A network-based transcriptomic landscape of HepG2 cells uncovering causal gene-cytotoxicity interactions underlying drug-induced liver injury

Drug-induced liver injury (DILI) remains the main reason for drug development attritions largely due to poor mechanistic understanding. Toxicogenomic to interrogate the mechanism of DILI has been broadly performed. Gene co-regulation network-based transcriptome analysis is a bioinformatics approach that potentially contributes to improve mechanistic interpretation of toxicogenomic data. Here we performed an extensive concentration time course response-toxicogenomic study in the HepG2 cell line exposed to 20 DILI compounds, 7 reference compounds for stress response pathways, and 10 agonists for cytokines and growth factor receptors. We performed whole transcriptome targeted RNA sequencing to more than 500 conditions to and applied weighted gene co-regulated network analysis (WGCNA) to the transcriptomics data followed by identification of gene co-regulated networks (modules) that were strongly modulated upon the exposure of DILI compounds. Preservation analysis on the module responses of HepG2 and PHH demonstrated highly preserved adaptive stress response gene co-regulated networks. We correlated gene co-regulated networks with cell death onset and causal relationships of 67 critical target genes of these modules with onset of cell death was evaluated using RNA interference screening. We identified GTPBP2, HSPA1B, IRF1, SIRT1 and TSC22D3 as essential modulators of DILI compound-induced cell death. These genes were also induced by DILI compounds in PHH. Altogether, we demonstrate the application of large transcriptome datasets combined with network-based analysis and biological validation to uncover the candidate determinants of DILI.Toxicolog

Novel similarity measures for differential invariant descriptors for generic object retrieval

Local feature matching is an essential component of many image and object retrieval algorithms. Euclidean and Mahalanobis distances are mostly used in order to quantify the similarity of two stipulated feature vectors. The Euclidean distance is inappropriate in the typical case where the components of the feature vector are incommensurable entities, and indeed yields unsatisfactory results in practice. The Mahalanobis distance performs better, but is less generic in the sense that it requires specific training data. In this paper we consider two alternative ways to construct generic distance measures for image and object retrieval, which do not suffer from any of these shortcomings. The first approach aims at obtaining a (image independent) covariance matrix for a Mahalonobis-like distance function without explicit training, and is applicable to feature vectors consisting of partial image derivatives. In the second approach a stability based similarity measure (SBSM) is introduced for feature vectors that are composed of arbitrary algebraic combinations of image derivatives, and likewise requires no explicit training. The strength and novelty of SBSM lies in the fact that the associated covariance matrix exploits local image structure. A performance analysis shows that feature matching based on SBSM outperforms algorithms based on Euclidean and Mahalanobis distance