Biology subjects

Little, D. R.

Publications and source records attributed to Little, D. R..

4 recordsLinked to original sources

bioRxiv2026

Crop-OCT: a Fully Integrated Imageomics Pipeline to Identify Regional and Focal Retinopathy in Murine Models

Imageomics uses machine learning to accelerate our understanding of biological traits and human disease processes. Some of the earliest imageomics applications used deep learning to assess human diseases. For example, retinal fundus images were analyzed to diagnose diabetic retinopathy. The imaging modality optical coherence tomography (OCT) is widely used to diagnose and monitor the progression of retinopathy in patients and preclinical models. The standardized instrumentation and image format of OCT lends itself to imageomics, but generalizable, automated pipelines for segmentation and quantitation of large numbers of OCT images are still in early development. Here, we present the automated, end-to-end pipeline Crop-OCT that extracts features from thousands of OCT images, while preserving their location within the eye. We used the Crop-OCT pipeline on a diverse dataset, including 13 genetic models of retinopathy, with more than 20,000 OCT images, which allowed us to analyze nearly 6 million measured features. The pipeline was generalized on an independent dataset that was analyzed in a blinded manner. The pipeline enabled us to monitor ocular changes associated with aging and progression of diseases, such as retinitis pigmentosa, Leber congenital amaurosis, achromatopsia, Stargardt disease, diabetic retinopathy, and age-related macular degeneration. We also characterized heterogeneity across animals and identified regional and focal lesions. Our pipeline will unify feature extraction for preclinical models of retinal disease and serve as a foundation for future multimodal data integration for artificial intelligence applications based on imageomics.

neuroscience↗

bioRxiv2023

Measuring the perception and metacognition of time

The ability of humans to identify and reproduce short time intervals (in the region of a second) may be affected by many factors ranging from the gender of the individual observer, through the attentional state, to the precise spatiotemporal structure of the stimulus. The relative roles of these very different factors are a challenge to describe and define; several methodological approaches have been used to achieve this to varying degrees of success. Here we describe a new paradigm affording not only a first-order measurement of the perceived duration of an interval but also a second-order metacognitive judgement of perceived time. This approach, we argue, expands the form of the data generally collected in duration-judgements and allows more detailed comparison of psychophysical behaviour to the underlying theory. We also describe a measurement model which provides estimates of the variability of the temporal estimates and the metacognitive judgments allowing comparison to an ideal observer. We fit the model to data collected for judgements of 750ms (bisecting 1500ms) and 1500ms (bisecting 3000ms) intervals across three stimulus modalities (Visual, Audio & Audiovisual). This enhanced form of data on a given interval judgement and the ability to track its progression on a trial-by-trial basis offers a way of looking at the different roles that subject-based, task-based and stimulus-based factors have on the perception of time.

neuroscience↗

bioRxiv2020

Lung lineage transcription factor NKX2-1 epigenetically resolves opposing cell fates in vivo

Differential use of identical DNA sequences leads to distinct tissue lineages and then multiple cell types within a lineage, an epigenetic process central to progenitor and stem cell biology. The associated genomic changes, especially in native tissues, remain insufficiently understood, and are hereby addressed in the mouse lung, where the same lineage transcription factor NKX2-1 promotes the diametrically opposed alveolar type 1 (AT1) and AT2 cell fates. We show that the cell-type-specific function of NKX2-1 is attributed to its differential chromatin binding that is acquired or retained during development in coordination with partner transcriptional factors. Loss of YAP/TAZ redirects NKX2-1 from its AT1-specific to AT2-specific binding sites, leading to transcriptionally exaggerated AT2 cells when deleted in progenitors or AT1-to-AT2 conversion when deleted after fate commitment. Nkx2-1 mutant AT1 and AT2 cells gain distinct accessible sites including those of the opposite fate while adopting the gastrointestinal fate, suggesting an epigenetic plasticity larger than a transcriptional one. Our genomic analysis of single or purified cells, coupled with precision genetics, provides an epigenetic roadmap of alveolar cell fate and potential, and introduces an experimental benchmark for unraveling the in vivo function of lineage transcription factors.

developmental biology↗

bioRxiv2020

Resolving the spatial and cellular architecture of lung adenocarcinoma by multi-region single-cell sequencing

Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from 5 early-stage LUADs and 14 multi-region normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to LUADs. LUADs also exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs. T regulatory cell phenotypes are increased in normal tissues with proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages and inflammatory dendritic cells. We further find that the LUAD ligand-receptor interactome harbors increased expression of epithelial CD24 which mediates pro-tumor phenotypes. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for its treatment. Statement of significanceThe geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multi-region single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecological evolution of LUAD from the lung that comprise high-potential targets for early interception.

cancer biology↗