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Lubbock, A. L. R.

Publications and source records attributed to Lubbock, A. L. R..

2 recordsLinked to original sources

Visualization and analysis of high-throughput in vitro dose-response datasets with Thunor

High-throughput cell proliferation assays to quantify drug-response are becoming increasingly common and powerful with the emergence of improved automation and multi-time point analysis methods. However, pipelines for analysis of these datasets that provide reproducible, efficient, and interactive visualization and interpretation are sorely lacking. To address this need, we introduce Thunor, an open-source software platform to manage, analyze, and visualize large, dose-dependent cell proliferation datasets. Thunor supports both end-point and time-based proliferation assays as input. It provides a simple, user-friendly interface with interactive plots and publication-quality images of cell proliferation time courses, dose-response curves, and derived dose-response metrics, e.g. IC50, including across datasets or grouped by tags. Tags are categorical labels for cell lines and drugs, used for aggregation, visualization, and statistical analysis, e.g. cell line mutation or drug class/target pathway. A graphical plate map tool is included to facilitate plate annotation with cell lines, drugs, and concentrations upon data upload. Datasets can be shared with other users via point-and-click access control. We demonstrate the utility of Thunor to examine and gain insight from two large drug response datasets: a large, publicly available cell viability database and an in-house, high-throughput proliferation rate dataset. Thunor is available from www.thunor.net.

pharmacology and toxicology

Functionally Coherent Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling and Oncogenic Notch

BackgroundCell identity is governed by gene expression, regulated by Transcription Factor (TF) binding at cis-regulatory modules. Decoding the relationship TF binding patterns and the regulation of cognate target genes is nontrivial, remaining a fundamental limitation in understanding cell decision-making mechanisms. Identification of TF physical binding that is biologically neutral is a current challenge. We studied cell identity in the context of Epithelial to Mesenchymal Transition (EMT), a cell programme fundamental for normal embryonic development that contributes to tumour progression and fibrosis.\n\nResultsWe developed the NetNC software for discovery of functionally coherent TF targets. NetNC was applied to analyse gene regulation by the EMT TFs Snail, Twist in early embryogenesis and also to modENCODE HOT regions. Predicted neutral binding accounted for 50% to [≥]80% of candidate target genes assigned from significant binding peaks. Novel gene functions and network modules were identified, including regulation of chromatin organisation and crosstalk with notch signalling. Orthologues of predicted TF targets discriminated breast cancer molecular subtypes and NetNC analysis predicted new gene functions; for example, evidencing networks that reshape Waddingtons landscape during EMT-like phenotype switching. Predicted invasion roles for SNX29, ATG3, UNK and IRX4 were validated using a tractable cell model.\n\nConclusionsWe found extensive neutral TF binding across the nine datasets examined and showed that NetNC performs well in identifying functionally coherent targets. HOT regions had comparatively high functional coherence. Our results illuminate conserved molecular networks that regulate epithelial remodelling in development and disease, with potential implications for precision medicine.

systems biology