Biology subjects

Turbyville, T.

Publications and source records attributed to Turbyville, T..

3 recordsLinked to original sources

bioRxiv2022

Single Particle Tracking With Compressive Sensing Using Progressive Refinement Method On Sparse Recovery (spt-PRIS)

Single particle tracking (SPT) is an indispensable tool for scientific studies. However, SPT for datasets with a high density of particles is still challenging, especially for the study of particle interactions where the point spread functions (PSFs) are overlapping. In this study, we present spt-PRIS, a new SPT solution where we apply compressive sensing to SPT by integrating the progressive refinement method on sparse recovery (PRIS) into the framework of the state-of-the-art SPT algorithm (uTrack). We systematically characterized and validated spt-PRIS performance using simulations, applied it to the experimental data of membrane-bound KRAS4b proteins in either 2-lipid or 8-lipid membrane supported lipid bilayers (SLB), and compared the results to the conventional method (uTrack). Our results show that spt-PRIS is effective for SPT when the data contains overlapping PSFs and provides unprecedented information about KRAS4b subpopulations. spt-PRIS is helpful for a broad range of scientific studies where precise and fast high-density localization is beneficial. spt-PRIS is also flexible for extensions for multi-species, multi-multi-channel, and multi-dimensional SPT methods with the generalization of PRIS reconstruction schemes.

biophysics↗

bioRxiv2021

Discovery of small molecule pathway regulators by image profile matching

Identifying chemical regulators of biological pathways is a time-consuming bottleneck in developing therapeutics and research compounds. Typically, thousands to millions of candidate small molecules are tested in target-based biochemical screens or phenotypic cell-based screens, both expensive experiments customized to each disease. Here, our uncustomized, virtual profile-based screening approach instead identifies compounds that match to pathways based on phenotypic information in public cell image data, created using the Cell Painting assay. Our straightforward correlation-based computational strategy retrospectively uncovered the expected, known small molecule regulators for 32% of positive-control gene queries. In prospective, discovery mode, we efficiently identified new compounds related to three query genes, and validated them in subsequent gene-relevant assays, including compounds that phenocopy or pheno-oppose YAP1 overexpression and kill a Yap1-dependent sarcoma cell line. This image profile-based approach could replace many customized labor- and resource-intensive screens and accelerate the discovery of biologically and therapeutically useful compounds. One sentence summaryIf a genetic perturbation impacts cell morphology, a computational query can reveal compounds whose morphology "matches".

bioinformatics↗

bioRxiv2019

RAS Internal Tandem Duplication Disrupts GAP-binding to Activate Oncogenic Signaling

Molecular testing of oncogenic RAS mutations in colorectal cancer (CRC) have led to increased identification of mutations in patients with CRC. NRAS-mutated CRC has not been well characterized because it is less common (<6%) than KRAS mutations. Here, we report a novel 10 amino acid internal tandem duplication (ITD) in NRAS, which disrupts the switch II domain, in a patient with widely disseminated CRC. Hotspot next generation sequencing of a brain metastasis identified the NRAS ITD and a TP53 missense mutation (p.P275F). Whole exome sequencing of the primary tumor and two metastatic lesions (lung and brain) confirmed that the NRAS ITD and TP53 mutation were conserved between the primary tumor and both metastatic tumors, and identified an additional pathogenic mutation in CSMD1 (a tumor suppressor gene). Structural biology and biochemical analyses demonstrated that the NRAS ITD prevented binding to GAP protein, leading to sustained RAS activation, increased interaction with RAF, and downstream MAPK activation. Additionally, we provide the first crystal structure of the RAS ITD. In conclusion, these studies indicate that the NRAS ITD was the probable primary driver mutation of this aggressive CRC. Identical or biologically similar ITDs in NRAS and KRAS may be rare drivers of CRC and other aggressive malignancies.

molecular biology↗