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| Open AccessCell-in-the-loop pattern formation with optogenetically emulated cell-to-cell signaling
Synthetic biological pattern formation is challenging to engineer due to theoretical complexity and practical limitations. Here, the authors introduce a cell-in-the-loop approach in which cells interact through in silico signaling.
- Melinda Liu Perkins
- , Dirk Benzinger
- & Mustafa Khammash
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Article
| Open AccessComplex microparticle architectures from stimuli-responsive intrinsically disordered proteins
The production of microparticles with complex geometries for biotechnological use historically requires sophisticated fabrication techniques. Here, the authors create complex particle geometries by exploiting the metastable region of the phase diagram of thermally responsive intrinsically disordered proteins within microdroplets.
- Stefan Roberts
- , Vincent Miao
- & Ashutosh Chilkoti
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Article
| Open AccessStructures of peptide-free and partially loaded MHC class I molecules reveal mechanisms of peptide selection
Major Histocompatibility Complex (MHC) class I molecules present tightly binding peptides on the cell surface for recognition by cytotoxic T cells. Here, the authors present the crystal structures of a disulfide-stabilized human MHC class I molecule in the peptide-free state and bound with dipeptides, and find that peptide binding is accompanied by concerted conformational switches of the amino acid side chains in the binding pockets.
- Raghavendra Anjanappa
- , Maria Garcia-Alai
- & Rob Meijers
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Article
| Open AccessCaliciviral protein-based artificial translational activator for mammalian gene circuits with RNA-only delivery
Synthetic RNA-based circuits allow for gene regulation without the risk of mutagenesis. Here the authors demonstrate a Caliciviral VPg-based Translational activator which allows translational activation of synthetic mRNAs.
- Hideyuki Nakanishi
- & Hirohide Saito
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Article
| Open AccessDecorating bacteria with self-assembled synthetic receptors
Cell surface proteins mediate the interactions between cells and their extracellular environment. Here the authors design synthetic biomemetic receptor-like sensors that facilitate programmable interactions between bacteria and their target.
- Naama Lahav-Mankovski
- , Pragati Kishore Prasad
- & David Margulies
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Article
| Open AccessA progesterone biosensor derived from microbial screening
Bacteria represent an unexploited reservoir of biosensing proteins. Here the authors use genomic screens and functional assays to isolate a progesterone sensing allosteric transcription factor and use a FRET-based method to develop an optical progesterone sensor.
- Chloé Grazon
- , R C. Baer
- & James E. Galagan
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Article
| Open AccessMajor antigenic site B of human influenza H3N2 viruses has an evolving local fitness landscape
Antigenic site B in influenza A virus hemagglutinin (HA) is immunodominant in circulating human H3N2 strains. Using deep mutational scanning, Wu et al. here define the local fitness landscapes of HA antigenic site B in six human H3N2 strains, providing insights into evolvability of influenza antigenicity.
- Nicholas C. Wu
- , Jakub Otwinowski
- & Ian A. Wilson
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Article
| Open AccessPrioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features
While genome-wide association studies have yielded thousands of trait-associated loci, identifying causal variants remains challenging. Here, the authors perform seven genomics assays in various cell types to prioritize genetic variants in the TNFAIP3 locus, and report high-priority variants within disease-associated haplotypes.
- John P. Ray
- , Carl G. de Boer
- & Nir Hacohen
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Article
| Open AccessBlackjack mutations improve the on-target activities of increased fidelity variants of SpCas9 with 5′G-extended sgRNAs
Mutations to SpCas9 can improve fidelity and mitigate off-target effects. Here the authors generate ‘Blackjack’ mutations that improve fidelity while retaining effectiveness with 21G-sgRNAs.
- Péter István Kulcsár
- , András Tálas
- & Ervin Welker
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Article
| Open AccessA genome-wide approach for identification and characterisation of metabolite-inducible systems
Inducible gene expression tools have important applications as genetically encoded biosensors. Here the authors conduct a genome-wide approach to identify and utilise functional sensors.
- Erik K. R. Hanko
- , Ana C. Paiva
- & Naglis Malys
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Article
| Open AccessGene clustering and copy number variation in alkaloid metabolic pathways of opium poppy
The opium poppy has been a source of painkilling drugs synthesized by the benzylisoquinoline alkaloid pathway. Here, the authors report an improved genome assembly and reveal gene clustering and copy number variation in alkaloid metabolic pathways.
- Qiushi Li
- , Sukanya Ramasamy
- & Sam Yeaman
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Article
| Open AccessMarker-free carotenoid-enriched rice generated through targeted gene insertion using CRISPR-Cas9
Existing examples of targeted gene insertion in plants either rely on a selectable marker gene or result in short DNA inserts. Here, the authors use an optimized CRISPR-Cas9 method to insert a 5.2 kb carotenoid biosynthesis cassette into genomic safe harbors in rice, and obtain marker-free lines with high carotenoid content.
- Oliver Xiaoou Dong
- , Shu Yu
- & Pamela C. Ronald
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Article
| Open AccessEmbracing the dropouts in single-cell RNA-seq analysis
The analysis of RNA-seq data is complicated by dropouts, and these are usually treated as a problem to be addressed. Here, Peng Qiu uses dropouts as a source of information and presents a co-occurrence clustering algorithm to cluster cells based on the dropout pattern; this could be a complementary approach to existing methods.
- Peng Qiu
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Article
| Open AccessA CRISPR-Cas9-based reporter system for single-cell detection of extracellular vesicle-mediated functional transfer of RNA
Extracellular vesicles (EV) facilitate intercellular transfer of biological material including RNA, but the regulatory mechanisms for their formation and transfer are incompletely known. Here the authors develop a CRISPR-based reporting system to detect the transfer of guide RNAs and identify genes not previously linked to EV-mediated RNA delivery.
- Olivier G. de Jong
- , Daniel E. Murphy
- & Pieter Vader
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Article
| Open AccessIn vitro ribosome synthesis and evolution through ribosome display
Directed evolution of the ribosome is challenging because the requirement of cell viability limits the mutations that can be made. Here the authors develop a platform for in vitro ribosome synthesis and evolution (RISE) to overcome these constraints.
- Michael J. Hammerling
- , Brian R. Fritz
- & Michael C. Jewett
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Article
| Open AccessA comparative genomics study of 23 Aspergillus species from section Flavi
Aspergillus fungi classified within the section Flavi include harmful and beneficial species. Here, Kjærbølling et al. analyse the genomes of 23 Flavi species, showing high genetic diversity and potential for synthesis of over 13,700 CAZymes and 1600 secondary metabolites.
- Inge Kjærbølling
- , Tammi Vesth
- & Mikael R. Andersen
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Article
| Open AccessA combined experimental and modelling approach for the Weimberg pathway optimisation
Metabolic engineering is often hampered by non-linear kinetics and allosteric regulatory mechanisms. Here, the authors construct a quantitative model for the pentose degradation Weimberg pathway in Caulobacter crescentus and demonstrate its biotechnological applications in cell-free system and standard metabolic engineering.
- Lu Shen
- , Martha Kohlhaas
- & Bettina Siebers
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Article
| Open AccessA toxin-antidote CRISPR gene drive system for regional population modification
CRISPR homing gene drives are highly invasive and can fail due to the rapid evolution of resistance. Here the authors present TARE drive, inspired by naturally occurring selfish genetic elements, which is less vulnerable to resistance and can potentially be confined to a target population.
- Jackson Champer
- , Esther Lee
- & Philipp W. Messer
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Article
| Open AccessOptogenetic engineering to probe the molecular choreography of STIM1-mediated cell signaling
Optogenetic tools have been used to control cellular behaviours but their use to probe structure-function relations of signalling proteins are underexplored. Here the authors engineer optogenetic modules into STIM1 to dissect molecular details of STIM1-mediated signalling and control various cellular events.
- Guolin Ma
- , Lian He
- & Yubin Zhou
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Article
| Open AccessNeural cell integration into 3D bioprinted skeletal muscle constructs accelerates restoration of muscle function
3D bioprinting of skeletal muscle using primary human muscle progenitor cells results in correct muscle architecture, but functional restoration in rodent models is limited. Here the authors include human neural stem cells into bioprinted skeletal muscle and observe improved architecture and function in vivo.
- Ji Hyun Kim
- , Ickhee Kim
- & Sang Jin Lee
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Article
| Open AccessNaturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA
Endosomal sequestration of lipid-based nanoparticles is a barrier to delivery of nucleic acids. Here the authors test an array of cholesterol variants and perform in-depth investigation of nanoparticle shape, internal structure and intracellular trafficking.
- Siddharth Patel
- , N. Ashwanikumar
- & Gaurav Sahay
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Article
| Open AccessGenome of Tripterygium wilfordii and identification of cytochrome P450 involved in triptolide biosynthesis
Tripterygium wilfordii is a medical plant that can produce antitumor activity compound triptolide. Here, the authors assemble its genome and identify a cytochrome P450 that can catalyze oxidation of a methyl to the acid moiety of dehydroabietic acid in triptolide biosynthesis by integrating multi-omics data.
- Lichan Tu
- , Ping Su
- & Wei Gao
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Article
| Open AccessDNA-based artificial molecular signaling system that mimics basic elements of reception and response
Cells communicate with the outside world to maintain homeostasis. Here the authors design a synthetic biology DNA-based signalling system AMSsys that responds to the presence of ATP.
- Ruizi Peng
- , Liujun Xu
- & Weihong Tan
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Article
| Open AccessA serine/threonine protein kinase encoding gene KERNEL NUMBER PER ROW6 regulates maize grain yield
Selection of kernel number per ear has improved maize yield, but the genetic base is unclear. Here, the authors reveal that a serine/threonine protein kinase KNR6 is a positive regulator of the trait and show in vitro evidences that KNR6 may function through phosphorylating an Arf GTPase-activating protein.
- Haitao Jia
- , Manfei Li
- & Zuxin Zhang
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Article
| Open AccessUltra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy
Although paclitaxel is widely used as a chemotherapy, it suffers from poor solubility and toxicity issues. Here, the authors develop thermostable RNA nanoparticles and report the RNA-paclitaxel complex to display improved stability, drug loading capacity and solubility for improved targeted cancer therapy and reduced immune responses.
- Sijin Guo
- , Mario Vieweger
- & Peixuan Guo
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Article
| Open AccessControlled division of cell-sized vesicles by low densities of membrane-bound proteins
Membrane fission of a cell into two daughters is a core ability of cell-based life. Here the authors show that in artificial cells division can be controlled by regulating membrane curvature using low protein density.
- Jan Steinkühler
- , Roland L. Knorr
- & Reinhard Lipowsky
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Article
| Open AccessExceptional subgenome stability and functional divergence in the allotetraploid Ethiopian cereal teff
Teff is an indigenous cereal critical to food security in the Horn of Africa. Here, the authors report an improved genome assembly and observe the surprisingly low levels of large-scale structural rearrangement, homoeologous exchanges, or bias gene loss after the formation of this tetraploid species.
- Robert VanBuren
- , Ching Man Wai
- & Todd P. Michael
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Article
| Open AccessInference and effects of barcode multiplets in droplet-based single-cell assays
It is assumed that single-cell analyses capture one barcode per cell. Here, the authors show that up to 21% of cell barcodes on the 10X Chromium scATAC-seq assay may be derived from barcode multiplets.
- Caleb A. Lareau
- , Sai Ma
- & Jason D. Buenrostro
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Article
| Open AccessCharacterizing chromatin landscape from aggregate and single-cell genomic assays using flexible duration modeling
Most currently available statistical tools for the analysis of ATAC-seq data were repurposed from tools developed for other functional genomics data (e.g. ChIP-seq). Here, Gabitto et al develop ChromA, a Bayesian statistical approach for the analysis of both bulk and single-cell ATAC-seq data.
- Mariano I. Gabitto
- , Anders Rasmussen
- & Richard Bonneau
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Article
| Open AccessGenetic screens in isogenic mammalian cell lines without single cell cloning
Isogenic pairs of cell lines are powerful tools but time-consuming to generate. Here the authors conduct genome-wide genetic interactions screens of ‘anchor’ genes with SaCas9 and SpCas9.
- Peter C. DeWeirdt
- , Annabel K. Sangree
- & John G. Doench
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Article
| Open AccessNeo-functionalization of a Teosinte branched 1 homologue mediates adaptations of upland rice
A transposon insertion in the regulatory region of maize Tb1 gene leads to increased apical dominance and a reduction of tillering. Here, the authors showed that a duplicated rice Tb1 orthologue, OsTb2, has gained a regulatory effect on tillering opposite that of OsTb1 during artificial selection only in upland japonica rice.
- Jun Lyu
- , Liyu Huang
- & Fengyi Hu
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Article
| Open AccessHigh-throughput identification of synthetic riboswitches by barcode-free amplicon-sequencing in human cells
Riboswitches can mediate ligand-dependent RNA cleavage and splicing to control gene expression. Here the authors present a method to functionally screen large libraries and identify functional variants.
- Benjamin Strobel
- , Maike Spöring
- & Sebastian Kreuz
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Perspective
| Open AccessOrganizing genome engineering for the gigabase scale
Genome-scale engineering requires the integration of a wide range of in silico and in vivo technologies, as well data management procedures and legal infrastructure. Here the authors provide a list of recommendations to address these challenges.
- Bryan A. Bartley
- , Jacob Beal
- & Elizabeth A. Strychalski
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Article
| Open AccessBridging non-overlapping reads illuminates high-order epistasis between distal protein sites in a GPCR
Epistasis effects among amino acids at distal sites within binding pockets can have important impacts on protein fitness landscapes. Here the authors present BRIDGE, which matches non-overlapping sequence reads with their cognate DNA templates.
- Justin I. Yoo
- , Patrick S. Daugherty
- & Michelle A. O’Malley
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Article
| Open AccessExpanding the genome-targeting scope and the site selectivity of high-precision base editors
Base editors can be limited by precision and the size of the target window. Here the authors test Cas9s that recognise alternative PAMs to obtain a series of high-precision editors.
- Junjie Tan
- , Fei Zhang
- & Ralph Bock
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Article
| Open AccessProbing the physical limits of reliable DNA data retrieval
The physical limits and reliability of PCR-based random access of DNA encoded data is unknown. Here the authors demonstrate reliable file recovery from as few as ten copies per sequence, providing a data density limit of 17 exabytes per gram.
- Lee Organick
- , Yuan-Jyue Chen
- & Luis Ceze
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Article
| Open AccessMicrochannel network hydrogel induced ischemic blood perfusion connection
Restoration of blood flow to damaged sites has commonly involved treatment with pro-angiogenic molecules but these have undesired side effects. Here the authors present a microchannel-patterned gelatin hydrogel that is able to rescue mouse and porcine models of hindlimb ischemia.
- Jung Bok Lee
- , Dae-Hyun Kim
- & Hak-Joon Sung
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Article
| Open AccessDual functionalized brain-targeting nanoinhibitors restrain temozolomide-resistant glioma via attenuating EGFR and MET signaling pathways
Receptor tyrosine kinases are often activated in malignant gliomas. Here, the authors develop a dual functionalized brain targeting nano-inhibitor to simultaneously target EGFR and MET pathways, and show this can overcome temozolomide resistance in glioma.
- Xiangqi Meng
- , Yu Zhao
- & Jinquan Cai
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Article
| Open AccessRewiring of endogenous signaling pathways to genomic targets for therapeutic cell reprogramming
Current cellular rewiring designs are typically tailored to detect single inputs. Here the authors present GEARs that function independently of engineered receptor/reporter systems and directly reroute endogenous signaling pathways to alternative genomic loci using dCas9-directed gene expression.
- Krzysztof Krawczyk
- , Leo Scheller
- & Martin Fussenegger
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Article
| Open AccessModeling medulloblastoma in vivo and with human cerebellar organoids
Group 3 medulloblastoma (MB) is considered one of the most aggressive forms of this cancer. Here, the authors show that Otx2 and c-MYC oncogenes can drive Group 3 MB formation in mouse and human cerebellar organoids while SMARCA4 overexpression or a EZH2-specific inhibitor can inhibit tumorigenesis.
- Claudio Ballabio
- , Marica Anderle
- & Luca Tiberi
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Article
| Open AccessAn optochemical tool for light-induced dissociation of adherens junctions to control mechanical coupling between cells
Adherens junctions (AJs) mediate cell-cell adhesion between epithelial cells but tools to study their dynamic regulation are lacking. Here the authors develop an optochemical tool to stimulate the assembly of AJs through addition of a photocleavable tool and their dissociation upon exposure to light.
- Dirk Ollech
- , Tim Pflästerer
- & Elisabetta Ada Cavalcanti-Adam
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Article
| Open AccessHigh-quality genome sequence of white lupin provides insight into soil exploration and seed quality
White lupin is an annual crop cultivated for protein rich seeds and can produce cluster roots for efficient phosphate acquisition. Here, the authors generate high quality genome assemblies of a cultivated accession, a landrace, and a wild relative and provides insight into soil exploration and seed quality.
- Bárbara Hufnagel
- , André Marques
- & Benjamin Péret
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Article
| Open AccessSingle AAV-mediated mutation replacement genome editing in limited number of photoreceptors restores vision in mice
Replacing mutant genes with wildtype copies using adeno-associated virus (AAV) has been explored for the treatment of inherited retinopathies, but the low cargo limit restricts its use. Here the authors describe a single AAV platform that allows local replacement of a mutated sequence with its wildtype counterpart, based on combined CRISPR-Cas9 and micro-homology-mediated end joining.
- Koji M. Nishiguchi
- , Kosuke Fujita
- & Toru Nakazawa
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Article
| Open AccessA common wild rice-derived BOC1 allele reduces callus browning in indica rice transformation
Callus browning heavily affects indica rice transformation regeneration. Here, the authors show transposon insertion in the promoter of BOC1 gene, encoding a SIMILAR TO RADICAL-INDUCED CELL DEATH ONE protein, can upregulate its expression and decrease callus browning in cultivated rice by releasing oxidative stress.
- Kun Zhang
- , Jingjing Su
- & Yongcai Fu
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Article
| Open AccessHaplotyping the Vitis collinear core genome with rhAmpSeq improves marker transferability in a diverse genus
Trait introgression requires universal markers, but cross-species transferability of current SNP markers can be as low as 2%. Here, the authors use an AmpSeq haplotype strategy targeting the collinear core genome for marker development and show transferability increases to 91.4% in the Vitis genus.
- Cheng Zou
- , Avinash Karn
- & Lance Cadle-Davidson
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Article
| Open AccessA transcomplementing gene drive provides a flexible platform for laboratory investigation and potential field deployment
Gene drives raise safety concerns around unintended propagation. Here the authors present a trans-complementing split-gene drive that requires inheritance of separate transgenes to assemble a fully functional drive.
- Víctor López Del Amo
- , Alena L. Bishop
- & Valentino M. Gantz
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Article
| Open AccessAn ultra-stable cytoplasmic antibody engineered for in vivo applications
Antibodies expressed in the cytosol often form insoluble aggregates, which makes it hard to target intracellular proteins. Here the authors engineer an ultra-stable cytoplasmic antibody (STAND) with a low isoelectric point that can be used in vivo.
- Hiroyuki Kabayama
- , Makoto Takeuchi
- & Katsuhiko Mikoshiba
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Article
| Open AccessMikania micrantha genome provides insights into the molecular mechanism of rapid growth
Mikania micrantha is an extremely fast-growing invasive plant species that can cause serious damage to natural ecosystems. Here, the authors assemble its chromosome-scale reference genome and explore possible mechanisms that contribute to its rapid growth.
- Bo Liu
- , Jian Yan
- & Fanghao Wan
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Article
| Open AccessAnti-BCMA chimeric antigen receptors with fully human heavy-chain-only antigen recognition domains
Chimeric antigen receptors (CAR) use antibody variable regions to activate anti-tumor immunity. Here the authors show that a mouse IgH/IgL variable region used in a clinical CAR induces host immune responses to possibly reduce therapy efficacy, but an IgH-only CAR T design achieves similar CAR T activity but is potentially less immunogenic.
- Norris Lam
- , Nathan D. Trinklein
- & James N. Kochenderfer
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