Biology subjects

Hess, P. R.

Publications and source records attributed to Hess, P. R..

3 recordsLinked to original sources

bioRxiv2026

A Manifold-Based Measure of Transcriptional Entropy for Quantifying Aging in Single Cells

Aging reshapes tissues through changes in cellular composition, coordinated transcriptional reprogramming, and loss of transcriptional coordination. Whereas the first two have been characterized across aging tissues, the third remains difficult to quantify. We introduce an unsupervised, first-principles framework for measuring transcriptional dyscoordination in single cells as deviation from a learned, predictable structure accounting for technical noise. Orthogonal validation links transcriptional dyscoordination to classical intrinsic noise and distinguishes it from coordinated change. In controlled perturbations, dyscoordination rises after genotoxic injury and senescence induction, then falls following senolytic depletion. Across mouse, rat, and human tissues, dyscoordination increases with chronological age, especially in regenerative compartments. In human T cells, dyscoordination increases with clonal expansion and effector function yet declines within persisting clones after checkpoint blockade. Cross-modal analyses further link dyscoordination to chromatin-based mitotic age and genome instability. These results identify loss of transcriptional coordination as a distinct and dynamic feature of cellular aging.

genomics↗

bioRxiv2025

Optimizing canine T cell activation, expansion, and transduction

Dogs are becoming an important model for human cancers, and successfully troubleshooting issues with genetically modified T cell immunotherapy for round cell and solid neoplasms in dogs provides a unique opportunity to improve efficacy, safety, and affordability for humans as well. Unfortunately, T cell activation in dogs for optimal viral transduction has not been determined, restricting advancements in canine T cell immunotherapy. Two CD3 and two CD28 antibody clones for canine T cell stimulation have been described in the literature, but no studies have been undertaken to evaluate which CD3/CD28 combination is most effective, nor has anyone directly compared the efficacy of the two most popular antibody presentation strategies: antibody-coated plates and antibody-conjugated beads. In evaluating the effects of plate- or bead-bound CD3 stimulation alone versus CD3/CD28 in combination, we tested 12 possible antibody stimulation strategies in addition to evaluating two largely unexplored mitogens in canine T cell transduction, phorbol myristate acetate (PMA) with ionomycin and concanavalin A (ConA). We investigated the impact of these stimulation strategies on canine T cell activation, expansion, and transduction. For stimulation strategies producing the best results, we also examined how each strategy affected the proportions of CD4/CD8 T cell subsets and regulatory T cell (Treg) prevalence. We determined that, in general, plate-bound antibodies were far superior to bead-bound antibodies for canine T cell stimulation, and that plate-bound CD3 clone CA17.6F9 in combination with CD28 clone 5B8 or the mitogen PMA with ionomycin produced better activation and expansion profiles, better transduction, and more desirable T cell subsets that are more likely to improve patient outcomes in dogs suffering from round cell and solid tumors.

immunology↗

bioRxiv2022

Cancer subclone detection based on DNA copy number in single cell and spatial omic sequencing data

In cancer, somatic mutations such as copy number alterations (CNAs) accumulate during disease progression and lead to functional intra-tumor heterogeneity that can influence the efficacy of cancer therapy. Therefore, studying the functional characteristics and spatial distribution of genetically distinct subclones is crucial to the understanding of tumor evolution and the design of cancer treatment. Here, we present Clonalscope, a method for subclone detection using copy number profiles that can be applied to spatial transcriptomics (ST) data and data from single-cell sequencing platforms such as scRNA-seq and scATAC-seq. Clonalscope implements a nested Chinese restaurant process to identify de novo subclones within one or multiple samples from the same patient. Clonalscope incorporates prior information from paired whole-genome or whole-exome sequencing (WGS/WES) data to achieve more reliable subclone detection and malignant cell labeling. On scRNA-seq and scATAC-seq data from four gastrointestinal tumor samples, Clonalscope successfully labeled malignant cells and identified genetically different subclones, which were validated in detail using matched scDNA-seq data. On ST data from a squamous cell carcinoma and two invasive ductal carcinoma samples, Clonalscope successfully labelled malignant spots, traced subclones between associated datasets, and identified spatially segregated subclones expressing genes associated with drug resistance and survival.

bioinformatics↗