Project description:Most malaria drug development focuses on parasite stages detected in red-blood cells even though to achieve eradication next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4,000 commercially available compounds with previously demonstrated blood stage activity (IC50 < 1 M-BM-5M), and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. Our orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 mg/kg) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms. Genome DNA from IP resistant strains vs. Reference 3D7 or Dd2
Project description:The circadian clock drives daily rhythms of gene expression and physiological functions across tissues throughout the body. Advances in next-generation DNA sequencing have provided extensive insights into gene expression at the RNA level, but more functional information at the protein level with sufficient depth has been limited by technical challenges. Recently, the next-generation mass spectrometer Orbitrap Astral was developed, allowing us to quantify protein abundance with greater sensitivity and accuracy. In this study, we generated a comprehensive mouse circadian proteome atlas (available in https://chiba1.dynacom.co.jp/mcp_atlas/) by analyzing protein abundance in 32 tissues including the suprachiasmatic nucleus (SCN) across the day using Orbitrap Astral. Data-independent acquisition of 584 samples including developmental samples revealed the spatiotemporal profiles of 18,956 proteins, accounting for 73.8% of all proteins registered in UniProt. Proteome and phospho-proteome analyses of whole-cell and nuclear proteins in the liver uncovered circadian profiles not only in protein abundance but also in subcellular localization and post-translational modification. Notably, proteome analysis revealed global changes in protein phosphorylation status in hPER2-S662G mutant mice, a genetic model of human familial advanced sleep phase (FASP). This multi-tissue circadian proteome atlas provides a fundamental resource for understanding when, where, and which proteins are expressed and function.
Project description:The circadian clock drives daily rhythms of gene expression and physiological functions across tissues throughout the body. Advances in next-generation DNA sequencing have provided extensive insights into gene expression at the RNA level, but more functional information at the protein level with sufficient depth has been limited by technical challenges. Recently, the next-generation mass spectrometer Orbitrap Astral was developed, allowing us to quantify protein abundance with greater sensitivity and accuracy. In this study, we generated a comprehensive mouse circadian proteome atlas (available in URL) by analyzing protein abundance in 32 tissues including the suprachiasmatic nucleus (SCN) across the day using Orbitrap Astral. Data-independent acquisition of 500 samples including developmental samples revealed the spatiotemporal profiles of 18,751 proteins, accounting for 73% of all proteins registered in UniProt. Proteome and phospho-proteome analyses of whole-cell and nuclear proteins in the liver uncovered circadian profiles not only in protein abundance but also in subcellular localization and post-translational modification. Notably, proteome analysis revealed global changes in protein phosphorylation status in hPER2-S662G mutant mice, a genetic model of human familial advanced sleep phase (FASP). This multi-tissue circadian proteome atlas provides a fundamental resource for understanding when, where, and which proteins are expressed and function.
Project description:The circadian clock drives daily rhythms of gene expression and physiological functions across tissues throughout the body. Advances in next-generation DNA sequencing have provided extensive insights into gene expression at the RNA level, but more functional information at the protein level with sufficient depth has been limited by technical challenges. Recently, the next-generation mass spectrometer Orbitrap Astral was developed, allowing us to quantify protein abundance with greater sensitivity and accuracy. In this study, we generated a comprehensive mouse circadian proteome atlas (available in URL) by analyzing protein abundance in 32 tissues including the suprachiasmatic nucleus (SCN) across the day using Orbitrap Astral. Data-independent acquisition of 500 samples including developmental samples revealed the spatiotemporal profiles of 18,751 proteins, accounting for 73% of all proteins registered in UniProt. Proteome and phospho-proteome analyses of whole-cell and nuclear proteins in the liver uncovered circadian profiles not only in protein abundance but also in subcellular localization and post-translational modification. Notably, proteome analysis revealed global changes in protein phosphorylation status in hPER2-S662G mutant mice, a genetic model of human familial advanced sleep phase (FASP). This multi-tissue circadian proteome atlas provides a fundamental resource for understanding when, where, and which proteins are expressed and function.
Project description:The circadian clock drives daily rhythms of gene expression and physiological functions across tissues throughout the body. Advances in next-generation DNA sequencing have provided extensive insights into gene expression at the RNA level, but more functional information at the protein level with sufficient depth has been limited by technical challenges. Recently, the next-generation mass spectrometer Orbitrap Astral was developed, allowing us to quantify protein abundance with greater sensitivity and accuracy. In this study, we generated a comprehensive mouse circadian proteome atlas (available in URL) by analyzing protein abundance in 32 tissues including the suprachiasmatic nucleus (SCN) across the day using Orbitrap Astral. Data-independent acquisition of 500 samples including developmental samples revealed the spatiotemporal profiles of 18,751 proteins, accounting for 73% of all proteins registered in UniProt. Proteome and phospho-proteome analyses of whole-cell and nuclear proteins in the liver uncovered circadian profiles not only in protein abundance but also in subcellular localization and post-translational modification. Notably, proteome analysis revealed global changes in protein phosphorylation status in hPER2-S662G mutant mice, a genetic model of human familial advanced sleep phase (FASP). This multi-tissue circadian proteome atlas provides a fundamental resource for understanding when, where, and which proteins are expressed and function.
Project description:The circadian clock drives daily rhythms of gene expression and physiological functions across tissues throughout the body. Advances in next-generation DNA sequencing have provided extensive insights into gene expression at the RNA level, but more functional information at the protein level with sufficient depth has been limited by technical challenges. Recently, the next-generation mass spectrometer Orbitrap Astral was developed, allowing us to quantify protein abundance with greater sensitivity and accuracy. In this study, we generated a comprehensive mouse circadian proteome atlas (available in URL) by analyzing protein abundance in 32 tissues including the suprachiasmatic nucleus (SCN) across the day using Orbitrap Astral. Data-independent acquisition of 500 samples including developmental samples revealed the spatiotemporal profiles of 18,751 proteins, accounting for 73% of all proteins registered in UniProt. Proteome and phospho-proteome analyses of whole-cell and nuclear proteins in the liver uncovered circadian profiles not only in protein abundance but also in subcellular localization and post-translational modification. Notably, proteome analysis revealed global changes in protein phosphorylation status in hPER2-S662G mutant mice, a genetic model of human familial advanced sleep phase (FASP). This multi-tissue circadian proteome atlas provides a fundamental resource for understanding when, where, and which proteins are expressed and function.