Biology subjects

DeLuca, M.

Publications and source records attributed to DeLuca, M..

4 recordsLinked to original sources

bioRxiv2025

TARRAGON: Therapeutic Target Applicability Ranking and Retrieval-Augmented Generation Over Networks

The identification of therapeutic protein targets is fundamental to the success of drug development and repurposing. Traditional approaches for target selection require extensive preclinical evaluation for toxicity and efficacy, making the process time-intensive and resource-heavy. Computational tools that efficiently prioritize and validate novel targets are needed to streamline drug discovery workflows. To address this gap, we developed TARRAGON: Therapeutic Target Applicability Ranking and Retrieval-Augmented Generation Over Networks, a computational framework that integrates data mining and machine learning to identify, rank, and assess target-disease relationships to nominate new therapeutic targets. TARRAGON mines knowledge graphs to uncover meta-paths, or rules of graph traversal, linking potential therapeutic targets to diseases. It employs a classification model to rank target-disease hypotheses based on evidence patterns and utilizes a retrieval-augmented generation workflow to prompt a large language model for generating feasibility reports on prioritized targets. Using TARRAGON, we prioritized potential drug targets for non-muscle invasive urinary bladder cancer. Top-ranked candidates were validated using CRISPR gene effect and expression data from the Broad Institute DepMap portal. We further proposed chemical modulators for these targets to inform combination drug screening alongside approved bladder cancer therapeutics. TARRAGON introduces a novel, interpretable computational pipeline for therapeutic target discovery and pharmaceutical candidate nomination, offering the potential to accelerate drug development across diverse disease areas.

bioinformatics↗

bioRxiv2024

Piggybacking functionalized DNA nanostructures into live cell nuclei

DNA origami (DO) are promising tools for in vitro or in vivo applications including drug delivery; biosensing, detecting biomolecules; and probing chromatin sub-structures. Targeting these nanodevices to mammalian cell nuclei could provide impactful approaches for probing visualizing and controlling important biological processes in live cells. Here we present an approach to deliver DO strucures into live cell nuclei. We show that labelled DOs do not undergo detectable structural degradation in cell culture media or human cell extracts for 24 hr. To deliver DO platforms into the nuclei of human U2OS cells, we conjugated 30 nm long DO nanorods with an antibody raised against the largest subunit of RNA Polymerase II (Pol II), a key enzyme involved in gene transcription. We find that DOs remain structurally intact in cells for 24hr, including within the nucleus. Using fluorescence microscopy we demonstrate that the electroporated anti-Pol II antibody conjugated DOs are efficiently piggybacked into nuclei and exihibit sub-diffusive motion inside the nucleus. Our results reveal that functionalizing DOs with an antibody raised against a nuclear factor is a highly effective method for the delivery of nanodevices into live cell nuclei.

bioengineering↗

bioRxiv2023

Mechanism of DNA origami folding elucidated by mesoscopic simulations

DNA nanotechnology leverages the canonical base-pairing rules and geometry of DNA to create highly precise nanoscale structures with many potential applications. While the design and fabrication of DNA nanostructures is well-established, the self-assembly process that produces these structures is still poorly understood, especially for DNA origami that involve the assembly of hundreds of strands. Many experimental and computational efforts have sought to better understand DNA origami folding, but the small length and time scales of individual binding events and the long timescale over which folding occurs have posed significant challenges. Here, we present a new mesoscopic model that uses a switchable force field to capture the mechanical behavior of single- and double-stranded DNA motifs and transition between them at a coarseness level of up to 8 nucleotides per particle, allowing access to the long assembly timescales of DNA origami up to several kilobases in size. Brownian dynamics simulations of 4-helix bundle (4HB) structures using this model reveal a hierarchical folding process involving the zipping of structural domains into a partially folded precursor structure followed by gradual crystallization into the final structure. We elucidate the role of hybridization strength, scaffold routing, and staple design in the folding order and kinetics. Simulation of larger 32HB structures reveals heterogeneous staple incorporation kinetics and frequent trapping in metastable states, as opposed to smaller, more accessible structures like the 4HB, which exhibit first-order kinetics and virtually defect-free folding. The development of this model opens an avenue to better understand and design DNA nanostructures for improved yield and folding performance.

biophysics↗

bioRxiv2022

Thermally Reversible Pattern Formation in Arrays of Molecular Rotors

Control over the mesoscale to microscale patterning of materials is of great interest to the soft matter community. Inspired by DNA origami rotors, we introduce a 2D nearest-neighbor lattice of spinning rotors that exhibit discrete orientational states and interactions with their neighbors. Monte Carlo simulations of rotor lattices reveal that they exhibit a variety of interesting ordering behaviors and morphologies that can be modulated through rotor design parameters. The rotor arrays exhibit diverse patterns including closed loops, radiating loops, and bricklayer structures in their ordered states. They exhibit specific heat peaks at very low temperatures for small system sizes, and some systems exhibit multiple order-disorder transitions depending on inter-rotor interaction design. We devise an energy-based order parameter and show via umbrella sampling and histogram reweighting that this order parameter captures well the order-disorder transitions occurring in these systems. We fabricate real DNA origami rotors which themselves can order via programmable DNA base-pairing interactions and demonstrate both ordered and disordered phases, illustrating how rotor lattices may be realized experimentally and used for responsive organization. This work establishes the feasibility of realizing structural nanomaterials that exhibit locally mediated microscale patterns which could have applications in sensing and precision surface patterning.

biophysics↗