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| Open AccessSplit intein-mediated selection of cells containing two plasmids using a single antibiotic
Engineering cell lines often requires multiple plasmids with different selection markers. Here the authors present SiMPl, a method based on rationally engineered split enzymes which get reconstituted via intein-mediated protein splicing to maintain two plasmids using a single antibiotic.
- Navaneethan Palanisamy
- , Anna Degen
- & Barbara Di Ventura
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Article
| Open AccessIncreased yields and biological potency of knob-into-hole-based soluble MHC class II molecules
Recombinant MHC class II molecules are instrumental in antigen-specific T-cell identification assays and showed efficacy as experimental medicines. Here, the authors engineer MHC class II molecules with species-specific knob-into-hole heteromerization domains, enabling a translatable purification process with improved stability, yields, and biological potency.
- Pau Serra
- , Nahir Garabatos
- & Pere Santamaria
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Article
| Open AccessChloroplastic metabolic engineering coupled with isoprenoid pool enhancement for committed taxanes biosynthesis in Nicotiana benthamiana
Engineering Taxol pathway in microbes needs to overcome the difficulty of expressing plant P450 enzymes. Here, the authors use a compartmentalized metabolic engineering strategy to construct the taxanes production pathway in chloroplasts of Nicotiana benthamiana and realize the production of taxadience-5α-ol.
- Jianhua Li
- , Ishmael Mutanda
- & Yong Wang
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Article
| Open AccessExpansion of phycobilisome linker gene families in mesophilic red algae
Widely distributed red algae have experienced massive genome reduction during evolution. Here, using an improved genome assembly of Porphyridium purpureum, Lee et al. show the role of endosymbiotic gene transfer in plastid evolution and the correlation between phycobilisome linker diversification and the red algal radiation.
- JunMo Lee
- , Dongseok Kim
- & Hwan Su Yoon
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Article
| Open AccessMice with hyper-long telomeres show less metabolic aging and longer lifespans
Telomere shortening is associated with aging. Here the authors analyze mice with hyperlong telomeres and demonstrate that longer telomeres than normal have beneficial effects such as delayed metabolic aging, increased longevity and less incidence of cancer.
- Miguel A. Muñoz-Lorente
- , Alba C. Cano-Martin
- & Maria A. Blasco
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Article
| Open AccessTransforming protein-polymer conjugate purification by tuning protein solubility
Therapeutic proteins are often conjugated with polymers, but separating the conjugate from unconjugated protein and free polymer is a major challenge. Here, the authors discover that proteins conjugated to charged or zwitterionic polymers maintain solubility in 100% ammonium sulfate, greatly simplifying purification.
- Stefanie L. Baker
- , Aravinda Munasinghe
- & Alan J. Russell
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Article
| Open AccessThe chromosome-scale reference genome of black pepper provides insight into piperine biosynthesis
Black pepper (Piper nigrum) belongs to the long-isolated lineage of basal angiosperm and its fruit has been used for food spice and phytomedicines for thousands of years. Here, the authors assemble the reference genome of this species and analyze gene families associated with piperine biosynthesis.
- Lisong Hu
- , Zhongping Xu
- & Shuangxia Jin
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Article
| Open AccessEvaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis
Knottin is a cystine knot peptide. Here, the authors develop a knottin-based tracer for positron emission tomography and demonstrate its ability to detect cancer and idiopathic pulmonary fibrosis through selective binding to integrin αvβ6.
- Richard H. Kimura
- , Ling Wang
- & Sanjiv S. Gambhir
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Article
| Open AccessCrossing the blood-brain-barrier with nanoligand drug carriers self-assembled from a phage display peptide
Bacteriophages can bind targets with only a few copies of a display peptide while most nanoparticles with thousands achieve poor binding. Here the authors form hierarchical arrangements of phage peptides to delivery siRNA across the blood brain barrier.
- Lin-Ping Wu
- , Davoud Ahmadvand
- & S. Moein Moghimi
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Article
| Open AccessIn vivo engineered extracellular matrix scaffolds with instructive niches for oriented tissue regeneration
Extracellular matrix (ECM) is an ideal scaffold for tissue engineering but tends to lack hierarchical structure. Here the authors implant sacrificial templates subcutaneously to build an organised ECM scaffold, and following template removal and decellularisation use these scaffolds to create functionally integrated muscle, nerve and artery in vivo.
- Meifeng Zhu
- , Wen Li
- & Deling Kong
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Article
| Open AccessBacterial variability in the mammalian gut captured by a single-cell synthetic oscillator
Synthetic gene oscillators can be used to control timed function and periodic expression of genes. Here the authors demonstrate in vivo implementation in the mammalian gut that can keep time over several days.
- David T. Riglar
- , David L. Richmond
- & Pamela A. Silver
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Article
| Open AccessDetection of spacer precursors formed in vivo during primed CRISPR adaptation
Primed adaptation in the CRISPR-Cas system helps recognition of previously encountered sequence elements and promotes the formation of new memories. Here the authors characterized spacer precursors of type I-E and type I-F CRISPR-Cas system using in vivo models.
- Anna A. Shiriaeva
- , Ekaterina Savitskaya
- & Ekaterina Semenova
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Article
| Open AccessEngineering transferrable microvascular meshes for subcutaneous islet transplantation
The success of engineered tissue depends on the integration of a dense vascular network to supply nutrients and remove waste products. Here the authors design high density microvascular meshes made through an anchored self-assembly mechanism, and use these meshes to support subcutaneous pancreatic islet survival in a mouse diabetes model.
- Wei Song
- , Alan Chiu
- & Minglin Ma
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Article
| Open AccessDissecting splicing decisions and cell-to-cell variability with designed sequence libraries
Alternative splicing is regulated by multiple mechanisms. Here the authors employed designed splice site libraries and massively parallel reporter assays to dissect the regulatory complexity and cell-to-cell variability of splicing decisions and to build accurate predictive models.
- Martin Mikl
- , Amit Hamburg
- & Eran Segal
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Article
| Open AccessGalactose to tagatose isomerization at moderate temperatures with high conversion and productivity
Production of tagatose, a sugar substitute, by isomerization of galactose suffers from unfavorable enzymatic kinetics, low enzyme stability, and low equilibrium constant. Here, the authors simultaneously overcome these limitations by encapsulating l-arabinose isomerase in permeabilized Lactobacillus plantarum.
- Josef R. Bober
- & Nikhil U. Nair
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Article
| Open AccessRestoration of visual function by transplantation of optogenetically engineered photoreceptors
A challenge in cell therapy for photoreceptor degeneration is inducing the grafted cells to grow and maintain light sensitive outer segments. Here, the authors use optogenetics to circumvent this problem and restore visual function in blind mice.
- Marcela Garita-Hernandez
- , Maruša Lampič
- & Jens Duebel
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Article
| Open Access3D extracellular matrix microenvironment in bioengineered tissue models of primary pediatric and adult brain tumors
The brain extracellular matrix (ECM) is altered in brain tumors, but its role in cancer progression and drug sensitivity are difficult to study. Here the authors develop a 3D bioengineered brain tissue model using patient-derived samples and tunable brain-derived ECM to examine the interplay between cells and the ECM.
- Disha Sood
- , Min Tang-Schomer
- & David L. Kaplan
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Article
| Open AccessIntegrated evolutionary analysis reveals antimicrobial peptides with limited resistance
Antimicrobial peptides (AMPs) are emerging as drug candidates, but the risk of pathogen resistance is not well understood. Here, the authors investigate AMP resistance evolution in E. coli, finding physicochemical features that make AMPs less prone to resistance and no cross- or horizontally-acquired resistance.
- Réka Spohn
- , Lejla Daruka
- & Csaba Pál
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Article
| Open AccessInsulin-producing organoids engineered from islet and amniotic epithelial cells to treat diabetes
Islet transplantation is a feasible approach to treat type I diabetes, however inflammation and poor vascularisation impair long-term engraftment. Here the authors show that incorporating human amniotic epithelial cells into islet organoids improves engraftment and function of organoids, through enhanced revascularisation.
- Fanny Lebreton
- , Vanessa Lavallard
- & Ekaterine Berishvili
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Article
| Open AccessZinc-doped Prussian blue enhances photothermal clearance of Staphylococcus aureus and promotes tissue repair in infected wounds
Here, the authors apply transition metal doping in combination with phototermal therapy to treat Staphylococcus aureus-infected wounds, and show that release of ions by local heat enhances bacteria clearance and promotes tissue repair in a rat model of MRSA-infected wounds
- Jun Li
- , Xiangmei Liu
- & Shuilin Wu
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Article
| Open AccessA tunable dual-input system for on-demand dynamic gene expression regulation
Cellular systems have numerous mechanisms to control gene expression. Here the authors build a Tet-On system with conditional destablising elements to regulate gene expression and protein stability, allowing fine modulation of mESC signalling pathways.
- Elisa Pedone
- , Lorena Postiglione
- & Lucia Marucci
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Article
| Open AccessFramework engineering to produce dominant T cell receptors with enhanced antigen-specific function
Increasing TCR cell surface expression can potentiate T cell responses to low-concentrations of antigen. Here the authors identify aminoacids in human TCR variable domains that impact its surface expression, and demonstrate how editing these residues can improve T cell activation and effector function without altering antigen specificity.
- Sharyn Thomas
- , Fiyaz Mohammed
- & Hans J. Stauss
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Article
| Open AccessHigh levels of AAV vector integration into CRISPR-induced DNA breaks
In-depth characterization of adeno-associated virus (AAV)-mediated CRISPR delivery is still lacking. Here, the authors show high levels of integration into Cas9-induced double-strand breaks (DSBs) in therapeutically relevant genes in vivo.
- Killian S. Hanlon
- , Benjamin P. Kleinstiver
- & Bence György
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Article
| Open AccessHuman immunoglobulin G hinge regulates agonistic anti-CD40 immunostimulatory and antitumour activities through biophysical flexibility
Conserved regions of the antibody molecule impact its downstream biological effects. Here the authors show that a rigid hinge conformation increases the agonistic activity of CD40 and DR5 antibodies, distinctly from FcγR-binding, suggesting that the hinge and FcR binding regions can be separately modified to optimize therapies.
- Xiaobo Liu
- , Yingjie Zhao
- & Fubin Li
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Article
| Open AccessThe ALFA-tag is a highly versatile tool for nanobody-based bioscience applications
Epitope tags are widely used in various applications, but often lack versatility. Here, the authors introduce a small, alpha helical tag, which is recognized by a high affinity nanobody and can be used in a range of different applications, from protein purification to super-resolution imaging and in vivo detection of proteins.
- Hansjörg Götzke
- , Markus Kilisch
- & Steffen Frey
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Article
| Open AccessSoybean antiviral immunity conferred by dsRNase targets the viral replication complex
Soybean mosaic virus (SMV) is a potyvirus that reduces soybean yield and seed quality worldwide. Here, the authors reveal that the resistance gene Rsv4 encodes an RNase H family protein with dsRNA-degrading activity, and it can enter the viral replication compartment and degrade viral dsRNA.
- Kazuhiro Ishibashi
- , Masayasu Saruta
- & Akito Kaga
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Article
| Open AccessManipulating energy migration within single lanthanide activator for switchable upconversion emissions towards bidirectional photoactivation
Orthogonal light based control of biology is of interest, yet the synthesis of materials capable of this is complex. Here, the authors report on the synthesis of simpler upconversion nanoparticles which used cross-relaxation to change emission spectra from red to green light with a change in NIR wavelength.
- Qingsong Mei
- , Akshaya Bansal
- & Yong Zhang
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Article
| Open AccessSpatiotemporal material functionalization via competitive supramolecular complexation of avidin and biotin analogs
Controlled patterning of functionality within hydrogels typically involves complex chemistry. Here, the authors report on a simple competitive binding strategy using avidin and biotin analogs in an injectable biomaterial for spatiotemporally controlled presentation of biochemical stimuli to cells.
- Tom Kamperman
- , Michelle Koerselman
- & Jeroen Leijten
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Article
| Open AccessCAR exosomes derived from effector CAR-T cells have potent antitumour effects and low toxicity
Genetically engineered T cells expressing a chimeric antigen receptor (CAR-T cells) are a promising new treatment for cancer, but are associated with unique toxicities. Here, the authors test CAR-T-cell-derived exosomes as a surrogate for CAR-T cells and show that they can elicit a potent antitumour immune response in preclinical models of breast cancer with reduced signs of cytokine release syndrome compared with CAR-T therapy.
- Wenyan Fu
- , Changhai Lei
- & Shi Hu
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Article
| Open AccessThermo-responsive triple-function nanotransporter for efficient chemo-photothermal therapy of multidrug-resistant bacterial infection
Antibiotic resistance is a major global health challenge. Here, the authors report on a thermoresponsive delivery system for combined photothermal and antibiotic delivery with fluorescent tracking abilities and demonstrate application against antibiotic resistant bacteria in vitro and in vivo.
- Guangchao Qing
- , Xianxian Zhao
- & Xing-Jie Liang
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Article
| Open AccessLinkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells
Lipid nanoparticles (LNPs) are potential platforms for RNA-based therapeutics, but the fate of LNP-RNAs upon internalization into the cell is unclear. Here, the authors show that LNP-mRNAs and ionizable lipids escape the endosomes and are re-released via extracellular vesicles which could deliver the functional mRNA to other cells.
- Marco Maugeri
- , Muhammad Nawaz
- & Hadi Valadi
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Article
| Open AccessUltra-long-acting tunable biodegradable and removable controlled release implants for drug delivery
Patient drug regime compliance is a major issue; sustained release implants could address this. Here, the authors report on a phase inverted in situ forming implant of PLGA for the sustained release of antiretroviral drugs and optimize and demonstrate the release of 6 different drugs over a period of up to a year.
- S. Rahima Benhabbour
- , Martina Kovarova
- & J. Victor Garcia
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Article
| Open AccessEnhanced CRISPR-based DNA demethylation by Casilio-ME-mediated RNA-guided coupling of methylcytosine oxidation and DNA repair pathways
DNA methylation plays an important role in regulating a wide variety of cellular processes and is implicated in a range of diseases. Here the authors present Casilio-ME to assemble protein complexes to demethylate target loci.
- Aziz Taghbalout
- , Menghan Du
- & Albert W. Cheng
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Article
| Open AccessDevelopment of a longevous two-species biophotovoltaics with constrained electron flow
Power densities of existing microbial biophotovoltaics (BPV) are low and unendurable. Here, the authors develop a BPV based on d-lactate mediated microbial consortium, which can generate an average power density of 135 mW·m−2 for over 40 days in a spatial-temporal separation setup with medium replenishment.
- Huawei Zhu
- , Hengkai Meng
- & Yin Li
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Article
| Open AccessModular enzyme assembly for enhanced cascade biocatalysis and metabolic flux
Metabolic enzymes often form supramolecular complexes to improve product yield. Here the authors use short peptide tags to create scaffold-free assemblies and synthetic metabolic nodes.
- Wei Kang
- , Tian Ma
- & Tiangang Liu
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Article
| Open AccessIn vivo epigenetic editing of Sema6a promoter reverses transcallosal dysconnectivity caused by C11orf46/Arl14ep risk gene
Although many neuropsychiatric risk genes are known to contribute to epigenetic regulation of gene expression, very little is known about specific chromatin-associated mechanisms that govern the formation and maintenance of neuronal connectivity. Here, the authors report that transcallosal connectivity is critically dependent on C11orf46/ARL14EP, a nuclear protein encoded in the chromosome 11p13 WAGR risk locus, and that RNA-guided epigenetic editing of hyperexpressed Sema6a gene promoters in C11orf46-knockdown neurons resulted in normalization of expression and rescue of transcallosal dysconnectivity via repressive chromatin remodeling.
- Cyril J. Peter
- , Atsushi Saito
- & Atsushi Kamiya
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Article
| Open AccessA highly conductive fibre network enables centimetre-scale electron transport in multicellular cable bacteria
Cable bacteria’ form long multicellular filaments that can transfer electrical currents over centimetre-long distances. Here, Meysman et al. show that the electrical currents run along highly conductive fibres embedded in the cell envelope, and charge transfer is electronic rather than ionic.
- Filip J. R. Meysman
- , Rob Cornelissen
- & Jean V. Manca
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Article
| Open AccessBacterial co-culture with cell signaling translator and growth controller modules for autonomously regulated culture composition
To avoid metabolic overload and divide tasks, synthetic biologists are turning to microbial consortia engineering. Here the authors design a co-culture controller that autonomously regulates population composition.
- Kristina Stephens
- , Maria Pozo
- & William E. Bentley
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Article
| Open AccessProduction of zosteric acid and other sulfated phenolic biochemicals in microbial cell factories
Toxicity and limited solubility inhibits the biological production of many organic compounds. Here the authors metabolically engineer sulfate uptake and activation in order to produce sulfate esters of phenolic compounds, such as zosteric acid, thereby addressing these issues.
- Christian Bille Jendresen
- & Alex Toftgaard Nielsen
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Article
| Open AccessCRISPR-Cas9-based mutagenesis frequently provokes on-target mRNA misregulation
CRISPR-Cas9 genome editing is presumed to knock out gene function by generating a frameshift during NHEJ repair. Here, the authors investigate mRNA and protein expression in edited lines and find genome editing can generate internal ribosome entry sites or alternatively spliced variants.
- Rubina Tuladhar
- , Yunku Yeu
- & Lawrence Lum
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Article
| Open AccessAn ancestral NB-LRR with duplicated 3′UTRs confers stripe rust resistance in wheat and barley
Stripe rust is a serious threat to wheat production. Here, the authors reveal that the resistance gene, only present in the wheat progenitor Aegilops tauschii and its derived synthetic wheat, encodes a nucleotide oligomerization domain-like receptor and confers resistance in common wheat and barley.
- Chaozhong Zhang
- , Lin Huang
- & Daolin Fu
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Article
| Open AccessMitigation of off-target toxicity in CRISPR-Cas9 screens for essential non-coding elements
Off-target effects in CRISPR screens for essential regulatory elements have not been systematically evaluated. Here the authors find Cas9 nuclease, CRISPRi/a each have distinct off-target effects, and that these can be accurately identified and removed using the GuideScan sgRNA specificity score.
- Josh Tycko
- , Michael Wainberg
- & Michael C. Bassik
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Article
| Open AccessPolyunsaturated fatty acid production by Yarrowia lipolytica employing designed myxobacterial PUFA synthases
Sustainable sources are needed to meet the demand for long-chain polyunsaturated fatty acids. Here the authors construct an artificial biosynthetic gene cluster in Y. lipolytica capable of producing a high concentration of PUFAs.
- Katja Gemperlein
- , Demian Dietrich
- & Rolf Müller
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Matters Arising
| Open AccessConcerns about the feasibility of using “precision guided sterile males” to control insects
- Jérémy Bouyer
- & Marc J. B. Vreysen
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Article
| Open AccessEmulating evolutionary processes to morph aureothin-type modular polyketide synthases and associated oxygenases
The wealth of complex polyketides is an essential source for drug discovery. Here, the authors report an evolution-guided rational morphing of modular polyketide synthases (PKSs) for aurothin and neoaurothin biosynthesis, and reveal engineering site suitable for diversifying PKS systems.
- Huiyun Peng
- , Keishi Ishida
- & Christian Hertweck
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Article
| Open AccessEngineered ribosomes with tethered subunits for expanding biological function
Ribo-T is a tethered ribosome complex capable of orthogonal ribosome-mRNA functionality, but has low activity. Here the authors evolve new tether designs that support faster growth and increased protein expression.
- Erik D. Carlson
- , Anne E. d’Aquino
- & Michael C. Jewett
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Article
| Open AccessGSNOR provides plant tolerance to iron toxicity via preventing iron-dependent nitrosative and oxidative cytotoxicity
How plants deal with iron toxicity is still unclear. Here, the authors reveal that S-nitrosoglutathione-reductase (GSNOR) provides tolerance to iron toxicity by preventing iron-dependent nitrosative and oxidative cytotoxicity in Arabidopsis, legumes, and rice.
- Baohai Li
- , Li Sun
- & Wolfgang Busch
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Article
| Open AccessIdentification of somatic mutations in single cell DNA-seq using a spatial model of allelic imbalance
Single cell whole-genome sequencing data harbors information about somatic genetic variation but is challenging to analyze. Here, the authors develop a spatial model to correct for allelic amplification imbalance and a somatic SNV genotyper SCAN-SNV for analyzing single cell DNA sequencing data.
- Lovelace J. Luquette
- , Craig L. Bohrson
- & Peter J. Park
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Article
| Open AccessMetabolic perceptrons for neural computing in biological systems
So far, synthetic genetic circuits have relied on digital logic for information processing. Here the authors present metabolic perceptrons that use analog weighted adders to vary the contributions of multiple inputs, resulting in different classification functions.
- Amir Pandi
- , Mathilde Koch
- & Jean-Loup Faulon
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