Diverse repertoires of hypervariable immunoglobulin receptors (TCR and BCR) recognize antigens in the adaptive immune system. The development of immunoglobulin receptor repertoire sequencing methods makes it possible to perform repertoire-wide disease association studies of antigen receptor sequences. We developed a statistical framework for associating receptors to disease from only a small cohort of patients, with no need for a control cohort. Our method successfully identifies previously validated Cytomegalovirus and type 1 diabetes responsive TCRβ sequences.
- Dmitriy M Chudakov
- Ilgar Z Mamedov
- Yuri B Lebedev
- Aleksandra M Walczak
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Arup K Chakraborty, Massachusetts Institute of Technology, United States
© 2018, Pogorelyy et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Downloads (link to download the article as PDF)
Download citations (links to download the citations from this article in formats compatible with various reference manager tools)
Open citations (links to open the citations from this article in various online reference manager services)
Our ability to discover effective drug combinations is limited, in part by insufficient understanding of how the transcriptional response of two monotherapies results in that of their combination. We analyzed matched time course RNAseq profiling of cells treated with single drugs and their combinations and found that the transcriptional signature of the synergistic combination was unique relative to that of either constituent monotherapy. The sequential activation of transcription factors in time in the gene regulatory network was implicated. The nature of this transcriptional cascade suggests that drug synergy may ensue when the transcriptional responses elicited by two unrelated individual drugs are correlated. We used these results as the basis of a simple prediction algorithm attaining an AUROC of 0.77 in the prediction of synergistic drug combinations in an independent dataset.
Cells use molecular circuits to interpret and respond to extracellular cues, such as hormones and cytokines, which are often released in a temporally varying fashion. In this study, we combine microfluidics, time-lapse microscopy, and computational modeling to investigate how the type I interferon (IFN)-responsive regulatory network operates in single human cells to process repetitive IFN stimulation. We found that IFN-α pretreatments lead to opposite effects, priming versus desensitization, depending on input durations. These effects are governed by a regulatory network composed of a fast-acting positive feedback loop and a delayed negative feedback loop, mediated by upregulation of ubiquitin-specific peptidase 18 (USP18). We further revealed that USP18 upregulation can only be initiated at the G1/early S phases of cell cycle upon the treatment onset, resulting in heterogeneous and delayed induction kinetics in single cells. This cell cycle gating provides a temporal compartmentalization of feedback loops, enabling duration-dependent desensitization to repetitive stimulations.