Biology subjects

Yadaw, A. S.

Publications and source records attributed to Yadaw, A. S..

3 recordsLinked to original sources

bioRxiv2025

predicTox: An integrated database of clinical risk frequencies and human gene expression signatures for cardiotoxic drugs

We have used drug-induced transcriptomic responses and whole-genome sequences in healthy human induced pluripotent stem cells (iPSC)-derived cardiomyocyte lines to identify cellular functional pathways and genomic variants potentially associated with the cardiotoxic effects of tyrosine kinase inhibitors (TKIs) and other cancer drugs. Here, we describe predicTox.org, an interactive website that organizes our data and its integration with knowledge from cell pathways and genomic databases. DrugTox summary cards give results of these analyses and metadata for each drug. Fields include FDA Adverse Event Reporting System (FAERS) cardiotoxicity risk scores, cell pathways, and genomic variants potentially associated with drug-induced cardiotoxicity. At a detailed level, predicTox provides ranked lists of pathway signatures that are common for cardiotoxic TKIs, up- and downregulated pathways associated with cardiotoxicity induced by specific TKIs and TKI-regulated genes mapping to those pathways. predicTox provides downloadable lists of drug-induced differentially expressed genes (DEGs) and pathways, drug-related genomic variants associated with cardiotoxicity, all with their statistical metrics, and mathematical models to simulate drug effects on heart physiology. Building on the results of our algorithm for independent reidentification of the well-known rs2229774 variant for anthracycline-induced cardiotoxicity, we describe how our data can be queried to identify potential variants associated with drug-induced cardiotoxicity by affecting a drugs pharmacodynamics and pharmacokinetics.

cancer biology↗

bioRxiv2018

Cannabinoid 1-Receptor regulation of deep and distributed subcellular processes enables neurite outgrowth

Neurite outgrowth is an integrated whole cell process that represents the earliest steps in neuronal differentiation. We studied cannabinoid-1 receptor regulated neurite outgrowth to identify the different subcellular processes (SCPs) involved and how they come together to produce a whole cell response. We identified the genes that were differentially expressed after CB1 receptor stimulation. From the differentially expressed components we identified the SCPs involved and how the SCPs connect to one another both horizontally and vertically. We used these SCP networks to identify genes, which when knocked down would validate the involvement of the SCP in neurite outgrowth. We identified a varied list of SCPs including those involved in pyrimidine metabolism, lipid biosynthesis, mitochondrial transport function, mRNA splicing and stability in addition to those involved in membrane vesicle production, transport and fusion and microtubule dynamics. Overall these data and computational analyses show that the downstream SCPs required for neurite outgrowth are widely distributed and involve a range of normal cellular functions. Additionally, several of these processes can be considered distal in terms of their proximity to cell signaling pathways and the microtubule and membrane vesicle dynamics, the proximal SCPs required for neurite outgrowth. Hence we conclude that receptor regulation of neurite outgrowth is distributed and deep.

cell biology↗

bioRxiv2017

Dynamic balance between vesicle transport and microtubule growth enables neurite growth

Whole cell responses involve multiple subcellular processes (SCPs). To understand how balance between SCPs controls the dynamics of whole cell responses we studied neurite outgrowth in rat primary cortical neurons in culture. We used a combination of dynamical models and experiments to understand the conditions that permitted growth at a specified velocity and when aberrant growth could lead to the formation of dystrophic bulbs. We hypothesized that dystrophic bulb formation is due to quantitative imbalances between SCPs. Simulations predict redundancies between lower level sibling SCPs within each type of high level SCP. In contrast, higher level SCPs, such as vesicle transport and exocytosis or microtubule growth characteristic of each type need to be strictly coordinated with each other and imbalances result in stalling of neurite outgrowth. From these simulations, we predicted the effect of changing the activities of SCPs involved in vesicle exocytosis or microtubule growth could lead to formation of dystrophic bulbs. siRNA ablation experiments verified these predictions. We conclude that whole cell dynamics requires balance between the higher-level SCPs involved and imbalances can terminate whole cell responses such as neurite outgrowth.

systems biology↗