Featured
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| Open AccessDesigner diatom episomes delivered by bacterial conjugation
Algae hold great promise for biofuel and chemical production but their use as model systems is hampered by the absence of suitable genetic tools. Here Karas et al. present a nuclear episomal vector for diatoms that is maintained in the absence of antibiotics, and a plasmid delivery method via conjugation with E. coli.
- Bogumil J. Karas
- , Rachel E. Diner
- & Philip D. Weyman
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Article
| Open AccessModelling breast cancer requires identification and correction of a critical cell lineage-dependent transduction bias
Clinical breast cancers predominantly present luminal features, but experimental models are essentially basal. Here the authors show that luminal cells are significantly less susceptible to viral transduction, and present methods to analyse and overcome the bias in heterogeneous populations.
- William C. Hines
- , Paul Yaswen
- & Mina J. Bissell
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High-throughput and quantitative assessment of enhancer activity in mammals by CapStarr-seq
Characterizing mammalian gene expression regulation by enhancer elements is complicated by the size and complexity of the genome. Here Vanhille et al.demonstrate CapStarr-Seq, a novel high-throughput method for assessing potential enhancers and deciphering the mechanisms regulating transcription
- Laurent Vanhille
- , Aurélien Griffon
- & Salvatore Spicuglia
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Article
| Open AccessMaking water-soluble integral membrane proteins in vivo using an amphipathic protein fusion strategy
The study of integral membrane proteins (IMPs) is hampered by yields and the difficulty in retaining activity once they have been solubilized. Here Mizrachi et al. develop a strategy for in vivoexpression and solubilization of IMPs in functionally relevant states by fusing them to truncated apolipoprotein A-I.
- Dario Mizrachi
- , Yujie Chen
- & Matthew P. DeLisa
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Metal ion-directed dynamic splicing of DNA through global conformational change by intramolecular complexation
Higher-order structured DNA molecules can be manipulated to carry out specific enzymatic functions. Here the authors demonstrate the metal ion-directed global conformational control of DNA structure, using intramolecular coordination chemistry to manipulate the DNAzyme activity.
- Toshihiro Ihara
- , Hiroyuki Ohura
- & Yusuke Kitamura
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| Open AccessA plug-and-play approach to antibody-based therapeutics via a chemoselective dual click strategy
Antibody–drug conjugates are a class of therapeutic combining the directing ability of antibodies with the cell-killing ability of cytotoxic drugs. Here the authors describe an approach based on click chemistry that enables the rapid assembly of dual-modified antibodies with potential for new therapeutic modalities.
- Antoine Maruani
- , Mark E.B. Smith
- & Stephen Caddick
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Article
| Open AccessOn the tear resistance of skin
It is known that skin has a large tear resistance, but little is known of the mechanism behind this. Here, the authors carry out a structural analysis of rabbit skin to show how the deformation of collagen fibrils in the skin results in a strong resistance to tear propagation.
- Wen Yang
- , Vincent R. Sherman
- & Marc A. Meyers
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Protease-degradable electrospun fibrous hydrogels
Electrospinning is a useful method of biomaterial fabrication, but a lack of bioactivity in the final construct can limit their application as mimics for biological matrices. Here, the authors fabricate a degradable electrospun scaffold as an in vitro and in vivomimic of the extracellular matrix.
- Ryan J. Wade
- , Ethan J. Bassin
- & Jason A. Burdick
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Trehalose glycopolymer resists allow direct writing of protein patterns by electron-beam lithography
The direct-write patterning of biomolecules can yield biologically active surfaces with intricate spacing arrangements. Here, the authors show how a glycopolymer resist can stabilize many different biomolecules for patterning by electron-beam lithography.
- Erhan Bat
- , Juneyoung Lee
- & Heather D. Maynard
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Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis
Tumour-targeted antibodies can kill cancer cells by blocking pro-survival signalling or by delivering a toxin. Here the authors show that glypican-3 antibody fused to a bacterial toxin suppresses tumour growth more efficiently if designed to block Wnt signalling downstream of glypican-3.
- Wei Gao
- , Zhewei Tang
- & Mitchell Ho
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Article
| Open AccessAbiotic ligation of DNA oligomers templated by their liquid crystal ordering
Some oligomers exhibit liquid-crystal-like ordering in concentrated aqueous solutions. Here, Fraccia et al. show that this kind of ordering can further facilitate DNA ligation in a way similar to a catalytic process that arises from a hierarchical self-assembly, namely liquid crystal autocatalysis.
- Tommaso P. Fraccia
- , Gregory P. Smith
- & Tommaso Bellini
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Article
| Open AccessDemonstration of asymmetric electron conduction in pseudosymmetrical photosynthetic reaction centre proteins in an electrical circuit
Photosynthetic reaction centres have been proposed for applications in bioelectronics. Here, the authors examine electron transport through the reaction centre from R. sphaeroidesusing conductive AFM, observing asymmetric conductance along only one cofactor wire under an applied bias.
- Muhammad Kamran
- , Vincent M. Friebe
- & Michael R. Jones
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Article
| Open AccessPredicting clinical response to anticancer drugs using an ex vivo platform that captures tumour heterogeneity
Efficacy of anticancer treatments vary across patients, imposing a need for personalized approaches. Here the authors show that responsiveness to chemotherapy can be predicted using tumour explant cultures in a patient-matched microenvironment, coupled with a machine-learning algorithm.
- Biswanath Majumder
- , Ulaganathan Baraneedharan
- & Pradip K. Majumder
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Gene silencing by CRISPR interference in mycobacteria
Recombination-based tools for generating targeted mutations in Mycobacterium tuberculosislack efficiency. Here the authors present a CRISPR interference approach that is able to efficiently repress the expression of target genes in mycobacteria, in a rapid and cost-effective manner.
- Eira Choudhary
- , Preeti Thakur
- & Nisheeth Agarwal
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Engineered pairs of distinct photoswitches for optogenetic control of cellular proteins
Photoreceptor-based photoswitches have proved to be powerful tools for the specific control of protein activity in live cells. Here the authors describe Magnets, a new set of photoswitches based on the Vivid photoreceptor with enhanced hetero-dimerization specificity and variable activation kinetics.
- Fuun Kawano
- , Hideyuki Suzuki
- & Moritoshi Sato
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Defined TLR3-specific adjuvant that induces NK and CTL activation without significant cytokine production in vivo
Activation of TLRs by microbial ligands induces complex innate immune responses to activate host defence. Here the authors show that a synthetic TLR3 ligand can boost protective immunity without robust inflammatory cytokine production, minimizing toxic effects of immunization.
- Misako Matsumoto
- , Megumi Tatematsu
- & Tsukasa Seya
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Article
| Open AccessEpigenetic and transcriptional determinants of the human breast
Epigenetic changes associated with post-natal differentiation have been characterized. Here the authors generate epigenomic and transcriptional profiles from primary human breast cells, providing insights into the transcriptional and epigenetic events that define post-natal cell differentiation in vivo.
- Philippe Gascard
- , Misha Bilenky
- & Martin Hirst
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Hierarchical structural design for fracture resistance in the shell of the pteropod Clio pyramidata
The hierarchical structural motifs of biomaterials can lead to advantageous mechanical properties. Here, the authors reveal that a fibre-like helical structure across the shell of a planktonic pteropod suppresses crack propagation and is responsible for a high fracture resistance.
- Ling Li
- , James C. Weaver
- & Christine Ortiz
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Article
| Open AccessDefining the phospho-adhesome through the phosphoproteomic analysis of integrin signalling
Protein phosphorylation is known to play an important role in cell adhesion signalling. Robertson et al. present a proteomic resource mapping the phosphorylation states of proteins isolated from adhesion complexes and, taking advantage of this data set, show that the cell cycle kinase CDK1 may influence cell adhesion.
- Joseph Robertson
- , Guillaume Jacquemet
- & Martin J. Humphries
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Article
| Open AccessMechanism of erosion of nanostructured porous silicon drug carriers in neoplastic tissues
The degradation of materials used in biological applications has an important bearing on their long term performance. Here, the authors show how porous silicon nanoparticle degradation can be accelerated in vivothrough the influence of local tissue pathology, likely influencing drug delivery performance.
- Adi Tzur-Balter
- , Zohar Shatsberg
- & Natalie Artzi
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Off-target-free gene delivery by affinity-purified receptor-targeted viral vectors
The clinical use of adeno-associated virus vectors (AAVs) has been limited by the lack of transduction specificity. Here the authors show that receptor-targeted, affinity-tagged, and purified AVVs reach tumours in mouse models with high selectivity and efficiency, outperforming therapeutic antibodies.
- Robert C. Münch
- , Anke Muth
- & Christian J. Buchholz
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Sulphur shuttling across a chaperone during molybdenum cofactor maturation
Microbial formate dehydrogenases (FDH) are molybdenum-containing enzymes that can catalyse the reduction of CO2 into formate. Here, the authors suggest a structural and functional basis for sulphuration of the molybdenum cofactor in E. coliFDH, a key step in the production of active formate dehydrogenase.
- Pascal Arnoux
- , Christian Ruppelt
- & Anne Walburger
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Article
| Open AccessGd-metallofullerenol nanomaterial as non-toxic breast cancer stem cell-specific inhibitor
A metallofullerenol nanomaterial, Gd@C82(OH)22, was shown to inhibit growth of several solid cancers in preclinical models and yet exhibit low toxicity. Herein the authors show that Gd@C82(OH)22functions as an inhibitor of breast cancer stem cell function via blocking TGF-β and HIF-1α signalling, while sparing normal tissue.
- Ying Liu
- , Chunying Chen
- & Yuliang Zhao
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Article
| Open AccessGene therapy restores vision in rd1 mice after removal of a confounding mutation in Gpr179
The rd1 mouse is the most widely used model to study retinal degeneration. Here, the authors identify a wide-spread mutation in these mice that may explain the failure of previous gene therapeutic approaches and show that long-lasting restoration of vision is possible in rd1 mice without this mutation.
- Koji M. Nishiguchi
- , Livia S. Carvalho
- & Robin R. Ali
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PD-L1hi B cells are critical regulators of humoral immunity
Follicular helper T cells promote antibody production by B cells, and regulatory B cells, in turn, can restrain T cell activation. Here, Khan et al. show that PD-L1 plays a critical role in regulatory B cell function, curbing excessive immune responses by engaging the PD-1 receptor on follicular helper T cells.
- Adnan R. Khan
- , Emily Hams
- & Padraic G. Fallon
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Article
| Open AccessStructure and boosting activity of a starch-degrading lytic polysaccharide monooxygenase
Lytic polysaccharide monooxygenases (LPMOs) are industrially important enzymes that oxidatively deconstruct polysaccharides. Here, Lo Leggio et al. report the activity, spectroscopy and three-dimensional structure of a LPMO of the new CAZy AA13 family active on recalcitrant-retrograded starch.
- Leila Lo Leggio
- , Thomas J. Simmons
- & Paul H. Walton
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An ultra-low-input native ChIP-seq protocol for genome-wide profiling of rare cell populations
Standard ChIP-seq protocols require large numbers of cells for high-quality datasets, limiting the application of this technique on rare cell types. Here, Brind’Amour et al. introduce an ultra-low-input ChIP-seq protocol to generate maps of covalent histone marks from as few as 1,000 cells.
- Julie Brind’Amour
- , Sheng Liu
- & Matthew C. Lorincz
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Sequencing of first-strand cDNA library reveals full-length transcriptomes
Strand-specific RNA-seq (ssRNA-seq) data often lack information on 5′ and 3′ ends of transcripts. Here the authors present a novel method for ssRNA-seq that enables the simultaneous profiling of gene expression, TSSs and polyadenylation sites at near-base resolution with a single library.
- Saurabh Agarwal
- , Todd S. Macfarlan
- & Shigeki Iwase
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Profiling lymphocyte interactions at the single-cell level by microfluidic cell pairing
Direct cell–cell interactions form the basis of the adaptive immune response. Here, Dura et al.present an advanced microfluidic platform that enables highly parallel pairing of primary immune cells and multiparametric and dynamic measurements of lymphocyte interactions and activation processes.
- Burak Dura
- , Stephanie K. Dougan
- & Joel Voldman
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Article
| Open AccessHigh-quality genome (re)assembly using chromosomal contact data
The correct assembly of genomes from sequencing data remains a challenge due to difficulties in correctly assigning the location of repeated DNA elements. Here the authors describe GRAAL, an algorithm that utilizes genome-wide chromosome contact data within a probabilistic framework to produce accurate genome assemblies.
- Hervé Marie-Nelly
- , Martial Marbouty
- & Romain Koszul
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An artificial PPR scaffold for programmable RNA recognition
Pentatricopeptide repeat (PPR) proteins bind RNA and control diverse aspects of RNA metabolism in eukaryotic cells. Here, Coquille et al.present the crystal structures of several engineered PPR domains, elucidate their RNA binding mode and suggest paths to the design of modular, sequence-specific PPR domains.
- Sandrine Coquille
- , Aleksandra Filipovska
- & Oliver Rackham
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Article
| Open AccessCell type-specific delivery of short interfering RNAs by dye-functionalised theranostic nanoparticles
A potential drug should specifically interact with its intended target in order to limit unwanted side effects. Here, the authors fabricate a biodegradable polymer nanoparticle with a fluorescent hepatic uptake transporter ligand to achieve targeted in vivosiRNA delivery and imaging of delivery.
- Adrian T. Press
- , Anja Traeger
- & Michael Bauer
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Somatic transcriptome priming gates lineage-specific differentiation potential of human-induced pluripotent stem cell states
Molecular and functional differences between induced pluripotent stem cells (iPSCs) derived from distinct cell types have been described. Here the authors show, by comparing human iPSCs derived from fibroblasts or cord blood, that the competence in activating developmental genes upon differentiation is influenced by the donor cell of origin.
- Jong-Hee Lee
- , Jung Bok Lee
- & Mickie Bhatia
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TALEN and CRISPR/Cas9-mediated genome editing in the early-branching metazoan Nematostella vectensis
Genome editing has yet to be performed in non-bilaterian phyla. Here, Ikmi et al. develop techniques to use both TALEN and CRISPR/Cas9 in the sea anemone, Nematostella vectensis, and further leverage a locus expressing an endogenous fluorescent protein as a landing site for homologous recombination-mediated transgenesis.
- Aissam Ikmi
- , Sean A. McKinney
- & Matthew C. Gibson
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Semi-permeable coatings fabricated from comb-polymers efficiently protect proteins in vivo
The attachment of polymers to protein molecules is known to shield them from biological breakdown. Here, the authors apply this concept to an asparaginase, in order to prevent its deactiviation by host immune responses during leukaemia treatment.
- Mi Liu
- , Pål Johansen
- & Marc A. Gauthier
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Article
| Open AccessMind-controlled transgene expression by a wireless-powered optogenetic designer cell implant
Brain–machine interfaces offer the possibility of controlling prosthetic devices using changes in brain activity. Folcher et al.couple such a system wirelessly to an optogenetic implant in mice to control expression of a transgene, demonstrating its potential for mind-controlled drug delivery.
- Marc Folcher
- , Sabine Oesterle
- & Martin Fussenegger
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Synthesizing AND gate genetic circuits based on CRISPR-Cas9 for identification of bladder cancer cells
Tools derived from synthetic biology offer powerful means to refine drug delivery and disease detection. Liu et al. engineer a logical AND gate using CRISPR-Cas9 to drive gene expression only cells in which two promoters are active, and use it to selectively inhibit the growth of bladder cancer cells in vitro.
- Yuchen Liu
- , Yayue Zeng
- & Zhiming Cai
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CD95 and CD95L promote and protect cancer stem cells
The death receptor CD95/Fas induces apoptosis of many normal cells but prevents necrotic death of cancer cells. Here the authors demonstrate that CD95 activation promotes a cancer stem cell (CSC) phenotype, and that CSCs but not differentiated cancer cells are resistant to CD95-mediated apoptosis and depend on CD95 signalling to prevent necrosis.
- Paolo Ceppi
- , Abbas Hadji
- & Marcus E. Peter
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MS-GF+ makes progress towards a universal database search tool for proteomics
The development of software tools to analyse large mass spectrometry data sets lags behind the increase in diversity of the data. Here the authors develop MS-GF+, a database search tool that outperforms other popular tools in identifying peptides from a variety of data sets.
- Sangtae Kim
- & Pavel A. Pevzner
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A system for the continuous directed evolution of proteases rapidly reveals drug-resistance mutations
Phage-assisted continuous evolution (PACE) has the potential to rapidly evolve drug-resistant mutations. Here, Dickinson et al.present a protease PACE system that identifies clinically relevant mutations conferring resistance to protease inhibitors in only a few days of continuous evolution.
- Bryan C. Dickinson
- , Michael S. Packer
- & David R. Liu
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Article
| Open AccessVesicle-based artificial cells as chemical microreactors with spatially segregated reaction pathways
In biological systems, cells are divided into compartments, typically with lipid layers. Here, the authors design a multipart vesicle system for sequential enzymatic reactions, where the product from one reaction traverses into the next, allowing multiple spatially separated reaction steps.
- Yuval Elani
- , Robert V. Law
- & Oscar Ces
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An authentic imaging probe to track cell fate from beginning to end
The availability of tracers to track the health of cells over long periods of time will be of value to optimize cell-based therapy. Here, Lee et al.design a nanoparticle that fluoresces red in living cells, but fluoresces green when cells begin to die from apoptosis or necrosis.
- Seung Koo Lee
- , Luke J. Mortensen
- & Ching-Hsuan Tung
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Highly modular bow-tie gene circuits with programmable dynamic behaviour
Engineering gene expression systems that can be programmed to respond to specific environmental conditions is challenging. Here, the authors develop a synthetic bow-tie circuit that is able to sense signals from microRNA molecules and affect a change in protein dynamics in mammalian cells.
- Laura Prochazka
- , Bartolomeo Angelici
- & Yaakov Benenson
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Article |
Magneto-fluorescent core-shell supernanoparticles
Magneto-fluorescent nanoparticles hold promise for bioimaging applications, but synthesizing uniform particles with tunable sizes remains challenging. Chen et al. propose an approach for co-assembling magnetic particles with fluorescent quantum dots, leading to well-defined core-shell structures.
- Ou Chen
- , Lars Riedemann
- & Moungi G. Bawendi
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Article
| Open AccessCombining high-throughput phenotyping and genome-wide association studies to reveal natural genetic variation in rice
Next-generation sequencing technology has made the generation of huge amounts of genetic data possible, but phenotype characterization remains slow and difficult. Here the authors develop a high-throughput phenotyping facility for rice that is able to accurately identify and characterize traits related to morphology, biomass and yield.
- Wanneng Yang
- , Zilong Guo
- & Lizhong Xiong
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Enzyme activity in liquid lipase melts as a step towards solvent-free biology at 150 °C
Enzymatic reactions typically occur in aqueous media or with hydrated enzymes. Here, the authors form fluid enzyme-polymer conjugates with sub-solvation levels of water, and demonstrate catalytic hydrolysis in the absence of a solvent at high temperatures.
- Alex P. S. Brogan
- , Kamendra P. Sharma
- & Stephen Mann
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Continuous wireless pressure monitoring and mapping with ultra-small passive sensors for health monitoring and critical care
Continuous monitoring of physiological parameters in clinical practice requires wired connections to the sensors that are attached to or implanted in patients. Here, Chen et al. demonstrate a wireless, millimetre-scale sensor, which can monitor intracranial pressure of mice in real-time.
- Lisa Y. Chen
- , Benjamin C. -K. Tee
- & Zhenan Bao
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A bistable genetic switch based on designable DNA-binding domains
Toggle switches can be engineered using pairs of transcriptional repressors; however, their bistability depends on nonlinear DNA-binding properties. Lebar et al. design a circuit that ensures bistability by artificially generating nonlinearity and use it to construct a toggle from programmable DNA-binding domains.
- Tina Lebar
- , Urban Bezeljak
- & Roman Jerala
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Retro-biosynthetic screening of a modular pathway design achieves selective route for microbial synthesis of 4-methyl-pentanol
Microbial pathways can be engineered for the sustainable production of chemical products such as transportation fuels. Here the authors design and implement a de novo biosynthetic pathway in E. colithat is capable of producing the gasoline replacement, 4-methyl-pentanol.
- Micah J. Sheppard
- , Aditya M. Kunjapur
- & Kristala L. J. Prather
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