Biology subjects

Trout, A.

Publications and source records attributed to Trout, A..

2 recordsLinked to original sources

bioRxiv2025

Macrophages drive a fibrogenic gene program of periductal fibroblasts in pediatric primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is an autoimmune, cholestatic liver disease characterized by inflammation and fibrosis surrounding bile ducts. The cellular crosstalk driving periductal fibrosis remains poorly defined. This study applied a multi-omics approach integrating MERSCOPE spatial transcriptomics, bulk RNA-seq, and SomaScan proteomics to characterize fibrotic periductal regions and their cell-cell communications. Macrophages (MP) expressing moderate-to-high CD163 were found co-localized with cholangiocytes, T cells, and collagen-producing hepatic stellate cells (HSC). Cell niche analysis identified periductal regions with elevated fibrotic signals, in which cell-cell communication analysis revealed MP-HSC interactions involving 17 fibrotic driver genes in MP (e.g., IFNGR1, CSF1R, CD163) and six fibrotic effector genes in HSC (e.g., COL1A2, VCAN, MMP2). In validation analyses, bulk RNA-seq data showed higher driver and effector gene scores in PSC with established fibrosis compared to early-stage PSC and autoimmune hepatitis (AIH). Plasma proteins encoded by MP driver genes were elevated in autoimmune liver disease (AILD) and in patients with elevated ([≥]3.29 kPa) liver stiffness on MR elastography. These findings suggest that macrophages engage in localized crosstalk with HSC, activating fibrotic gene programs and contributing to periductal fibrosis in PSC, thereby identifying potential molecular targets for therapeutic intervention.

immunology↗

bioRxiv2017

Natural selection can favor the evolution of ratchet robustness over evolution of mutational robustness

The vast majority of fitness-affecting mutations are deleterious. How natural populations evolve to cope is a question of fundamental interest. Previous studies have reported the evolution of mutational robustness, that is, natural selection favoring populations with less deleterious mutations. By definition, mutational robustness provides a short-term fitness advantage. However, this overlooks the fact that mutational robustness decreases finite asexual populations ability to purge recurrent deleterious mutations. Thus, mutational robustness also results in higher risk of long-term extinction by Mullers ratchet. Here, we explore the tension between short- and long- term response to deleterious mutations. We first show that populations can resist the ratchet if either the selection coefficient or the ratio of beneficial to deleterious mutations increases as fitness declines. We designate these properties as ratchet robustness, which fundamentally reflects a negative feedback between mutation rate and the tendency to accumulate more mutations. We also find in simulations that populations can evolve ratchet robustness when challenged by deleterious mutations. We conclude that mutational robustness cannot be selected for in the long term, but it can be favored in the short-term, purely because of temporary fitness advantage. We also discuss other potential causes of mutational robustness in nature.

evolutionary biology↗