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Presentation about computational models of developing pathways and systems.

For predictive toxicology, in vitro data and biological information must be organized and assimilated into computer models that bridge different levels of biological organization. This concept has been demonstrated with several virtual tissue model prototypes that predict adverse...

Computational Systems Models for Neurovascular Development Thomas B. Knudsen, Research Triangle Park, NC &nbsp; Morphogenesis of the blood-brain barrier (BBB) is a complex process linked to neovascularization of the embryonic neural tube. This selective transport interface forms...

Translating in vitro data and biological information into a predictive model for human toxicity poses a significant challenge. This is especially true for complex adaptive systems such as the embryo where cellular dynamics are precisely orchestrated in space and time. Computer ce...

Skeletal defects are one of the major adverse outcomes observed across many prenatal developmental toxicity studies. We mined the ToxCast database (ToxCastDB) for in vitro chemical-bioactivity profiles that significantly correlated with skeletal defects in the Toxicity Reference ...

Discuss how the US EPA/NCCT is trying to sole the problem of too many chemicals, too high cost, and too much biological uncertainty

Discuss how the US EPA/NCCT is trying to sole the problem of too many chemicals, too high cost, and too much biological uncertainty

Microcephaly is associated with reduced cortical surface area and ventricular dilations. Many genetic and environmental factors precipitate this malformation, including prenatal alcohol exposure and maternal Zika infection. This complexity motivates the engineering of computation...

Chemical regulation is challenged by the large number of chemicals requiring assessment for potential human health and environmental impacts. For example, the USEPA lists more than 85,000 chemicals on its inventory of substances that fall under the Toxic Substances Control Act (T...

All-trans retinoic acid (ATRA) gradients determine skeletal patterning morphogenesis and can be disrupted by diverse genetic or environmental factors during pregnancy, leading to fetal skeleton defects. Adverse Outcome Pathway (AOP) frameworks for ATRA metabolism, signaling, and ...

Development of a functional blood-brain barrier (BBB) is a complex process regulated by multiple cell types. BBB development consists of several key events during heterotypic cellularization of the embryonic neuroepithelium: vascular invasion and patterning from the perineural va...

Closure of the caudal neural tube is a critical event that occurs early in development, around day 27 in human gestation. Its failure underlies spina bifida and other neural tube defects (NTD), which are among the most prevalent human congenital malformations. Human and environme...

Development of a functional blood-brain barrier (BBB) is a complex process regulated by multiple cell types at different developmental stages. One important aspect of the developing neurovascular unit (NVU) involves interaction between invading endothelial cells, neuroprogenitor ...

Development of the neurovascular unit (NVU) involves interactions between endothelial cells, pericytes, neuroprogenitor cells, and microglia. We constructed an in silico model of the developing neuroepithelium in CompuCell3D which recapitulated a suite of critical signaling pathw...

Previous screening of the ToxCast chemical library in a pluripotent H9 human stem cell (hPSC) assay predicted developmental toxicity with a balanced accuracy 78-84% for well-curated reference compounds [Zurlinden et al. 2020]. Since the molecular biology of hPSCs in culture most ...

Multiple opportunities exist for using high-throughput and computational approaches to address challenges in toxicology and risk assessment. Using high-throughput approaches will require systematically addressing key technical and data analysis challenges. Enabling application of...

New understanding of common signaling pathways for reproduction and developmental biology has provided a mechanistic framework for risk assessment of these endpoints. Building upon the ToxCast database and computer simulations of biological systems, this presentation will discus...

Assessing developmental toxicity has a critical role in environmental health policy. New approach methodologies (NAMs) that enable in vitro profiling aim to quickly evaluate the human toxicity potential of thousands of chemicals with less reliance on animal testing. This comes wi...

High-throughput screening (HTS) is providing a rich source of in vitro data for predictive toxicology. ToxCast™ HTS data presently covers 1060 broad-use chemicals and captures >650 in vitro features for diverse biochemical and receptor binding activities, multiplexed reporter gen...

Lecture presentation at Johns Hopkins University - Institute for Computational Medicine lecture

see attached presentation slides

Rationale: Recent progress in systems toxicology and synthetic biology have paved the way to new thinking about in vitro/in silico modeling of developmental processes and toxicities, both for embryological and reproductive impacts. Novel in vitro platforms such as 3D organotypic ...

This presentation will cover work at EPA under the CSS program for: (1) Virtual Tissue Models built from the known biology of an embryological system and structured to recapitulate key cell signals and responses; (2) running the models with real (in vitro) or synthetic (in silico...

(1) Standard practice for assessing developmental toxicity is the observation of apical endpoints (intrauterine death, fetal growth retardation, structural malformations) in pregnant rats/rabbits following exposure during organogenesis. EPA’s computational toxicology research pro...

The 2016 amendment of the Toxic Substance Control Act mandated that the EPA must accelerate development of scientifically valid test methods to prioritize large numbers of chemicals with less reliance on animal testing. ‘Advancing actionable alternatives to vertebrate animal test...