Featured
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Article
| Open AccessHigh-affinity peptides developed against calprotectin and their application as synthetic ligands in diagnostic assays
A peptide was developed that binds to calprotectin, a marker of major inflammatory disorders, and found to be suited for diagnostic tests. The use of synthetic peptides in assays is of great interest due to their high precision, robustness and low price.
- Cristina Díaz-Perlas
- , Benjamin Ricken
- & Christian Heinis
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Article
| Open AccessElucidating the molecular programming of a nonlinear non-ribosomal peptide synthetase responsible for fungal siderophore biosynthesis
Fungal siderophores are biosynthesised by nonribosomal peptide synthetases (NRPSs) with highly unusual domain architectures. Here, the authors characterise cryptic programming events occurring within SidC NRPS, responsible for ferricrocin biosynthesis in Aspergillus nidulans.
- Matthew Jenner
- , Yang Hai
- & Yi Tang
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Article
| Open AccessStructural analysis and architectural principles of the bacterial amyloid curli
Using Alpha fold modelling and cryo-EM reconstruction the authors reveal the structural and architectural principles of the bacterial functional amyloid curli, encompassing the continuous stacking of β-solenoid pseudo repeats within and across subunits.
- Mike Sleutel
- , Brajabandhu Pradhan
- & Han Remaut
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Article
| Open AccessTurn air-captured CO2 with methanol into amino acid and pyruvate in an ATP/NAD(P)H-free chemoenzymatic system
The use of gaseous and air-captured CO2 for technical biosynthesis is highly desired but challenging due to high energy demands. Here, the authors present an ATP and NAD(P)H-free chemoenzymatic system for glycine, serine, and pyruvate biosynthesis by coupling methanol with gaseous and air-captured CO2.
- Jianming Liu
- , Han Zhang
- & An-Ping Zeng
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Article
| Open AccessSpatial metabolomics reveals glycogen as an actionable target for pulmonary fibrosis
Spatial metabolomics are used to describe the location and chemistry of small molecules involved in metabolic phenotypes. Here, Conroy et al. present a bioinformatic pipeline to analyze MALDI data and show that it can be used to identify actionable targets such as glycogen in fibrotic lungs of both human and mice.
- Lindsey R. Conroy
- , Harrison A. Clarke
- & Ramon C. Sun
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Article
| Open AccessMonoterpenoid aryl hydrocarbon receptor allosteric antagonists protect against ultraviolet skin damage in female mice
The aryl hydrocarbon receptor regulates the expression of genes involved in many cell processes and its dysregulation has been implicated in different diseases. Here, the authors identify dietary monoterpenoid carvone as an atypical non-competitive antagonist of human aryl hydrocarbon receptor and demonstrate that it can protect against ultraviolet skin damage in female mice.
- Karolína Ondrová
- , Iveta Zůvalová
- & Zdeněk Dvořák
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Article
| Open AccessCap analogs with a hydrophobic photocleavable tag enable facile purification of fully capped mRNA with various cap structures
Removing immunogenic uncapped mRNA from transcribed mRNA can be challenging, but is critical in mRNA research and clinical applications such as vaccines. Here, authors develop hydrophobic photocaged tag-modified cap analogs, which can be used to separate capped mRNA from uncapped mRNA, with subsequent tag removal using photo-irradiation.
- Masahito Inagaki
- , Naoko Abe
- & Hiroshi Abe
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Article
| Open AccessInositol pyrophosphates activate the vacuolar transport chaperone complex in yeast by disrupting a homotypic SPX domain interaction
Pipercevic et al resolve how inositol molecules activate the VTC protein complex. The VTC complex stores phosphate in yeast and is controlled by SPX domains. The inositol molecules break an interaction between SPX domains to activate the complex.
- Joka Pipercevic
- , Bastian Kohl
- & Sebastian Hiller
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Article
| Open AccessEngineered repeat proteins as scaffolds to assemble multi-enzyme systems for efficient cell-free biosynthesis
Multi-enzymatic cascades benefit from precise nanometric organization but achieving this using available scaffolds is challenging. Here the authors present strategy for organizing multienzymatic systems using a protein scaffold based on TRAP domains, and demonstrate improved catalytic output.
- Alba Ledesma-Fernandez
- , Susana Velasco-Lozano
- & Aitziber L. Cortajarena
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Article
| Open AccessChemical imaging reveals diverse functions of tricarboxylic acid metabolites in root growth and development
Chemical imaging of maize roots reveals differential patterns of TCA cycle metabolites along the axis of development. Root growth is affected in distinct ways by exogenous treatments and tissue-specific genetic manipulation of TCA metabolites.
- Tao Zhang
- , Sarah E. Noll
- & Alexandra J. Dickinson
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Article
| Open AccessUnveiling an indole alkaloid diketopiperazine biosynthetic pathway that features a unique stereoisomerase and multifunctional methyltransferase
Diketopiperazine (DKP) natural products have diverse structures and biological functions. Here, the authors elucidate the biosynthetic pathway for indole alkaloid DKP nocardioazine B which includes DKP stereoisomerization by an unusual aspartate/glutamate racemase homolog and N- and C-methylation by a dual function methyltransferase.
- Garrett Deletti
- , Sajan D. Green
- & Amy L. Lane
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Article
| Open AccessPulcherriminic acid modulates iron availability and protects against oxidative stress during microbial interactions
Microbes often produce molecules (termed siderophores) that bind iron and then are taken up using specific receptors for iron acquisition. Here, the authors show that a compound produced by Bacillus subtilis plays a more complex role, by modulating iron availability and conferring protection against oxidative stress during inter-species competition.
- Vincent Charron-Lamoureux
- , Lounès Haroune
- & Pascale B. Beauregard
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Review Article
| Open AccessEngineering protein-based therapeutics through structural and chemical design
Ebrahimi and Samanta review the key advances in the chemical and structural modification of proteins that have enabled their rise as indispensable tools in medicine and outline emerging protein engineering strategies that can potentially unlock structures with improved therapeutic properties.
- Sasha B. Ebrahimi
- & Devleena Samanta
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Article
| Open AccessChemical evolution of an autonomous DNAzyme with allele-specific gene silencing activity
Low activity currently prevents the wider use of DNA enzymes (DNAzymes). Here the authors report the chemical evolution of a DNAzyme with high catalytic activity under near physiological conditions: the enzyme achieves ~65 turnovers in 30 minutes.
- Kim Nguyen
- , Turnee N. Malik
- & John C. Chaput
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Article
| Open AccessDesigned Rubredoxin miniature in a fully artificial electron chain triggered by visible light
Living organisms regulate their energy demand by managing electron trafficking in complex transport chains. Here, the authors pioneer a fully artificial electron chain triggered by visible light using designed proteins, unlocking possibilities in bioengineering.
- Marco Chino
- , Luigi Franklin Di Costanzo
- & Vincenzo Pavone
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Article
| Open AccessSiglec-6 mediates the uptake of extracellular vesicles through a noncanonical glycolipid binding pocket
Siglec-glycolipid interactions are often studied outside the context of a lipid bilayer. Here, the authors combine a variety of chemical biology techniques to demonstrate a unique and physiologically relevant ability of Siglec-6 to recognize glycolipids in a membrane.
- Edward N. Schmidt
- , Dimitra Lamprinaki
- & Matthew S. Macauley
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Article
| Open AccessTranscription tuned by S-nitrosylation underlies a mechanism for Staphylococcus aureus to circumvent vancomycin killing
Antibiotic resistance in Staphylococcus aureus is increasingly emerging. Here, Shu et al demonstrate that transcriptional regulation by S-nitrosylation underlies vancomycin resistance.
- Xueqin Shu
- , Yingying Shi
- & Baolin Sun
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Article
| Open AccessLncRNA modulates Hippo-YAP signaling to reprogram iron metabolism
Iron metabolism dysregulation is associated with various diseases including cancer. Here, the authors show that one iron-triggered lncRNA LncRIM regulates cellular iron metabolism effectively by wiring up the Hippo-YAP signaling pathway and promotes breast cancer development.
- Xin-yu He
- , Xiao Fan
- & Aifu Lin
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Article
| Open AccessAllosteric role of the citrate synthase homology domain of ATP citrate lyase
ATP citrate lyase (ACLY) is the main nucleocytosolic source of acetyl-CoA and the enzyme contains citrate synthase homology (CSH) and acyl-CoA synthetase homology (ASH) domains. Here, the authors report data on an ACLY mutant that supports an allosteric role for the CSH domain in ACLY catalysis.
- Xuepeng Wei
- , Kollin Schultz
- & Ronen Marmorstein
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Article
| Open AccessDisrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson’s disease
ESCRT-III is involved in the endolysosomal system and disturbed in neurodegenerative diseases. Here the authors show that disruption of an interaction between ESCRT-III member CHMP2B and α-synuclein by a peptide inhibitor mitigates neurodegeneration in Parkinson’s disease models.
- Satra Nim
- , Darren M. O’Hara
- & Philip M. Kim
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Article
| Open AccessControlling protein stability with SULI, a highly sensitive tag for stabilization upon light induction
Tools for the spatiotemporal control of protein abundance are valuable in studying diverse complex biological processes. Here, authors engineered a protein tag which is stabilized upon light induction but which quickly degrades the protein of interest in the dark, demonstrating control of protein stability in yeast and zebrafish.
- Miaowei Mao
- , Yajie Qian
- & Yi Yang
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Article
| Open AccessRepurposing host-guest chemistry to sequester virulence and eradicate biofilms in multidrug resistant Pseudomonas aeruginosa and Acinetobacter baumannii
Rapid antibiotic resistance in bacteria is putting pressure on both existing therapies as well as the development pipeline. Here, the authors present a dual-acting anti-virulence treatment that evades antibiotic resistance mechanisms and remains effective against Top Priority pathogens.
- Christopher Jonkergouw
- , Ngong Kodiah Beyeh
- & Markus B. Linder
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Article
| Open AccessConstrained catecholamines gain β2AR selectivity through allosteric effects on pocket dynamics
Constrained catecholamines gain β2AR selectivity. Although the orthosteric pockets are identical in β1AR and β2AR, surrounding residues allosterically modify the pockets and contribute to the β2AR selectivity of the constrained catecholamines.
- Xinyu Xu
- , Jeremy Shonberg
- & Peter Gmeiner
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Article
| Open AccessBi-terminal fusion of intrinsically-disordered mussel foot protein fragments boosts mechanical strength for protein fibers
High-yield production of well-performing protein materials is challenging due to their high molecular weights and repetitive sequences. Here the authors develop a method to boost the strength of low molecular-weight protein materials by bi-terminal fusion of intrinsically-disordered mussel foot protein fragments, while achieving high yield.
- Jingyao Li
- , Bojing Jiang
- & Fuzhong Zhang
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Article
| Open AccessProgramming bacteria for multiplexed DNA detection
DNA is a universal and programmable signal of living organisms. Here, the authors develop cell-based DNA sensors by engineering the naturally competent bacterium Bacillus subtilis to detect specific DNA sequences in the environment.
- Yu-Yu Cheng
- , Zhengyi Chen
- & Ophelia S. Venturelli
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Review Article
| Open AccessTrimming the genomic fat: minimising and re-functionalising genomes using synthetic biology
Naturally evolved genomes tend to be unnecessarily large and redundant, and are not optimised for biotechnological or research applications. In this review, the authors explore genome minimization and re-functionalisation approaches, and discuss their potential for industrial applications.
- Xin Xu
- , Felix Meier
- & Thomas C. Williams
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Article
| Open AccessSegmentation strategy of de novo designed four-helical bundles expands protein oligomerization modalities for cell regulation
New protein assemblies can be introduced through the fusion of selected proteins with di/oligomerization domains, which interact specifically with their partners but not with other cellular proteins. Here the authors demonstrate that a single four-helical bundle protein can be segmented into several different parts, defining up to four interacting molecules for enzyme reconstitution, gene expression, or CAR-T cell regulation.
- Estera Merljak
- , Benjamin Malovrh
- & Roman Jerala
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Article
| Open AccessCollateral sensitivity profiling in drug-resistant Escherichia coli identifies natural products suppressing cephalosporin resistance
Collateral sensitivity (CS), whereby resistance to one drug is accompanied by increased sensitivity to another, provides new opportunities for antimicrobial drug discovery. Here, Liu et al. screen large chemical libraries across 29 drug-resistant E. coli strains to identify multiple CS interactions, including natural products with potent CS activities against cephalosporin-resistant strains.
- Dennis Y. Liu
- , Laura Phillips
- & Roger G. Linington
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Article
| Open AccessPredicting compound activity from phenotypic profiles and chemical structures
Experimental assays are used to determine if compounds cause a desired activity in cells. Here the authors demonstrate that computational methods can predict compound bioactivity given their chemical structure, imaging and gene expression data from historic screening libraries.
- Nikita Moshkov
- , Tim Becker
- & Juan C. Caicedo
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Perspective
| Open AccessA roadmap to establish a comprehensive platform for sustainable manufacturing of natural products in yeast
Yeasts, Saccharomyces cerevisiae and Pichia pastoris, are promising chassis for the production of nature products (NPs). Here, the author discusses establishing a comprehensive platform for sustainable production of NPs via system-associated optimization at genetics, temporal controllers, productivity screening, and scalability levels.
- Gita Naseri
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Article
| Open AccessNemacol is a small molecule inhibitor of C. elegans vesicular acetylcholine transporter with anthelmintic potential
Harrington et al report their discovery of Nemacol, which is a small molecule inhibitor of the vesicular acetylcholine transporter (VAChT). VAChT loads synaptic vesicles with acetylcholine and is a key point of vulnerability in animals. Harrington et al show that Nemacol has nematode selectivity and potential utility against nematode parasites.
- Sean Harrington
- , Jacob Pyche
- & Peter J. Roy
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Article
| Open AccessBacterial detoxification of plant defence secondary metabolites mediates the interaction between a shrub and frugivorous birds
The interactions between plants and frugivores are mediated by plants’ secondary metabolites. Here the authors demonstrate that specific bacteria, capable of consuming these metabolites, can alter these interactions, benefiting both plants and fruit consumers.
- Beny Trabelcy
- , Nimrod Shteindel
- & Yoram Gerchman
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Article
| Open AccessMitochondrial ATP synthase as a direct molecular target of chromium(III) to ameliorate hyperglycaemia stress
Despite common use as a diabetes mellitus supplement, chromium(III)’s pharmacological effects remain unknown. We identified the Cr(III)-proteome in cells with a metalloproteomic approach and uncovered ATP synthase as a vital target to relieve hyperglycaemia stress.
- Haibo Wang
- , Ligang Hu
- & Hongzhe Sun
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Article
| Open AccessNeutron-encoded diubiquitins to profile linkage selectivity of deubiquitinating enzymes
Most insights into deubiquitinase (DUB) substrate specificity originate from studies with isolated di-ubiquitins (diUb), but in cells diUbs with different linkage types coexist. Here, the authors develop a mass spectrometric DUB activity assay that can probe all diUbs simultaneously under substrate competition conditions.
- Bianca D. M. van Tol
- , Bjorn R. van Doodewaerd
- & Paul P. Geurink
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Article
| Open AccessSmall molecule-nanobody conjugate induced proximity controls intracellular processes and modulates endogenous unligandable targets
Induced proximity can be used to control diverse cellular processes. Here, the authors develop nanobody-based proximity inducers called SNACIPs, which can be used to regulate either tagged or endogenous proteins, and demonstrate their use in blocking microtubule nucleation for tumour growth inhibition in vivo.
- Xiaofeng Sun
- , Chengjian Zhou
- & Xi Chen
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Article
| Open AccessTransmembrane signaling by a synthetic receptor in artificial cells
Transmembrane signaling is the core adaptation in nature that allows cells to communicate. Here, the authors engineer signaling through the lipid bilayer using chemical, synthetic receptors for their use in the design of artificial cells.
- Ane Bretschneider Søgaard
- , Andreas Bøtker Pedersen
- & Alexander N. Zelikin
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Article
| Open AccessGenome mining unveils a class of ribosomal peptides with two amino termini
RiPP discovery has expanded the scope of post-translational modification chemistry, but genome mining of RiPP classes remains an unsolved challenge. Here, the authors employed bioinformatics and synthetic biology approaches to discover and characterize an unknown class of RiPPs, defined by an unusual amino-modified C-terminus.
- Hengqian Ren
- , Shravan R. Dommaraju
- & Huimin Zhao
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Article
| Open AccessHighly-sensitive label-free deep profiling of N-glycans released from biomedically-relevant samples
Glycans can serve as disease biomarkers. Here, the authors use label-free capillary electrophoresis-mass spectrometry for N-glycan profiling of minute sample amounts, resolving and characterizing previously undetected highly sialylated glycans and linkage isomers in a single analysis.
- Anne-Lise Marie
- , Somak Ray
- & Alexander R. Ivanov
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Article
| 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 AccessDigital nanoreactors to control absolute stoichiometry and spatiotemporal behavior of DNA receptors within lipid bilayers
Resolving the stoichiometry of membrane protein interactions is challenging but is vital to understand cell signalling. Using lipid-bound DNA receptors as a model for membrane proteins, the authors present a platform to achieve stoichiometric, spatial and temporal control over their interactions.
- Vishal Maingi
- , Zhao Zhang
- & Paul W. K. Rothemund
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Article
| Open AccessAmide-to-ester substitution as a stable alternative to N-methylation for increasing membrane permeability in cyclic peptides
Naturally occurring peptides with high membrane permeability often have backbone ester bonds. Here, the authors investigated the effect of an amide-to-ester substitution on membrane permeability of peptides and found the substitution is useful for improving membrane permeability of cyclic peptides.
- Yuki Hosono
- , Satoshi Uchida
- & Shinsuke Sando
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Article
| Open AccessInsights into membrane association of the SMP domain of extended synaptotagmin
The SMP domain of E-Syts is a newly identified lipid transfer module with unclear mechanisms. Here, authors show that it uses its tip region to associate with the extremely curved or negatively charged membranes to extract and unload lipids.
- Yunyun Wang
- , Zhenni Li
- & Xin Bian
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Article
| Open AccessRibozyme-mediated RNA synthesis and replication in a model Hadean microenvironment
Non-equilibrium conditions at heated water-air interfaces can model Hadean microenvironments. Here, the authors show that such conditions enable one-pot synthesis, strand release and folding of functional RNAs similar to modern biological systems.
- Annalena Salditt
- , Leonie Karr
- & Hannes Mutschler
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Article
| Open AccessPrecise programming of multigene expression stoichiometry in mammalian cells by a modular and programmable transcriptional system
Context-dependency of mammalian transcriptional elements has hindered the quantitative investigation of multigene expression stoichiometry and its biological functions. Here the authors present a host-orthogonal transcriptional system that drives tunable gene expression in mammalian cells, enabling predictive fine-tuning of multi-gene expression stoichiometry and the production optimization of virus-like particles from mammalian cells.
- Chenrui Qin
- , Yanhui Xiang
- & Chunbo Lou
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Article
| Open AccessTrio-pharmacophore DNA-encoded chemical library for simultaneous selection of fragments and linkers
Dual-pharmacophore DNA-Encoded Libraries (DELs) can generate large libraries, but linker optimisation is challenging. Here, the authors report a trio-pharmacophore DEL (T-DEL) for both de novo fragment identification and linker optimization of known fragment pairs.
- Meiying Cui
- , Dzung Nguyen
- & Yixin Zhang
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Article
| Open AccessStructural basis of selective cannabinoid CB2 receptor activation
Cannabinoid CB2 receptor (CB2R) agonists are investigated as therapeutic agents in the clinic. Here, authors report the discovery of LEI-102, a CB2R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate selective CB2R activation.
- Xiaoting Li
- , Hao Chang
- & Tian Hua
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Article
| Open AccessReference compounds for characterizing cellular injury in high-content cellular morphology assays
Cellular nuisance compounds are a burden in chemical biology and drug screening. Here the authors profile prototypical cytotoxic and nuisance compounds using the cell painting assay to systematically characterise cellular morphologies associated with compound-dependent cellular injury and nuisance activity.
- Jayme L. Dahlin
- , Bruce K. Hua
- & Bridget K. Wagner
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Article
| Open AccessAutocatalytic base editing for RNA-responsive translational control
Genetic circuits that control transgene expression in response to pre-defined transcriptional cues would enable the development of smart therapeutics. Here the authors engineer programmable RNA sensors, DART VADARs, in which ADARs autocatalytically convert target hybridization into a translational output, thus amplifying editing by endogenous ADAR via positive feedback and conferring high dynamic range and a small genetic footprint.
- Raphaël V. Gayet
- , Katherine Ilia
- & James J. Collins
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Article
| Open AccessDecrypting the programming of β-methylation in virginiamycin M biosynthesis
Biosynthesis of complex polyketides by polyketide synthases often relies on trans-acting enzymes to modify the intermediates. Here, the authors elucidate how β-methylation enzymes identify their substrates. The recognition is imperfect, resulting in a doubly β-methylated virginiamycin derivative.
- Sabrina Collin
- , Russell J. Cox
- & Arnaud Gruez
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