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| Open AccessA robust yeast biocontainment system with two-layered regulation switch dependent on unnatural amino acid
Synthetic auxotrophy in which cell viability depends on the presence of an unnatural amino acid provides a powerful strategy to restrict unwanted propagation of genetically modified organisms in open environments and potentially prevent industrial espionage. Here the authors establish a general framework for the creation and optimization of synthetic auxotrophs in yeast.
- Tiantian Chang
- , Weichao Ding
- & Xian Fu
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Article
| Open AccessAutomated imaging and identification of proteoforms directly from ovarian cancer tissue
Identification of tissue proteoforms by top-down mass spectrometry remains challenging. Here, the authors present AutoPiMS, a semi-automated multiplexed tandem mass spectrometry workflow for proteoform identification directly from tissue contexts.
- John P. McGee
- , Pei Su
- & Neil L. Kelleher
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Article
| Open AccessMitigating a TDP-43 proteinopathy by targeting ataxin-2 using RNA-targeting CRISPR effector proteins
TDP43 proteinopathies are a devastating group of neurodegenerative disorders. Here the authors show that RNA-targeting CRISPR effector proteins can be used to mitigate TDP-43 pathology when targeting ataxin-2, a modifier of TDP-43-associated toxicity, and apply this to a mouse model.
- M. Alejandra Zeballos C.
- , Hayden J. Moore
- & Thomas Gaj
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Article
| Open AccessDigital data storage on DNA tape using CRISPR base editors
DNA is an alternative to data storage materials for its durability, density, and energetics. Here the authors demonstrate the storage of digital information on DNA molecules using base-editing.
- Afsaneh Sadremomtaz
- , Robert F. Glass
- & Reza Zadegan
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Article
| Open AccessCharacterization of the horse chestnut genome reveals the evolution of aescin and aesculin biosynthesis
Horse chestnut (Aesculus chinensis) is a tree species that can produce medicinal compounds such as aescin and aesculin. Here, the authors assemble its genome, identify key genes involved in the biosynthesis of these two group of compounds, and achieve the de novo synthesis of aesculin in E. coli.
- Wei Sun
- , Qinggang Yin
- & Shilin Chen
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Article
| Open AccessNext-generation CRISPR gene-drive systems using Cas12a nuclease
One method for reducing the impact of vector-borne diseases is through the use of CRISPR-based gene drives, which manipulate insect populations due to their ability to rapidly propagate desired genetic traits into a target population. Here the authors describe a Cas12a gene drive system whose activity can be finetuned in a temperature-dependent manner.
- Sara Sanz Juste
- , Emily M. Okamoto
- & Víctor López Del Amo
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Article
| Open AccessProteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis
Myelofibrosis is a form of myeloproliferative neoplasm with few treatment options available. Here, the authors profiled drug responses and proteomics ex vivo and identify molecularly-guided treatment strategies, including HDAC and BET inhibitors for CALR mutant myelofibrosis patients.
- Mattheus H. E. Wildschut
- , Julien Mena
- & Berend Snijder
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Article
| Open AccessDeposition and water repelling of temperature-responsive nanopesticides on leaves
Weak adhesion is a common hindrance to efficient utilization of pesticides in agricultural applications. Here, authors demonstrate leaf-adhesive tebuconazole nanopesticides which can be water-dispersed via flash nanoprecipitation using temperature-responsive copolymers PDMAEMA-b-PCL as the carrier.
- Jie Tang
- , Xiaojing Tong
- & Yisheng Xu
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Article
| Open AccessCreating resistance to avian influenza infection through genome editing of the ANP32 gene family
In chickens, influenza A virus relies on host protein ANP32A. Here the authors use CRISPR/Cas9 to generate homozygous gene edited chickens containing two ANP32A amino acid substitutions that prevent viral polymerase interaction.
- Alewo Idoko-Akoh
- , Daniel H. Goldhill
- & Mike J. McGrew
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Article
| Open AccessUnaltered hepatic wound healing response in male rats with ancestral liver injury
How much the environment influences inherited adaptive traits is debated and challenging to demonstrate in mammals. Here the authors performed a multigeneration study that failed to morphologically replicate enhanced wound healing response following ancestral liver injury in rats. However, heritable transcriptional effects suggest transmission at the molecular level, albeit of unclear functional relevance.
- Johanna Beil
- , Juliane Perner
- & Rémi Terranova
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Article
| Open AccessInjectable and biodegradable piezoelectric hydrogel for osteoarthritis treatment
The use of biomaterial scaffolds-based cartilage grafts could potentially innovate the Osteoarthritis (OA) treatment, but has been limited by toxicity concerns and invasive surgical procedures. Here, the authors report an injectable and biodegradable piezoelectric hydrogel with ultrasound activation to offer a minimally invasive approach for OA treatment.
- Tra Vinikoor
- , Godwin K. Dzidotor
- & Thanh D. Nguyen
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Article
| Open AccessChronological adhesive cardiac patch for synchronous mechanophysiological monitoring and electrocoupling therapy
Flexible electronic hydrogels that allow conformal tissue integration, online precision diagnosis, and simultaneous tissue regeneration are desired for advancing the treatment of myocardial infarction. Here, the authors report a chronological adhesive hydrogel patch integrating diagnostic and therapeutic functions through mechanophysiological monitoring and electrocoupling therapy.
- Chaojie Yu
- , Mingyue Shi
- & Junjie Li
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Article
| Open AccessA natural mutation in the promoter of Ms-cd1 causes dominant male sterility in Brassica oleracea
A dominant genic male sterility (DGMS) mutant of Brassica oleracea was identified in 1970s and has been widely used for hybrid cabbage breeding, but its genetic basis is unclear. Here, the authors reveal that a 1-bp deletion in the promoter of the gene encoding a PHD-finger motif transcription factor is responsible for DGMS.
- Fengqing Han
- , Kaiwen Yuan
- & Honghao Lv
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Article
| Open AccessIntegration of 3D-printed cerebral cortical tissue into an ex vivo lesioned brain slice
Brain injuries can result in significant damage to the cerebral cortex, and restoring the cellular architecture of the tissue remains challenging. Here, the authors use a droplet printing technique to fabricate a simplified human cerebral cortical column and demonstrate its functionality and potential for future personalized therapy approaches.
- Yongcheng Jin
- , Ellina Mikhailova
- & Hagan Bayley
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Article
| Open AccessNanoparticle display of prefusion coronavirus spike elicits S1-focused cross-reactive antibody response against diverse coronavirus subgenera
Most current anti-coronavirus nanoparticle vaccines target epitopes within the RBD. Here, the authors developed nanoparticles displaying an array of spike fusion proteins derived from various coronaviruses and show that immunizing mice with these vaccines elicits broad and potent cross-reactive antibodies.
- Geoffrey B. Hutchinson
- , Olubukola M. Abiona
- & Kizzmekia S. Corbett-Helaire
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Article
| Open AccessPAM-flexible genome editing with an engineered chimeric Cas9
CRISPR enzymes require a defined protospacer adjacent motif (PAM) which can be limiting for editing applications. Here the authors recombine the PAM-interacting domain of SpRY with the N-terminus of Sc + + to generate a chimeric enzyme with highly flexible PAM preference: SpRYc.
- Lin Zhao
- , Sabrina R. T. Koseki
- & Pranam Chatterjee
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Article
| Open AccessA thermostable type I-B CRISPR-Cas system for orthogonal and multiplexed genetic engineering
Thermophilic genetic manipulation tools are limited. Here the authors report a thermophilic type I-B CRISPR-Cas system and show it displays efficient transcriptional repression or DNA cleavage activity: they develop a tool for genome editing and transcriptional repression in both thermophile and mesophile hosts.
- Zhiheng Yang
- , Zilong Li
- & Weishan Wang
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Article
| Open AccessAn end-to-end pipeline for succinic acid production at an industrially relevant scale using Issatchenkia orientalis
Microbial production of succinic acid at an industrially relevant scale has been hindered by high downstream processing costs arising from neutral pH fermentation. Here, the authors report an end-to-end pipeline for succinic acid production at low pH using engineered acid-tolerant Issatchenkia orientalis strain.
- Vinh G. Tran
- , Somesh Mishra
- & Huimin Zhao
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Article
| Open AccessSecondary structures that regulate mRNA translation provide insights for ASO-mediated modulation of cardiac hypertrophy
The GAT4A transcription factor mediates cardiac development. Here the authors identify that the 5′ UTR of GATA4 mRNA contains a double stranded structure downstream of an upstream open reading frame (uORF) that promotes uORF-mediated suppression of the main ORF.
- Omar M. Hedaya
- , Kadiam C. Venkata Subbaiah
- & Peng Yao
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Article
| Open AccessMechanically induced pyroptosis enhances cardiosphere oxidative stress resistance and metabolism for myocardial infarction therapy
Therapeutic options for myocardial infarction therapy remain limited. Here the authors report the application of an optimized liquid crystal substrate in the mass production and effective preconditioning of cardiospheres, which could generate cardiospheres with improved cell bioactivity and resistance to oxidative stress for myocardial infarction therapy.
- Yingwei Wang
- , Qi Li
- & Zheng Wu
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Article
| Open AccessFitness cost associated with cell phenotypic switching drives population diversification dynamics and controllability
Generating and controlling cell collective behavior is important for synthetic biology and bioproduction. Here, the authors show the diversification dynamic and the fitness cost associated with cell switching are coupled in yeast and bacteria, and demonstrate the feasibility of controlling diversification regimes.
- Lucas Henrion
- , Juan Andres Martinez
- & Frank Delvigne
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Article
| Open AccessHypersensitive MR angiography based on interlocking stratagem for diagnosis of cardiac-cerebral vascular diseases
Current contrast-enhanced magnetic resonance angiography approaches are sub-optimal. Here the authors present a hypersensitive MR angiography strategy based on interlocking stratagem of zwitterionic Gd-chelate contrast agents (PAA-Gd), enabling sophisticated micro-vessel angiography of cardiac-cerebrovascular diseases with ultrahigh resolution.
- Peisen Zhang
- , Junwei Cheng
- & Yi Hou
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Article
| Open AccessIron oxide nanozymes stabilize stannous fluoride for targeted biofilm killing and synergistic oral disease prevention
Ferumoxytol (Fer) is an FDA-approved iron oxide formulation that disrupts caries-causing biofilms with high specificity but cannot interfere with enamel acid demineralization. Here, Fer is combined with stannous fluoride (SnF2), resulting in enhanced stability of SnF2 and inhibition of both biofilm accumulation and enamel damage more effectively than either alone.
- Yue Huang
- , Yuan Liu
- & Hyun Koo
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Article
| Open AccessTunable backbone-degradable robust tissue adhesives via in situ radical ring-opening polymerization
Adhesives with both robust adhesion and tunable degradability are clinically and ecologically vital, but their fabrication remains a formidable challenge. Here, the authors report in situ radical ring-opening polymerization-based design and potential biomedical applications of a backbone degradable robust adhesive.
- Ran Yang
- , Xu Zhang
- & Shifang Luan
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Article
| Open AccessA digital twin for DNA data storage based on comprehensive quantification of errors and biases
Archiving data in synthetic DNA offers unprecedented storage density and longevity. To understand how experimental choices affect the integrity of digital data stored in DNA, the authors study the evolution of errors and bias and with a digital twin they supply tools for experimental planning and design of error-correcing codes.
- Andreas L. Gimpel
- , Wendelin J. Stark
- & Robert N. Grass
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Article
| Open AccessMechanically enhanced biogenesis of gut spheroids with instability-driven morphomechanics
Understanding and controlling morphogenesis is vital for biology and organoid technology. Here, the authors report an efficient biomechanical system to generate gut spheroids, and reveal instability-driven morphogenetic transitions with computational models.
- Feng Lin
- , Xia Li
- & Yue Shao
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Comment
| Open AccessEngineered and natural gene drives: mechanistically the same, yet not same in kind
We propose the use of the terms natural gene drive (NGD) and engineered gene drive (EGD) arguing against James et al.
1 , who think both should be included within the term “gene drive”, based on their mechanistic similarities.- Raul F. Medina
- & Jennifer Kuzma
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Article
| Open AccessTracing immune cells around biomaterials with spatial anchors during large-scale wound regeneration
Skin scarring devoid of dermal appendages has unfavorable effects on aesthetic and physiological functions. Here, the authors present a treatment based on extracellular matrix scaffolds and perform multimodal analysis to highlight the role of Tregs recruited by the biomaterial in mitigating tissue fibrous by suppressing excessive inflammation.
- Yang Yang
- , Chenyu Chu
- & Yili Qu
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Article
| Open AccessmRNA vaccine quality analysis using RNA sequencing
mRNA vaccines must be rigorously analysed to measure their integrity and detect contaminants, which can be time-consuming and costly. Here, authors describe a method to analyse mRNA vaccine quality using long-read sequencing and a custom bioinformatic pipeline.
- Helen M. Gunter
- , Senel Idrisoglu
- & Tim R. Mercer
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Article
| Open AccessNongenetic surface engineering of mesenchymal stromal cells with polyvalent antibodies to enhance targeting efficiency
Limited delivery of therapeutic cells to diseased tissue hampers the effective application of mesenchymal stromal cells (MSCs). Here, authors modify the cell surface with polyvalent antibodies using DNA-templated assembly, and show that polyvalent interactions can be used to improve the targeting efficiency of MSCs.
- Tenghui Ye
- , Xi Liu
- & Peng Shi
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Article
| Open AccessMetabolic Reprogramming via ACOD1 depletion enhances function of human induced pluripotent stem cell-derived CAR-macrophages in solid tumors
The functional-metabolic state of macrophages fundamentally influences the tumour microenvironment, making adoptive cell therapy with pro-inflammatory macrophages an attractive anti-tumour approach. Here authors introduce pluripotent stem cell-derived CAR-macrophage that are depleted of ACOD1, an essential gene in itaconate metabolism, which reprograms them to a pro-inflammatory state enabling enhanced anti-tumour function.
- Xudong Wang
- , Siyu Su
- & Jin Zhang
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Article
| Open AccessEfficient intervention for pulmonary fibrosis via mitochondrial transfer promoted by mitochondrial biogenesis
Using healthy mitochondria to restore impaired mitochondrial homeostasis is a promising therapy for pulmonary fibrosis. Here the authors use joint-engineered mesenchymal stem cells for efficient mitochondrial delivery to injured lung cells, showing a successful mitigation of the disease.
- Ting Huang
- , Ruyi Lin
- & Jianqing Gao
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Article
| Open AccessGenome-wide promoter responses to CRISPR perturbations of regulators reveal regulatory networks in Escherichia coli
Measuring gene expression responses for every transcription factor (TF)-gene pair in living prokaryotic cells is challenging. Here the authors report pooled promoter responses to TF perturbation sequencing (PPTP-seq) using CRISPRi, which they use to address this problem in E. coli.
- Yichao Han
- , Wanji Li
- & Fuzhong Zhang
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Article
| Open AccessC3N nanodots inhibits Aβ peptides aggregation pathogenic path in Alzheimer’s disease
In this work, the authors report the utilization of nano-inhibito C3N nanodots to inhibit Aβ peptides aggregation and fibrils disassembly, and show how they induce a cognitive enhancement in treated AD mice.
- Xiuhua Yin
- , Hong Zhou
- & Ruhong Zhou
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Article
| Open AccessPre-activated nanoparticles with persistent luminescence for deep tumor photodynamic therapy in gallbladder cancer
Phototherapy of deep tumors suffers from many obstacles, such as limited near-infrared tissue penetration depth and low accumulation efficiency within the target sites. Here, the authors report stimuli sensitive tumor-targeted photodynamic nanoparticles with persistent luminescence for the treatment of deep tumors.
- Sarun Juengpanich
- , Shijie Li
- & Mingyu Chen
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Article
| Open AccessA landscape of complex tandem repeats within individual human genomes
Haplotype-resolved long, complex tandem repeats remain largely hidden despite their potential relevance to disease. Here, the authors reveal and analyze the genome-wide landscape of these repeats using a high-precision algorithm.
- Kazuki Ichikawa
- , Riki Kawahara
- & Shinichi Morishita
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Article
| Open AccessHuman OPRM1 and murine Oprm1 promoter driven viral constructs for genetic access to μ-opioidergic cell types
Tools for gaining long-term genetic access to mu-opioid receptor (MOR) neural cell types are limited. Here, the authors develop a suite of adeno-associated viral tools allowing selective genetic access to MOR cell types, and showcase their use across species.
- Gregory J. Salimando
- , Sébastien Tremblay
- & Gregory Corder
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Article
| Open AccessFacile hermetic TEM grid preparation for molecular imaging of hydrated biological samples at room temperature
Electron microscopy of native hydrated biological samples close to physiological temperature is challenging. Here, authors encapsulate proteins and cells as an efficient, cost-effective complement to other microscopy technique in addressing biological questions at the molecular level.
- Lingli Kong
- , Jianfang Liu
- & Gang Ren
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Article
| Open AccessMembrane manipulation by free fatty acids improves microbial plant polyphenol synthesis
The inherent toxicity of the aromatic compounds to the chassis strain hampers further improvement of bioproduction. Here, the authors show that membrane rigidifying effect of resveratrol can be attenuated by exogenous supplementation of palmitelaidic acid or linoleic acid in fermentation of Corynebacterium glutamicum.
- Apilaasha Tharmasothirajan
- , Josef Melcr
- & Jan Marienhagen
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Article
| Open AccessJanus particle-engineered structural lipiodol droplets for arterial embolization
Embolization is one of the most promising strategies for clinical disease treatments, however, the existing embolic materials normally have poor embolization effectiveness. Here, the authors report Janus particle-engineered structural lipiodol droplets by programming the self-assembly of Janus particles at the lipiodol-water interface to achieve highly efficient renal embolization.
- Sijian Tao
- , Bingquan Lin
- & Jun-Bing Fan
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Article
| Open AccessA magneto-activated nanoscale cytometry platform for molecular profiling of small extracellular vesicles
Exosomal PD-L1 (exoPD-L1) is a biomarker predicting immunotherapeutic responses. Here the authors report NanoEPIC, a nanoscale cytometry platform that enables phenotypic sorting and exoPD-L1 profiling from blood plasma by using magnetic-activated ranking to differentiate exosomal subpopulations.
- Kangfu Chen
- , Bill T. V. Duong
- & Shana O. Kelley
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Article
| Open AccessPhylotranscriptomics unveil a Paleoproterozoic-Mesoproterozoic origin and deep relationships of the Viridiplantae
Evolutionary relationships among green plants are unresolved and, in particular, the phylogenetic position of Prasinodermophyta remains controversial. Here, the authors conduct phylogenomic analyses to resolve relationships within Viridiplantae, suggesting that this group diverged between the Great Oxidation Event and the Neoproterozoic Oxygenation Event.
- Zhiping Yang
- , Xiaoya Ma
- & Bojian Zhong
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Article
| Open AccessA split and inducible adenine base editor for precise in vivo base editing
TadA deaminases widely used in many base editors lack post-translational control in cells. Here the authors report a split adenine base editor (sABE) using chemically induced dimerisation (CID) to control the catalytic activity of TadA8e and show this can be used for PCSK9 gene editing in the mouse liver.
- Hongzhi Zeng
- , Qichen Yuan
- & Xue Gao
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Article
| Open AccessA Type II-B Cas9 nuclease with minimized off-targets and reduced chromosomal translocations in vivo
SpCas9 unintended editing is a major concern. Here the authors report an off-target method using Duplex Sequencing with increased sensitivity for Cas9 mutation detection; they also identify a Cas9 variant of the II-B subfamily with intrinsic high fidelity (PsCas9) and see improved specificity.
- Burcu Bestas
- , Sandra Wimberger
- & Marcello Maresca
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Article
| Open AccessProgrammable RNA detection with CRISPR-Cas12a
Cas12a is widely used in diagnostic platforms. Here the authors show that Cas12a can be programmed to directly detect RNA substrates, this is due to the 3’-end of the crRNA tolerating both RNA and DNA substrates: they use this to report a method, SAHARA, to detect RNA sequences.
- Santosh R. Rananaware
- , Emma K. Vesco
- & Piyush K. Jain
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Article
| Open AccessRescue of dendritic cells from glycolysis inhibition improves cancer immunotherapy in mice
While glycolysis inhibition impairs cancer cell tumourigenic capacities, it also affects immune cells anti-tumour activity. Here, the authors show that rescuing glycolytic inhibition of dendritic cells improves the efficacy of combining immunotherapy with glycolysis inhibition.
- Sahil Inamdar
- , Abhirami P. Suresh
- & Abhinav P. Acharya
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Article
| Open AccessScreening non-conventional yeasts for acid tolerance and engineering Pichia occidentalis for production of muconic acid
Baker’s yeast is a workhorse of industrial biotechnology, but it is not suited to overproduce many bulk bioproducts, especially organic acids. Here, the authors identify Pichia occidentalis as an acid tolerant yeast and engineer it for the production of muconic acid using a newly developed genome editing toolkit.
- Michael E. Pyne
- , James A. Bagley
- & Vincent J. J. Martin
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Article
| Open AccessProtein engineering and iterative multimodule optimization for vitamin B6 production in Escherichia coli
Pyridoxine (PN), the most common commercial form of vitamin B6, has been chemically synthesized using expensive and toxic chemicals. Here, the authors employ parallel pathway engineering, protein engineering, and iterative multimodule optimization for high level PN production in E. coli.
- Linxia Liu
- , Jinlong Li
- & Dawei Zhang
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Article
| Open AccessTargeted mechanical stimulation via magnetic nanoparticles guides in vitro tissue development
Highly localized mechanical forces that shape in vivo tissue development remain challenging to recapitulate in vitro. Here the authors use magnetically actuated nanoparticles to generate spatially defined forces within organoids, which guide the spatial organization of tissue patterning and growth.
- Abdel Rahman Abdel Fattah
- , Niko Kolaitis
- & Adrian Ranga
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