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| Open AccessA modified serine cycle in Escherichia coli coverts methanol and CO2 to two-carbon compounds
Assimilating the abundant one-carbon compounds by an industrially-relevant microorganism can broaden the substrate range and achieve reactions that are difficult for chemical process. Here the authors show a modified serine cycle can convert methanol and CO2 to two-carbon compounds in an engineered E. coli strain.
- Hong Yu
- & James C. Liao
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Article
| Open AccessTowards a comprehensive understanding of the structural dynamics of a bacterial diterpene synthase during catalysis
The bacterial diterpene synthase CotB2 catalyses the cyclisation of geranylgeranyl diphosphate to cyclooctat-9-en7-ol. Here the authors present various CotB2 structures including a trapped abrupt reaction product that were used for molecular dynamic simulations and allowed them to model all intermediates along the reaction cascade.
- Ronja Driller
- , Sophie Janke
- & Bernhard Loll
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Article
| Open AccessInsights into a dual function amide oxidase/macrocyclase from lankacidin biosynthesis
The monoamine oxidase family member LkcE is an enzyme from the lankacidin polyketide biosynthetic pathway, where it catalyzes an amide oxidation followed by an intramolecular Mannich reaction, yielding the polyketide macrocycle. Here the authors characterize LkcE and present several of its crystal structures, which explains the unusual dual activity of LkcE.
- Jonathan Dorival
- , Fanny Risser
- & Kira J. Weissman
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Article
| Open AccessClopidogrel as a donor probe and thioenol derivatives as flexible promoieties for enabling H2S biomedicine
Hydrogen sulphide (H2S) is a gaseous signalling molecule, which has shown therapeutic value. Here, the authors show that a thioenol metabolite of the antithrombotic drug clopidogrel is an efficient H2S donor and masked thioenols can be linked to existing compounds to develop H2S-releasing agents.
- Yaoqiu Zhu
- , Elkin L. Romero
- & Bin Geng
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Article
| Open AccessStrobilurin biosynthesis in Basidiomycete fungi
Strobilurins are fungal metabolites that inspired the creation of β-methoxyacrylate agricultural fungicides. Here, Nofiani et al. identify the strobilurin biosynthesis gene cluster, encoding a polyketide synthase as well as an FAD-dependent oxygenase for an oxidative rearrangement leading to β-methoxyacrylate formation.
- Risa Nofiani
- , Kate de Mattos-Shipley
- & Russell J. Cox
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Article
| Open AccessA conformational sensor based on genetic code expansion reveals an autocatalytic component in EGFR activation
Upon ligand binding epidermal growth factor receptor (EGFR) dimerizes and activates its intrinsic kinase to auto-phosphorylate EGFR. Here, the authors engineer and image a FRET-based conformational EGFR indicator which reveals that activation loop phosphorylation induces a catalytically active conformation in EGFR monomers.
- Martin Baumdick
- , Márton Gelléri
- & Philippe I. H. Bastiaens
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Article
| Open AccessAsymmetric assembly of high-value α-functionalized organic acids using a biocatalytic chiral-group-resetting process
Alpha-functionalized organic acids are building blocks of many bioactive compounds. Here, the authors developed a toolbox-like, modular set of enzymes that reset chiral groups, turning achiral glycine and simple aldehydes into stereodefined α-keto acids, α-hydroxy acids, and α-amino acids.
- Wei Song
- , Jin-Hui Wang
- & Li-Ming Liu
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Article
| Open AccessEvolution of gene knockout strains of E. coli reveal regulatory architectures governed by metabolism
The function of metabolic genes in the context of regulatory networks is not well understood. Here, the authors investigate the adaptive responses of E. coli after knockout of metabolic genes and highlight the influence of metabolite levels in the evolution of regulatory function.
- Douglas McCloskey
- , Sibei Xu
- & Bernhard O. Palsson
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Article
| Open AccessDifferential processing of HIV envelope glycans on the virus and soluble recombinant trimer
HIV envelope (Env) is a potential vaccine antigen and its N-glycans are part of the epitope of broadly neutralizing antibodies. Here, the authors show that glycosylation of Env from infectious virus closely matches Env from recombinant membrane-bound trimers, while it differs significantly from recombinant soluble, cleaved Env trimers.
- Liwei Cao
- , Matthias Pauthner
- & James C. Paulson
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Article
| Open AccessGlutamic acid is a carrier for hydrazine during the biosyntheses of fosfazinomycin and kinamycin
The natural products fosfazinomycin A and kinamycin D are structurally distinct except for a nitrogen-nitrogen (N-N) bond. Here, the authors show that fosfazinomycin and kinamycin share a common pathway for N-N bond formation that is different from pathways found for other natural products.
- Kwo-Kwang A. Wang
- , Tai L. Ng
- & Wilfred A. van der Donk
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Article
| Open AccessA rationally designed JAZ subtype-selective agonist of jasmonate perception
The phytohormone JA-Ile can promote plant resistance against herbivores and fungal pathogens but also inhibits growth, limiting its potential use in agriculture. Here, the authors design a stereoisomer of JA-Ile analog and demonstrate that it can promote defense while having minimal impact on growth.
- Yousuke Takaoka
- , Mana Iwahashi
- & Minoru Ueda
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Article
| Open AccessLuciferase-induced photoreductive uncaging of small-molecule effectors
Bioluminescence resonance energy transfer (BRET) has been mostly employed in imaging applications. Here the authors use BRET to activate a ruthenium-based photocatalyst and perform a bioorthogonal chemical reaction, which can be used to uncage small molecule drugs in a cellular context.
- Eric Lindberg
- , Simona Angerani
- & Nicolas Winssinger
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Article
| Open AccessSolution structures of multiple G-quadruplex complexes induced by a platinum(II)-based tripod reveal dynamic binding
DNA G-quadruplexes occur in oncologically relevant regions, thus are interesting targets for cancer research and treatment. Here, the authors solved the 1:1 and 4:2 (ligand/DNA) NMR structures of human telomeric DNA in complex with platinum(II)-tripod ligand and show that the binding is dynamic.
- Wenting Liu
- , Yi-Fang Zhong
- & Zong-Wan Mao
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Article
| Open AccessLysine benzoylation is a histone mark regulated by SIRT2
Histone marks regulate chromatin structure and function. Here the authors identify and characterize lysine benzoylation, a histone mark that can be modulated by sodium benzoate, a widely used chemical food preservative, associated with specific regulation of gene expression.
- He Huang
- , Di Zhang
- & Yingming Zhao
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Article
| Open AccessModeling the impact of drug interactions on therapeutic selectivity
While drugs can interact in both target and off-target cell types, more favorable interaction in the target cell may nevertheless allow for a therapeutic window. Here, the authors show, using two yeast species as a model, that differential drug interactions indeed adjust the selective window.
- Zohar B. Weinstein
- , Nurdan Kuru
- & Murat Cokol
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Article
| Open AccessPeptide-guided functionalization and macrocyclization of bioactive peptidosulfonamides by Pd(II)-catalyzed late-stage C–H activation
Aryl sulfonamides and sultams are important pharmacophores in medicinal chemistry. Here, the authors report a practical palladium-catalyzed C–H activation assisted by amino-acid residues in the substrate leading to arylsulfonamides and bioactive peptidosulfonamide macrocycles.
- Jian Tang
- , Hongfei Chen
- & Huan Wang
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Article
| Open AccessSelective N-terminal acylation of peptides and proteins with a Gly-His tag sequence
His-tagged proteins can undergo N-terminal acylation as an undesired side-reaction. Here, the authors utilize this to develop a method for highly selective acylation and further modification of peptides and proteins using an optimized His sequence and 4-methoxyphenyl esters as acyl donors.
- Manuel C. Martos-Maldonado
- , Christian T. Hjuler
- & Knud J. Jensen
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Article
| Open AccessDiscovery of cationic nonribosomal peptides as Gram-negative antibiotics through global genome mining
Microbial genomes encode enzymes for biosynthesis of many uncharacterized peptides. Here, the authors screen over 7,300 bacterial genomes for potential biosynthesis of cationic non-ribosomal peptides, and identify two novel peptides with activities against antibiotic-resistant Gram-negative pathogens.
- Yong-Xin Li
- , Zheng Zhong
- & Pei-Yuan Qian
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Article
| Open AccessTargeting AURKA-CDC25C axis to induce synthetic lethality in ARID1A-deficient colorectal cancer cells
ARID1A is highly inactivated in cancer. Here, the authors show that ARID1A has a synthetic lethal interaction with AURKA in colorectal cancer cells and that ARID1A deficiency activates the AURKA target CDC25C, whose inhibitors also cause cell death in the ARID1A-deficient cell lines.
- Changjie Wu
- , Junfang Lyu
- & Joong Sup Shim
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Correspondence
| Open AccessC-C bond cleavage in biosynthesis of 4-alkyl-L-proline precursors of lincomycin and anthramycin cannot precede C-methylation
- Zdenek Kamenik
- , Radek Gazak
- & Jiri Janata
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Correspondence
| Open AccessReply to ‘C–C bond cleavage in biosynthesis of 4-alkyl-l-proline precursors of lincomycin and anthramycin cannot precede C-methylation’
- Guannan Zhong
- , Hua Chen
- & Wen Liu
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Article
| Open AccessSmall molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment
Intracellular antibodies can inhibit disease-relevant protein interactions, but inefficient cellular uptake limits their utility. Using a RAS-targeting intracellular antibody as a screening tool, the authors here identify small molecules that inhibit RAS-effector interactions and readily penetrate cells.
- Camilo E. Quevedo
- , Abimael Cruz-Migoni
- & Terence H. Rabbitts
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Article
| Open AccessPalladium prompted on-demand cysteine chemistry for the synthesis of challenging and uniquely modified proteins
Cysteine side chains are reactive sites of protein synthesis and modification. Here, the authors show that tuning palladium chemoselectivity allows for selective removal of several cysteine protection groups, and use their method to synthesize challenging protein analogues.
- Muhammad Jbara
- , Shay Laps
- & Ashraf Brik
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Article
| Open AccessMonitoring the action of redox-directed cancer therapeutics using a human peroxiredoxin-2-based probe
Current sensors for intracellular H2O2 are not sensitive enough to detect all biologically relevant H2O2 fluctuations. Here the authors develop a peroxiredoxin-2-based FRET probe that is sensitive enough to measure changes in H2O2 concentration in response to the cancer therapeutic piperlongumine.
- Troy F. Langford
- , Beijing K. Huang
- & Hadley D. Sikes
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Article
| Open AccessThe identification of carbon dioxide mediated protein post-translational modifications
Carbon dioxide can interact with proteins to form carbamate post-translational modifications. Here, the authors developed a strategy to identify carbamate post-translational modifications by trapping carbon dioxide and subsequently identifying the carbamylated proteins.
- Victoria L. Linthwaite
- , Joanna M. Janus
- & Martin J. Cann
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Article
| Open AccessSalvage of the 5-deoxyribose byproduct of radical SAM enzymes
5-Deoxyribose is formed from 5′-deoxyadenosine, a toxic byproduct of radical S-adenosylmethionine enzymes. Here, the authors identify and biochemically characterize a bacterial salvage pathway for 5-deoxyribose, consisting of three enzymes, and solve the crystal structure of the key aldolase.
- Guillaume A. W. Beaudoin
- , Qiang Li
- & Andrew D. Hanson
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Article
| Open AccessSensor-regulator and RNAi based bifunctional dynamic control network for engineered microbial synthesis
Engineering dynamic control can improve microbial production of target chemicals. Here, the authors design a sensor-regulator and RNAi based bifunctional dynamic control network that can simultaneously and independently turn up and down cellular metabolism for engineered muconic acid production in E. coli.
- Yaping Yang
- , Yuheng Lin
- & Yajun Yan
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Correspondence
| Open AccessTrace N-glycans including sulphated species may originate from various plasma glycoproteins and not necessarily IgG
- Gordan Lauc
- , Frano Vučković
- & Manfred Wuhrer
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Article
| Open AccessDesigning a norepinephrine optical tracer for imaging individual noradrenergic synapses and their activity in vivo
The noradrenergic system plays numerous physiological roles but tools to study it are scarce. Here the authors develop a fluorescent analogue of norepinephrine that can be used to label noradrenergic neurons and the synaptic vesicles, and use it to measure single synaptic vesicle release sites in living mice.
- Matthew Dunn
- , Adam Henke
- & Dalibor Sames
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Article
| Open AccessThe solute carrier SLC9C1 is a Na+/H+-exchanger gated by an S4-type voltage-sensor and cyclic-nucleotide binding
The sperm-specific solute carrier SLC9C1 is a phylogenetic chimaera that carries a voltage-sensing (VSD) and a cyclic nucleotide-binding domain (CNBD). Here authors show by electrophysiology and fluorimetry that SLC9C1 is a genuine Na+/H+ exchanger gated by voltage and cAMP.
- F. Windler
- , W. Bönigk
- & U. B. Kaupp
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Article
| Open AccessControlled gene and drug release from a liposomal delivery platform triggered by X-ray radiation
X-ray radiation has excellent tissue penetration depth, making it a useful trigger for deep tissue cancer therapy. Here, the authors design X-ray triggered drug/gene-loaded liposomes by embedding photosensitizers and gold nanoparticles in the liposome bilayer, and demonstrate their efficacy in cancer and gene therapy.
- Wei Deng
- , Wenjie Chen
- & Ewa M. Goldys
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Article
| Open AccessSingle-molecule insights into surface-mediated homochirality in hierarchical peptide assembly
Most chiral molecules and structures in living organisms exist as single enantiomers, but why? Here, the authors investigated surface-mediated homochirality on the single-molecule level and show that it can be triggered by the chirality unbalance of two adsorption configuration monomers.
- Yumin Chen
- , Ke Deng
- & Chen Wang
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Article
| Open AccessSingle-pot glycoprotein biosynthesis using a cell-free transcription-translation system enriched with glycosylation machinery
The ability to produce homogeneous glycoproteins is expected to advance fundamental understanding in glycoscience, but current in vivo-based production systems have several limitations. Here, the authors develop an E. coli extract-based one-pot system for customized production of N-linked glycoproteins.
- Thapakorn Jaroentomeechai
- , Jessica C. Stark
- & Matthew P. DeLisa
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Article
| Open AccessEngineering circular RNA for potent and stable translation in eukaryotic cells
Circular RNAs have recently been shown to have protein-coding potential. Here the authors design a self-splicing RNA that, when circularized, provides for stable high-yield protein production.
- R. Alexander Wesselhoeft
- , Piotr S. Kowalski
- & Daniel G. Anderson
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Article
| Open AccessNovofumigatonin biosynthesis involves a non-heme iron-dependent endoperoxide isomerase for orthoester formation
Novofumigatonin is a meroterpenoid found in the fungus Aspergillus novofumigatus. Here, the authors elucidate the biosynthetic pathway of novofumigatonin and show that the endoperoxidase NvfI and the endoperoxide isomerase NvfE are involved in it.
- Yudai Matsuda
- , Tongxuan Bai
- & Thomas O. Larsen
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Article
| Open AccessOridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity
The small molecule oridonin (Ori) from the traditional Chinese herb Rabdosia rubescens has anti-inflammatory activity. Here the authors show that Ori can be covalently linked to NLRP3 to prevent assembly of the NLRP3 inflammasome, and to ameliorate inflammation in several mouse disease models.
- Hongbin He
- , Hua Jiang
- & Rongbin Zhou
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Article
| Open AccessGlutamic acid–valine–citrulline linkers ensure stability and efficacy of antibody–drug conjugates in mice
The valine-citrulline dipeptide, which is used as a cleavable linker for antibody-drug conjugates, is instable in mouse plasma. Here, the authors developed a glutamic acid–valine–citrulline tripeptide sequence as a stable alternative that still is susceptible to cathepsin-mediated cleavage.
- Yasuaki Anami
- , Chisato M. Yamazaki
- & Kyoji Tsuchikama
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Article
| Open AccessA promiscuous cytochrome P450 aromatic O-demethylase for lignin bioconversion
Catabolizing lignin-derived aromatic compounds requires an aryl-O-demethylation step. Here the authors present the structures of GcoA and GcoB, a cytochrome P450-reductase pair that catalyzes aryl-O-demethylations and show that GcoA displays broad substrate specificity, which is of interest for biotechnology applications.
- Sam J. B. Mallinson
- , Melodie M. Machovina
- & John E. McGeehan
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Article
| Open AccessAn antifungal polyketide associated with horizontally acquired genes supports symbiont-mediated defense in Lagria villosa beetles
Burkholderia bacteria protect the offspring of Lagria beetles against pathogens. Here, Flórez et al. identify an antifungal polyketide that is likely encoded by a horizontally acquired gene cluster on the genome of a dominant, uncultured Burkholderia symbiont of Lagria villosa.
- Laura V. Flórez
- , Kirstin Scherlach
- & Martin Kaltenpoth
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Article
| Open AccessRevealing the immune perturbation of black phosphorus nanomaterials to macrophages by understanding the protein corona
The formation of a protein corona around nanomaterials is known to have significant effects upon materials in biological applications. Here, the authors report on a study into understanding the protein corona formed on black phosphorus and the implications for interactions with macrophages.
- Jianbin Mo
- , Qingyun Xie
- & Jing Zhao
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Article
| Open AccessPrecision therapeutic targeting of human cancer cell motility
In this study, the authors identify and validate a halogen-substituted isoflavanone able to inhibit prostate cancer cell motility, invasion and metastasis in vitro and in vivo. They demonstrate its ability to selectively inhibit activation of client proteins that stimulate cell motility.
- Li Xu
- , Ryan Gordon
- & Raymond Bergan
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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 AccessBiosynthesis of thiocarboxylic acid-containing natural products
Thioplatensimycin (thioPTM) and thioplatencin (thioPTN) are recently discovered thiocarboxylic acid congeners of the antibacterial compounds PTM and PTN. Here, the authors identify a thioacid cassette encoding PtmA3 and PtmU4 that are responsible for carboxylate activation and sulfur transfer, respectively.
- Liao-Bin Dong
- , Jeffrey D. Rudolf
- & Ben Shen
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Article
| Open AccessAn anionic phthalocyanine decreases NRAS expression by breaking down its RNA G-quadruplex
Hyperactivity of the gene NRAS contributes to the proliferation and metastatic nature of many types of cancer cells. Here, the authors show that NRAS can be controlled by an anionic phthalocyanine coordinating Zn2+ in combination with photo-irradiation.
- Keiko Kawauchi
- , Wataru Sugimoto
- & Daisuke Miyoshi
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Article
| Open AccessModular cell-internalizing aptamer nanostructure enables targeted delivery of large functional RNAs in cancer cell lines
Large RNAs and ribonucleoprotein complexes have shown potential as novel therapeutic agents, but their targeted delivery to cells is still challenging. Here the authors present a modular aptamer nanostructure for intracellular delivery of RNAs up to 250 nucleotides to cancer cells.
- David Porciani
- , Leah N. Cardwell
- & Donald H. Burke
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Article
| Open AccessChemical warfare between leafcutter ant symbionts and a co-evolved pathogen
Acromyrmex ants cultivate fungus gardens that can be parasitized by Escovopsis sp., leading to colony collapse. Here, Heine et al. identify two secondary metabolites produced by Escovopsis that accumulate in Acromyrmex tissue, reduce behavioural defenses and suppress symbiotic Pseudonocardia bacteria.
- Daniel Heine
- , Neil A. Holmes
- & Barrie Wilkinson
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Article
| Open AccessAlternative assembly of respiratory complex II connects energy stress to metabolic checkpoints
Mitochondrial complex II is normally composed of four subunits. Here the authors show that bioenergetic stress conditions give rise to a partially assembled variant of complex II, which shifts the anabolic pathways to less energy demanding processes.
- Ayenachew Bezawork-Geleta
- , He Wen
- & Jiri Neuzil
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Article
| Open AccessTargeting repair pathways with small molecules increases precise genome editing in pluripotent stem cells
Small molecule inhibitors can influence the choice of repair pathways, enhancing nucleotide substitution and gene integration in CRISPR-mediated genome editing. Here the authors introduce CRISPY, a mix of small molecules that can enhance precise editing with Cpf1 and Cas9D10A in hiPSCs.
- Stephan Riesenberg
- & Tomislav Maricic
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Article
| Open AccessBudding-like division of all-aqueous emulsion droplets modulated by networks of protein nanofibrils
The cytoskeleton, a network of fibrils, controls how cells divide. Here, the authors show that synthetic protein fibrils added to an emulsion can control the division of droplets and that this method can be used to control the morphology of microparticles during biomaterial preparation.
- Yang Song
- , Thomas C. T. Michaels
- & Ho Cheung Shum
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