SUMMARY: Multi-electrode array (MEA) recordings are widely utilized to characterize neuronal network activity. However, currently each manufacturer distributes proprietary software that operates exclusively on its own file format. Since no cross-platform, open-source pipeline currently exists. Thus, we created CASCADE (Criticality Avalanche Spike Cross-platform Analysis Detection Engine), a Python-based command-line (bash) pipeline to analyze MEA recordings from 3Brain, Axion Biosystems, Cortical Labs, Maxwell Biosystems, and Multi-Channel Systems MEA devices. CASCADE measures the standard parameters such as: network, burst, firing rate frequency, and also measures criticality and avalanches. CASCADE criticality calculation was benchmarked across six MEA recordings from five manufacturers, resulting in comparable values because all recordings were analyzed using identical computational methods regardless of manufacturer file format. Thus, CASCADE provides a flexible and robust MEA analysis pipeline that can also analyze neuronal avalanches and criticality from multiple MEA devices from different manufacturers. AVAILABILITY AND IMPLEMENTATION: CASCADE is freely available at GitHub repository (https://github.com/FA387/cascade-mea) and can be installed via PyPI (pip install cascade-mea). The source code is archived at Zenodo (https://doi.org/10.5281/zenodo.20840795). Data used in this work is available at Zenodo repository (https://doi.org/10.5281/zenodo.19161615). The data underlying this article are available in the article and in its online supplementary material.

BACKGROUND: Event extraction from the biomedical literature is one of the most actively researched areas in biomedical text mining and natural language processing. However, most approaches have focused on events within single sentence boundaries, and have thus paid much less attention to events spanning multiple sentences. The Bacteria-Biotope event (BB-event) subtask presented in BioNLP Shared Task 2016 is one such example; a significant amount of relations between bacteria and biotope span more than one sentence, but existing systems have treated them as false negatives because labeled data is not sufficiently large enough to model a complex reasoning process using supervised learning frameworks. RESULTS: We present an unsupervised method for inferring cross-sentence events by propagating intra-sentence information to adjacent sentences using context trigger expressions that strongly signal the implicit presence of entities of interest. Such expressions can be collected from a large amount of unlabeled plain text based on simple syntactic constraints, helping to overcome the limitation of relying only on a small number of training examples available. The experimental results demonstrate that our unsupervised system extracts cross-sentence events quite well and outperforms all the state-of-the-art supervised systems when combined with existing methods for intra-sentence event extraction. Moreover, our system is also found effective at detecting long-distance intra-sentence events, compared favorably with existing high-dimensional models such as deep neural networks, without any supervised learning techniques. CONCLUSIONS: Our linguistically motivated inference model is shown to be effective at detecting implicit events that have not been covered by previous work, without relying on training data or curated knowledge bases. Moreover, it also helps to boost the performance of existing systems by allowing them to detect additional cross-sentence events. We believe that the proposed model offers an effective way to infer implicit information beyond sentence boundaries, especially when human-annotated data is not sufficient enough to train a robust supervised system.

Automatic event location extraction from text plays a crucial role in many applications such as infectious disease surveillance and natural disaster monitoring. The fundamental limitation of previous work such as SpaceEval is the limited scope of extraction, targeting only at locations that are explicitly stated in a syntactic structure. This leads to missing a lot of implicit information inferable from context in a document, which amounts to nearly 40% of the entire location information. To overcome this limitation for the first time, we present a system that infers the implicit event locations from a given document. Our system exploits distributional semantics, based on the hypothesis that if two events are described by similar expressions, it is likely that they occur in the same location. For example, if “A bomb exploded causing 30 victims” and “many people died from terrorist attack in Boston” are reported in the same document, it is highly likely that the bomb exploded in Boston. Our system shows good performance of a 0.58 F1-score, where state-of-the-art classifiers for intra-sentential spatiotemporal relations achieve around 0.60 F1-scores.

Semantic fluency is a commonly used task in psychology that provides data about executive function and semantic memory. Performance on the task is affected by conditions ranging from depression to dementia. The task involves participants naming as many members of a given category (e.g. animals) as possible in sixty seconds. Most of the analyses reported in the literature only rely on word counts and transcribed data, and do not take into account the evidence of utterance planning present in the speech signal. Using data from Korean, we show how prosodic analyses can be combined with computational linguistic analyses of the words produced to provide further insights into the processes involved in producing fluency data. We compare our analyses to an established analysis method for semantic fluency data, manual determination of lexically coherent clusters of words.

Robot storytelling has the potential for its practical use in various domains such as entertainment, education, and rehabilitation. However, relying on human-recorded voices for natural storytelling is costly, and automation with text-to-speech systems is not readily applicable due to the difficulty of reflecting the full nature of stories in TTS systems. In this paper, we address the problem of automating robot storytelling with a particular focus on two issues: speaker identification and speaker-TTS voice mapping. We first conduct text analysis with rich linguistic clues to identify speakers from a given textual story. We then consider the task of speaker-TTS voice mapping as the graph coloring problem and propose effective algorithms for assigning voices to speakers given a limited number of TTS voices. Finally, we perform a user experiment on validating the usefulness of our method. The results demonstrate that our system significantly outperforms baseline systems and is also more acceptable to users.

BACKGROUND: In order to access the large amount of information in biomedical literature about genes implicated in various cancers both efficiently and accurately, the aid of text mining (TM) systems is invaluable. Current TM systems do target either gene-cancer relations or biological processes involving genes and cancers, but the former type produces information not comprehensive enough to explain how a gene affects a cancer, and the latter does not provide a concise summary of gene-cancer relations. RESULTS: In this paper, we present a corpus for the development of TM systems that are specifically targeting gene-cancer relations but are still able to capture complex information in biomedical sentences. We describe CoMAGC, a corpus with multi-faceted annotations of gene-cancer relations. In CoMAGC, a piece of annotation is composed of four semantically orthogonal concepts that together express 1) how a gene changes, 2) how a cancer changes and 3) the causality between the gene and the cancer. The multi-faceted annotations are shown to have high inter-annotator agreement. In addition, we show that the annotations in CoMAGC allow us to infer the prospective roles of genes in cancers and to classify the genes into three classes according to the inferred roles. We encode the mapping between multi-faceted annotations and gene classes into 10 inference rules. The inference rules produce results with high accuracy as measured against human annotations. CoMAGC consists of 821 sentences on prostate, breast and ovarian cancers. Currently, we deal with changes in gene expression levels among other types of gene changes. The corpus is available at http://biopathway.org/CoMAGCunder the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0). CONCLUSIONS: The corpus will be an important resource for the development of advanced TM systems on gene-cancer relations.

This paper proposes a robotic agent named 'Genie' that understands a user's wish and gives its possible answers on a social network platform. Once a potential wish is detected upon monitoring the text updates in the micro-blog of the user, the agent initiates a task to help the user with both NLP and metadata analysis. As an interaction scenario, we set the type of a robot as an agent that identifies wishful products by searching for and analyzing product information on the web. After an analysis of the vast amount of data, the agent provides possible answers to the user as a way of granting the wish that might require additional time and effort to achieve. In order to draw the user's attention, the agent makes a physical movement as a push notification with more user-friendliness.

In order to achieve a believable interaction between humans and robots, synthesizing the reasonable and natural emotion is important. Furthermore, improving the adjustability of parameters' values in the model is essential for the designer of a robot. In this paper we developed a hybrid emotion generation architecture and defined the generalized context inputs of emotion generation model for convenient use by a robot designer. We also developed the personality model based on the Big-Five personality factors to generate the various emotions and action colorings. The personality model affected not only the intensity of the generated emotion, mood state, and emotion decay, but also the action selection of the robot. So, for each circumstance, the robot can show the distinct emotional state and modified actions, which we call action colorings. The developed emotion generation system is integrated into a robot which responds to the user's calling, and manages the schedule of the human.

This paper describes the design of a new robot head which has three special parts for emotional expression. The emotion of robots has become an issue of interest in the field of robotics. This robot head, EEEX(exaggerating emotion expresser) is developed to efficiently express various emotions. EEEX is useful in the human-robot interaction. EEEX has 3 special elements that humans do not possess to clearly express emotions. The first is arm-type antennae which consist of a 3-DOFs link system on each side to make dynamically emotional movements. They are specialized parts to show emotion by copying the humanpsilas arm motion. Second, emoticon-eyes help to represent emotions intuitively since the eyes are the most important parts to convey emotions. Lastly, exaggerating jaw & cheeks when expressing exaggerative emotions should assist in emotional expression as well, particularly surprise and anger. These 3 parts, the arm-type antennae, emoticon-eyes and exaggerating jaw & cheeks, would help human to recognize a robotpsilas emotions more clearly.

BACKGROUND: Much effort is currently made to develop the Gene Ontology (GO). Due to the dynamic nature of information it addresses, GO undergoes constant updates whose results are released at regular intervals as separate versions. Although there are a large number of computational tools to aid the development of GO, they are operating on a particular version of GO, making it difficult for GO curators to anticipate the full impact of particular changes along the time axis on a larger scale. We present a method for tapping into such an evolutionary aspect of GO, by making it possible to keep track of important temporal changes to any of the terms and relations of GO and by consequently making it possible to recognize associated trends. RESULTS: We have developed visualization methods for viewing the changes between two different versions of GO by constructing a colour-coded layered graph. The graph shows both versions of GO with highlights to those GO terms that are added, removed and modified between the two versions. Focusing on a specific GO term or terms of interest over a period, we demonstrate the utility of our system that can be used to make useful hypotheses about the cause of the evolution and to provide new insights into more complex changes. CONCLUSIONS: GO undergoes fast evolutionary changes. A snapshot of GO, as presented by each version of GO alone, overlooks such evolutionary aspects, and consequently limits the utilities of GO. The method that highlights the differences of consecutive versions or two different versions of an evolving ontology with colour-coding enhances the utility of GO for users as well as for developers. To the best of our knowledge, this is the first proposal to visualize the evolutionary aspect of GO.

Social capability of a robot becomes one of important issues in human-robot interaction (HRI). Especially, for a robot to form a social relationship with people is significant for improving believability of a robot through more natural communication with people. In this paper, we propose a formal approach to make a robot establish and learn a social relationship based on affective relation in sociological perspectives. The main idea is based on representing sentiment relation (liking/disliking) within social individuals, which is regarded as a basis for forming interpersonal relation in sociology. Our Sentiment Relation model can be applied to loyalty implementation of service robots in underlying assumptions that a service robot must have high positive relationship to her host and tends to behave to minimize tension(stress) by unbalanced states, which are generated by different affective states between individuals in social group. To confirm the possibility of our model, the reinforcement learning-based behavior coordination using loyalty level is simulated in the simple grid world.

This paper introduces an emotion interaction system for a service robot. The purpose of emotion interaction systems in service robots is to make people feel that the robot is not a mere machine, but reliable living assistant in the home. The emotion interaction system is composed of the emotion recognition, generation, and expression systems. A user's emotion is recognized by multi-modality, such as voice, dialogue, and touch. The robot's emotion is generated according to a psychological theory about emotion: OCC (Ortony, Clore, and Collins) model, which focuses on the user's emotional state and the information about environment and the robot itself. The generated emotion is expressed by facial expression, gesture, and the musical sound of the robot. Because the proposed system is composed of all the three components that are necessary for a full emotional interaction cycle, it can be implemented in the real robot system and be tested. Even though the multi- modality in emotion recognition and expression is still in its rudimentary stages, the proposed system is shown to be extremely useful in service robot applications. Furthermore, the proposed framework can be a cornerstone for the design of emotion interaction and generation systems for robots.

MOTIVATION: Contrasts are useful conceptual vehicles for learning processes and exploratory research of the unknown. For example, contrastive information between proteins can reveal what similarities, divergences and relations there are of the two proteins, leading to invaluable insights for better understanding about the proteins. Such contrastive information are found to be reported in the biomedical literature. However, there have been no reported attempts in current biomedical text mining work that systematically extract and present such useful contrastive information from the literature for exploitation. RESULTS: Our BioContrasts system extracts protein-protein contrastive information from MEDLINE abstracts and presents the information to biologists in a web-application for exploitation. Contrastive information are identified in the text abstracts with contrastive negation patterns such as 'A but not B'. A total of 799 169 pairs of contrastive expressions were successfully extracted from 2.5 million MEDLINE abstracts. Using grounding of contrastive protein names to Swiss-Prot entries, we were able to produce 41 471 pieces of contrasts between Swiss-Prot protein entries. These contrastive pieces of information are then presented via a user-friendly interactive web portal that can be exploited for applications such as the refinement of biological pathways. AVAILABILITY: BioContrasts can be accessed at http://biocontrasts.i2r.a-star.edu.sg. It is also mirrored at http://biocontrasts.biopathway.org. SUPPLEMENTARY INFORMATION: Supplementary materials are available at Bioinformatics online.

MOTIVATION: Gene Ontology (GO) has been manually developed to provide a controlled vocabulary for gene product attributes. It continues to evolve with new concepts that are compiled mostly from existing concepts in a compositional way. If we consider the relatively slow growth rate of GO in the face of the fast accumulation of the biological data, it is much desirable to provide an automatic means for predicting new concepts from the existing ones. RESULTS: We present a novel method that predicts more detailed concepts by utilizing syntactic relations among the existing concepts. We propose a validation measure for the automatically predicted concepts by matching the concepts to biomedical articles. We also suggest how to find a suitable direction for the extension of a constantly growing ontology such as GO. AVAILABILITY: http://autogo.biopathway.org SUPPLEMENTARY INFORMATION: Supplementary materials are available at Bioinformatics online.

Expressions of negation in the biomedical literature often encode information of contrast as a means for explaining significant differences between the objects that are so contrasted. We show that such information gives additional insights into the nature of the structures and/or biological functions of these objects, leading to valuable knowledge for subcategorization of protein families by the properties that the involved proteins do not have in common. Based on the observation that the expressions of negation employ mostly predictable syntactic structures that can be characterized by subclausal coordination and by clause-level parallelism, we present a system that extracts such contrastive information by identifying those syntactic structures with natural language processing techniques and with additional linguistic resources for semantics. The implemented system shows the performance of 85.7% precision and 61.5% recall, including 7.7% partial recall, or an F score of 76.6. We apply the system to the biological interactions as extracted by our biomedical information-extraction system in order to enrich proteome databases with contrastive information.

10.1145/1131348.1131349

MOTIVATION: Protein interactions provide an important context for the understanding of function. Experimental approaches have been complemented with computational ones, such as PSIMAP, which computes domain-domain interactions for all multi-domain and multi-chain proteins in the Protein Data Bank (PDB). PSIMAP has been used to determine that superfamilies occurring in many species have many interaction partners, to show examples of convergent evolution through shared interaction partners and to uncover complexes in the interaction map. To determine an interaction, the original PSIMAP algorithm checks all residue pairs of any domain pair defined by classification systems such as SCOP. The computation takes several days for the PDB. The computation of PSIMAP has two shortcomings: first, the original PSIMAP algorithm considers only interactions of residue pairs rather than atom pairs losing information for detailed analysis of contact patterns. At the atomic level the original algorithm would take months. Second, with the superlinear growth of PDB, PSIMAP is not sustainable. RESULTS: We address these two shortcomings by developing a family of new algorithms for the computation of domain-domain interactions based on the idea of bounding shapes, which are used to prune the search space. The best of the algorithms improves on the old PSIMAP algorithm by a factor of 60 on the PDB. Additionally, the algorithms allow a distributed computation, which we carry out on a farm of 80 Linux PCs. Overall, the new algorithms reduce the computation at atomic level from months to 20 min. The combination of pruning and distribution makes the new algorithm scalable and sustainable even with the superlinear growth in PDB.

UNLABELLED: The Human Protein Interaction Database (http://www.hpid.org) was designed (1) to provide human protein interaction information pre-computed from existing structural and experimental data, (2) to predict potential interactions between proteins submitted by users and (3) to provide a depository for new human protein interaction data from users. Two types of interaction are available from the pre-computed data: (1) interactions at the protein superfamily level and (2) those transferred from the interactions of yeast proteins. Interactions at the superfamily level were obtained by locating known structural interactions of the PDB in the SCOP domains and identifying homologs of the domains in the human proteins. Interactions transferred from yeast proteins were obtained by identifying homologs of the yeast proteins in the human proteins. For each human protein in the database and each query submitted by users, the protein superfamilies and yeast proteins assigned to the protein are shown, along with their interacting partners. We have also developed a set of web-based programs so that users can visualize and analyze protein interaction networks in order to explore the networks further. AVAILABILITY: http://www.hpid.org.

BACKGROUND: Large-scale protein interaction maps provide a new, global perspective with which to analyse protein function. PSIMAP, the Protein Structural Interactome Map, is a database of all the structurally observed interactions between superfamilies of protein domains with known three-dimensional structure in the PDB. PSIMAP incorporates both functional and evolutionary information into a single network. RESULTS: We present a global analysis of PSIMAP using several distinct network measures relating to centrality, interactivity, fault-tolerance, and taxonomic diversity. We found the following results: Centrality: we show that the center and barycenter of PSIMAP do not coincide, and that the superfamilies forming the barycenter relate to very general functions, while those constituting the center relate to enzymatic activity. Interactivity: we identify the P-loop and immunoglobulin superfamilies as the most highly interactive. We successfully use connectivity and cluster index, which characterise the connectivity of a superfamily's neighbourhood, to discover superfamilies of complex I and II. This is particularly significant as the structure of complex I is not yet solved. Taxonomic diversity: we found that highly interactive superfamilies are in general taxonomically very diverse and are thus amongst the oldest. Fault-tolerance: we found that the network is very robust as for the majority of superfamilies removal from the network will not break up the network. CONCLUSIONS: Overall, we can single out the P-loop containing nucleotide triphosphate hydrolases superfamily as it is the most highly connected and has the highest taxonomic diversity. In addition, this superfamily has the highest interaction rank, is the barycenter of the network (it has the shortest average path to every other superfamily in the network), and is an articulation vertex, whose removal will disconnect the network. More generally, we conclude that the graph-theoretic and taxonomic analysis of PSIMAP is an important step towards the understanding of protein function and could be an important tool for tracing the evolution of life at the molecular level.

Abstract We review recent results in literature data mining for biology and discuss the need and the steps for a challenge evaluation for this field. Literature data mining has progressed from simple recognition of terms to extraction of interaction relationships from complex sentences, and has broadened from recognition of protein interactions to a range of problems such as improving homology search, identifying cellular location, and so on. To encourage participation and accelerate progress in this expanding field, we propose creating challenge evaluations, and we describe two specific applications in this context. Contact: [email protected]@[email protected]@[email protected] * To whom correspondence should be addressed.

For large scale structural assignment to sequences, as in computational structural genomics, a fast yet sensitive homology search procedure is essential. A new approach using intermediate sequences was tested as a shortcut to iterative multiple sequence search methods such as PSI-BLAST and hidden Markov models. A library containing potential intermediate sequences for proteins of known structure (PDB_ISL) was constructed. The sequences in the library were collected from a large sequence database using the sequences of the domains of proteins of known structure as the query sequences and the program PSI-BLAST. Sequences of proteins of unknown structure can be matched to distantly related proteins of known structure by using any pairwise sequence comparison methods to find homologues in PDB_ISL. Searches of PDB_ISL were calibrated, and the number of correct matches found at a given error rate was the same as that found by PSI_BLAST. The advantage of this library is that it uses pairwise sequence comparison methods, such as FASTA or BLAST2, and can, therefore, be searched easily and, in many cases, much more quickly than an iterative multiple sequence comparison method. The procedure is roughly twenty times faster than PSI-BLAST for small genomes and several hundred times for large genomes such as C. elegans.

Abstract Summary: DaliLite is a program for pairwise structure comparison and for structure database searching. It is a standalone version of the search engine of the popular Dali server. A web interface is provided to view the results, multiple alignments and 3D superimpositions of structures. Availability: DaliLite has been ported to the Linux and Irix operating systems and can be compiled in many other UNIX operating systems. It is found at http://www.embl-ebi.ac.uk/dali/DaliLite. Contact: [email protected]

MOTIVATION: How critical is the sequence order information in predicting protein secondary structure segments? We tried to get a rough insight on it from a theoretical approach using both a prediction algorithm and structural fragments from Protein Databank (PDB). RESULTS: Using reverse protein sequences and PDB structural fragments, we theoretically estimated the significance of the order for protein secondary structure and prediction. On average: (1) 79% of protein sequence segments resulted in the same prediction in both normal and reverse directions, which indicated a relatively high conservation of secondary structure propensity in the reverse direction; (2) the reversed sequence prediction alone performed less accurately than the normal forward sequence prediction, but comparably high (2% difference); (3) the commonly predicted regions showed a slightly higher prediction accuracy (4%) than the normal sequences prediction; and (4) structural fragments which have counterparts in reverse direction in the same protein showed a comparable degree of secondary structure conservation (73% identity with reversed structures on average for pentamers). CONTACT: [email protected]; [email protected]; [email protected]; [email protected]

MOTIVATION: The Sequence Search Algorithm Assessment and Testing Toolkit (SAT) aims to be a complete package for the comparison of different protein homology search algorithms. The structural classification of proteins can provide us with a clear criterion for judgment in homology detection. There have been several assessments based on structural sequences with classifications but a good deal of similar work is now being repeated with locally developed procedures and programs. The SAT will provide developers with a complete package which will save time and produce more comparable performance assessments for search algorithms. The package is complete in the sense that it provides a non-redundant large sequence resource database, a well-characterized query database of proteins domains, all the parsers and some previous results from PSI-BLAST and a hidden markov model algorithm. RESULTS: An analysis on two different data sets was carried out using the SAT package. It compared the performance of a full protein sequence database (RSDB100) with a non-redundant representative sequence database derived from it (RSDB50). The performance measurement indicated that the full database is sub-optimal for a homology search. This result justifies the use of much smaller and faster RSDB50 than RSDB100 for the SAT. AVAILABILITY: A web site is up. The whole packa ge is accessible via www and ftp. ftp://ftp.ebi.ac.uk/pub/contrib/jong/SAT http://cyrah.ebi.ac.uk:1111/Proj/Bio/SAT http://www.mrc-lmb.cam.ac.uk/genomes/SAT In the package, some previous assessment results produced by the package can also be found for reference. CONTACT: [email protected]

MOTIVATION: Biological sequence databases are highly redundant for two main reasons: 1. various databanks keep redundant sequences with many identical and nearly identical sequences 2. natural sequences often have high sequence identities due to gene duplication. We wanted to know how many sequences can be removed before the databases start losing homology information. Can a database of sequences with mutual sequence identity of 50% or less provide us with the same amount of biological information as the original full database? RESULTS: Comparisons of nine representative sequence databases (RSDB) derived from full protein databanks showed that the information content of sequence databases is not linearly proportional to its size. An RSDB reduced to mutual sequence identity of around 50% (RSDB50) was equivalent to the original full database in terms of the effectiveness of homology searching. It was a third of the full database size which resulted in a six times faster iterative profile searching. The RSDBs are produced at different granularity for efficient homology searching. AVAILABILITY: All the RSDB files generated and the full analysis results are available through internet: ftp://ftp.ebi.ac. uk/pub/contrib/jong/RSDB/http://cyrah.e bi.ac.uk:1111/Proj/Bio/RSDB

MOTIVATION: For large-scale structural assignment to sequences, as in computational structural genomics, a fast yet sensitive sequence search procedure is essential. A new approach using intermediate sequences was tested as a shortcut to iterative multiple sequence search methods such as PSI-BLAST. RESULTS: A library containing potential intermediate sequences for proteins of known structure (PDB-ISL) was constructed. The sequences in the library were collected from a large sequence database using the sequences of the domains of proteins of known structure as the query sequences and the program PSI-BLAST. Sequences of proteins of unknown structure can be matched to distantly related proteins of known structure by using pairwise sequence comparison methods to find homologues in PDB-ISL. Searches of PDB-ISL were calibrated, and the number of correct matches found at a given error rate was the same as that found by PSI-BLAST. The advantage of this library is that it uses pairwise sequence comparison methods, such as FASTA or BLAST2, and can, therefore, be searched easily and, in many cases, much more quickly than an iterative multiple sequence comparison method. The procedure is roughly 20 times faster than PSI-BLAST for small genomes and several hundred times for large genomes. AVAILABILITY: Sequences can be submitted to the PDB-ISL servers at http://stash.mrc-lmb.cam.ac.uk/PDB_ISL/ or http://cyrah.ebi.ac.uk:1111/Serv/PDB_ISL/ and can be downloaded from ftp://ftp.ebi.ac.uk/pub/contrib/jong/PDB_+ ++ISL/ CONTACT: [email protected] and [email protected]

MOTIVATION: Large-scale determination of relationships between the proteins produced by genome sequences is now common. All protein sequences are matched and those that have high match scores are clustered into families. In cases where the proteins are built of several domains or duplication modules, this can lead to misleading results. Consider the very simple example of three proteins: 1, formed by duplication modules A and B; 2, formed by duplication modules B' and C; and 3, formed by duplication modules C' and D. Duplication modules B and B' are homologous, as are C and C'. Matching the sequences of 1, 2 and 3 followed by simple single-linkage clustering would put all three in the same family, even though proteins 1 and 3 are not related. This is because the different parts of 2 match 1 and 3. This paper describes a procedure, DIVCLUS, that divides such complex clusters of partially related sequences into simple clusters that contain only related duplication modules. In the example just given, it would produce two groups of sequences: the first with domains B of sequence 1 and B of sequence 2, and the second with domain C of sequence 2 and C of sequence 3. DIVCLUS is part of a package called GEANFAMMER, for GEnome ANalysis and protein FAMily MakER. The package automates the detection of families of duplication modules from a protein sequence database. RESULTS: DIVCLUS has been applied to the division of single-linkage clusters generated from the protein sequences of six completely sequenced bacterial genomes. Out of 12 013 genes in these six genomes, 4563 single- and multi-domain sequences formed 1071 complex clusters. Application of the DIVCLUS program resolved these clusters into 2113 clusters corresponding to single duplication modules. AVAILABILITY: The perl5 program and its documentation are available at the following address: http://www.mrc-lmb.cam.ac.uk/genomes/ and by anonymous ftp at ftp.mrc-lmb.cam.ac.uk in the directory /pub/genomes/Software/. CONTACT: [email protected]; jong@mrc-lmb. cam.ac.uk