9 results on '"David T. Breault"'
Search Results
2. Identification of TFPI as a receptor reveals recombination-driven receptor switching in Clostridioides difficile toxin B variants
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Songhai Tian, Xiaozhe Xiong, Ji Zeng, Siyu Wang, Benjamin Jean-Marie Tremblay, Peng Chen, Baohua Chen, Min Liu, Pengsheng Chen, Kuanwei Sheng, Daniel Zeve, Wanshu Qi, David T. Breault, César Rodríguez, Ralf Gerhard, Rongsheng Jin, Andrew C. Doxey, and Min Dong more...
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Science - Abstract
Abstract Toxin B (TcdB) is a major exotoxin responsible for diseases associated with Clostridioides difficile infection. Its sequence variations among clinical isolates may contribute to the difficulty in developing effective therapeutics. Here, we investigate receptor-binding specificity of major TcdB subtypes (TcdB1 to TcdB12). We find that representative members of subtypes 2, 4, 7, 10, 11, and 12 do not recognize the established host receptor, frizzled proteins (FZDs). Using a genome-wide CRISPR-Cas9-mediated screen, we identify tissue factor pathway inhibitor (TFPI) as a host receptor for TcdB4. TFPI is recognized by a region in TcdB4 that is homologous to the FZD-binding site in TcdB1. Analysis of 206 TcdB variant sequences reveals a set of six residues within this receptor-binding site that defines a TFPI binding-associated haplotype (designated B4/B7) that is present in all TcdB4 members, a subset of TcdB7, and one member of TcdB2. Intragenic micro-recombination (IR) events have occurred around this receptor-binding region in TcdB7 and TcdB2 members, resulting in either TFPI- or FZD-binding capabilities. Introduction of B4/B7-haplotype residues into TcdB1 enables dual recognition of TFPI and FZDs. Finally, TcdB10 also recognizes TFPI, although it does not belong to the B4/B7 haplotype, and shows species selectivity: it recognizes TFPI of chicken and to a lesser degree mouse, but not human, dog, or cattle versions. These findings identify TFPI as a TcdB receptor and reveal IR-driven changes on receptor-specificity among TcdB variants. more...
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- 2022
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Catalog
3. A non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine
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Carlos Sebastian, Christina Ferrer, Maria Serra, Jee-Eun Choi, Nadia Ducano, Alessia Mira, Manasvi S. Shah, Sylwia A. Stopka, Andrew J. Perciaccante, Claudio Isella, Daniel Moya-Rull, Marianela Vara-Messler, Silvia Giordano, Elena Maldi, Niyati Desai, Diane E. Capen, Enzo Medico, Murat Cetinbas, Ruslan I. Sadreyev, Dennis Brown, Miguel N. Rivera, Anna Sapino, David T. Breault, Nathalie Y. R. Agar, and Raul Mostoslavsky more...
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Science - Abstract
Metabolic reprogramming upon SIRT6 loss induces tumour formation in the intestine but the mechanism is unclear. Here, the authors show that loss of SIRT6 leads to the expansion of epithelial cells with high pyruvate dehydrogenase kinase activity resulting in enhanced stem cell activity and tumour-initiating potential more...
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- 2022
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4. Robust differentiation of human enteroendocrine cells from intestinal stem cells
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Daniel Zeve, Eric Stas, Joshua de Sousa Casal, Prabhath Mannam, Wanshu Qi, Xiaolei Yin, Sarah Dubois, Manasvi S. Shah, Erin P. Syverson, Sophie Hafner, Jeffrey M. Karp, Diana L. Carlone, Jose Ordovas-Montanes, and David T. Breault more...
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Science - Abstract
Hormone-producing enteroendocrine cells (EEC) regulate of energy homeostasis and gastrointestinal function. Here the authors report protocols to induce human intestinal stem cells into EECs producing multiple gut hormones, including SST, 5-HT, CCK and GIP, using directed differentiation with small molecules targeting FOXO1, JNK and CB1 signalling. more...
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- 2022
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5. Angiotensin II induces coordinated calcium bursts in aldosterone-producing adrenal rosettes
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Nick A. Guagliardo, Peter M. Klein, Christina A. Gancayco, Adam Lu, Sining Leng, Rany R. Makarem, Chelsea Cho, Craig G. Rusin, David T. Breault, Paula Q. Barrett, and Mark P. Beenhakker
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Science - Abstract
Aldosterone-producing zona glomerulosa cells in the adrenal gland arrange into rosette structures known to be important for morphogenesis. Here the authors show that the cells in the rosettes produce coordinated calcium activity bursts in response to angiotensin II that correlate with aldosterone production level. more...
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- 2020
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6. β-Catenin and FGFR2 regulate postnatal rosette-based adrenocortical morphogenesis
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Sining Leng, Emanuele Pignatti, Radhika S. Khetani, Manasvi S. Shah, Simiao Xu, Ji Miao, Makoto M. Taketo, Felix Beuschlein, Paula Q. Barrett, Diana L. Carlone, and David T. Breault
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Science - Abstract
Multicellular rosettes are known to mediate complex cellular reorganization such as epithelial folding and branching during embryonal organogenesis. Here the authors show that rosette formation regulated by β-Catenin and FGFR2 mediate postnatal adrenal cortex zona glomerulosa morphogenesis. more...
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- 2020
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7. Robust differentiation of human enteroendocrine cells from intestinal stem cells
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David T. Breault, Wanshu Qi, Jose Ordovas-Montanes, Sarah Dubois, Diana L. Carlone, Manasvi S. Shah, Daniel Zeve, Joshua de Sousa Casal, Sophie Hafner, Eric Stas, Jeffrey M. Karp, Xiaolei Yin, Erin Syverson, and Prabhath Mannam more...
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endocrine system ,Enteroendocrine Cells ,Cellular differentiation ,Science ,Cell ,Stem-cell differentiation ,General Physics and Astronomy ,Enteroendocrine cell ,Quinolones ,Biology ,digestive system ,Article ,Energy homeostasis ,General Biochemistry, Genetics and Molecular Biology ,Directed differentiation ,Glucagon-Like Peptide 1 ,medicine ,Humans ,Peptide YY ,Secretion ,Intestinal Mucosa ,Anthracenes ,Multidisciplinary ,Stem Cells ,Intestinal stem cells ,Cell Differentiation ,General Chemistry ,Cell biology ,stomatognathic diseases ,medicine.anatomical_structure ,Differentiation ,Chromogranin A ,Rimonabant ,Stem cell ,Somatostatin ,Gastrointestinal function ,hormones, hormone substitutes, and hormone antagonists ,Endocannabinoids ,Signal Transduction ,Transcription Factors - Abstract
Enteroendocrine (EE) cells are the most abundant hormone-producing cells in humans and are critical regulators of energy homeostasis and gastrointestinal function. Challenges in converting human intestinal stem cells (ISCs) into functional EE cells, ex vivo, have limited progress in elucidating their role in disease pathogenesis and in harnessing their therapeutic potential. To address this, we employed small molecule targeting of the endocannabinoid receptor signaling pathway, JNK, and FOXO1, known to mediate endodermal development and/or hormone production, together with directed differentiation of human ISCs from the duodenum and rectum. We observed marked induction of EE cell differentiation and gut-derived expression and secretion of SST, 5HT, GIP, CCK, GLP-1 and PYY upon treatment with various combinations of three small molecules: rimonabant, SP600125 and AS1842856. Robust differentiation strategies capable of driving human EE cell differentiation is a critical step towards understanding these essential cells and the development of cell-based therapeutics., Hormone-producing enteroendocrine cells (EEC) regulate of energy homeostasis and gastrointestinal function. Here the authors report protocols to induce human intestinal stem cells into EECs producing multiple gut hormones, including SST, 5-HT, CCK and GIP, using directed differentiation with small molecules targeting FOXO1, JNK and CB1 signalling. more...
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- 2022
8. Angiotensin II induces coordinated calcium bursts in aldosterone-producing adrenal rosettes
- Author
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Mark P. Beenhakker, Nick A. Guagliardo, Rany R. Makarem, Craig G. Rusin, Christina A. Gancayco, Chelsea Cho, Paula Q. Barrett, Sining Leng, Peter M. Klein, Adam C Lu, and David T. Breault
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0301 basic medicine ,Male ,Cell signaling ,endocrine system ,Intravital Microscopy ,Science ,Green Fluorescent Proteins ,General Physics and Astronomy ,chemistry.chemical_element ,Mice, Transgenic ,Calcium ,Cellular imaging ,General Biochemistry, Genetics and Molecular Biology ,Article ,Rosette (botany) ,Tissue Culture Techniques ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Genes, Reporter ,medicine ,Animals ,Cytochrome P-450 CYP11B2 ,lcsh:Science ,Aldosterone ,Multidisciplinary ,Adrenal cortex ,Chemistry ,Adrenal gland ,Angiotensin II ,Calcium-Binding Proteins ,General Chemistry ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Microscopy, Fluorescence ,Zona glomerulosa ,Female ,Zona Glomerulosa ,lcsh:Q ,030217 neurology & neurosurgery ,Cell signalling - Abstract
Aldosterone-producing zona glomerulosa (zG) cells of the adrenal gland arrange in distinct multi-cellular rosettes that provide a structural framework for adrenal cortex morphogenesis and plasticity. Whether this cyto-architecture also plays functional roles in signaling remains unexplored. To determine if structure informs function, we generated mice with zG-specific expression of GCaMP3 and imaged zG cells within their native rosette structure. Here we demonstrate that within the rosette, angiotensin II evokes periodic Cav3-dependent calcium events that form bursts that are stereotypic in form. Our data reveal a critical role for angiotensin II in regulating burst occurrence, and a multifunctional role for the rosette structure in activity-prolongation and coordination. Combined our data define the calcium burst as the fundamental unit of zG layer activity evoked by angiotensin II and highlight a novel role for the rosette as a facilitator of cell communication., Aldosterone-producing zona glomerulosa cells in the adrenal gland arrange into rosette structures known to be important for morphogenesis. Here the authors show that the cells in the rosettes produce coordinated calcium activity bursts in response to angiotensin II that correlate with aldosterone production level. more...
- Published
- 2020
9. A non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine
- Author
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Carlos Sebastian, Christina Ferrer, Maria Serra, Jee-Eun Choi, Nadia Ducano, Alessia Mira, Manasvi S. Shah, Sylwia A. Stopka, Andrew J. Perciaccante, Claudio Isella, Daniel Moya-Rull, Marianela Vara-Messler, Silvia Giordano, Elena Maldi, Niyati Desai, Diane E. Capen, Enzo Medico, Murat Cetinbas, Ruslan I. Sadreyev, Dennis Brown, Miguel N. Rivera, Anna Sapino, David T. Breault, Nathalie Y. R. Agar, and Raul Mostoslavsky more...
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Animals ,Cell Transformation, Neoplastic ,Glycolysis ,Intestines ,Mice ,Pyruvate Dehydrogenase Acetyl-Transferring Kinase ,Neoplasms ,Sirtuins ,Neoplastic ,Multidisciplinary ,General Physics and Astronomy ,General Chemistry ,Cell Transformation ,General Biochemistry, Genetics and Molecular Biology - Abstract
Although reprogramming of cellular metabolism is a hallmark of cancer, little is known about how metabolic reprogramming contributes to early stages of transformation. Here, we show that the histone deacetylase SIRT6 regulates tumor initiation during intestinal cancer by controlling glucose metabolism. Loss of SIRT6 results in an increase in the number of intestinal stem cells (ISCs), which translates into enhanced tumor initiating potential in APCmin mice. By tracking down the connection between glucose metabolism and tumor initiation, we find a metabolic compartmentalization within the intestinal epithelium and adenomas, where a rare population of cells exhibit features of Warburg-like metabolism characterized by high pyruvate dehydrogenase kinase (PDK) activity. Our results show that these cells are quiescent cells expressing +4 ISCs and enteroendocrine markers. Active glycolysis in these cells suppresses ROS accumulation and enhances their stem cell and tumorigenic potential. Our studies reveal that aerobic glycolysis represents a heterogeneous feature of cancer, and indicate that this metabolic adaptation can occur in non-dividing cells, suggesting a role for the Warburg effect beyond biomass production in tumors. more...
- Published
- 2021
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