Biology subjects

Farley, D.

Publications and source records attributed to Farley, D..

2 recordsLinked to original sources

bioRxiv2026

Environmentally Relevant Polylactic Acid Microplastics from 3D Printing Induce Germline Apoptosis and Reproductive Decline in Caenorhabditis elegans

Bio-based plastics, such as polylactic acid, offer an alternative to petroleum-based plastics and a prospect to address the plastic pollution problem. While mounting evidence suggests that microplastics pose a human health threat, the risk posed by bio-based plastics remains unknown. Here, we use Caenorhabditis elegans to investigate the effects of secondary microplastics from 3D-printed polylactic acid on fertility and lifespan. We have created and characterized microplastics from a 3D-printed item using cryogenic milling. Using these microplastics, we exposed C. elegans and assessed lifespan, reproduction, and various stress responses. Our studies demonstrate that exposure to 1 {micro}g/L polylactic acid microplastics reduces fertility and alters the gonad structure. When examining germline integrity, we find chromosomal disorganization in the gonad after polylactic acid microplastic exposure and increased apoptotic cell death, which correlates with a DAF-16/FOXO and gst-4 oxidative stress responses. While lifespan has been observed to decrease with exposure to microplastics of different polymer types, we did not observe a change in lifespan with exposure to polylactic acid microplastics. The germline is likely more sensitive than somatic tissues under our exposure conditions. The reduction in fertility is driven by alterations to the germline, characterized by chromosome aberrations, oxidative stress, and cell death.

pharmacology and toxicology↗

bioRxiv2019

In-Depth Characterization and Validation in BRG1-Mutant Lung Cancers Define Novel Catalytic Inhibitors of SWI/SNF Chromatin Remodeling

Members of the ATP-dependent SWI/SNF chromatin remodeling complexes are among the most frequently mutated genes in cancer, suggesting their dysregulation plays a critical role. The synthetic lethality between SWI/SNF catalytic subunits BRM/SMARCA2 and BRG1/SMARCA4 has instigated great interest in targeting BRM. Here we have performed a critical and in-depth investigation of novel dual inhibitors (BRM011 and BRM014) of BRM and BRG1 in order to validate their utility as chemical probes of SWI/SNF catalytic function, while obtaining insights into the therapeutic potential of SWI/SNF inhibition. In corroboration of on-target activity, we discovered compound resistant mutations through pooled screening of BRM variants in BRG1-mut cancer cells. Strikingly, genome-wide transcriptional and chromatin profiling (ATAC-Seq) provided further evidence of pharmacological perturbation of SWI/SNF chromatin remodeling as BRM011 treatment induced specific changes in chromatin accessibility and gene expression similar to genetic depletion of BRM. Finally, these compounds have the capacity to inhibit the growth of tumor-xenografts, yielding important insights into the feasibility of developing BRM/BRG1 ATPase inhibitors for the treatment of BRG1-mut lung cancers. Overall, our studies not only establish the feasibility of inhibiting SWI/SNF catalytic function, providing a framework for SWI/SNF therapeutic targeting, but have also yielded successful elucidation of small-molecule inhibitors that will be of importance in probing SWI/SNF function in various disease contexts.

cancer biology↗