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| Open AccessAmphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer
Treatment of pancreatic ductal adenocarcinoma is still challenging and patients survival has only marginally improved in the last decade. Here the authors produce a PGA-based polymeric nanocarrier for the dual delivery of miR-34a-mimic and PLK1-targeting siRNA resulting in killing of pancreatic cancer cells in vivo.
- Hadas Gibori
- , Shay Eliyahu
- & Ronit Satchi-Fainaro
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Article
| Open AccessTrapping IgE in a closed conformation by mimicking CD23 binding prevents and disrupts FcεRI interaction
IgE is linked to allergic diseases and there is a great interest in developing anti-IgE therapeutics. Here the authors characterize the binding of human IgE Fc to a single domain antibody (sdab) and show that the sdab induces a closed conformation, which prevents and disrupts IgE binding to its receptor FcεRI and abrogates allergen mediated activation.
- Frederic Jabs
- , Melanie Plum
- & Edzard Spillner
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Article
| Open AccessMammalian display screening of diverse cystine-dense peptides for difficult to drug targets
Pathologies related to protein:protein interaction are hard to treat but cystine-dense peptides have the potential to disrupt such interactions. Here the authors develop a high-diversity mammalian cell screen for cystine-dense peptides with drug potential and use it to identify a YAP:TEAD inhibitor.
- Zachary R. Crook
- , Gregory P. Sevilla
- & James M. Olson
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| Open AccessEngineering cell sensing and responses using a GPCR-coupled CRISPR-Cas system
G-protein-coupled receptors are a large and diverse group of eukaryotic membrane receptors. Here the authors couple GPCRs to dCas9 to link extracellular sensing to genome regulation.
- Nathan H. Kipniss
- , P. C. Dave P. Dingal
- & Lei S. Qi
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Article
| Open AccessMetas-Chip precisely identifies presence of micrometastasis in live biopsy samples by label free approach
Detecting metastatic cells in tumor/lymph node samples of breast cancer patients is extremely important for diagnosis. Here the authors develop a microelectronic biochip that detect the presence of invasive/metastatic cells in unprocessed biopsies and performs better than the current gold standards.
- Mohammad Saeid Nikshoar
- , Mohammad Ali Khayamian
- & Mohammad Abdolahad
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Article
| Open AccessNanoparticle conjugates of a highly potent toxin enhance safety and circumvent platinum resistance in ovarian cancer
Improving the safety and efficacy of chemotherapeutics will help to enhance their effects. Here, the authors show that intraperitoneal delivery of nanoparticle conjugates of a potent toxin prolongs tumor inhibition and survival as compared to cisplatin in advanced-stage and platinum-resistant ovarian cancer mouse models.
- Ruogu Qi
- , Yongheng Wang
- & P. Peter Ghoroghchian
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Article
| Open AccessEvolutionary action and structural basis of the allosteric switch controlling β2AR functional selectivity
Ligand-induced biased signaling is thought to result in part from ligand-specific receptor conformations that cause the engagement of distinct effectors. Here the authors trace and evaluate the impact of mutations of the β2–adrenergic receptor on multiple signaling outputs to provide structural-level insight into the determinants of GPCR functional selectivity.
- Anne-Marie Schönegge
- , Jonathan Gallion
- & Michel Bouvier
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Article
| Open AccessEstrogen-related receptor γ causes osteoarthritis by upregulating extracellular matrix-degrading enzymes
The pathogenesis of osteoarthritis is unclear. The authors show that estrogen-related receptor gamma is upregulated in cartilage from patients and mouse models, where it drives production of matrix-degrading MMPs in chondrocytes, and that its downregulation ameliorates pathology in mice.
- Young-Ok Son
- , Seulki Park
- & Jang-Soo Chun
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Article
| Open AccessEngineering cell signaling using tunable CRISPR–Cpf1-based transcription factors
Cpf1 has been repurposed as a transcriptional repressor in bacteria and plants. Here, the authors construct activators and repressors in human cells using Cpf1 coupled to riboswitches and GPCRs.
- Yuchen Liu
- , Jinghong Han
- & Guohui Nie
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Article
| Open AccessHigh efficiency and long-term intracellular activity of an enzymatic nanofactory based on metal-organic frameworks
Cellular delivery of proteins is currently limited by inefficient release from their carrier or by altering the protein structure after chemical modification. Here the authors use metal-organic frameworks which act as nanofactories and show a supported enzymatic activity for an extended period of time.
- Xizhen Lian
- , Alfredo Erazo-Oliveras
- & Hong-Cai Zhou
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Article
| Open AccessPolymorphic design of DNA origami structures through mechanical control of modular components
The use of staple strands paired with scaffold strands allows the creation of a diverse array of DNA origami nanostructures. Here the authors rationally design a set of staples with variable hinges allowing controllable geometry and flexibility of the final structure.
- Chanseok Lee
- , Jae Young Lee
- & Do-Nyun Kim
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Article
| Open AccessMultiplexed in vivo homology-directed repair and tumor barcoding enables parallel quantification of Kras variant oncogenicity
Genome editing technologies enable the rapid interrogation of genetic alterations. Here, the authors present a CRISPR/Cas9-based platform to simultaneously investigate multiple activating point mutations in de novo cancers in mice; and generate panels of Kras-variants in different tissues to induce cancer.
- Ian P. Winters
- , Shin-Heng Chiou
- & Monte M. Winslow
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Article
| Open AccessTuning the interactions between chiral plasmonic films and living cells
Chiral surfaces are emerging as important biomaterial components, as they can modulate cell behavior. Here, the authors modify plasmonic nanoparticle films with amino acid isomers, and find that the chirality of the film remarkably affects cell proliferation, adhesion, and directional differentiation.
- Xueli Zhao
- , Liguang Xu
- & Hua Kuang
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Article
| Open AccessDifferentially evolved glucosyltransferases determine natural variation of rice flavone accumulation and UV-tolerance
In contrast to flavonols, the functions of plant flavones are largely unknown. Here, the authors report the two differentially evolved glucosyltranferases (flavone 7-O-glucosyltransferase and flavone 5-O-glucosyltransferase) determine natural variation of rice flavone accumulation and UV-tolerance.
- Meng Peng
- , Raheel Shahzad
- & Jie Luo
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Article
| Open AccessWarhead biosynthesis and the origin of structural diversity in hydroxamate metalloproteinase inhibitors
Metalloproteinase inhibitors are leads for drug development, but their biosynthetic pathways are often unknown. Here the authors show that the acyl branched warhead of actinonin and matlystatins derives from an ethylmalonyl-CoA-like pathway and the structural diversity of matlystatins is due to the activity of a decarboxylase-dehydrogenase enzyme.
- Franziska Leipoldt
- , Javier Santos-Aberturas
- & Leonard Kaysser
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Article
| Open AccessAllosteric nanobodies uncover a role of hippocampal mGlu2 receptor homodimers in contextual fear consolidation
G protein-coupled receptors are considered promising therapeutic targets. Here, the authors have identified nanobodies, or single-domain llama antibodies, that specifically enhance agonist-induced activity of a type of G protein-coupled receptor, the mGlu2 receptor.
- Pauline Scholler
- , Damien Nevoltris
- & Jean-Philippe Pin
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Article
| Open AccessIn vivo transplantation of 3D encapsulated ovarian constructs in rats corrects abnormalities of ovarian failure
Cell-based hormone replacement therapy (cHRT) may be an alternative therapy to pharmacological (p)HRT. Here, the authors show that implanted 3D bioengineered ovarian constructs of granulosa and theca cells in ovariectomized rats recapitulate native cell interactions and improve efficacy compared to similar doses of pHRT.
- Sivanandane Sittadjody
- , Justin M. Saul
- & Emmanuel C. Opara
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Article
| Open AccessAlbumin/vaccine nanocomplexes that assemble in vivo for combination cancer immunotherapy
Albumin conjugates can enhance drug delivery. Here, the authors repurpose albumin-binding Evans blue to develop nanovaccines that co-deliver adjuvants and tumor neoantigens to antigen-presenting cells in lymph nodes, resulting in potent and durable antitumour immunity in combination immunotherapy.
- Guizhi Zhu
- , Geoffrey M. Lynn
- & Xiaoyuan Chen
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Article
| Open AccessThe Kalanchoë genome provides insights into convergent evolution and building blocks of crassulacean acid metabolism
Crassulacean acid metabolism (CAM) is a metabolic adaptation of photosynthesis that enhances water use efficiency. Here, via genomic analysis of Kalanchoë, the authors provide evidence for convergent evolution of protein sequence and temporal gene expression underpinning the multiple independent emergences of CAM.
- Xiaohan Yang
- , Rongbin Hu
- & Gerald A. Tuskan
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Article
| Open AccessStructural basis of respiratory syncytial virus subtype-dependent neutralization by an antibody targeting the fusion glycoprotein
Monoclonal antibodies to prevent respiratory syncytial virus (RSV) disease are under development, but the molecular requirements for cross-subtype neutralization are unclear. Here, the authors show that residue 201 in RSV fusion protein determines subtype specific neutralization for the clinically-relevant monoclonal antibody, 5C4.
- Daiyin Tian
- , Michael B. Battles
- & Barney S. Graham
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Article
| Open AccessRestoration of patterned vision with an engineered photoactivatable G protein-coupled receptor
To restore sight after retinal degeneration, one approach is to express light-sensitive proteins in remaining cells. Here the authors combine a light-sensitive engineered G protein-coupled receptor and ion channels to restore ON and OFF responses as well as superior visual pattern discrimination.
- Michael H. Berry
- , Amy Holt
- & Ehud Y. Isacoff
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Article
| Open AccessGraphene-edge dielectrophoretic tweezers for trapping of biomolecules
The capability of positioning target molecules onto the edges of patterned graphene nanostructures is highly desirable. Here, the authors demonstrate that the atomically sharp edges of graphene can be used as dielectrophoretic tweezers for gradient-force-based trapping applications.
- Avijit Barik
- , Yao Zhang
- & Sang-Hyun Oh
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Article
| Open AccessCardiopatch platform enables maturation and scale-up of human pluripotent stem cell-derived engineered heart tissues
Cardiomyocytes derived from human induced pluripotent stem cells could be used to generate cardiac tissues for regenerative purposes. Here the authors describe a method to obtain large bioengineered heart tissues showing advanced maturation, functional features and engraftment capacity.
- Ilya Y. Shadrin
- , Brian W. Allen
- & Nenad Bursac
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Article
| Open AccessProgrammed biomolecule delivery to enable and direct cell migration for connective tissue repair
Dense connective tissues do not easily heal, in part due to a low supply of reparative cells. Here, the authors develop a fibrous scaffold for meniscal repair that sequentially releases collagenase and a growth factor at the injury site, breaking down the extracellular matrix and recruiting endogenous cells.
- Feini Qu
- , Julianne L. Holloway
- & Robert L. Mauck
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Article
| Open AccessMicrobial volatile communication in human organotypic lung models
There is a need for improved in vitro models of host-microbe interactions in the lung. Here, Barkal et al. present a microscale organotypic model of the human bronchiole for studying pulmonary infection, including volatile compound communication between microbial populations and host cells.
- Layla J. Barkal
- , Clare L. Procknow
- & David J. Beebe
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Article
| Open AccessAn activity-dependent proximity ligation platform for spatially resolved quantification of active enzymes in single cells
The interrogation of enzyme activity involves the ensemble averaging of many cells, loss of spatial relationships and is often biased to abundant proteins. Here the authors develop activity-dependent proximity ligation to quantify enzyme activity at the cellular and sub-cellular level in relevant biological contexts.
- Gang Li
- , Jeffrey E. Montgomery
- & Raymond E. Moellering
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Article
| Open AccessT cell-targeting nanoparticles focus delivery of immunotherapy to improve antitumor immunity
Targeted delivery of immunomodulatory compounds to defined subsets of endogenous immune cells may improve the efficacy of combination immunotherapies. Here, the authors use PD-1-targeting nanoparticles containing a TGFβ inhibitor or a TLR7/8 agonist to deliver these payloads to T cells or via T cells to the tumor microenvironment, respectively, leading to anti-tumor efficacy in vivo.
- Daniela Schmid
- , Chun Gwon Park
- & Michael S. Goldberg
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Article
| Open AccessGenome-wide identification and differential analysis of translational initiation
Translation initiation sequencing (TI-seq) has revealed unexpected diversity in protein isoforms. Here, Zhang et al. present Ribo-TISH, a computational toolkit that can detect and compare TIs across conditions and improve open reading frame prediction from different types of ribosome profiling data.
- Peng Zhang
- , Dandan He
- & Yiwen Chen
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Article
| Open AccessA signal-amplifiable biochip quantifies extracellular vesicle-associated RNAs for early cancer detection
Extracellular vesicles (EV)-associated RNAs are serum biomarkers potentially exploitable for early cancer diagnosis. Here the authors develop a catalyzed hairpin DNA circuit within a cationic lipid-polymer hybrid nanoparticle that can detect low–level EV-associated RNAs in early stage cancer patients.
- Jiaming Hu
- , Yan Sheng
- & L. James Lee
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Article
| Open AccessCombinatorial metabolic engineering using an orthogonal tri-functional CRISPR system
Metaboli engineering through gene overexpression, knock-down and knock-out is often carried out sequentially in a high labor, low-throughput manner. Here, the authors use CRISPR-mediated gene activation, interference and deletion to rapidly rewire S. cerevisiae metabolism in a single step.
- Jiazhang Lian
- , Mohammad HamediRad
- & Huimin Zhao
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Article
| Open AccessBiosynthesis of helvolic acid and identification of an unusual C-4-demethylation process distinct from sterol biosynthesis
The biosynthetic pathway of fusidane-type antibiotics, such as helvolic acid, is largely undiscovered. Here, the authors investigate the biosynthesis of helvolic acid, thereby determining the sequence of the enzymatic reactions involved in the process and the intermediates formed.
- Jian-Ming Lv
- , Dan Hu
- & Xin-Sheng Yao
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Article
| Open AccessA multiplexable TALE-based binary expression system for in vivo cellular interaction studies
Binary expression systems enable researchers to deliver loss-of-function or gain-of-function transgenes with spatial-temporal resolution in vivo. Here, the authors present a programmable TALE-based system for multiplexed orthogonal activation of transgenes in Drosophila.
- Markus Toegel
- , Ghows Azzam
- & Tudor A. Fulga
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Article
| Open AccessDNA nanomapping using CRISPR-Cas9 as a programmable nanoparticle
Physical mapping of DNA can be used to detect structural variants and for whole-genome haplotype assembly. Here, the authors use CRISPR-Cas9 and high-speed atomic force microscopy to ‘nanomap’ single molecules of DNA.
- Andrey Mikheikin
- , Anita Olsen
- & Jason Reed
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Article
| Open AccessSelenoprotein P-neutralizing antibodies improve insulin secretion and glucose sensitivity in type 2 diabetes mouse models
Selenoprotein P is secreted by the liver and when present in excess it promotes development of type 2 diabetes. Here the authors develop neutralizing antibodies to target human and mouse selenoprotein P, and show that they improve insulin secretion and glucose tolerance in mouse models.
- Yuichiro Mita
- , Kaho Nakayama
- & Yoshiro Saito
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Article
| Open AccessBL-Hi-C is an efficient and sensitive approach for capturing structural and regulatory chromatin interactions
Chromatin interactions and genome architecture are key regulators of gene expression. Here the authors present Bridge-Linker-Hi-C to map active chromatin loops and enhancer-promoter interactions.
- Zhengyu Liang
- , Guipeng Li
- & Yang Chen
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Article
| Open AccessHuman Cyclophilin B forms part of a multi-protein complex during erythrocyte invasion by Plasmodium falciparum
Invasion of red blood cells by Plasmodium falciparum is a complex process and relies on several receptor-ligand interactions. Here, the authors show that human cyclophilin B binds Plasmodium surface protein PfRhopH3 and that interruption of this interaction reduces invasion by 80%.
- Prem Prakash
- , Mohammad Zeeshan
- & Pawan Malhotra
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Article
| Open AccessThe industrial anaerobe Clostridium acetobutylicum uses polyketides to regulate cellular differentiation
Polyketides are secondary metabolites mainly found in aerobic organisms with wide applications in medicine and agriculture. Here, the authors uncover new polyketides native to the anaerobic bacterium Clostridium acetobutylicum and show their role in triggering sporulation and granulose accumulation.
- Nicolaus A. Herman
- , Seong Jong Kim
- & Wenjun Zhang
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Article
| Open AccessPhage display and selection of lanthipeptides on the carboxy-terminus of the gene-3 minor coat protein
Lanthipeptides are a class of cyclic post-translationally modified peptides with potential drug-like properties. Here the authors develop a phage display system by expressing lanthipeptide precursors as C-terminal fusions to the phage M13 coat protein pIII in E. coli along with the heterologous modifying enzymes.
- Johannes H. Urban
- , Markus A. Moosmeier
- & Josef Prassler
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Article
| Open AccessImaging the transient heat generation of individual nanostructures with a mechanoresponsive polymer
Remote thermometers with a high spatiotemporal resolution are very desirable for applications in the life sciences, including photothermal therapy. Here, Chen et al. develop polymer coated gold nanorods with a temperature sensitivity of 80 mK and a 4 ms response time for thermometry in the life sciences.
- Xueqin Chen
- , Qing Xia
- & Jun-Jie Zhu
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Article
| Open AccessDevelopment of a genetic sensor that eliminates p53 deficient cells
TP53 is mutated in many cancers, a system to detect and selectively eliminate p53 mutant cells is an attractive therapeutic strategy. Here, the authors present a genetic sensor that can detect p53 activity and is coupled to the thymidine kinase gene, which can activate the drug Ganciclovir, resulting in cell death.
- Jovan Mircetic
- , Antje Dietrich
- & Frank Buchholz
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Article
| Open AccessThermostable exoshells fold and stabilize recombinant proteins
Improving recombinant protein expression and stabilization remains a significant challenge. Here, the authors engineer Archaeoglobus fulgidus ferritin as a thermostable exoshell to provide steric accommodation and charge complementation for recombinant proteins, which can improve yields by 100 fold.
- Siddharth Deshpande
- , Nihar D. Masurkar
- & Chester L. Drum
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Article
| Open AccessA water-soluble nucleolin aptamer-paclitaxel conjugate for tumor-specific targeting in ovarian cancer
Paclitaxel, a first line chemotherapeutic drug, suffers from poor water solubility and low tissue selectivity. Here, the authors report a water-soluble nucleolin aptamer-paclitaxel conjugate that selectively accumulates in ovarian tumor issues displaying reduced toxicity and improved activity profiles.
- Fangfei Li
- , Jun Lu
- & Ge Zhang
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Article
| Open AccessPrevalence and detection of low-allele-fraction variants in clinical cancer samples
High-throughput sequencing is used to identify somatic variants in cancer patients. Here, the authors perform panel-based profiling of 5095 clinical samples and demonstrate that many clinically-actionable variants have low variant allele fractions, requiring assays with high detection sensitivity.
- Hyun-Tae Shin
- , Yoon-La Choi
- & Woong-Yang Park
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Article
| Open AccessSelf-assembling dipeptide antibacterial nanostructures with membrane disrupting activity
Peptide-based supramolecular assemblies are a promising class of nanomaterials with important biomedical applications, but their antibacterial properties can be overlooked. Here the authors show the antibacterial activity of self-assembled diphenylalanine, which emerges as the minimal model for antibacterial supramolecular polymers.
- Lee Schnaider
- , Sayanti Brahmachari
- & Ehud Gazit
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Article
| Open AccessElectricity generation from digitally printed cyanobacteria
Cyanobacteria can be exploited to convert light energy into electrical current, however utilising them efficiently for power generation is a challenge. Here, the authors use a simple commercial inkjet printer to fabricate a thin-film paper-based biophotovoltaic cell capable of driving low-power devices.
- Marin Sawa
- , Andrea Fantuzzi
- & Peter J. Nixon
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Article
| Open AccessDense and accurate whole-chromosome haplotyping of individual genomes
Haplotype information is important in investigating many biological phenomena. Here, Porubsky et al. combine Strand-seq with long-read or linked-read sequencing to obtain complete and genome-wide haplotypes of a single individual genome at manageable costs.
- David Porubsky
- , Shilpa Garg
- & Tobias Marschall
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Article
| Open AccessDiversity oriented biosynthesis via accelerated evolution of modular gene clusters
Reengineering polyketide synthase encoding genes to produce analogues of natural products can be slow and low-yielding. Here the authors use accelerated evolution to recombine the gene cluster for rapid production of rapamycin-related products.
- Aleksandra Wlodek
- , Steve G. Kendrew
- & Matthew A. Gregory
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Article
| Open AccessCombining chemical and genetic approaches to increase drought resistance in plants
Plants respond to abiotic stress via the phytohormone ABA. Here, Cao et al. report a series of new ABA receptor agonists, named AMFs, which have higher receptor-binding affinities and show that, when employed in tandem with ABA receptor overexpression, can significantly increase drought resistance
- Min-Jie Cao
- , Yu-Lu Zhang
- & Jian-Kang Zhu
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Article
| Open AccessAn automated platform for high-throughput mouse behavior and physiology with voluntary head-fixation
Transgenic approaches and improvements in functional imaging have necessitated an advance in the behavioral toolkit. Here the authors describe an automated high-throughput voluntary head fixation system for training mice on complex psychophysical decision tasks compatible with concurrent two-photon microscopy.
- Ryo Aoki
- , Tadashi Tsubota
- & Andrea Benucci
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