Biology subjects

Iredale, J. P.

Publications and source records attributed to Iredale, J. P..

3 recordsLinked to original sources

bioRxiv2019

qPaLM: quantifying occult microarchitectural relationships in histopathological landscapes

Optimal tissue imaging methods should be easy to apply, not require use-specific algorithmic training, and should leverage feature relationships central to subjective gold-standard assessment. We reinterpret histological images as landscapes to describe quantitative pathological landscape metrics (qPaLM), a generalisable framework defining topographic relationships in tissue using geoscience approaches. qPaLM requires no user-dependent training to operate on all image datasets in a classifier-agnostic manner to quantify occult abnormalities, derive mechanistic insights, and define a new feature class for machine-learning diagnostic classification.

pathology↗

bioRxiv2019

Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics

Currently there are no effective antifibrotic therapies for liver cirrhosis, a major killer worldwide. To obtain a cellular resolution of directly-relevant pathogenesis and to inform therapeutic design, we profile the transcriptomes of over 100,000 primary human single cells, yielding molecular definitions for the major non-parenchymal cell types present in healthy and cirrhotic human liver. We uncover a novel scar-associated TREM2+CD9+ macrophage subpopulation with a fibrogenic phenotype, that has a distinct differentiation trajectory from circulating monocytes. In the endothelial compartment, we show that newly-defined ACKR1+ and PLVAP+ endothelial cells expand in cirrhosis and are topographically located in the fibrotic septae. Multi-lineage ligand-receptor modelling of specific interactions between the novel scar-associated macrophages, endothelial cells and collagen-producing myofibroblasts in the fibrotic niche, reveals intra-scar activity of several major pathways which promote hepatic fibrosis. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides the conceptual framework required to discover rational therapeutic targets in liver cirrhosis.

immunology↗

bioRxiv2017

Detecting Drug-Target Binding In Cells Using Fluorescence Activated Cell Sorting Coupled With Mass Spectrometry Analysis

The assessment of drug-target engagement for determining the efficacy of a compound inside cells remains challenging, particularly for difficult target proteins. Existing techniques are more suited to soluble protein targets. Difficult target proteins include those with challenging in vitro solubility, stability or purification properties that preclude target isolation. Here, we report a novel technique that measures intracellular compound-target complex formation, as well as cellular permeability, specificity and cytotoxicity - the Toxicity-Affinity-Permeability-Selectivity (TAPS) technique. The TAPS assay is exemplified here using human kynurenine 3-monooxygenase (KMO), a challenging intracellular membrane protein target of significant current interest. TAPS confirmed target binding of known KMO inhibitors inside cells. We conclude that the TAPS assay can be used to facilitate intracellular hit validation on most, if not all intracellular drug targets.

pharmacology and toxicology↗