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Thyroid hormone signaling has been known for a long time to be required for proper neurodevelopment and the maintenance of cognitive functions in the adult brain. As thyroid hormone excess or deficiency is usually well handled by clinicians, research dedicated to the neural function of thyroid hormone, have not been a priority within the field. This is changing mainly for two reasons. First, new genetic diseases have been discovered, altering thyroid hormone signaling in brain (THRA, MCT8, SBP2), with neurodevelopmental consequences which are currently incurable. Second, there is a growing concern that exposition of the general population to environmental chemicals able to interfere with thyroid hormone signaling compromises children neurodevelopment or induces central disorders in adults. Finally thyroid hormone is acting directly on gene transcription, by binding nuclear receptors, and therefore is an interesting entry point to identify genetic programs controlling brain development and function. Reaching a broad understanding of the multiple processes involving thyroid hormone in brain is a tremendous task which will necessitate a multidisciplinary approach: animal genetics, molecular biology, brain imaging, developmental biology, genomics, etc... This topic will be the occasion to combine recent contributions in the field and to identify priorities for future investigations. Due to devastating consequences of congenital hypothyroidism, the neurodevelopmental consequences of altered thyroid hormone signaling have been extensively studied over the years. The discovery of new genetic diseases, the concern about the possible neurotoxicity of environmental thyroid hormone disruptors, recently renewed the interest for an important research field. This Ebook gathers reviews and original data from experts in various disciplines. It provides a broad view of ongoing research and outlines key issues for future investigation.

thyroid hormone --- neurodevelopment --- transporter --- nuclear receptor --- brain --- deiodinase --- thyroid hormone --- neurodevelopment --- transporter --- nuclear receptor --- brain --- deiodinase

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Thyroid hormone signaling has been known for a long time to be required for proper neurodevelopment and the maintenance of cognitive functions in the adult brain. As thyroid hormone excess or deficiency is usually well handled by clinicians, research dedicated to the neural function of thyroid hormone, have not been a priority within the field. This is changing mainly for two reasons. First, new genetic diseases have been discovered, altering thyroid hormone signaling in brain (THRA, MCT8, SBP2), with neurodevelopmental consequences which are currently incurable. Second, there is a growing concern that exposition of the general population to environmental chemicals able to interfere with thyroid hormone signaling compromises children neurodevelopment or induces central disorders in adults. Finally thyroid hormone is acting directly on gene transcription, by binding nuclear receptors, and therefore is an interesting entry point to identify genetic programs controlling brain development and function. Reaching a broad understanding of the multiple processes involving thyroid hormone in brain is a tremendous task which will necessitate a multidisciplinary approach: animal genetics, molecular biology, brain imaging, developmental biology, genomics, etc... This topic will be the occasion to combine recent contributions in the field and to identify priorities for future investigations. Due to devastating consequences of congenital hypothyroidism, the neurodevelopmental consequences of altered thyroid hormone signaling have been extensively studied over the years. The discovery of new genetic diseases, the concern about the possible neurotoxicity of environmental thyroid hormone disruptors, recently renewed the interest for an important research field. This Ebook gathers reviews and original data from experts in various disciplines. It provides a broad view of ongoing research and outlines key issues for future investigation.

thyroid hormone --- neurodevelopment --- transporter --- nuclear receptor --- brain --- deiodinase

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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact

Medicine --- Endocrinology --- cholesterol (chol) --- oxysterol --- cancer --- signal molecules --- nuclear receptor (NR) --- cholesterol (chol) --- oxysterol --- cancer --- signal molecules --- nuclear receptor (NR)

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Tens of thousands of chemicals are released into the environment every day. High-throughput screening (HTS) has offered a more efficient and cost-effective alternative to traditional toxicity tests that can profile these chemicals for potential adverse effects with the aim to prioritize a manageable number for more in depth testing and to provide clues to mechanism of toxicity. The Tox21 program, a collaboration between the National Institute of Environmental Health Sciences (NIEHS)/National Toxicology Program (NTP), the U.S. Environmental Protection Agency’s (EPA) National Center for Computational Toxicology (NCCT), the National Institutes of Health (NIH) National Center for Advancing Translational Sciences (NCATS), and the U.S. Food and Drug Administration (FDA), has generated quantitative high-throughput screening (qHTS) data on a library of 10K compounds, including environmental chemicals and drugs, against a panel of nuclear receptor and stress response pathway assays during its production phase (phase II). The Tox21 Challenge, a worldwide modeling competition, was launched that asks a “crowd” of researchers to use these data to elucidate the extent to which the interference of biochemical and cellular pathways by compounds can be inferred from chemical structure data. In the Challenge participants were asked to model twelve assays related to nuclear receptor and stress response pathways using the data generated against the Tox21 10K compound library as the training set. The computational models built within this Challenge are expected to improve the community’s ability to prioritize novel chemicals with respect to potential concern to human health. This research topic presents the resulting computational models with good predictive performance from this Challenge.

stress response --- predictive model --- QSAR --- HTS --- nuclear receptor --- in vitro assay --- Tox21 --- stress response --- predictive model --- QSAR --- HTS --- nuclear receptor --- in vitro assay --- Tox21

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The transcription factor (TF) mediated regulation of gene expression is a process fundamental to all biological and physiological processes. Genetic changes and epigenetic modifications of TFs affect target gene expression during the formation of malignant cells. Extensive work has been done on the critical TFs in various disease models. Despite the success of numerous TF-targeted therapies, there remain significant hurdles understanding the mechanisms, transcriptional targets and networks of physiologic pathways that govern TF action. This effort is now beginning to produce exciting new avenues of research. A clinically relevant topic for genetic change of TF is the mutant isoforms of p53, the most famous tumor suppressor. The p53 mutations either results in loss of function, or acting as dominant negative for wild-type protein, or ‘gain of function’ specifically promoting cancer survival. The gain of function is achieved by shifting p53 binding partner proteins, or changed genomic binding landscape leading to a cancer-promoting transcriptome. Another example of genetic change of TF causing malignancy is the AML-ETO fusion protein in the human t(8;21)-leukemia. The fusion protein is an active TF, and more interestingly, new studies link the disease causing role of AML-ETO to the unique transcriptome in the hematopoietic stem cells. Nuclear receptors (NR) are a group of ligand-dependent TFs governing the expression of genes involved in a broad range of reproductive, developmental and metabolic programs. Genetic changes and epigenetic modifications of NRs lead to cancers and metabolic diseases. Androgen receptor (AR), estrogen receptor (ER) and progesterone receptor (PR) are well studied NRs in prostate, breast and endometrial cancers. The development in sequencing technology and computational genomics enable us to investigate the transcription programs of these master TFs in an unprecedented level. This Research Topic aims to present the most up-to-date progress in the field of transcription regulation in cancers and metabolic diseases.

senescence --- Cell Cycle --- Cancer stem cell --- nuclear receptor --- microRNA --- p63 --- exosome --- tran --- epigenetics --- p53