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| Open AccessUltra-sensitive and rapid detection of nucleic acids and microorganisms in body fluids using single-molecule tethering
Culture-based diagnostic methods for microorganism detection are time-consuming but still the gold standard for conditions such as sepsis. Here the authors present an amplification and purification-free method to detect microorganisms in bodily fluids with high sensitivity: Single MOLecule Tethering (SMOLT).
- Wen-Chih Cheng
- , Troy Horn
- & Alfredo Celedon
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Article
| Open AccessResequencing of 1,143 indica rice accessions reveals important genetic variations and different heterosis patterns
Hybrid rice cultivars are widely planted around the world. Here, the authors resequence 1,143 indica accessions, focusing on the parents of superior hybrid rice lines in China, and reveal genetic loci that are associated with heterosis via measuring frequency of parental variation difference (FPVD).
- Qiming Lv
- , Weiguo Li
- & Dingyang Yuan
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Article
| Open AccessRational programming of history-dependent logic in cellular populations
Automated frameworks to systematically implement robust history-dependent genetic programs in cellular populations.
- Ana Zúñiga
- , Sarah Guiziou
- & Jerome Bonnet
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Article
| Open AccessMapping cellular-scale internal mechanics in 3D tissues with thermally responsive hydrogel probes
Local mechanical properties are important to cellular function; but conventional measurement techniques are limited in intact, living, 3D tissues. Here, the authors report on swellable hydrogel microparticles to monitor mechanical properties in situ via a temperature change.
- Stephanie Mok
- , Sara Al Habyan
- & Christopher Moraes
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Article
| Open AccessUltrasensitive and visual detection of SARS-CoV-2 using all-in-one dual CRISPR-Cas12a assay
Rapid and early detection of SARS-CoV-2 will aid intervention to stop disease spread. Here the authors present a one-pot CRISPR-based rapid detection system with visual readout.
- Xiong Ding
- , Kun Yin
- & Changchun Liu
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Article
| Open AccessPrecise allele-specific genome editing by spatiotemporal control of CRISPR-Cas9 via pronuclear transplantation
Injecting Cas9 and gRNA into an animal zygote often produces mosaicism and random biallelic targeting. Here, the authors use pronuclear transfer to reduce mosaicism and selectively target parental alleles.
- Yanhe Li
- , Yuteng Weng
- & Shaorong Gao
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Article
| Open AccessDiversity analysis of 80,000 wheat accessions reveals consequences and opportunities of selection footprints
Genebanks hold comprehensive collections of wild species, wild relatives, and landraces that are useful for genetic improvement. Here, the authors report the genotype of nearly 80,000 wheat accessions using DArTseq technology to show the less explored genetic diversity.
- Carolina Sansaloni
- , Jorge Franco
- & Kevin Pixley
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Article
| Open AccessEfficient rational modification of non-ribosomal peptides by adenylation domain substitution
Non-ribosomal peptide synthases are multimodular enzymes comprised of adenylation (A), condensation (C) and thiolation domains. Here, the authors show that non-ribosomal peptides can be generated solely by A domain substitutions, providing evidence that the postulated substrate specifying role of C-domains may be rare in nature.
- Mark J. Calcott
- , Jeremy G. Owen
- & David F. Ackerley
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Article
| Open AccessA role for Biofoundries in rapid development and validation of automated SARS-CoV-2 clinical diagnostics
The SARS-CoV-2 pandemic has created large demand on global testing capability. Here the authors use the London Biofoundry, an automated synthetic biology platform, and develop an open-source virus-like particle to implement high-throughput diagnostics.
- Michael A. Crone
- , Miles Priestman
- & Paul S. Freemont
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Article
| Open AccessFonio millet genome unlocks African orphan crop diversity for agriculture in a changing climate
Fonio millet is a fast growing orphan cereal crop with a great potential for dryland agriculture. Here, the authors report chromosome-scale reference genome assembly and population genomic resources to shed light on genetic diversity, population structure and domestication of fonio millet.
- Michael Abrouk
- , Hanin Ibrahim Ahmed
- & Simon G. Krattinger
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Article
| Open AccessEngineering multiple species-like genetic incompatibilities in insects
Natural speciation can be driven by pre-zygotic and post-zygotic barriers. Here the authors use a dominant lethal transgene coupled to a recessive resistance allele to engineer species-like barriers in Drosophila.
- Maciej Maselko
- , Nathan Feltman
- & Michael J. Smanski
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Article
| Open AccessEngineered systems of inducible anti-repressors for the next generation of biological programming
Transcriptional anti-repressors have been largely absent in the design of regulated genetic circuits. Here, the authors present a workflow of the engineering of non-natural anti-reperssors that can be built into NOT oriented logic gates.
- Thomas M. Groseclose
- , Ronald E. Rondon
- & Corey J. Wilson
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Article
| Open AccessChanging local recombination patterns in Arabidopsis by CRISPR/Cas mediated chromosome engineering
The heterochromatic knob (hk4S) on Arabidopsis chromosome 4 prevents the recombination between accessions with and without hk4S. Here, via egg-cell specific expression of the Cas9 nuclease, the authors demonstrate targeted reversal of the 1.1 Mb long hk4S-inversion in Col-0 and restore the crossovers with Ler-1.
- Carla Schmidt
- , Paul Fransz
- & Holger Puchta
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Article
| Open AccessChromosome drives via CRISPR-Cas9 in yeast
Self-propagating drives allow for non-Mendelian inheritance. Here the authors use CRISPR to build a chromosome drive, showing elimination of entire chromosomes, endoreduplication of desired chromosomes and enabling preferential transmissions of complex genetic traits on a chromosomal scale in yeast.
- Hui Xu
- , Mingzhe Han
- & Ying-Jin Yuan
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Article
| Open AccessOsteoclast-associated receptor blockade prevents articular cartilage destruction via chondrocyte apoptosis regulation
Osteoarthritis (OA) is associated with cartilage disruption, but the underlying mechanisms remain unclear. Here, the authors show that expression of osteoclast-associated receptor (OSCAR) is associated with OA, that its genetic ablation or targeting with OSCAR-Fc fusion protein ameliorates OA in mice by decreasing chondrocyte apoptosis.
- Doo Ri Park
- , Jihee Kim
- & Soo Young Lee
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Article
| Open AccessIsobutanol production freed from biological limits using synthetic biochemistry
A cell free or synthetic biochemistry approach offers a way to circumvent the many constraints of living cells. Here, the authors demonstrate, via enzyme and process enhancements, the production of isobutanol with the metrics exceeding highly developed ethanol fermentation.
- Saken Sherkhanov
- , Tyler P. Korman
- & James U. Bowie
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Article
| Open AccessRibosome-mediated polymerization of long chain carbon and cyclic amino acids into peptides in vitro
Backbone extended monomers are poorly compatible with the natural ribosomes, impeding their polymerization into polypeptides. Here the authors design non-canonical amino acid analogs with cyclic structures or extended carbon chains and used an engineered ribosome to improve tRNA-charging and incorporation into peptides.
- Joongoo Lee
- , Kevin J. Schwarz
- & Michael C. Jewett
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Article
| Open AccessMultiplexed single-cell transcriptional response profiling to define cancer vulnerabilities and therapeutic mechanism of action
Large-scale screens of chemical and genetic vulnerabilities in cancer are typically limited to simple readouts of cell viability. Here, the authors develop a method for profiling post-perturbation transcriptional responses across large pools of cancer cell lines, enabling deep characterization of shared and context-specific responses.
- James M. McFarland
- , Brenton R. Paolella
- & Aviad Tsherniak
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Article
| Open AccessUse of ratiometrically designed nanocarrier targeting CDK4/6 and autophagy pathways for effective pancreatic cancer treatment
Aberrant cell cycle machinery and loss of the CDKN2A tumor suppressor locus make CDK4/6 a potential target in pancreatic ductal adenocarcinoma (PDAC). Here, the authors use ratiometrically designed nanoparticles to codeliver the CDK4/6 inhibitor palbociclib and the autophagy inhibitor hydroxychloroquine, and show their synergistic therapeutic effects in mouse model of PDAC.
- Ying Ji
- , Xiangsheng Liu
- & Huan Meng
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Article
| Open AccessDe novo design of an intercellular signaling toolbox for multi-channel cell–cell communication and biological computation
Intercellular signalling is fundamental for the formation of complex structures from single cells. Here the authors design six orthogonal cell–cell signalling channels for cell consortia communication and bio-computation.
- Pei Du
- , Huiwei Zhao
- & Chunbo Lou
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Article
| Open AccessContinuous bioactivity-dependent evolution of an antibiotic biosynthetic pathway
Biosynthetic gene clusters (BGCs) make small molecules with fitness-enhancing activities that drive BGC evolution. Here, the authors show that synthetic biology can leverage bioactivity to achieve continuous evolution of an antibiotic BGC in the lab and improve antibiotic production in a new host.
- Chad W. Johnston
- , Ahmed H. Badran
- & James J. Collins
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Article
| Open AccessCRISPR GUARD protects off-target sites from Cas9 nuclease activity using short guide RNAs
Off-target editing remains a concern for therapeutic applications of CRISPR-Cas9. Here the authors present CRISPR GUARD, which uses very short non-cleaving gRNAs to prevent editing at off-target sites.
- Matthew A. Coelho
- , Etienne De Braekeleer
- & Benjamin J. M. Taylor
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Article
| Open AccessVulnerability of progeroid smooth muscle cells to biomechanical forces is mediated by MMP13
Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disease and smooth muscle cells are the most affected cells in HGPS individuals. Here, the authors report a microfluidics platform with HGPS induced pluripotent stem cells and show that inhibition of metalloprotease 13 may reduce smooth muscle cell loss.
- Patricia R. Pitrez
- , Luís Estronca
- & Lino Ferreira
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Article
| Open AccessDevelopment of light-responsive protein binding in the monobody non-immunoglobulin scaffold
The ability to reversibly control monobody binding affinity would find use in biotechnology and research applications. Here the authors fuse the light-sensitive AsLOV2 domain to a monobody against the Abl SH2 domain to obtain a light dependent monobody and apply it in vitro and in mammalian cells.
- César Carrasco-López
- , Evan M. Zhao
- & José L. Avalos
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Article
| Open AccessGenome-wide specificity of dCpf1 cytidine base editors
Cas12a-linked base editors can broaden the targeting scope of programmable cytidine deaminases. Here the authors assess their target specificity in an in vitro genome-wide assay.
- Daesik Kim
- , Kayeong Lim
- & Jin-Soo Kim
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Article
| Open AccessOptogenetic control of protein binding using light-switchable nanobodies
The ability to regulate nanobody affinity with light would expand the applications toolbox for these reagents. Here the authors insert an optimised photoswitchable AsLOV2 domain into multiple nanobodies and demonstrate photoswitchable binding to fluorescent proteins and endogenous proteins in cells.
- Agnieszka A. Gil
- , César Carrasco-López
- & Jared E. Toettcher
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Article
| Open AccessIdentification of modified peptides using localization-aware open search
Mass spectrometry-based proteomics is the method of choice for the global mapping of post-translational modifications, but matching and scoring peaks with unknown masses remains challenging. Here, the authors present a refined open search strategy to score all peaks with higher sensitivity and accuracy.
- Fengchao Yu
- , Guo Ci Teo
- & Alexey I. Nesvizhskii
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Article
| Open AccessTargeted gene correction of human hematopoietic stem cells for the treatment of Wiskott - Aldrich Syndrome
In recent years, hematopoietic stem cells gene editing has emerged as a promising tool to treat blood disorders. Here the authors develop a CRISPR/Cas9-based genome editing strategy that allows the precise correction of Wiskott-Aldrich Syndrome in vitro and in vivo with high efficiency.
- Rajeev Rai
- , Marianna Romito
- & Alessia Cavazza
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Article
| Open AccessPyropia yezoensis genome reveals diverse mechanisms of carbon acquisition in the intertidal environment
The nori producing seaweed Pyropia yezoensis has heteromorphic generations that occupy distinct habitats. Here, via genome assembly, transcriptome analysis, and 13 C isotope labeling, the authors show the interplay between inorganic carbon availability and life cycle evolution in the intertidal environment.
- Dongmei Wang
- , Xinzi Yu
- & Yunxiang Mao
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Article
| Open AccessEnhancing myocardial repair with CardioClusters
Despite recent progress to advance cardiac cell-based therapy for patients, heart failure mortality rivals most cancers. Here, the authors describe an approach to control and pattern 3 distinct human cardiac cell populations to promote superior repair and regeneration after myocardial infarction.
- Megan M. Monsanto
- , Bingyan J. Wang
- & Mark A. Sussman
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Article
| Open AccessMultiplexed Optical Sensors in Arrayed Islands of Cells for multimodal recordings of cellular physiology
Existing fluorescent protein-based sensor measurements are limited to 4 or fewer simultaneously recorded modalities due to spectral overlap. Here the authors introduce Multiplexed Optical Sensors in Arrayed Islands of Cells (MOSAIC), which enables parallel recording of tens of physiological parameters using dense arrays of cell islands, each expressing a different fluorescent sensor.
- Christopher A. Werley
- , Stefano Boccardo
- & Adam E. Cohen
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Article
| Open AccessEngineered immunological niches to monitor disease activity and treatment efficacy in relapsing multiple sclerosis
Monitoring changes in immune phenotype during the progression of multiple sclerosis can provide insight into disease progression and inform treatment. Here the authors develop engineered biomaterial-based immunological niches for easy access to innate immune cells in a mouse model of multiple sclerosis.
- Aaron H. Morris
- , Kevin R. Hughes
- & Lonnie D. Shea
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Article
| Open AccessA protein-independent fluorescent RNA aptamer reporter system for plant genetic engineering
Fluorescent RNA aptamers could potentially be used as protein-independent reporters of transgene expression in plants. Here, the authors report that an optimized RNA aptamer, developed from Broccoli, can be used to detect transgene expression in stable and transiently transformed plant tissue.
- Jiuyuan Bai
- , Yao Luo
- & Yun Zhao
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Article
| Open AccessStrategies to enable large-scale proteomics for reproducible research
Clinical proteomics critically depends on the ability to acquire highly reproducible data over an extended period of time. Here, the authors assess reproducibility over four months across different mass spectrometers and develop a computational approach to mitigate variation among instruments over time.
- Rebecca C. Poulos
- , Peter G. Hains
- & Qing Zhong
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Article
| Open AccessSynthetic microbial communities of heterotrophs and phototrophs facilitate sustainable growth
Successful application of microbial community for bioproduction relies on the selection of appropriate heterotroph and phototroph partners. Here, the authors construct community metabolic models to guide strain selection and experimentally validate metabolic exchanges that sustain the heterotrophs in minimal media.
- Cristal Zuñiga
- , Tingting Li
- & Karsten Zengler
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Article
| Open AccessEx vivo editing of human hematopoietic stem cells for erythroid expression of therapeutic proteins
A platform for systemic therapeutic transgene expression independent of patient mutations needs a safe and highly transcribed locus. Here the authors ex vivo edit HPSCs using CRISPR-Cas9 to integrate transgenes under the α-globin promoter to achieve erythroid specific expression.
- Giulia Pavani
- , Marine Laurent
- & Mario Amendola
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Article
| Open AccessDevelopmental GABA polarity switch and neuronal plasticity in Bioengineered Neuronal Organoids
Brain organoids are important tools to study early development and disease but little is known of their network activity and plasticity. Here the authors generate iPSC-derived neuronal organoids that display early network formation and maturation with evidence for a GABA polarity switch and long-term potentiation.
- Maria-Patapia Zafeiriou
- , Guobin Bao
- & Wolfram-Hubertus Zimmermann
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Article
| Open AccessGradual polyploid genome evolution revealed by pan-genomic analysis of Brachypodium hybridum and its diploid progenitors
Existing plant pan-genomic studies usually report considerable intraspecific whole gene presence-absence variation. Here, the authors use pan-genomic approach to reveal gradual polyploid genome evolution by analyzing of Brachypodium hybridum and its diploid progenitors.
- Sean P. Gordon
- , Bruno Contreras-Moreira
- & John P. Vogel
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Article
| Open AccessGenome assembly of wild tea tree DASZ reveals pedigree and selection history of tea varieties
Wild teas are considered as valuable resource for studying domestication and breeding. Here, Zhang et al. report genome of wild tea DASZ and transcriptome of 217 accessions, which clarify pedigree of Chinese tea cultivars and show tea may not have undergone long-term artificial directional selection on flavor-related metabolites.
- Weiyi Zhang
- , Youjun Zhang
- & Weiwei Wen
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Article
| Open AccessA non-invasive far-red light-induced split-Cre recombinase system for controllable genome engineering in mice
Current light-inducible Cre-loxP systems have minimal capacity for deep tissue penetration. Here, the authors present a far-red light-induced split Cre-loxP system for in vivo genome engineering.
- Jiali Wu
- , Meiyan Wang
- & Haifeng Ye
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Article
| Open AccessRapid, deep and precise profiling of the plasma proteome with multi-nanoparticle protein corona
Large-scale, unbiased proteomics studies of biological samples like plasma are constrained by the complexity of the proteome. Herein, the authors develop a highly parallel protein quantitation platform leveraging multi nanoparticle protein coronas for deep proteome sampling and biomarker discovery.
- John E. Blume
- , William C. Manning
- & Omid C. Farokhzad
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Article
| Open AccessNon-invasive early detection of cancer four years before conventional diagnosis using a blood test
Patients whose disease is diagnosed in its early stages have better outcomes. In this study, the authors develop a non invasive blood test based on circulating tumor DNA methylation that can potentially detect cancer occurrence even in asymptomatic patients.
- Xingdong Chen
- , Jeffrey Gole
- & Li Jin
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Article
| Open AccessPrediction-based highly sensitive CRISPR off-target validation using target-specific DNA enrichment
Off-target mutations that occur at a frequency below 0.5% can be difficult to detect. Here the authors use predicted off-target amplification to increase detection sensitivity.
- Seung-Hun Kang
- , Wi-jae Lee
- & Seung Hwan Lee
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Article
| Open AccessHigh-performance CRISPR-Cas12a genome editing for combinatorial genetic screening
Reliable, multiplexed gene editing to uncover synergies between targets remains challenging. Here, the authors engineer AsCas12a and the crRNA to improve double knockout for synthetic sick/lethal interaction genetic screening.
- Rodrigo A. Gier
- , Krista A. Budinich
- & Junwei Shi
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Article
| Open AccessMechano-modulatory synthetic niches for liver organoid derivation
3D liver organoids hold great promise for regenerative medicine but the use of ill-defined matrices limits their potential. Here, the authors generate human and mouse liver organoids using a chemically defined matrix, and reveal a link between matrix stiffness and organoid growth that does not require acto-myosin contraction.
- Giovanni Sorrentino
- , Saba Rezakhani
- & Kristina Schoonjans
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Article
| Open AccessAccessing unexplored regions of sequence space in directed enzyme evolution via insertion/deletion mutagenesis
Insertions/Deletions (InDels) remain an untapped source of protein diversity in laboratory evolution. The method TRIAD generates libraries of random variants with short in-frame InDels using transposons, allowing a comparison of their evolutionary potential with widely-used point mutant libraries.
- Stephane Emond
- , Maya Petek
- & Florian Hollfelder
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Article
| Open AccessSearching large-scale scRNA-seq databases via unbiased cell embedding with Cell BLAST
Single-cell RNA-seq (scRNA-seq) is being widely used to resolve cellular heterogeneity. Here, the authors present a cell-querying method built on a neural network-based generative model and a customized cell-to-cell similarity metric.
- Zhi-Jie Cao
- , Lin Wei
- & Ge Gao
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Article
| 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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