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| Open AccessCytosolic lipid droplets as engineered organelles for production and accumulation of terpenoid biomaterials in leaves
Cytosolic lipid droplets are ER-derived organelles that accumulate in seeds to fuel germination. Here, Sadre et al. show that by boosting lipid production and anchoring key terpenoid biosynthetic enzymes to the droplet surface, an efficient terpenoid production platform can be established in leaves.
- Radin Sadre
- , Peiyen Kuo
- & Bjoern Hamberger
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Article
| Open AccessIntradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes
Chemically modified mRNA is a new approach for therapeutic protein expression that could be applied to angiogenesis. Here the authors show in a phase 1 clinical trial that a modified mRNA encoding VEGF-A is well tolerated in patients with type 2 diabetes.
- Li-Ming Gan
- , Maria Lagerström-Fermér
- & Regina Fritsche-Danielson
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Article
| Open AccessSingle gold-bridged nanoprobes for identification of single point DNA mutations
The identification of single point mutations is an important step toward personalizing detection and treatment. Here the authors design a gold-bridged nanoparticle for sensing MutS affinities to point mutations, and compile an atlas of the affinity data for detecting BRCA1 mutations in cell lines.
- Xingyi Ma
- , Sojin Song
- & Sang Jun Sim
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Article
| Open AccessFraC nanopores with adjustable diameter identify the mass of opposite-charge peptides with 44 dalton resolution
Using Fragaceatoxin C nanopores to study peptides below 1.6 kDa is challenging. Here the authors demonstrate that nanopores can be engineered to different sizes to detect a range of peptide lengths below the previous resolution limit, and show that the mass of a peptide can be identified by ionic current blockades.
- Gang Huang
- , Arnout Voet
- & Giovanni Maglia
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Article
| Open AccessHigh-speed mechano-active multielectrode array for investigating rapid stretch effects on cardiac tissue
While strain is known to affect cardiac electrophysiology, experimental systems to interrogate the effect of rapid strain cycles on cardiac tissue are lacking. Here the authors introduce a multielectrode array that can induce rapid dynamic strain cycles on cardiomyocyte strands and see effects of strain amplitude but not strain rate on impulse conduction.
- Matthias Imboden
- , Etienne de Coulon
- & Stephan Rohr
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Article
| Open AccessEliciting the impacts of cellular noise on metabolic trade-offs by quantitative mass imaging
How cellular noise impacts metabolic trade-offs remains unknown. Here, the authors use a quantitative single-cell mass imaging strategy to reveal that cellular noise impacts cellular biomass and triacylglycerol accumulation, as well as protein and fatty-acid recycling under starvation, differently.
- A. E. Vasdekis
- , H. Alanazi
- & G. Stephanopoulos
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Article
| Open AccessIntravenous treatment of choroidal neovascularization by photo-targeted nanoparticles
Current treatments of wet age-related macular degeneration require repeated injections of active drugs into the vitreous. Here Wang et al. develop nanoparticles that when injected intravenously can be targeted to the eye by irradiation with blue light, allowing local and enhanced drug release in the back of the eye, and providing an alternative to current delivery strategies.
- Yanfei Wang
- , Chi-Hsiu Liu
- & Daniel S. Kohane
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Article
| Open AccessDisulfide-mediated conversion of 8-mer bowl-like protein architecture into three different nanocages
Shape transformation of proteins created by design in the laboratory is challenging. Here, the authors present a disulfide-mediated approach for the preparation of 16-mer, 24-mer, and 48-mer nanocages from an 8-mer bowl-like protein building block.
- Jiachen Zang
- , Hai Chen
- & Guanghua Zhao
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Article
| Open AccessSingle gametophyte sequencing reveals that crossover events differ between sexes in maize
Meiotic crossover (CO) landscape differs inter- and intra-species, as well as between sexes. Here, the authors show that male meiosis produces more COs than female in maize and detect CO maturation inefficiency in some genetic backgrounds, which may help to improve breeding efficiency.
- Cheng Luo
- , Xiang Li
- & Jianbing Yan
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Article
| Open AccessTear resistance of soft collagenous tissues
Defect tolerance is important in order to ensure the mechanical integrity of synthetic materials and biological tissues. Here the authors demonstrate that toughening mechanisms provide soft collagenous tissues with high defect tolerance, with important implications for biomedical applications.
- Kevin Bircher
- , Manuel Zündel
- & Edoardo Mazza
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Article
| Open AccessSite-specific manipulation of Arabidopsis loci using CRISPR-Cas9 SunTag systems
Few approaches for targeted manipulation of the epigenome are available in plants. Here, the authors adapt the dCas9-SunTag system to engineer targeted gene activation and site-specific manipulation of DNA methylation in Arabidopsis.
- Ashot Papikian
- , Wanlu Liu
- & Steven E. Jacobsen
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Article
| Open AccessImprovement of antibody functionality by structure-guided paratope engraftment
Quaternary contacts mediated by an extended heavy-chain framework region 3 (FR3) have been shown to improve binding to HIV envelope and virus neutralization for a few antibodies. Here, Liu et al. engraft such an FR3 loop onto several potent broadly neutralizing antibodies, resulting in improved neutralization activity and pharmacokinetics.
- Qingbo Liu
- , Yen-Ting Lai
- & Paolo Lusso
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Article
| Open AccessGeneration of pluripotent stem cell-derived mouse kidneys in Sall1-targeted anephric rats
The use of pluripotent-stem cell derived organs for transplantation would be promising, if organs can be grown in a suitable host. Here, the authors use interspecific blastocyst complementation to generate a mouse pluripotent stem cell-derived kidney in anephric Sall1 mutant rats.
- Teppei Goto
- , Hiromasa Hara
- & Masumi Hirabayashi
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Article
| Open AccessPatterned human microvascular grafts enable rapid vascularization and increase perfusion in infarcted rat hearts
Heart grafts need good vascularization to survive. Here, the authors engineer perfusable constructs of human embryonic stem cell-derived endothelial cells seeded in collagen matrix in patterned microchannels that form anastomosed vessels in vitro and have increased coronary vascular perfusion on transplantation in rats.
- Meredith A. Redd
- , Nicole Zeinstra
- & Ying Zheng
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Article
| Open AccessEngineered microbial biofuel production and recovery under supercritical carbon dioxide
End-product toxicity, culture contamination, and energy efficient product recovery are long-standing issues in bioprocessing. Here, the authors address these problems using a fermentation strategy that combines microbial production of branched alcohols with supercritical carbon dioxide extraction.
- Jason T. Boock
- , Adam J. E. Freedman
- & Janelle R. Thompson
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Article
| Open AccessImmune modulation of liver sinusoidal endothelial cells by melittin nanoparticles suppresses liver metastasis
Liver sinusoidal endothelial cells are known to promote immune tolerance in liver. Here, the authors target these cells using melittin nanoparticles and show alterations in the liver immune environment and suppression of liver metastases.
- Xiang Yu
- , Lu Chen
- & Zhihong Zhang
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Article
| Open AccessA cell-free platform for the prenylation of natural products and application to cannabinoid production
Producing individual cannabinoids by metabolically engineered microbes has proven challenging. Here, the authors develop a cell-free enzymatic prenylating system to generate isoprenyl pyrophosphate substrates directly from glucose and produce both common and rare cannabinoids at >1 g/L.
- Meaghan A. Valliere
- , Tyler P. Korman
- & James U. Bowie
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Article
| Open AccessPluripotency and X chromosome dynamics revealed in pig pre-gastrulating embryos by single cell analysis
Lineage segregation from conception to gastrulation has been mapped at the single cell level in mouse, human and monkey. Here, the authors provide a comprehensive analysis of porcine preimplantation development using single cell RNA-seq; mapping metabolic changes, X chromosome inactivation and signalling pathways.
- Priscila Ramos-Ibeas
- , Fei Sang
- & Ramiro Alberio
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Article
| Open AccessNext-generation muscle-directed gene therapy by in silico vector design
Adeno-associated viral vectors (AAV) are being developed for gene therapy of skeletal muscle, but it is a challenge to achieve robust gene expression. Here, the authors identify muscle-specific cisregulatory elements that lead to a substantial increase in micro-dystrophin and follistatin expression, resulting in a safe and sustainable rescue of the dystrophic phenotype in mouse models.
- S. Sarcar
- , W. Tulalamba
- & M. K. Chuah
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Article
| Open AccessA tetracycline-dependent ribozyme switch allows conditional induction of gene expression in Caenorhabditis elegans
Tools for conditional induction of gene expression in C. elegans are limited compared to other organisms. Here the authors present a tetracycline-dependent ribozyme that allows conditional control of a gene of interest.
- Lena A. Wurmthaler
- , Monika Sack
- & Martin Gamerdinger
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Article
| Open AccessHierarchical composition of reliable recombinase logic devices
Genetic logic devices allow the host cell to incorporate multiple inputs to determine output behaviour. Here the authors provide a framework for engineering reliable recombinase-based devices and demonstrate 4-input logic in a multicellular system.
- Sarah Guiziou
- , Pauline Mayonove
- & Jerome Bonnet
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Article
| Open AccessDeconvolution of single-cell multi-omics layers reveals regulatory heterogeneity
Heterogeneity in gene expression and epigenetic states exists across individual cells. Here, the authors develop scCAT-seq, a technique for simultaneously performing ATAC-seq and RNA-seq within the same single cell.
- Longqi Liu
- , Chuanyu Liu
- & Xun Xu
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Article
| Open AccessThe functional synergism of microRNA clustering provides therapeutically relevant epigenetic interference in glioblastoma
The delivery of single therapeutic microRNAs in brain cancers is challenging. Here, the authors engineer three neuronal microRNAs (miR-124, 128 and 137) into a cluster that, targeting oncogenic chromatin repressors, increases survival of GBM-bearing mice when combined with chemotherapy.
- Vivek Bhaskaran
- , Michal O. Nowicki
- & Pierpaolo Peruzzi
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Article
| Open AccessEngineering of high-precision base editors for site-specific single nucleotide replacement
Base editors can target multiple bases within a window around the target site, reducing their specificity. Here the authors engineer the connection between the deaminase and Cas domain to narrow the window of activity.
- Junjie Tan
- , Fei Zhang
- & Ralph Bock
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Article
| Open AccessChromosome conformation capture resolved near complete genome assembly of broomcorn millet
Broomcorn millet is one of the oldest crops cultivated by human that has strong abiotic stress tolerance. To facilitate genome assisted breeding of this and related species, the authors report its genome assembly and conduct comparative genome structure and evolution analyses with foxtail millet.
- Junpeng Shi
- , Xuxu Ma
- & Jinsheng Lai
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Article
| Open AccessComparative oncogenomics identifies combinations of driver genes and drug targets in BRCA1-mutated breast cancer
It is difficult to identify cancer driver genes in cancers, for instance BRCA1 mutated breast cancer, that are characterised by large scale genomic alterations. Here, the authors develop genetically engineered mouse models of BRCA1-deficient breast cancer that allow highthroughput in vivo perturbation of candidate driver genes, validating drivers Myc, Met, Pten and Rb1, and identifying MCL1 as a collaborating driver whose targeting can impact efficacy of PARP inhibition.
- Stefano Annunziato
- , Julian R. de Ruiter
- & Jos Jonkers
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Article
| Open AccessEngineering of CRISPR-Cas12b for human genome editing
The Cas12b family of CRISPR nucleases has been underutilized in mammalian cells due to the high temperature requirement of known members. Here the authors engineer BhCas12b to overcome this limitation for robust and specific genome editing applications in human cells.
- Jonathan Strecker
- , Sara Jones
- & Feng Zhang
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Article
| Open AccessC1 CAGE detects transcription start sites and enhancer activity at single-cell resolution
Single-cell transcriptomic profiling allows the exploration of cellular heterogeneity but commonly focuses on the 3′-end of the transcript. Here the authors introduce C1 CAGE, which detects the 5′ transcript end in a multiplexed microfluidic system.
- Tsukasa Kouno
- , Jonathan Moody
- & Jay W. Shin
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Article
| Open AccessEfficient oral vaccination by bioengineering virus-like particles with protozoan surface proteins
Giardia lamblia express a dense coat of variant-specific surface proteins (VSPs) on trophozoites that protects the parasite inside the host´s intestine. Here the authors show that stability and immunomodulatory properties of VSPs can be exploited to both protect and adjuvant vaccine antigens for oral administration.
- Marianela C. Serradell
- , Lucía L. Rupil
- & Hugo D. Luján
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Article
| Open AccessHematopoietic PBX-interacting protein mediates cartilage degeneration during the pathogenesis of osteoarthritis
Osteoarthritis (OA) is associated with cartilage degeneration, and no effective therapy exists. Here, the authors show that the HPIP protein modulates OA progression by regulating Wnt signaling, and that its knockdown in joints via AAV-mediated gene silencing attentuates pathology.
- Quanbo Ji
- , Xiaojie Xu
- & Yan Wang
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Article
| Open AccessNoninvasive optical activation of Flp recombinase for genetic manipulation in deep mouse brain regions
Most approaches to control gene expression in vivo require generation of knock-in mouse lines and often lack spatiotemporal control. Here the authors develop a photo-activatable Flp recombinase system and demonstrate its use by controlling object-exploration behavior in mice through Cav3.1 silencing.
- Hyunjin Jung
- , Seong-Wook Kim
- & Won Do Heo
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Article
| Open AccessExosomes harbor B cell targets in pancreatic adenocarcinoma and exert decoy function against complement-mediated cytotoxicity
The humoral immune response role in cancer is unclear. Here the authors perform an in-depth proteomic profiling of immunoglobulin-bound proteins in plasma from pancreatic ductal adenocarcinoma patients and find cancer-cell specific antibodies neutralized by binding to cancer-cell derived exosomes.
- Michela Capello
- , Jody V. Vykoukal
- & Samir M. Hanash
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Article
| Open AccessChromosome-level assembly of the water buffalo genome surpasses human and goat genomes in sequence contiguity
Despite technological advances, chromosome-level assemblies of mammalian genomes are still rare. Here, the authors use PacBio, Chicago and Hi-C approaches to generate a highly contiguous and partially-phased genome assembly for the water buffalo, Bubalus bubalis
- Wai Yee Low
- , Rick Tearle
- & John L. Williams
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Article
| Open AccessA micro-dispenser for long-term storage and controlled release of liquids
The integration and release of reagents in portable diagnostic devices is critical for the good functioning of such devices. Here the authors propose a device with a reservoir for long-term storage of reagents with integrated, pressure operated, normally closed, passive check-valve for dispensing.
- Amin Kazemzadeh
- , Anders Eriksson
- & Aman Russom
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Article
| Open AccessAnti-CRISPR-mediated control of gene editing and synthetic circuits in eukaryotic cells
Anti-CRISPR proteins derived from phage can abrogate CRISPR activity. The authors repurpose these molecules for demonstrating genomic write-protection and pre-programmed gene expression circuits.
- Muneaki Nakamura
- , Prashanth Srinivasan
- & Lei S. Qi
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Article
| Open AccessRNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome
Multiple organ dysfunction syndrome (MODS) is a serious event that can occur following infection or tissue injury, and is partly mediated by histones released in circulation. Here, the authors develop aptamers that neutralise histones involved in MODS, and demonstrate efficacy in human cells and in mouse models.
- Kevin T. Urak
- , Giselle N. Blanco
- & Paloma H. Giangrande
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Article
| Open AccessTransforming insect population control with precision guided sterile males with demonstration in flies
Sterile Insect Technique (SIT) is used to suppress wild populations. Here the authors integrate CRISPR-based technology and SIT to develop a precision guided SIT (pgSIT), and demonstrate its proof-of-principle by generating 100% sterile males.
- Nikolay P. Kandul
- , Junru Liu
- & Omar S. Akbari
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Article
| Open AccessRetrotranspositional landscape of Asian rice revealed by 3000 genomes
Transposable elements (TE) are the dominant constituent of plant genomes. Here the authors develop a tool to analyze TE insertion sites in 3000 rice genomes and provide evidence for recent TE activity during cultivation and that external, rather than genetic, stimuli trigger most activations.
- Marie-Christine Carpentier
- , Ernandes Manfroi
- & Olivier Panaud
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Article
| Open AccessGenome editing in primary cells and in vivo using viral-derived Nanoblades loaded with Cas9-sgRNA ribonucleoproteins
A current challenge in genome editing is delivering Cas9 and sgRNA into target cells. Here the authors engineer a delivery system based on murine leukemia virus-like particles loaded with Cas9-sgRNA ribonucleoproteins to induce efficient genome editing in both cell culture and in vivo in mouse.
- Philippe E. Mangeot
- , Valérie Risson
- & Emiliano P. Ricci
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Article
| Open AccessHuman genome-wide measurement of drug-responsive regulatory activity
Quantification of genomic responses to environmental stimuli by current genome-scale assays is limited to indirect measurements or requires knowledge of the transcription factors involved. Here, the authors use genome-wide high-throughput reporter assays to agnostically map enhancer activity in response to glucocorticoid treatment across the human genome.
- Graham D. Johnson
- , Alejandro Barrera
- & Timothy E. Reddy
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Article
| Open AccessOptimized libraries for CRISPR-Cas9 genetic screens with multiple modalities
Genome-wide libraries for CRISPR knockout, interference, and activation have allowed the systemic interrogation of gene function. Here, the authors evaluate the Brunello CRISPRko library and introduce Dolcetto and Calabrese for CRISPRi and CRISPRa, respectively.
- Kendall R. Sanson
- , Ruth E. Hanna
- & John G. Doench
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Article
| Open AccessOrigin and evolution of qingke barley in Tibet
The origin of Tibetan barley (qingke) has been a controversial issue for many years. Here, the authors conduct population genomics study to support that qingke is derived from eastern domesticated barley instead of Tibetan wild barley and suggest southern Tibetan Plateau as its introduction route.
- Xingquan Zeng
- , Yu Guo
- & Nyima Tashi
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Article
| Open AccessHigh-resolution acoustophoretic 3D cell patterning to construct functional collateral cylindroids for ischemia therapy
Engineering 3D tissues faces the challenge of adequate vascularisation for nutrient delivery and gas exchange deep inside the construct. Here the authors use surface acoustic waves to create an aligned array of blood vessels in a hyaluronic acid hydrogel and use it to improve function in a mouse hindlimb ischemia model.
- Byungjun Kang
- , Jisoo Shin
- & Hyungsuk Lee
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Article
| Open AccessA rapid and robust method for single cell chromatin accessibility profiling
ATAC-seq is widely used to identify regulatory regions in the genome. Here the authors develop a simple and robust plate-based single-cell ATAC-seq method that works in fresh and cryopreserved cells.
- Xi Chen
- , Ricardo J. Miragaia
- & Sarah A. Teichmann
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Article
| Open AccessMoVE identifies metabolic valves to switch between phenotypic states
Interventions in metabolic networks can improve microbes for chemical production. Here, the authors develop a tool to identify metabolic valves that can decouple growth and production to systematically improve the rate and yield of biochemical production processes.
- Naveen Venayak
- , Axel von Kamp
- & Radhakrishnan Mahadevan
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Article
| Open AccessClosed-loop functional optogenetic stimulation
Optogenetics is a promising alternative approach for restoration of neuromuscular function. Here the authors establish a closed-loop functional optogenetic stimulation for the control of limb joint angle in murine models, which demonstrates improved control and less fatigue than electrical stimulation systems.
- Shriya S. Srinivasan
- , Benjamin E. Maimon
- & Hugh M. Herr
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Article
| Open AccessBioconjugation strategy for cell surface labelling with gold nanostructures designed for highly localized pH measurement
Understanding the pH changes at cell surfaces is important for understanding the mechanisms of different physiological processes. Here, the authors report on the development of a cell membrane anchored gold nanoparticle for surface enhanced Raman spectroscopy determination of pH.
- Leonardo Puppulin
- , Shigekuni Hosogi
- & Yoshinori Marunaka
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Article
| Open AccessDiscovering de novo peptide substrates for enzymes using machine learning
The discovery of peptide substrates for enzymes with selective activities is a central goal in chemical biology. Here, the authors develop a hybrid method combining machine learning and experimental testing for fast optimization of peptides for specific, orthogononal functions.
- Lorillee Tallorin
- , JiaLei Wang
- & Nathan C. Gianneschi
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Article
| Open AccessDecoding arm speed during reaching
Brain–machine interfaces typically decode arm velocity from motor cortical neurons to move neuroprostheses, but performance of these devices is degraded by erroneous extraction of speed from the neuronal firing patterns. Here, the authors show that this error can be corrected by using a hybrid artificial neural network approach.
- Yoh Inoue
- , Hongwei Mao
- & Andrew B. Schwartz
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