Dataset Information

ScreenCube: A 3D Printed System for Rapid and Cost-Effective Chemical Screening in Adult Zebrafish.

ABSTRACT: Phenotype-based small molecule screens in zebrafish embryos and larvae have been successful in accelerating pathway and therapeutic discovery for diverse biological processes. Yet, the application of chemical screens to adult physiologies has been relatively limited due to additional demands on cost, space, and labor associated with screens in adult animals. In this study, we present a 3D printed system and methods for intermittent drug dosing that enable rapid and cost-effective chemical administration in adult zebrafish. Using prefilled screening plates, the system enables dosing of 96 fish in ?3?min, with a 10-fold reduction in drug quantity compared to that used in previous chemical screens in adult zebrafish. We characterize water quality kinetics during immersion in the system and use these kinetics to rationally design intermittent dosing regimens that result in 100% fish survival. As a demonstration of system fidelity, we show the potential to identify two known chemical inhibitors of adult tail fin regeneration, cyclopamine and dorsomorphin. By developing methods for rapid and cost-effective chemical administration in adult zebrafish, this study expands the potential for small molecule discovery in postembryonic models of development, disease, and regeneration.

SUBMITTER: Monstad-Rios AT

PROVIDER: S-EPMC5792243 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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ScreenCube: A 3D Printed System for Rapid and Cost-Effective Chemical Screening in Adult Zebrafish.

Monstad-Rios Adrian T AT Watson Claire J CJ Kwon Ronald Y RY

Zebrafish 20171030 1

Phenotype-based small molecule screens in zebrafish embryos and larvae have been successful in accelerating pathway and therapeutic discovery for diverse biological processes. Yet, the application of chemical screens to adult physiologies has been relatively limited due to additional demands on cost, space, and labor associated with screens in adult animals. In this study, we present a 3D printed system and methods for intermittent drug dosing that enable rapid and cost-effective chemical admini ...[more]

PMID: 29083959

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Project description:Micro-CT imaging can be used as an effective method for non-destructive testing (NDT) of metal 3D printed parts-including titanium biomedical components fabricated using laser powder-bed-fusion (LPBF). Unfortunately, the cost of commercially available micro-CT scanners renders routine NDT for biomedical applications prohibitively expensive. This study describes the design, manufacturing, and implementation of a cost-effective scanner tailored for NDT of medium-size titanium 3D printed biomedical components. The main elements of the scanner; which include a low-energy (80 kVp) portable x-ray unit, and a low-cost lens-coupled detector; can be acquired with a budget less than $ 11000 USD. The low-cost detector system uses a rare-earth phosphor screen, lens-coupled to a dSLR camera (Nikon D800) in a front-lit tilted configuration. This strategy takes advantage of the improved light-sensitivity of modern full-frame CMOS camera sensors and minimizes source-to-detector distance to maximize x-ray flux. The imaging performance of the system is characterized using a comprehensive CT quality-assurance phantom, and two titanium 3D-printed test specimens. Results show that the cost-effective scanner can survey the porosity and cracks in titanium parts with thicknesses of up to 13 mm of solid metal. Quantitatively, the scanner produced geometrically stable reconstructions, with a voxel size of 118 μm, and noise levels under 55 HU. The cost-effective scanner was able to estimate the porosity of a 17 mm diameter titanium 3D-printed cylindrical lattice structure, with a 0.3% relative error. The proposed scanner will facilitate the implementation of titanium LPBF-printed components for biomedical applications by incorporating routine cost-effective NDT as part of the process control and validation steps of medical-device quality-management systems. By reducing the cost of the x-ray detector and shielding, the scan cost will be commensurate with the overall cost of the validated component.

Project description:BackgroundDespite continued efforts using chemical similarity methods in virtual screening, currently developed approaches suffer from time-consuming multistep procedures and low success rates. We recently developed a machine learning-based chemical binding similarity model considering common structural features from molecules binding to the same, or evolutionarily related targets. The chemical binding similarity measures the resemblance of chemical compounds in terms of binding site similarity to better describe functional similarities that arise from target binding. In this study, we have shown how the chemical binding similarity could be used in virtual screening together with the conventional structure-based methods.ResultsThe chemical binding similarity, receptor-based pharmacophore, chemical structure similarity, and molecular docking methods were evaluated to identify an effective virtual screening procedure for desired target proteins. When we tested the chemical binding similarity method with test sets of 51 kinases, it outperformed the traditional structural similarity-based methods as well as structure-based methods, such as molecular docking and receptor-based pharmacophore modeling, in terms of finding active compounds. We further validated the results by performing virtual screening (using the chemical binding similarity and receptor-based pharmacophore methods) against a completely blind dataset for mitogen-activated protein kinase kinase 1 (MEK1), ephrin type-B receptor 4 (EPHB4) and wee1-like protein kinase (WEE1). The in vitro kinase binding assay confirmed that 6 out of 13 (46.2%) for MEK1 and 2 out of 12 (16.7%) for EPHB4 were newly identified only by the chemical binding similarity model.ConclusionsWe report that the virtual screening results could further be improved by combining the chemical binding similarity model with 3D-QSAR pharmacophore and molecular docking models. Not only the new inhibitors are identified in this study, but also many of the identified molecules have low structural similarity scores against already reported inhibitors and that show the revelation of novel scaffolds.

Dataset Information

ScreenCube: A 3D Printed System for Rapid and Cost-Effective Chemical Screening in Adult Zebrafish.

Publications

ScreenCube: A 3D Printed System for Rapid and Cost-Effective Chemical Screening in Adult Zebrafish.

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