Deciphering the specificity of T-cell receptor (TCR) repertoires is crucial for monitoring adaptive immune responses and developing targeted immunotherapies and vaccines. To elucidate the specificity of previously unseen TCRs, many methods employ the BLOSUM62 matrix to find TCRs with similar amino acid (AA) sequences. However, while BLOSUM62 reflects the AA substitutions within conserved regions of proteins with similar functions, the remarkable diversity of TCRs means that both TCRs with similar and dissimilar sequences can bind the same epitope. Therefore, reliance on BLOSUM62 may bias detection towards epitope-specific TCRs with similar biochemical properties, overlooking those with more diverse AA compositions. In this study, we introduce tcrBLOSUMa and tcrBLOSUMb, specialized AA substitution matrices for CDR3 alpha and CDR3 beta TCR chains, respectively. The matrices reflect AA frequencies and variations occurring within TCRs that bind the same epitope, revealing that both CDR3 alpha and CDR3 beta display tolerance to a wide range of AA substitutions and differ noticeably from the standard BLOSUM62. By accurately aligning distant TCRs employing tcrBLOSUMb, we were able to improve clustering performance and capture a large number of epitope-specific TCRs with diverse AA compositions and physicochemical profiles overlooked by BLOSUM62. Utilizing both the general BLOSUM62 and specialized tcrBLOSUM matrices in existing computational tools will broaden the range of TCRs that can be associated with their cognate epitopes, thereby enhancing TCR repertoire analysis.

The prediction of epitope recognition by T-cell receptors (TCRs) has seen many advancements in recent years, with several methods now available that can predict recognition for a specific set of epitopes. However, the generic case of evaluating all possible TCR-epitope pairs remains challenging, mainly due to the high diversity of the interacting sequences and the limited amount of currently available training data. In this work, we provide an overview of the current state of this unsolved problem. First, we examine appropriate validation strategies to accurately assess the generalization performance of generic TCR-epitope recognition models when applied to both seen and unseen epitopes. In addition, we present a novel feature representation approach, which we call ImRex (interaction map recognition). This approach is based on the pairwise combination of physicochemical properties of the individual amino acids in the CDR3 and epitope sequences, which provides a convolutional neural network with the combined representation of both sequences. Lastly, we highlight various challenges that are specific to TCR-epitope data and that can adversely affect model performance. These include the issue of selecting negative data, the imbalanced epitope distribution of curated TCR-epitope datasets and the potential exchangeability of TCR alpha and beta chains. Our results indicate that while extrapolation to unseen epitopes remains a difficult challenge, ImRex makes this feasible for a subset of epitopes that are not too dissimilar from the training data. We show that appropriate feature engineering methods and rigorous benchmark standards are required to create and validate TCR-epitope predictive models.

MOTIVATION: The T-cell receptor (TCR) determines the specificity of a T-cell towards an epitope. As of yet, the rules for antigen recognition remain largely undetermined. Current methods for grouping TCRs according to their epitope specificity remain limited in performance and scalability. Multiple methodologies have been developed, but all of them fail to efficiently cluster large datasets exceeding 1 million sequences. To account for this limitation, we developed ClusTCR, a rapid TCR clustering alternative that efficiently scales up to millions of CDR3 amino acid sequences, without knowledge about their antigen specificity. RESULTS: Benchmarking comparisons revealed similar accuracy of ClusTCR as compared to other TCR clustering methods, as measured by cluster retention, purity and consistency. ClusTCR offers a drastic improvement in clustering speed, which allows the clustering of millions of TCR sequences in just a few minutes through ultraefficient similarity searching and sequence hashing. AVAILABILITY AND IMPLEMENTATION: ClusTCR was written in Python 3. It is available as an anaconda package (https://anaconda.org/svalkiers/clustcr) and on github (https://github.com/svalkiers/clusTCR). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Abstract Summary The growing availability of biomolecular networks has led to a need for analysis methods that are able to extract biologically meaningful information from these complex data structures. Here we present MILES (MIning Labeled Enriched Subgraphs), a Java-based subgraph mining tool for discovering motifs that are associated to a given set of nodes of interest, such as a list of genes or proteins, in biomolecular networks. It provides a unique extension to the widely used enrichment analysis methodologies by integrating network structure and functional annotations in order to discern novel biological subgraphs which are enriched in the targets of interest. The tool can handle various types of input data, including (un)directed, (un)connected and multi-label networks, and is thus compatible with most types of biomolecular networks. Availability and implementation MILES is available as a platform-independent Java application at https://github.com/pmoris/miles-subgraph-miner alongside a user manual, example datasets and the source code. Supplementary information Supplementary data are available at Bioinformatics online.

MOTIVATION: The T-cell receptor (TCR) is responsible for recognizing epitopes presented on cell surfaces. Linking TCR sequences to their ability to target specific epitopes is currently an unsolved problem, yet one of great interest. Indeed, it is currently unknown how dissimilar TCR sequences can be before they no longer bind the same epitope. This question is confounded by the fact that there are many ways to define the similarity between two TCR sequences. Here we investigate both issues in the context of TCR sequence unsupervised clustering. RESULTS: We provide an overview of the performance of various distance metrics on two large independent datasets with 412 and 2835 TCR sequences respectively. Our results confirm the presence of structural distinct TCR groups that target identical epitopes. In addition, we put forward several recommendations to perform unsupervised T-cell receptor sequence clustering. AVAILABILITY AND IMPLEMENTATION: Source code implemented in Python 3 available at https://github.com/pmeysman/TCRclusteringPaper. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

In this paper, we present a subgroup discovery method to find subgraphs in a graph that are associated with a given set of vertices. The association between a subgraph pattern and a set of vertices is defined by its significant enrichment based on a Bonferroni-corrected hypergeometric probability value. This interestingness measure requires a dedicated pruning procedure to limit the number of subgraph matches that must be calculated. The presented mining algorithm to find associated subgraph patterns in large graphs is therefore designed to efficiently traverse the search space. We demonstrate the operation of this method by applying it on three biological graph data sets and show that we can find associated subgraphs for a biologically relevant set of vertices and that the found subgraphs themselves are biologically interesting.

Nuclear Magnetic Resonance (NMR) spectroscopy is, together with liquid chromatography-mass spectrometry (LC-MS), the most established platform to perform metabolomics. In contrast to LC-MS however, NMR data is predominantly being processed with commercial software. Meanwhile its data processing remains tedious and dependent on user interventions. As a follow-up to speaq, a previously released workflow for NMR spectral alignment and quantitation, we present speaq 2.0. This completely revised framework to automatically analyze 1D NMR spectra uses wavelets to efficiently summarize the raw spectra with minimal information loss or user interaction. The tool offers a fast and easy workflow that starts with the common approach of peak-picking, followed by grouping, thus avoiding the binning step. This yields a matrix consisting of features, samples and peak values that can be conveniently processed either by using included multivariate statistical functions or by using many other recently developed methods for NMR data analysis. speaq 2.0 facilitates robust and high-throughput metabolomics based on 1D NMR but is also compatible with other NMR frameworks or complementary LC-MS workflows. The methods are benchmarked using a simulated dataset and two publicly available datasets. speaq 2.0 is distributed through the existing speaq R package to provide a complete solution for NMR data processing. The package and the code for the presented case studies are freely available on CRAN (https://cran.r-project.org/package=speaq) and GitHub (https://github.com/beirnaert/speaq).

SUMMARY: We describe sfinx, an R package providing access to the straightforward filtering index (SFINX) for the separation of true positive from false positive protein interactions in affinity purification - mass spectrometry datasets. This package maintains the reliability and user-friendliness of the SFINX web site interface but is faster, unlimited in input size, and can be run locally within R. AVAILABILITY AND IMPLEMENTATION: The sfinx R package is available for download at the comprehensive R archive network (CRAN) https://cran.r-project.org/web/packages/sfinx/ under the Apache License 2.0. CONTACT: [email protected] or [email protected]. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Starting a professional society is not something that should be entered into lightly: it requires work and dedication that can detract from your research projects and other career objectives [15]. It certainly should not be attempted on your own. But there are many potential benefits and rewards in terms of promoting the profile of your discipline (which, in turn, can affect your grant success), boosting your own profile, developing useful management and leadership skills, finding mentors, and forming essential contacts and partnerships, as science is becoming increasingly collaborative. A successful society will be a source of lifelong learning and new ideas, will open up career opportunities for students and investigators, and will provide a much stronger voice for your discipline than an isolated scientist.

Table of contents A1 Highlights from the eleventh ISCB Student Council Symposium 2015 Katie Wilkins, Mehedi Hassan, Margherita Francescatto, Jakob Jespersen, R. Gonzalo Parra, Bart Cuypers, Dan DeBlasio, Alexander Junge, Anupama Jigisha, Farzana Rahman O1 Prioritizing a drug’s targets using both gene expression and structural similarity Griet Laenen, Sander Willems, Lieven Thorrez, Yves Moreau O2 Organism specific protein-RNA recognition: A computational analysis of protein-RNA complex structures from different organisms Nagarajan Raju, Sonia Pankaj Chothani, C. Ramakrishnan, Masakazu Sekijima; M. Michael Gromiha O3 Detection of Heterogeneity in Single Particle Tracking Trajectories Paddy J Slator, Nigel J Burroughs O4 3D-NOME: 3D NucleOme Multiscale Engine for data-driven modeling of three-dimensional genome architecture Przemysław Szałaj, Zhonghui Tang, Paul Michalski, Oskar Luo, Xingwang Li, Yijun Ruan, Dariusz Plewczynski O5 A novel feature selection method to extract multiple adjacent solutions for viral genomic sequences classification Giulia Fiscon, Emanuel Weitschek, Massimo Ciccozzi, Paola Bertolazzi, Giovanni Felici O6 A Systems Biology Compendium for Leishmania donovani Bart Cuypers, Pieter Meysman, Manu Vanaerschot, Maya Berg, Hideo Imamura, Jean-Claude Dujardin, Kris Laukens O7 Unravelling signal coordination from large scale phosphorylation kinetic data Westa Domanova, James R. Krycer, Rima Chaudhuri, Pengyi Yang, Fatemeh Vafaee, Daniel J. Fazakerley, Sean J. Humphrey, David E. James, Zdenka Kuncic

Over the past two decades, pattern mining techniques have become an integral part of many bioinformatics solutions. Frequent itemset mining is a popular group of pattern mining techniques designed to identify elements that frequently co-occur. An archetypical example is the identification of products that often end up together in the same shopping basket in supermarket transactions. A number of algorithms have been developed to address variations of this computationally non-trivial problem. Frequent itemset mining techniques are able to efficiently capture the characteristics of (complex) data and succinctly summarize it. Owing to these and other interesting properties, these techniques have proven their value in biological data analysis. Nevertheless, information about the bioinformatics applications of these techniques remains scattered. In this primer, we introduce frequent itemset mining and their derived association rules for life scientists. We give an overview of various algorithms, and illustrate how they can be used in several real-life bioinformatics application domains. We end with a discussion of the future potential and open challenges for frequent itemset mining in the life sciences.

In this meeting report, we give an overview of the talks, presentations and posters presented at the third European Symposium of the International Society for Computational Biology (ISCB) Student Council. The event was organized as a satellite meeting of the 13th European Conference for Computational Biology (ECCB) and took place in Strasbourg, France on September 6th, 2014.

All cells are subject to ever-changing environments to which they have to adapt, using their sensory system to provide input for the regulatory systems that integrate the information and trigger the eventual effectors. These cascades constitute a very complex cellular wiring that is highly relevant due to its medical importance. The omni-present application of high-throughput analysis techniques has resulted in an unprecedented level of available detail about gene expression and various aspects of cellular proteins, such as abundance, function and localization, often captured in well-curated compendia that are publicly available. Although these information-rich inventories exist, the adaptive nature of protein complexes and signalling cascades remain poorly understood, as the current predominant approaches are not always suited to describe the associations between proteins. For example, binary protein interactions do not necessarily occur in vivo as the proteins could be expressed in different compartments of the cell or at different time points. This severely complicates the analysis of any protein interaction data. It thus remains a challenge to find out how biological entities cooperate to regulate cellular response to stimuli. We used an integrative method, reliant on advanced pattern mining approaches to gain a deeper understanding of protein network dynamics. To this end, we created a compendium consisting of a large amount of proteomics papers for Homo sapiens that report differentially expressed proteins in cell lines. Next, we analysed this collection with frequent itemset mining to identify proteins that are often co-occurring in publications and used these patterns as the backbone structure of our further analysis. These patterns of co-occurring proteins were enriched with additional attributes, such as gene expression correlation, protein localization and functional coherence metrics derived from the Gene Ontology tree [ 1 ] and used as a filter on top of an integrated binary protein interaction network, obtained by fusing several of the most popular resources. We found that several proteins and GO-functions, such as transcriptional regulation, are consistently reported and deemed significant regardless of the research topic. Furthermore, we were able to find associations across the various "omics" levels that are conserved in a wide range of human cancers and managed to identify lists of frequently occuring patterns that can be used to classify between pre- and post-metastasic tumour development. Pattern-based analysis on multiple "omics" levels can be used to identify the cellular logic circuits and holds many promising applications in the biotechnological and biomedical areas.

Abstract Summary: To facilitate the exploration of publicly available Zea mays expression data, we constructed a maize expression compendium, making use of an integration methodology and a consistent probe to gene mapping based on the 5b.60 sequence release of Z. mays. The compendium is made available through a web portal MAGIC that hosts a variety of analysis tools to easily browse and analyze the data. Our compendium is different from previous initiatives in combining expression values across different experiments by providing a consistent gene annotation across different platforms. Availability and implementation: http://bioinformatics.intec.ugent.be/magic/ Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics online.

Contributing to a student organization, such as the International Society for Computational Biology Student Council (ISCB-SC) and its Regional Student Group (RSG) program, takes time and energy. Both are scarce commodities, especially when you are trying to find your place in the world of computational biology as a graduate student. It comes as no surprise that organizing ISCB-SC-related activities sometimes interferes with day-to-day research and shakes up your priority list. However, we unanimously agree that the rewards, both in the short as well as the long term, make the time spent on these extracurricular activities more than worth it. In this article, we will explain what makes this so worthwhile: soft skills.

In this paper we present a cohesive structural itemset miner aiming to discover interesting patterns in a set of data objects within a multidimensional spatial structure by combining the cohesion and the support of the pattern. We propose two ways to build the itemset miner, VertexOne and VertexAll, in an attempt to find a balance between accuracy and run-times. The experiments show that VertexOne performs better, and finds almost the same itemsets as VertexAll in a much shorter time. The usefulness of the method is demonstrated by applying it to find interesting patterns of amino acids in spatial proximity within a set of proteins based on their atomic coordinates in the protein molecular structure. Several patterns found by the cohesive structural itemset miner contain amino acids that frequently co-occur in the spatial structure, even if they are distant in the primary protein sequence and only brought together by protein folding. Further various indications were found that some of the discovered patterns seem to represent common underlying support structures within the proteins.

BACKGROUND: With the availability of large scale expression compendia it is now possible to view own findings in the light of what is already available and retrieve genes with an expression profile similar to a set of genes of interest (i.e., a query or seed set) for a subset of conditions. To that end, a query-based strategy is needed that maximally exploits the coexpression behaviour of the seed genes to guide the biclustering, but that at the same time is robust against the presence of noisy genes in the seed set as seed genes are often assumed, but not guaranteed to be coexpressed in the queried compendium. Therefore, we developed ProBic, a query-based biclustering strategy based on Probabilistic Relational Models (PRMs) that exploits the use of prior distributions to extract the information contained within the seed set. RESULTS: We applied ProBic on a large scale Escherichia coli compendium to extend partially described regulons with potentially novel members. We compared ProBic's performance with previously published query-based biclustering algorithms, namely ISA and QDB, from the perspective of bicluster expression quality, robustness of the outcome against noisy seed sets and biological relevance.This comparison learns that ProBic is able to retrieve biologically relevant, high quality biclusters that retain their seed genes and that it is particularly strong in handling noisy seeds. CONCLUSIONS: ProBic is a query-based biclustering algorithm developed in a flexible framework, designed to detect biologically relevant, high quality biclusters that retain relevant seed genes even in the presence of noise or when dealing with low quality seed sets.