution model. Phylogenetic softwareavailable includes PhyML, RAxML and MrBayes. Availability: Freely downloadable from http://www.topali.orgfor Windows, Mac OS X, Linux and Solaris. Contact: iain.milne{at}scri.ac.uk Associate Editor: Martin Bishop     

A neural network model of the cerebellar cortex performing dynamic associations

The present paper proposes a model which applies formal neural network modeling techniques to construct a theoretical representation of the cerebellar cortex and its performances in motor control. A schema that makes explicit use of propagation delays of neural signals, is introduced to describe the ability to store temporal sequences of patterns in the Golgi-granule cell system. A perceptron association is then performed on these sequences of patterns by the Purkinje cell layer. The model conforms with important biological constraints, such as the known excitatory or inhibitory nature of the various synapses. Also, as suggested by experimental evidence, the synaptic plasticity underlying the learning ability of the model, is confined to the parallel fiber — Purkinje cell synapses, and takes place under the control of the climbing fibers. The result is a neural network model, constructed according to the anatomy of the cerebellar cortex, and capable of learning and retrieval of temporal sequences of patterns. It provides a framework to represent and interpret properties of learning and control of movements by the cerebellum, and to assess the capacity of formal neural network techniques for modeling of real neural systems.     

A precise and scalable method for querying genes in chromosomal banding regions based on cytogenetic annotations

Motivation: Staining the human metaphase chromosomes revealscharacteristic banding patterns known as cytogenetic bands orcytobands. Using technologies based on metaphase chromosomes,researchers have accumulated much knowledge about the correlationsbetween human diseases and specific cytoband aberrations, indicatingthe presence of disease-associated genes in those bands. Withthe progress of human genome project and techniques such asfluorescent in situ hybridization, many genes have been assignedto the cytobands and annotated in public databases, making itpossible to find all genes in the disease-related cytobandsthrough database queries. However, finding genes in cytobandsremains an imprecise process, partly due to the insufficiencyof current methods for cytoband queries, especially for thosebased on cytogenetic annotations. Results: By transforming the cytoband annotations into numericalsegments, a new query method is developed that is able to accuratelydefine any cytogenetic ranges in human chromosomes. A querysystem (designated cytoband query sys CQS) is implemented usingcytogenetic annotations in the public domain. Judged by a performancetest, CQS executed as accurately as expected using cytogeneticannotations from NCBI Map Viewer. The new method is scalableand can be applied to genomes from other species. Availability: The CQS is freely accessible over the Internetat http://moris.csie.ncku.edu.tw/cqs/ Contact: clh9{at}mail.ncku.edu.tw Supplementary information: http://moris.csie.ncku.edu.tw/cqs/     

Inferring long-term changes in the physical chemical environment of the shallow, enriched Lake Nero from statistical and functional analyses of its phytoplankton

The qualitative and quantitative studies of the phytoplankton,concentration of inorganic nitrogen and phosphate and chlorophylla in the water column and its seasonal and spatial variationhave been studied in the open water of the large, shallow andhighly eutrophic Lake Nero over periods representing more thanone decade (1988–1989 and 1999–2003). The averagequalitative characteristics of phytoplankton have remained stableover the period of observations; however, structural and functionalcharacteristics have been highly unstable in the short term.This is controversial but may be due to the high robustnessof the ecosystem to the environmental stresses. The frequenciesof species within seasonal-abundance parameters have been used,together with additional data on the dominance of the communityexpressed in terms of evaluated Species of the Functional Groups(SFG). Correlation and factor analyses were used to estimatethe strength of selected environmental factors on the developmentof SFG. In the periods covered by our analyses, the selectedparameters were always strongly correlated with first principalcomponents, which were dominated by properties relating to theunderwater light field. According to our investigation, thephytoplankton of Lake Nero supports a commonly occurring combinationS1 filamentous cyanobacteria with C diatoms and participationJ greens, M and H1 dinitrogen–fixing types. It is typicalof shallow, nutrient-rich lakes, comprising species that performwell under conditions of poor light. Individual species dominancevaries but strictly among species making up the S1 association.Full accord with the two hypotheses of the PROTECH (PhytoplanktonRespOnses To Environmental CHange) model has been demonstrated.     

Conditional random pattern algorithm for LOH inference and segmentation

Motivation: Loss of heterozygosity (LOH) is one of the mostimportant mechanisms in the tumor evolution. LOH can be detectedfrom the genotypes of the tumor samples with or without pairednormal samples. In paired sample cases, LOH detection for informativesingle nucleotide polymorphisms (SNPs) is straightforward ifthere is no genotyping error. But genotyping errors are alwaysunavoidable, and there are about 70% non-informative SNPs whoseLOH status can only be inferred from the neighboring informativeSNPs. Results: This article presents a novel LOH inference and segmentationalgorithm based on the conditional random pattern (CRP) model.The new model explicitly considers the distance between twoneighboring SNPs, as well as the genotyping error rate and theheterozygous rate. This new method is tested on the simulatedand real data of the Affymetrix Human Mapping 500K SNP arrays.The experimental results show that the CRP method outperformsthe conventional methods based on the hidden Markov model (HMM). Availability: Software is available upon request. Contact: xzhou{at}tmhs.org Supplementary information: Supplementary data are availableat Bioinformatics online. Associate Editor: Alex Bateman     

3D-Garden: a system for modelling protein-protein complexes based on conformational refinement of ensembles generated with the marching cubes algorithm

Motivation: Reliable structural modelling of protein–proteincomplexes has widespread application, from drug design to advancingour knowledge of protein interactions and function. This workaddresses three important issues in protein–protein docking:implementing backbone flexibility, incorporating prior indicationsfrom experiment and bioinformatics, and providing public accessvia a server. 3D-Garden (Global And Restrained Docking ExplorationNexus), our benchmarked and server-ready flexible docking system,allows sophisticated programming of surface patches by the uservia a facet representation of the interactors’ molecularsurfaces (generated with the marching cubes algorithm). Flexibilityis implemented as a weighted exhaustive conformer search foreach clashing pair of molecular branches in a set of 5000 modelsfiltered from around 340 000 initially. Results: In a non-global assessment, carried out strictly accordingto the protocols for number of models considered and model qualityof the Critical Assessment of Protein Interactions (CAPRI) experiment,over the widely-used Benchmark 2.0 of 84 complexes, 3D-Gardenidentifies a set of ten models containing an acceptable or bettermodel in 29/45 test cases, including one with large conformationalchange. In 19/45 cases an acceptable or better model is rankedfirst or second out of 340 000 candidates. Availability: http://www.sbg.bio.ic.ac.uk/3dgarden (server) Contact: v.lesk{at}ic.ac.uk Supplementary information: Supplementary data are availableat Bioinformatics online. Associate Editor: Burkhard Rost     

Slider--maximum use of probability information for alignment of short sequence reads and SNP detection

Motivation: A plethora of alignment tools have been createdthat are designed to best fit different types of alignment conditions.While some of these are made for aligning Illumina SequenceAnalyzer reads, none of these are fully utilizing its probability(prb) output. In this article, we will introduce a new alignmentapproach (Slider) that reduces the alignment problem space byutilizing each read base's probabilities given in the prb files. Results: Compared with other aligners, Slider has higher alignmentaccuracy and efficiency. In addition, given that Slider matchesbases with probabilities other than the most probable, it significantlyreduces the percentage of base mismatches. The result is thatits SNP predictions are more accurate than other SNP predictionapproaches used today that start from the most probable sequence,including those using base quality. Contact: nmalhis{at}bcgsc.ca Supplementary information and availability: http://www.bcgsc.ca/platform/bioinfo/software/slider Associate Editor: Dmitrij Frishman