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| Open AccessA general approach to engineer positive-going eFRET voltage indicators
Genetically encoded voltage indicators (GEVIs) allow visualisation of fast action potentials in neurons but most are bright at rest and dimmer during an action potential. Here, the authors engineer electrochromic FRET GEVIs with fast, bright and positive-going fluorescence signals for in vivo imaging.
- Ahmed S. Abdelfattah
- , Rosario Valenti
- & Eric R. Schreiter
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Article
| Open AccessSelf-amplifying RNA SARS-CoV-2 lipid nanoparticle vaccine candidate induces high neutralizing antibody titers in mice
Here, the authors develop a self-amplifying RNA encoding the SARS-CoV-2 spike protein encapsulated within a lipid nanoparticle as a vaccine candidate and show induction of neutralization antibody titers in mice that are comparable to titers in convalescent sera of patients.
- Paul F. McKay
- , Kai Hu
- & Robin J. Shattock
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Article
| Open AccessDevelopment of A4 antibody for detection of neuraminidase I223R/H275Y-associated antiviral multidrug-resistant influenza virus
Rapid detection of antiviral resistant strains is important for effective clinical treatment. Here the authors develop an antibody which specifically binds to multidrug-resistant influenza virus and demonstrated detection in a number of different systems using the antibody.
- Kyeonghye Guk
- , Hyeran Kim
- & Juyeon Jung
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Article
| Open AccessAntisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression
Restoration of normal gene expression is one way to treat monogenic disorders. Here the authors target naturally occurring non-productive alternative splicing using antisense oligonucleotides to promote the production of functional proteins.
- Kian Huat Lim
- , Zhou Han
- & Isabel Aznarez
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Article
| Open AccessA user guide for the online exploration and visualization of PCAWG data
The Pan-Cancer Analysis of Whole Genomes project generated a vast array of data. In this article, the authors describe five different online resources to enable readers to explore and visualize the data.
- Mary J. Goldman
- , Junjun Zhang
- & Miguel Vazquez
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Article
| Open AccessUncovering mutation-specific morphogenic phenotypes and paracrine-mediated vessel dysfunction in a biomimetic vascularized mammary duct platform
In vitro models of the human mammary gland have struggled to mimic the 3D morphogenic processes that occur in vivo. Here the authors develop a 3D microfluidic platform of a vascularized human mammary duct that simulates diverse morphogenic transitions and paracrine crosstalk.
- Matthew L. Kutys
- , William J. Polacheck
- & Christopher S. Chen
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Article
| Open AccessPre-clinical study of induced pluripotent stem cell-derived dopaminergic progenitor cells for Parkinson’s disease
Induced pluripotent stem cell (iPSC) derived dopaminergic neurons are a promising source for cell-based Parkinson’s disease (PD) therapy. Here the authors report a comprehensive pre-clinical evaluation of the safety and efficacy of dopaminergic progenitors derived from a clinical-grade human iPSC line.
- Daisuke Doi
- , Hiroaki Magotani
- & Jun Takahashi
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Article
| Open AccessEngineering monocyte/macrophage−specific glucocerebrosidase expression in human hematopoietic stem cells using genome editing
Gaucher disease is a lysosomal storage disorder caused by insufficient glucocerebrosidase expression. Here, the authors describe a CRISPR/Cas9-based gene-editing approach to re-express this enzyme in human blood stem cells and show that they can engraft in NSG mice and differentiate into functional macrophages.
- Samantha G. Scharenberg
- , Edina Poletto
- & Natalia Gomez-Ospina
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Article
| Open AccessThe Seminavis robusta genome provides insights into the evolutionary adaptations of benthic diatoms
Available genomics studies have mostly focused on planktonic centric diatom. Here, the authors report the genome assembly of the marine biofilm-forming diatom Seminavis robusta and the resequencing data of a panel of accessions to reveal their evolutionary adaptations.
- Cristina Maria Osuna-Cruz
- , Gust Bilcke
- & Klaas Vandepoele
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Article
| Open AccessRational flux-tuning of Halomonas bluephagenesis for co-production of bioplastic PHB and ectoine
Halomonas bluephagenesis is a halophilic platform bacterium for next generation industrial biotechnology. Here, the authors employ a stimulus response-based flux-tuning method for coproduction of bioplastic PHB and ectoine under open unsterile and continuous growth conditions.
- Hong Ma
- , Yiqing Zhao
- & Guo-Qiang Chen
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Article
| Open AccessA yeast platform for high-level synthesis of tetrahydroisoquinoline alkaloids
Plants synthesize more than 3000 tetrahydroisoquinoline (THIQ) alkaloids, but only a few of them have been produced by engineered microbes and titers are very low. Here, the authors increase (S)-reticuline titer to 4.6 g/L and repurpose the yeast Ehrlich pathway to synthesize a diverse array of THIQ scaffolds.
- Michael E. Pyne
- , Kaspar Kevvai
- & Vincent J. J. Martin
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Article
| Open AccessQuantifying molecular bias in DNA data storage
DNA is an attractive digital data storing medium due to high information density and longevity. Here the authors use millions of sequences to investigate inherent biases in DNA synthesis and PCR amplification.
- Yuan-Jyue Chen
- , Christopher N. Takahashi
- & Karin Strauss
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Article
| Open AccessLong-term culture of human pancreatic slices as a model to study real-time islet regeneration
The ability to culture live pancreatic tissue slices for long periods of time would enable longitudinal studies ex vivo. Here the authors culture human and mouse pancreatic slices in a perfluorocarbon-based culture system and show stable endocrine and exocrine function for up to ten days in culture.
- Mirza Muhammad Fahd Qadir
- , Silvia Álvarez-Cubela
- & Juan Domínguez-Bendala
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Article
| Open AccessSystemic nanoparticle delivery of CRISPR-Cas9 ribonucleoproteins for effective tissue specific genome editing
Therapeutic targets of CRISPR-Cas can often not be accessed due to lack of carriers to deliver RNPs systematically. Here, the authors engineer modified lipid nanoparticles for delivery of gene editing proteins to specific tissues.
- Tuo Wei
- , Qiang Cheng
- & Daniel J. Siegwart
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Article
| Open AccessNOTCH1 activation compensates BRCA1 deficiency and promotes triple-negative breast cancer formation
BRCA1 mutation carriers have higher chances of developing triple-negative breast cancer (TNBC). Here, the authors use the Sleeping Beauty mutagenesis system in Brca1 deficient mice and identify 169 putative driver genes, of which NOTCH1 accelerates TNBC formation through promoting epithelial-mesenchymal transition and cell cycle progression.
- Kai Miao
- , Josh Haipeng Lei
- & Chu-Xia Deng
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Article
| Open AccessFocus on the spectra that matter by clustering of quantification data in shotgun proteomics
Matching mass spectra to peptide sequences is the usual first step in proteomics data analysis, often followed by peptide quantification. Here, the authors show that clustering and quantifying mass spectral features prior to peptide identification can increase the sensitivity of label-free quantitative proteomics.
- Matthew The
- & Lukas Käll
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Article
| Open AccessAn entropy-based metric for assessing the purity of single cell populations
Single cell RNA-seq is a powerful method to assign cell identity, but the purity of cell clusters arising from this data is not clear. Here the authors present an entropy-based statistic called ROGUE to quantify the purity of cell clusters, and identify subtypes within clusters.
- Baolin Liu
- , Chenwei Li
- & Zemin Zhang
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Article
| Open AccessChimeric design of pyrrolysyl-tRNA synthetase/tRNA pairs and canonical synthetase/tRNA pairs for genetic code expansion
Orthogonal aminoacyl-tRNA synthetase/tRNA pairs are crucial for the incorporation of unnatural amino acids in a site-specific manner. Here the authors use rational chimera design to create multiple efficient pairs that function in bacterial and mammalian systems for genetic code expansion.
- Wenlong Ding
- , Hongxia Zhao
- & Shixian Lin
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Article
| Open AccessEliminating the capsule-like layer to promote glucose uptake for hyaluronan production by engineered Corynebacterium glutamicum
Bioproduction of hyaluronan needs increases in yield and greater diversity of the molecular weights. Here, the author increases hyaluronan production and diversifies the molecular weights through engineering the hyaluronan biosynthesis pathway and disruption of Corynebacterium glutamicum encapsulation caused by secreted hyaluronan.
- Yang Wang
- , Litao Hu
- & Zhen Kang
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Article
| Open AccessHolistic engineering of cell-free systems through proteome-reprogramming synthetic circuits
Synthetic biological modules can be used to reprogram host proteomes, which in turn enhance the function of the synthetic modules. The authors use this holistic synthetic biology approach to engineer a more favorable environment for cell-free protein synthesis.
- Luis E. Contreras-Llano
- , Conary Meyer
- & Cheemeng Tan
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Article
| Open AccessRepurposing type I–F CRISPR–Cas system as a transcriptional activation tool in human cells
Class 1 type I CRISPR–Cas systems have not been as extensively developed for genome engineering as Class 2 systems. Here the authors modify the Type I–F CRISPR–Cas system for transcriptional activation of gene expression.
- Yuxi Chen
- , Jiaqi Liu
- & Zhou Songyang
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Article
| Open AccessGenetic breakdown of a Tet-off conditional lethality system for insect population control
Insect population control using conditional lethal systems could break down due to spontaneous mutations that render the system ineffective. Here the authors analyse the structure and frequency of such mutations in Drosophila and suggest the use of dual lethality systems to mitigate their survival.
- Yang Zhao
- , Marc F. Schetelig
- & Alfred M. Handler
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Article
| Open AccessPhosphoregulated orthogonal signal transduction in mammalian cells
Phosphoregulation is a key mechanism of signal processing. Here the authors build a phosphoregulated relay system in mammalian cells for orthogonal signal transduction.
- Leo Scheller
- , Marc Schmollack
- & Martin Fussenegger
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Article
| Open AccessCharacterization of a pluripotent stem cell-derived matrix with powerful osteoregenerative capabilities
Production of a safe and manufacturable material to mimic anabolic bone for tissue engineering has been hard to achieve to date. Here the authors use a mesenchymal stem cell line generated from induced pluripotent stem cells to produce osteogenic cell-matrix, displaying significant healing properties in mice.
- Eoin P. McNeill
- , Suzanne Zeitouni
- & Carl A. Gregory
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Article
| Open AccessDynamic and scalable DNA-based information storage
The physical architectures of information storage dictate how data is encoded, organised and accessed. Here the authors use DNA with a single-strand overhang as a physical address to access specific data and do in-storage file operations in a scalable and reusuable manner.
- Kevin N. Lin
- , Kevin Volkel
- & Albert J. Keung
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Article
| Open AccessQuantification of ongoing APOBEC3A activity in tumor cells by monitoring RNA editing at hotspots
The DNA cytosine deaminases APOBEC3A and APOBEC3B have emerged from cancer genomics studies as drivers of mutation in cancers and tumor heterogeneity. Here the authors present a computational approach to identify the RNA mutations specifically driven by APOBEC3A, and developed an RNA mutation-based assay to quantify ongoing APOBEC3A activity in tumor cells.
- Pégah Jalili
- , Danae Bowen
- & Rémi Buisson
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Article
| Open AccessSub-nanowatt microfluidic single-cell calorimetry
Calorimetrically measuring the heat of single cells is currently not possible due to the sensitivity of existing calorimeters. Here the authors present on-chip single cell calorimetry, with a sensitivity over ten-fold greater than the current gold-standard.
- Sahngki Hong
- , Edward Dechaumphai
- & Renkun Chen
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Article
| Open AccessTargeted inhibition of activated protein C by a non-active-site inhibitory antibody to treat hemophilia
Activated protein C (APC) is a plasma serine protease with antithrombotic and cytoprotective functions. Here, the authors develop a monoclonal antibody that specifically inhibits APC’s anticoagulant function without compromising its cytoprotective function, and shows efficacy in animal models.
- Xiao-Yan Zhao
- , Andreas Wilmen
- & Volker Laux
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Article
| Open AccessCRISPR artificial splicing factors
Control over splicing could be used for both therapeutic and engineering applications. Here the authors create artificial splicing factors using RNA-targeting CRISPR systems under small molecule control.
- Menghan Du
- , Nathaniel Jillette
- & Albert Wu Cheng
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Article
| Open AccessRational design of aptamer switches with programmable pH response
Previous design strategies for pH sensitive aptamers were not readily tunable across pH ranges. Here the authors present a general method to convert aptamers into pH-responsive switches using two orthogonal motifs.
- Ian A. P. Thompson
- , Liwei Zheng
- & H. Tom Soh
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Article
| Open AccessReverse engineering synthetic antiviral amyloids
Some human amyloid proteins have been shown to interact with viral proteins, suggesting that they may have potential as therapeutic agents. Here the authors design synthetic amyloids specific for influenza A and Zika virus proteins, respectively, and show that they can inhibit viral replication.
- Emiel Michiels
- , Kenny Roose
- & Joost Schymkowitz
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Article
| Open AccessAnalysis of human metabolism by reducing the complexity of the genome-scale models using redHUMAN
The complexity of genome-scale metabolic networks (GEMs) hinders their application in specific physiological contexts. Here, the authors introduce a framework to reduce thermodynamically curated GEMs to the subnetworks of interest and demonstrate its application by deriving leukemia-specific models.
- Maria Masid
- , Meric Ataman
- & Vassily Hatzimanikatis
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Article
| Open AccessMultiplexed relative and absolute quantitative immunopeptidomics reveals MHC I repertoire alterations induced by CDK4/6 inhibition
Immunopeptidomics allows identifying the cellular repertoire of MHC-bound peptides, but quantifying them remains challenging. Here, the authors present a method to efficiently generate internal peptide MHC standards and calibration curves, facilitating relative and absolute quantitative immunopeptidomics.
- Lauren E. Stopfer
- , Joshua M. Mesfin
- & Forest M. White
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Article
| Open AccessDevelopment of an exon skipping therapy for X-linked Alport syndrome with truncating variants in COL4A5
Alport syndrome is a progressive inherited nephritis accompanied by sensorineural loss of hearing and ocular abnormalities, for which there is currently no effective therapy. Here, the authors develop an exon-skipping therapy using an antisense-oligonucleotide and show it is effective in mouse models.
- Tomohiko Yamamura
- , Tomoko Horinouchi
- & Kandai Nozu
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Article
| Open AccessCephalopod-inspired optical engineering of human cells
While organisms like squid can adaptively modulate the optical properties of their tissues, human cells lack analogous abilities. Here the authors engineer human cells to produce protein architectures with tunable light scattering functionalities.
- Atrouli Chatterjee
- , Juana Alejandra Cerna Sanchez
- & Alon A. Gorodetsky
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Article
| Open AccessImproving the safety of human pluripotent stem cell therapies using genome-edited orthogonal safeguards
Human pluripotent stem cell derived therapies can have serious safety risks. Here the authors design two drug inducible genetic safeguards to deplete undifferentiated hPSCs and hPSC-derived cell types.
- Renata M. Martin
- , Jonas L. Fowler
- & Kyle M. Loh
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Article
| Open AccessA genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor
Here the authors perform a gain-of-function screen and identify CDKN2C as a host factor for HBV replication, inducing cell cycle arrest and expression of HBV transcription enhancers. CDKN2C expression correlates with disease progression suggesting a potential role in HBV-induced liver disease.
- Carla Eller
- , Laura Heydmann
- & Thomas F. Baumert
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Article
| Open AccessImmunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity
Synthetic biology can be used to create rationally designed living therapeutics. Here the authors engineer E. coli Nissle to target STING activation in antigen presenting cells for the treatment of solid tumors and demonstrate preclinical activity in murine models.
- Daniel S. Leventhal
- , Anna Sokolovska
- & Jose M. Lora
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Article
| Open AccessFunctional reconstruction of injured corpus cavernosa using 3D-printed hydrogel scaffolds seeded with HIF-1α-expressing stem cells
Injury of corpus cavernosa results in erectile dysfunction, and repair leading to restoration of function is difficult. Here the authors construct 3D printed hydrogel constructs seeded with HIF-1α-expressing muscle derived stem cells to restore corpus function in a rabbit model.
- Geng An
- , Feixiang Guo
- & Chuanbin Mao
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Article
| Open AccessIntegrative analysis of reference epigenomes in 20 rice varieties
Comprehensive epigenomic maps of various rice varieties are still unavailable. Here, the authors report the development of eChIP as a fast and low-input upgrade of regular plant ChIP-seq protocol for epigenome analysis of 20 rice varieties and annotate over 80% of the genome with different epigenome properties for transcriptional regulation.
- Lun Zhao
- , Liang Xie
- & Xingwang Li
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Article
| Open AccessUDP-glucosyltransferase regulates grain size and abiotic stress tolerance associated with metabolic flux redirection in rice
Increasing grain yield needs to be put in the context of environmental stress. Here, the authors reveal that a UDP-glucosyltransferase is associated with regulation of rice grain size, abiotic stress tolerance, flavonoid-mediated auxin signaling, and redirection of carbon flux to flavonoid glycosides synthesis.
- Nai-Qian Dong
- , Yuwei Sun
- & Hong-Xuan Lin
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Article
| Open AccessUltrasensitive digital quantification of cytokines and bacteria predicts septic shock outcomes
Ultrasensitive methods for detection of biomarkers for infectious disease are needed for diagnosing, monitoring and targeting treatment. Here the authors develop a digital assay for inflammatory markers, bacterial DNA and antibotic-resistance genes and apply it to characterise asthma patients and predict mortality from septic shock.
- M. Fatih Abasıyanık
- , Krysta Wolfe
- & Savaş Tay
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Article
| Open AccessDiscrete populations of isotype-switched memory B lymphocytes are maintained in murine spleen and bone marrow
Memory B cells are important for protecting the host from pathogen rechallenge, but their properties and locations remain ill-defined. Here the authors show, using single-cell transcriptomics and repertoire analyses, that mouse spleen and bone marrow host distinct populations of isotype-switched memory B cells to potentially optimize for rapid recall responses.
- René Riedel
- , Richard Addo
- & Andreas Radbruch
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Article
| Open AccessAllele-aware chromosome-level genome assembly and efficient transgene-free genome editing for the autotetraploid cultivated alfalfa
Alfalfa is an important forage crop, but genetic improvement is challenging due to the lack of a reference genome and an efficient genome editing protocol. Here, the authors report the chromosome-level assembly of the autotetraploid genome and a CRISPR/Cas9-based transgene-free genome editing protocol.
- Haitao Chen
- , Yan Zeng
- & Qiang Qiu
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Article
| Open AccessThe mutational impact of culturing human pluripotent and adult stem cells
Genetic changes acquired during in vitro culture pose a challenge to application of stem cells. Here the authors use whole genome sequencing to show that cultured human adult and pluripotent stem cells have a high mutational load caused by oxidative stress and reduced oxygen tension in culture lowers mutation rates.
- Ewart Kuijk
- , Myrthe Jager
- & Edwin Cuppen
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Article
| Open AccessA Cas9 with PAM recognition for adenine dinucleotides
Protospacer adjacent motif (PAM) requirements limit the target range of CRISPR endonucleases. Here, the authors graft the 5\(^{\prime}\)-NAAN-3\(^{\prime}\) PAM-interacting domain of SmacCas9 onto SpyCas9 to create adenine dinucleotide targeting chimeras.
- Pranam Chatterjee
- , Jooyoung Lee
- & Noah Jakimo
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Article
| Open AccessA redox-based electrogenetic CRISPR system to connect with and control biological information networks
Redox-responsive transcriptional regulators can enable user-specified electronic control over biological functions. Here the authors demonstrate electronic control of CRISPRa and CRISPRi using redox signalling.
- Narendranath Bhokisham
- , Eric VanArsdale
- & William E. Bentley
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Article
| Open AccessSynergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver
Lipid-like nanoparticles have applications as non-viral delivery systems for mRNA. Here, the authors develop biodegradable lipids with improved clearance and reduced toxicity.
- Lei Miao
- , Jiaqi Lin
- & Daniel G. Anderson
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Review Article
| Open AccessApplication of combinatorial optimization strategies in synthetic biology
Our efforts to build complex synthetic biology circuits are impeded by limited knowledge of optimal combinations. In this review, the authors consider current combinatorial methods and look to emerging technologies.
- Gita Naseri
- & Mattheos A. G. Koffas
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