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Rapid response to emerging biomedical challenges and threats.

ABSTRACT: As part of the global mobilization to combat the present pandemic, almost 100 000 COVID-19-related papers have been published and nearly a thousand models of macromolecules encoded by SARS-CoV-2 have been deposited in the Protein Data Bank within less than a year. The avalanche of new structural data has given rise to multiple resources dedicated to assessing the correctness and quality of structural data and models. Here, an approach to evaluate the massive amounts of such data using the resource https://covid19.bioreproducibility.org is described, which offers a template that could be used in large-scale initiatives undertaken in response to future biomedical crises. Broader use of the described methodology could considerably curtail information noise and significantly improve the reproducibility of biomedical research.

SUBMITTER: Grabowski M

PROVIDER: S-EPMC8086160 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Rapid response to emerging biomedical challenges and threats.

Grabowski Marek M Macnar Joanna M JM Cymborowski Marcin M Cooper David R DR Shabalin Ivan G IG Gilski Miroslaw M Brzezinski Dariusz D Kowiel Marcin M Dauter Zbigniew Z Rupp Bernhard B Wlodawer Alexander A Jaskolski Mariusz M Minor Wladek W

IUCrJ 20210326 Pt 3

As part of the global mobilization to combat the present pandemic, almost 100 000 COVID-19-related papers have been published and nearly a thousand models of macromolecules encoded by SARS-CoV-2 have been deposited in the Protein Data Bank within less than a year. The avalanche of new structural data has given rise to multiple resources dedicated to assessing the correctness and quality of structural data and models. Here, an approach to evaluate the massive amounts of such data using the resour ...[more]

PMID: 33953926

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Project description:Growing evidence suggests that chemicals in disparate structural classes activate specific subsets of PPARγ’s transcriptional programs to generate adipocytes with distinct phenotypes. Our objectives were to 1) establish a novel classification method to predict PPARγ-interacting and modifying chemicals and 2) create taxonomy labels to group chemicals based on their effects on PPARγ’s transcriptome and downstream metabolic functions. We tested the hypothesis that an environmental ligand highly ranked by the taxonomy, but that segregated from the therapeutic ligands, would induce white but not brite adipogensis. 3T3-L1 cells were differentiated in the presence of 76 chemicals (negative controls, synthetic nuclear receptor ligands known to influence adipocyte biology, suspected environmental PPARγ ligands). Differentiation was assessed by measuring lipid accumulation. mRNA expression was determined by highly multiplexed RNA-Seq and validated by RT-qPCR. A novel classification model was developed using an amended random forest procedure. A subset of environmental contaminants identified as strong PPARγ agonists were characterized further for lipid handling, mitochondrial biogenesis and cellular respiration in 3T3-L1 cells and primary human preadipocytes. The 76 chemicals generated a spectrum of adipogenic differentiation. We used lipid accumulation and RNA sequencing data to develop a classification system that 1) identified PPARγ agonists and 2) sorted agonists into likely white or brite adipocyte inducers. Expression of Cidec, was the most efficacious indicator for strong PPARγ activation. Two known environmental PPARγ ligands, tetrabromobisphenol A, and triphenyl phosphate, which sorted distinctly from therapeutic ligands, induced white but not brite adipocyte genes and induced fatty acid uptake but not mitochondrial biogenesis in 3T3-L1 cells. The highly ranked agonists, tonalid and quinoxyfen, also induced white adipogenesis in 3T3-L1 cells and primary human preadipocytes. A novel classification procedure accurately identified environmental chemicals as PPARγ-modifying chemicals distinct from known PPARγ-modifying therapeutics.

Dataset Information

Rapid response to emerging biomedical challenges and threats.

Publications

Rapid response to emerging biomedical challenges and threats.

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