The co-transcriptome of uropathogenic Escherichia coli-infected mouse macrophages reveals new insights into host-pathogen interactions

© 2014 The Authors. Cellular Microbiology published by John Wiley & Sons Ltd. Urinary tract infections (UTI) are among the most common infections in humans. Uropathogenic Escherichia coli (UPEC) can invade and replicate within bladder epithelial cells, and some UPEC strains can also survive within macrophages. To understand the UPEC transcriptional programme associated with intramacrophage survival, we performed host-pathogen co-transcriptome analyses using RNA sequencing. Mouse bone marrow-derived macrophages (BMMs) were challenged over a 24h time course with two UPEC reference strains that possess contrasting intramacrophage phenotypes: UTI89, which survives in BMMs, and 83972, which is killed by BMMs. Neither of these strains caused significant BMM cell death at the low multiplicity of infection that was used in this study. We developed an effective computational framework that simultaneously separated, annotated and quantified the mammalian and bacterial transcriptomes. Bone marrow-derived macrophages responded to the two UPEC strains with a broadly similar gene expression programme. In contrast, the transcriptional responses of the UPEC strains diverged markedly from each other. We identified UTI89 genes up-regulated at 24h post-infection, and hypothesized that some may contribute to intramacrophage survival. Indeed, we showed that deletion of one such gene (pspA) significantly reduced UTI89 survival within BMMs. Our study provides a technological framework for simultaneously capturing global changes at the transcriptional level in co-cultures, and has generated new insights into the mechanisms that UPEC use to persist within the intramacrophage environment

Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network

Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism

A computational framework for complex disease stratification from multiple large-scale datasets.

BACKGROUND: Multilevel data integration is becoming a major area of research in systems biology. Within this area, multi-'omics datasets on complex diseases are becoming more readily available and there is a need to set standards and good practices for integrated analysis of biological, clinical and environmental data. We present a framework to plan and generate single and multi-'omics signatures of disease states. METHODS: The framework is divided into four major steps: dataset subsetting, feature filtering, 'omics-based clustering and biomarker identification. RESULTS: We illustrate the usefulness of this framework by identifying potential patient clusters based on integrated multi-'omics signatures in a publicly available ovarian cystadenocarcinoma dataset. The analysis generated a higher number of stable and clinically relevant clusters than previously reported, and enabled the generation of predictive models of patient outcomes. CONCLUSIONS: This framework will help health researchers plan and perform multi-'omics big data analyses to generate hypotheses and make sense of their rich, diverse and ever growing datasets, to enable implementation of translational P4 medicine

Machine learning meets complex networks via coalescent embedding in the hyperbolic space

Complex network topologies and hyperbolic geometry seem specularly connected, and one of the most fascinating and challenging problems of recent complex network theory is to map a given network to its hyperbolic space. The Popularity Similarity Optimization (PSO) model represents - at the moment - the climax of this theory. It suggests that the trade-off between node popularity and similarity is a mechanism to explain how complex network topologies emerge - as discrete samples - from the continuous world of hyperbolic geometry. The hyperbolic space seems appropriate to represent real complex networks. In fact, it preserves many of their fundamental topological properties, and can be exploited for real applications such as, among others, link prediction and community detection. Here, we observe for the first time that a topological-based machine learning class of algorithms - for nonlinear unsupervised dimensionality reduction - can directly approximate the network's node angular coordinates of the hyperbolic model into a two-dimensional space, according to a similar topological organization that we named angular coalescence. On the basis of this phenomenon, we propose a new class of algorithms that offers fast and accurate coalescent embedding of networks in the hyperbolic space even for graphs with thousands of nodes

Newton’s Gravitational Law for Link Prediction in Social Networks

Link prediction is an important research area in network science due to a wide range of real-world application. There are a number of link prediction methods. In the area of social networks, these methods are mostly inspired by social theory, such as having more mutual friends between two people in a social network platform entails higher probability of those two people becoming friends in the future. In this paper we take our inspiration from a different area, which is Newton’s law of universal gravitation. Although this law deals with physical bodies, based on our intuition and empirical results we found that this could also work in networks, and especially in social networks. In order to apply this law, we had to endow nodes with the notion of mass and distance. While node importance could be considered as mass, the shortest path, path count, or inverse similarity (AdamicAdar, Katz score etc.) could be considered as distance. In our analysis, we have primarily used degree centrality to denote the mass of the nodes, while the lengths of shortest paths between them have been used as distances. In this study we compare the proposed link prediction approach to 7 other methods on 4 datasets from various domains. To this end, we use the ROC curves and the AUC measure to compare the methods. As the results show that our approach outperforms the other 7 methods on 2 out of the 4 datasets, we also discuss the potential reasons of the observed behaviour