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| Open AccessModulation of MRSA virulence gene expression by the wall teichoic acid enzyme TarO
The two-component regulatory system VraRS regulates transcription of penicillin-binding protein 2 in response to cell wall antimicrobials. Here, Lu et al. show that an enzyme from the wall teichoic acid biosynthetic pathway of MRSA can also modulate the expression of virulence factors such as Staphylococcal protein A via VraRS.
- Yunfu Lu
- , Feifei Chen
- & Lefu Lan
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Article
| Open AccessEndogenous formaldehyde scavenges cellular glutathione resulting in redox disruption and cytotoxicity
Formaldehyde (FA) is known to exert cytotoxicity through DNA damage. Here, the authors show that FA also triggers cellular redox imbalance by reacting with glutathione (GSH), and that FA cytotoxicity is prevented by GSH synthesis and by ADH5, an enzyme that metabolizes FA-GSH products.
- Carla Umansky
- , Agustín E. Morellato
- & Lucas B. Pontel
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| Open AccessA synthetic BRET-based optogenetic device for pulsatile transgene expression enabling glucose homeostasis in mice
Pulsing cellular dynamics in genetic circuits have been shown to provide critical capabilities to cells in diverse cellular activities. Here the authors show a synthetic BRET-based transgene expression system that allows pulsatile and quantitative activation of gene expression both in live cells and in vivo.
- Ting Li
- , Xianjun Chen
- & Yi Yang
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Article
| Open AccessSite-specific incorporation of citrulline into proteins in mammalian cells
Citrullination of arginine is crucial for several physiological processes. Here the authors report the site-specific incorporation of citrulline into proteins in mammalian cells using an engineered tRNA synthetase/tRNA pair and a photocaged-citrulline.
- Santanu Mondal
- , Shu Wang
- & Paul R. Thompson
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Article
| Open AccessQuantitative and multiplexed chemical-genetic phenotyping in mammalian cells with QMAP-Seq
Identifying chemical-genetic interactions in mammalian cells is limited to low-throughput or computational methods. Here, the authors present QMAP-Seq, a broadly accessible and scalable approach that uses NGS for pooled high-throughput chemical-genetic profiling in mammalian cells.
- Sonia Brockway
- , Geng Wang
- & Marc L. Mendillo
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Article
| Open AccessGenetic screens reveal a central role for heme metabolism in artemisinin susceptibility
Artemisinin (ART) resistance poses a problem for malaria elimination. Here, the authors perform genome-wide CRISPR screens in Toxoplasma gondii and identify that the putative transporter Tmem14c and mitochondrial heme metabolism, through mitochondrial protease DegP2, affect ART susceptibility.
- Clare R. Harding
- , Saima M. Sidik
- & Sebastian Lourido
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Article
| Open AccessChemical genetics strategy to profile kinase target engagement reveals role of FES in neutrophil phagocytosis
Chemical tools to monitor drug-target engagement of endogenous enzymes are essential for preclinical target validation. Here, the authors present a chemical genetics strategy to study target engagement of endogenous kinases, achieving specific labeling and inactivation of FES kinase to provide insights into FES’ role in neutrophil phagocytosis.
- Tom van der Wel
- , Riet Hilhorst
- & Mario van der Stelt
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| Open AccessChemical-genetic profiling reveals limited cross-resistance between antimicrobial peptides with different modes of action
The genetics underlying bacterial susceptibility to antimicrobial peptides (AMPs) remain unclear. Here, using a genome-wide chemical-genetic approach, the authors map the diversity of resistance determinants across AMPs in Escherichia coli and provide evidence that cross-resistance is prevalent only between AMPs with similar modes of action.
- Bálint Kintses
- , Pramod K. Jangir
- & Balázs Papp
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Article
| Open AccessA high-throughput screen identifies that CDK7 activates glucose consumption in lung cancer cells
Many cancer cells have increased glucose consumption compared to normal cells, a feature that can be exploited therapeutically. Here, the authors carry out a chemical screen and identify compounds that selectively blocks glucose metabolism in non-small-cell lung cancer cell lines.
- Chiara Ghezzi
- , Alicia Wong
- & Peter M. Clark
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Article
| Open AccessZebrafish behavioural profiling identifies GABA and serotonin receptor ligands related to sedation and paradoxical excitation
Some anesthetics despite being generally associated with sedation, can also increase brain activity—a phenomenon called paradoxical excitation. The authors identified dozens of compounds that generally decrease neuronal activity, but increase activity in the caudal hindbrain of zebrafish.
- Matthew N. McCarroll
- , Leo Gendelev
- & David Kokel
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Article
| Open AccessThe marginal cells of the Caenorhabditis elegans pharynx scavenge cholesterol and other hydrophobic small molecules
The C. elegans nematode worm is a filter-feeder and requires dietary sources of cholesterol. Here, the authors show that the C. elegans pharynx works as a filter to scavenge hydrophobic small molecules from its surrounding liquid environment.
- Muntasir Kamal
- , Houtan Moshiri
- & Peter J. Roy
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Article
| Open AccessChemical genomics reveals histone deacetylases are required for core regulatory transcription
Core regulatory transcription factors are usually regulated by cell-type specific super enhancers (SEs). Here, the authors screen for chemical probes able to distinguish between SE-driven and promoter-driven transcription and find that histone deacetylases are selectively required for core regulatory transcription.
- Berkley E. Gryder
- , Lei Wu
- & Javed Khan
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Article
| Open AccessEngineered transfer RNAs for suppression of premature termination codons
Premature termination codon suppression therapy could be used to treat a range of genetic disorders. Here the authors present a high-throughput cell-based assay to identify anticodon engineered tRNAs with high suppression activity.
- John D. Lueck
- , Jae Seok Yoon
- & Christopher A. Ahern
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Article
| Open AccessComputational design of chemogenetic and optogenetic split proteins
Designing split protein approaches is time consuming and often results in high background activity due to spontaneous assembly. Here the authors present an automated approach which uses a split energy scoring function to identify optimal protein split sites and reduces spontaneous assembly.
- Onur Dagliyan
- , Andrey Krokhotin
- & Nikolay V. Dokholyan
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Article
| Open AccessImproving formaldehyde consumption drives methanol assimilation in engineered E. coli
Engineering E. coli for metabolization of methanol to produce fuels and chemicals has not been fully achieved. Here, the authors combine metabolic engineering and chemical inhibition to improve methanol assimilation and distinguish the role of kinetics and thermodynamics under various culture conditions.
- Benjamin M. Woolston
- , Jason R. King
- & Gregory Stephanopoulos
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Article
| Open AccessSplicing modulators act at the branch point adenosine binding pocket defined by the PHF5A–SF3b complex
A number of natural occurring small-molecule splicing modulators are known. Here, the authors combine chemogenomic, structural and biochemical methods and show that these compounds also target the spliceosome-associated protein PHF5A and propose a potential modulator binding site in the PHF5A–SF3B1 complex.
- Teng Teng
- , Jennifer HC Tsai
- & Ping Zhu
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Article
| Open AccessEphB4 forward signalling regulates lymphatic valve development
The bidirectional Eph-ephrin signalling regulates a myriad of developmental programmes. Zhang et al. show that EphB4 forward signalling is crucial for lymphatic valve development, providing new insight into this important developmental process previously thought to be regulated by ephrinB2-dependent reverse signalling.
- Gu Zhang
- , John Brady
- & Minhong Yan
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| Open AccessChemical–genetic attenuation of focal neocortical seizures
Focal epilepsy is difficult to treat with currently available drugs or surgical approaches. Kätzel et al.express mutant inhibitory receptors in the brains of rats with focal epilepsy and selectively activate these receptors by an exogenous compound, which results in region- and time-specific suppression of focal seizures
- Dennis Kätzel
- , Elizabeth Nicholson
- & Dimitri M. Kullmann