Featured
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Article
| Open AccessThe ETFL formulation allows multi-omics integration in thermodynamics-compliant metabolism and expression models
Accounting for the effects of genetic expression in genome-scale metabolic models is challenging. Here, the authors introduce a model formulation that efficiently simulates thermodynamic-compliant fluxes, enzyme and mRNA concentration levels, allowing omics integration and broad analysis of in silico cellular physiology.
- Pierre Salvy
- & Vassily Hatzimanikatis
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Article
| Open AccessNatural variation of an EF-hand Ca2+-binding-protein coding gene confers saline-alkaline tolerance in maize
Saline-alkaline stress affects worldwide crops production, but the tolerance mechanisms have not been fully elucidated. Here, the authors show that EF-hand Ca2 + -binding-protein coding gene ZmNSA1 can regulate root H + efflux, Na + homeostasis, and saline-alkaline tolerance in maize.
- Yibo Cao
- , Ming Zhang
- & Caifu Jiang
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Article
| Open AccessIntegrin-specific hydrogels modulate transplanted human bone marrow-derived mesenchymal stem cell survival, engraftment, and reparative activities
Mesenchymal stromal cells enhance bone and cartilage repair, but are limited by poor survival and retention after transplantation. Here, the authors show that synthetic hydrogels presenting integrin-specific peptides enhance the survival and persistence of human mesenchymal stromal cells after transplant, as well as bone repair.
- Amy Y. Clark
- , Karen E. Martin
- & Andrés J. García
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Article
| Open AccessImplementing digital computing with DNA-based switching circuits
DNA strand displacement reactions can be difficult to scale up for computational tasks. Here the authors develop DNA switching circuits that achieve high-speed computing with fewer molecules.
- Fei Wang
- , Hui Lv
- & Chunhai Fan
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Article
| Open AccessClinically accurate diagnosis of Alzheimer’s disease via multiplexed sensing of core biomarkers in human plasma
Detection of Alzheimer’s disease (AD) biomarkers from patients’ blood is challenging because these are present in very low concentrations in the plasma. Here the authors develop a sensor array of densely aligned single-walled carbon nanotubes for clinically accurate detection of femtomolar AD biomarkers in human plasma samples.
- Kayoung Kim
- , Min-Ji Kim
- & Chan Beum Park
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Article
| Open AccessGenerating ring-shaped engineered heart tissues from ventricular and atrial human pluripotent stem cell-derived cardiomyocytes
The cellular composition of previous engineered heart tissue is often heterogeneous. Here, the authors create chamber-specific human pluripotent stem cell-derived cardiomyocytes to form both ventricular and atrial cells before embedding in collagen-based matrix to form ring-shaped engineered heart tissue.
- Idit Goldfracht
- , Stephanie Protze
- & Lior Gepstein
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Article
| Open AccessAutomated mass spectrometry imaging of over 2000 proteins from tissue sections at 100-μm spatial resolution
Imaging mass spectrometry is a powerful emerging tool for mapping the spatial distribution of biomolecules across tissue surfaces. Here the authors showcase an automated technology for deep proteome imaging that utilizes ultrasensitive microfluidics and a mass spectrometry workflow to analyze tissue voxels, generating quantitative cell-type-specific images.
- Paul D. Piehowski
- , Ying Zhu
- & Kristin E. Burnum-Johnson
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Article
| Open AccessLong-read sequencing reveals genomic structural variations that underlie creation of quality protein maize
The South African quality protein maize (QPM) cultivars have the desired high lysine content and kernel hardness due to o2 mutation and the introgression of modifiers of o2 (Mo2) QTLs, respectively. Here, the authors assemble the genome of a QPM line and identify candidate genes underlying Mo2 QTLs.
- Changsheng Li
- , Xiaoli Xiang
- & Wenqin Wang
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Article
| Open AccessAn in vitro platform for engineering and harnessing modular polyketide synthases
A robust platform to study modular polyketide synthases (PKSs) in vitro is still unavailable. Here, the authors report the reconstitution of the venemycin PKS, engineer hybrid venemycin/pikromycin PKSs, and obtain much improved yields through employing the updated module boundaries.
- Takeshi Miyazawa
- , Melissa Hirsch
- & Adrian T. Keatinge-Clay
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Article
| Open AccessGenome-scale reconstructions of the mammalian secretory pathway predict metabolic costs and limitations of protein secretion
The secretory pathway is used in the production of most biopharmaceuticals, but the associated biosynthetic costs are little understood. Here, the authors integrate the core secretory pathway into genome-scale metabolic models of human, mouse, and CHO cells, enabling in silico analysis.
- Jahir M. Gutierrez
- , Amir Feizi
- & Nathan E. Lewis
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Article
| Open AccessForces during cellular uptake of viruses and nanoparticles at the ventral side
Many intracellular pathogens mimic extracellular matrix motifs to specifically interact with the host membrane which may influences virus particle uptake. Here authors use single molecule tension sensors to reveal the minimal forces exerted on single virus particles and demonstrate that the uptake forces scale with the adhesion energy.
- Tina Wiegand
- , Marta Fratini
- & Joachim P. Spatz
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Article
| Open AccessMulti-functional genome-wide CRISPR system for high throughput genotype–phenotype mapping
Genome-scale engineering is generally limited to single methods of alteration such as overexpression, repression or deletion. Here the authors present a tri-functional CRISPR system that can engineer complex synergistic interactions in a genome-wide manner.
- Jiazhang Lian
- , Carl Schultz
- & Huimin Zhao
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Article
| Open AccessBiointerfacial self-assembly generates lipid membrane coated bacteria for enhanced oral delivery and treatment
Oral microbiota delivery is an approach to treat and prevent disease but suffers from low retention and bioavailability. Here the authors report on a lipid coating to protect against environmental assault maintaining viability and bioactivity of the bacteria and demonstrate effective application in a colitis model.
- Zhenping Cao
- , Xinyue Wang
- & Jinyao Liu
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Article
| Open AccessA short translational ramp determines the efficiency of protein synthesis
Several factors contribute to the efficiency of protein expression. Here the authors show that the identity of amino acids encoded by codons at position 3–5 significantly impact translation efficiency and protein expression levels.
- Manasvi Verma
- , Junhong Choi
- & Sergej Djuranovic
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Article
| Open AccessIn vitro implementation of robust gene regulation in a synthetic biomolecular integral controller
Feedback mechanisms for synthetic gene circuits are necessary to provide robustness to external perturbations. Here the authors validate a biomolecular controller based on a sigma and anti-sigma factor to achieve stable gene expression in the face of external disturbances in an in vitro synthetic gene circuit.
- Deepak K. Agrawal
- , Ryan Marshall
- & Eduardo D Sontag
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Article
| Open AccessAn artificial metalloenzyme biosensor can detect ethylene gas in fruits and Arabidopsis leaves
Existing methods to detect ethylene in plant tissue typically require gas chromatography or use ethylene-dependent gene expression as a proxy. Here Vong et al. show that an artificial metalloenzyme-based ethylene probe can be used to detect ethylene in plants with improved spatiotemporal resolution.
- Kenward Vong
- , Shohei Eda
- & Katsunori Tanaka
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Article
| Open AccessClassification of mouse B cell types using surfaceome proteotype maps
Analysis of the cell surface proteome (surfaceome) is essential for cell classification but is technically challenging. Here the authors miniaturize and automate the Cell Surface Capture method to increase sensitivity, reproducibility and throughput, and use it to create population-specific surfaceome maps of developing mouse B cells.
- Marc van Oostrum
- , Maik Müller
- & Bernd Wollscheid
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Article
| Open AccessExamining multiple cellular pathways at once using multiplex hextuple luciferase assaying
Multiplexed detection of luciferase-based sensors in the same sample is challenging and limited by the substrates’ emission spectra. Here the authors establish a system based on three different luciferases and sequential detection to achieve measurements of up to six parameters within the same experiment.
- Alejandro Sarrion-Perdigones
- , Lyra Chang
- & Koen J. T. Venken
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Article
| Open AccessPan-cancer molecular subtypes revealed by mass-spectrometry-based proteomic characterization of more than 500 human cancers
Mass-spectrometry-based profiling can be used to stratify tumours into molecular subtypes. Here, by classifying over 500 tumours, the authors show that this approach reveals proteomic subgroups which cut across tumour types.
- Fengju Chen
- , Darshan S. Chandrashekar
- & Chad J. Creighton
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Article
| Open AccessA large size-selective DNA nanopore with sensing applications
Artificial nanopores can perform selective gating of molecules analogous to transmembrane proteins. Here, the authors design a DNA origami pore with a controllable lid for size-selective gating and translocation of macromolecules and evaluate its biosensing properties by single particle assay.
- Rasmus P. Thomsen
- , Mette Galsgaard Malle
- & Jørgen Kjems
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Article
| Open AccessExtracellular matrix hydrogel derived from decellularized tissues enables endodermal organoid culture
Organoid cultures have been developed from multiple tissues, opening new possibilities for regenerative medicine. Here the authors demonstrate the derivation of GMP-compliant hydrogels from decellularized porcine small intestine which support formation and growth of human gastric, liver, pancreatic and small intestinal organoids.
- Giovanni Giuseppe Giobbe
- , Claire Crowley
- & Paolo De Coppi
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Article
| Open AccessMonkeys mutant for PKD1 recapitulate human autosomal dominant polycystic kidney disease
Most cases of autosomal dominant polycystic kidney disease (ADPKD) are due to mutations in PKD1. Here, Tsukiyama et al. generate monkeys with mutations in PKD1 and show that animals recapitulate key pathological features of the human disease, suggesting these may provide insights into ADPKD pathogenesis and contribute to the development of future therapeutic strategies.
- Tomoyuki Tsukiyama
- , Kenichi Kobayashi
- & Masatsugu Ema
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Article
| Open AccessGiant single molecule chemistry events observed from a tetrachloroaurate(III) embedded Mycobacterium smegmatis porin A nanopore
Engineered biological nanopores enable observation of single molecule chemistry events; however a cylindrical pore geometry can have undesired effects. The authors report a conical biological pore which was embedded with tetrachloroaurate(III) to allow for discrimination between different biothiols.
- Jiao Cao
- , Wendong Jia
- & Shuo Huang
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Matters Arising
| Open AccessReply to “Conformational fitting of a flexible oligomeric substrate does not explain the enzymatic PET degradation”
- Hogyun Seo
- , In Jin Cho
- & Kyung-Jin Kim
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Article
| Open AccessEngineered E. coli Nissle 1917 for the delivery of matrix-tethered therapeutic domains to the gut
Anti-inflammatory treatments for gastrointestinal diseases can often have detrimental side effects. Here the authors engineer E. coli Nissle 1917 to create a fibrous matrix that has a protective effect in DSS-induced colitis mice.
- Pichet Praveschotinunt
- , Anna M. Duraj-Thatte
- & Neel S. Joshi
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Article
| Open AccessCRISPR-Cas3 induces broad and unidirectional genome editing in human cells
Class 1 CRISPR systems are not as developed for genome editing as Class 2 systems are. Here the authors show that Cas3 can be used to generate functional knockouts and knock-ins, as well as Cas3-mediated exon-skipping in DMD cells.
- Hiroyuki Morisaka
- , Kazuto Yoshimi
- & Tomoji Mashimo
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Article
| Open AccessThe tin1 gene retains the function of promoting tillering in maize
Unlike the other domesticated maize, sweet maize and popcorn retain tillering growth habit, but the underlying mechanism is unknown. Here, the authors identify a transcription factor tin1 that maintains outgrowth of tiller independent of tb1 and show its conservation in foxtail millet and rice.
- Xuan Zhang
- , Zhelong Lin
- & Zhongwei Lin
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Article
| Open AccessLinkedSV for detection of mosaic structural variants from linked-read exome and genome sequencing data
Compared to single nucleotide variants and short indels, structural variants (SVs) are often more challenging to detect using high-throughput sequencing based methods. Here, the authors develop LinkedSV, a computational tool for SV detection using linked-read exome and genome sequencing data.
- Li Fang
- , Charlly Kao
- & Kai Wang
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Article
| Open AccessDynamic and tunable metabolite control for robust minimal-equipment assessment of serum zinc
Tightly controlling cell output is challenging, which has limited development and applications of bacterial sensors. Here the authors develop tunable, fast-responding sensors to control production of metabolic pigments and use them to assess zinc deficiency in a low-cost, minimal equipment fashion.
- Monica P. McNerney
- , Cirstyn L. Michel
- & Mark P. Styczynski
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Article
| Open AccessTrio deep-sequencing does not reveal unexpected off-target and on-target mutations in Cas9-edited rhesus monkeys
The off-target effects and on-target mutations of CRISPR editing in higher non-human primates are complex. Here the authors perform whole genome trio sequencing of rhesus monkeys and see no unexpected mutations.
- Xin Luo
- , Yaoxi He
- & Bing Su
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Article
| Open AccessSynthetic chimeric nucleases function for efficient genome editing
CRISPR-Cas systems have well characterized, modular structures. Here the authors use that architecture to design a Cas12a library of 560 synthetic chimeras, with altered PAM preferences and specificities.
- R. M. Liu
- , L. L. Liang
- & R. T. Gill
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Article
| Open AccessA cancer rainbow mouse for visualizing the functional genomics of oncogenic clonal expansion
Pre-malignant cells harbouring oncogenic mutations can populate and spread throughout a tissue. Here, using a rainbow mouse system, the authors explore how clonal expansion in the mouse intestine might explain high levels of intra-tumoural heterogeneity observed in the disease.
- Peter G. Boone
- , Lauren K. Rochelle
- & Joshua C. Snyder
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Article
| Open AccessAutomated sequence design of 2D wireframe DNA origami with honeycomb edges
Wireframe DNA origami is a powerful approach to creating 2D and 3D geometries. Here the authors introduce an automated computational design approach that programs structures with high structural fidelity.
- Hyungmin Jun
- , Xiao Wang
- & Mark Bathe
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Article
| Open AccessCytoplasmic glycoengineering enables biosynthesis of nanoscale glycoprotein assemblies
Established bacterial glycoengineering platforms limit access to protein and glycan substrates. Here the authors design a cytoplasmic protein glycosylation system, Glycoli, to generate a variety of multivalent glycostructures.
- Hanne L. P. Tytgat
- , Chia-wei Lin
- & Timothy G. Keys
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Article
| Open AccessA cell-free biosynthesis platform for modular construction of protein glycosylation pathways
Constructing biosynthetic pathways to study and engineer glycoprotein structures is difficult. Here, the authors use GlycoPRIME, a cell-free workflow for mixing-and-matching glycosylation enzymes, to evaluate 37 putative glycosylation pathways and discover routes to 18 new glycoprotein structures
- Weston Kightlinger
- , Katherine E. Duncker
- & Michael C. Jewett
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Article
| Open AccessHigh-efficiency and integrable DNA arithmetic and logic system based on strand displacement synthesis
Current DNA computational systems are constrained by integration efficiency, device structures and limited functions. Here the authors design a DNA arithmetic logic unit that uses polymerase-mediated strand displacement.
- Haomiao Su
- , Jinglei Xu
- & Xiang Zhou
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Article
| Open AccessExtravascular gelation shrinkage-derived internal stress enables tumor starvation therapy with suppressed metastasis and recurrence
The efficacy of tumour starvation therapy is limited by lack of persistent tumour suppression, tumour metastasis and recurrence. Here, the authors report biocompatible gold nanorods and thermal-sensitive hydrogel to promote narrowing of blood vessels and show this to reduce tumour growth and metastasis.
- Kun Zhang
- , Yan Fang
- & Huixiong Xu
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Article
| Open AccessOn-target restoration of a split T cell-engaging antibody for precision immunotherapy
The restriction of appropriate tumour-specific antigens is a current limitation for T cell-engaging immunotherapy. Here, the authors have designed a new system constituted by two halve antibodies, which engage T cells once binding to two different antigens, to specifically eliminate double positive cells in preclinical leukemia and breast cancer mouse models.
- Agnes Banaszek
- , Thomas G. P. Bumm
- & Gernot Stuhler
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Article
| Open AccessPoly(A) inclusive RNA isoform sequencing (PAIso−seq) reveals wide-spread non-adenosine residues within RNA poly(A) tails
The poly(A) tails on mRNA are vital for their function but it is difficult to map full-length sequences of mRNA isoforms with the entire poly(A) tails. Here the authors develop PAIso−seq which can measure isoform specific poly(A) tail length and base composition at single-cell sensitivity.
- Yusheng Liu
- , Hu Nie
- & Falong Lu
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Article
| Open AccessGenome-wide associated study identifies NAC42-activated nitrate transporter conferring high nitrogen use efficiency in rice
Improving crop nitrogen use efficiency can facilitate sustainable production, however, the genetic mechanisms have not been fully revealed. Here, the authors discover the NAC42-NPF6.1 signaling cascade mainly derives from indica and wild rice and demonstrate the potential of using the allele for cultivar improvement.
- Weijie Tang
- , Jian Ye
- & Jianmin Wan
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Perspective
| Open AccessPathways to cellular supremacy in biocomputing
Synthetic biology uses cells as its computing substrate, often based on the genetic circuit concept. In this Perspective, the authors argue that existing synthetic biology approaches based on classical models of computation limit the potential of biocomputing, and propose that living organisms have under-exploited capabilities.
- Lewis Grozinger
- , Martyn Amos
- & Angel Goñi-Moreno
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Article
| Open AccessMicrobial reduction of metal-organic frameworks enables synergistic chromium removal
Interactions between electroactive bacteria and metal oxides are used for bioremediation. Here, the authors report on the application of Fe(III)-containing metal organic frameworks as substrates for bacterial growth which allow for remediation of lethal levels of chromium with high efficacy over several cycles.
- Sarah K. Springthorpe
- , Christopher M. Dundas
- & Benjamin K. Keitz
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Article
| Open AccessInhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome
Hutchinson–Gilford progeria syndrome causes premature aging. Here the authors show that activation of the DNA damage response at dysfunctional telomeres and transcription of telomeric non-coding RNAs contributes to the pathogenesis, which can be ameliorated by treatment with sequence-specific telomeric antisense oligonucleotides.
- Julio Aguado
- , Agustin Sola-Carvajal
- & Fabrizio d’Adda di Fagagna
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Article
| Open AccessThe indica nitrate reductase gene OsNR2 allele enhances rice yield potential and nitrogen use efficiency
Indica rice has higher nitrate assimilation and nitrogen use efficiency (NUE) than japonica rice, but the mechanism is unclear. Here, the authors reveal that the difference is partly due to allelic variation of a nitrate reductase encoding gene and this indica allele can increase yield potential and NUE.
- Zhenyu Gao
- , Yufeng Wang
- & Qian Qian
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Article
| Open AccessPathways to defense metabolites and evading fruit bitterness in genus Solanum evolved through 2-oxoglutarate-dependent dioxygenases
Steroidal glycoalkaloids (SGAs) accumulate in Solanum, but their hydroxylating enzymes are unknown. Here, the authors report 2-OXOGLUTARATE DEPENDENT DIOXYGENASE enzymes that catalyze the committed hydroxylation steps in the biosynthesis of leptinine insecticidal compounds in wild potato or non-bitter SGAs in cultivated tomato.
- Pablo D. Cárdenas
- , Prashant D. Sonawane
- & Asaph Aharoni
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Article
| Open AccessRenal clearable nanochelators for iron overload therapy
The build-up of iron in the body can have serious consequences; current treatment therapies suffer from adverse side effects and toxicity. Here, the authors developed renal clearable nanochelators with improved pharmacodynamics and demonstrated their efficacy and safety in iron overload animal models.
- Homan Kang
- , Murui Han
- & Jonghan Kim
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Article
| Open AccessTowards a fully automated algorithm driven platform for biosystems design
Existing efforts have been focused on one of the elements in the automation of the design, build, test, and learn (DBTL) cycle for biosystems design. Here, the authors integrate a robotic system with machine learning algorithms to fully automate the DBTL cycle and apply it in optimizing the lycopene biosynthetic pathway.
- Mohammad HamediRad
- , Ran Chao
- & Huimin Zhao
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Article
| Open AccessDesigning yeast as plant-like hyperaccumulators for heavy metals
Existing heavy metal bioremediation systems are mainly based on plants, which require long growing time in specific conditions. Here, the authors mimic the characteristics of plant hyperaccumulators to engineer more tractable baker’s yeast and achieve 10–100-fold higher accumulation of chromium, arsenic, or cadmium.
- George L. Sun
- , Erin. E. Reynolds
- & Angela M. Belcher
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Article
| Open AccessExpanding the limits of the second genetic code with ribozymes
Flexizymes have been used to expand the scope of chemical substrates for ribosome-directed polymerization in vitro. Here the authors deduce design rules of Flexizyme-mediated tRNA acylation that more effectively predict the incorporation of new monomers into peptides.
- Joongoo Lee
- , Kenneth E. Schwieter
- & Michael C. Jewett
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