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"Hunt, John"
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Codon influence on protein expression in E. coli correlates with mRNA levels
Degeneracy in the genetic code, which enables a single protein to be encoded by a multitude of synonymous gene sequences, has an important role in regulating protein expression, but substantial uncertainty exists concerning the details of this phenomenon. Here we analyse the sequence features influencing protein expression levels in 6,348 experiments using bacteriophage T7 polymerase to synthesize messenger RNA in
Escherichia coli
. Logistic regression yields a new codon-influence metric that correlates only weakly with genomic codon-usage frequency, but strongly with global physiological protein concentrations and also mRNA concentrations and lifetimes
in vivo
. Overall, the codon content influences protein expression more strongly than mRNA-folding parameters, although the latter dominate in the initial ~16 codons. Genes redesigned based on our analyses are transcribed with unaltered efficiency but translated with higher efficiency
in vitro
. The less efficiently translated native sequences show greatly reduced mRNA levels
in vivo
. Our results suggest that codon content modulates a kinetic competition between protein elongation and mRNA degradation that is a central feature of the physiology and also possibly the regulation of translation in
E. coli
.
In-depth analyses of protein expression studies are used to derive a new codon-influence metric that correlates with global protein levels, mRNA levels and mRNA lifetimes
in vivo
, indicating tight coupling between translation efficiency and mRNA stability; genes redesigned based on these analyses consistently yield high protein expression levels both
in vivo
and
in vitro
.
Improving protein translation
All living organisms use the same set of 64 possible triplet codons to encode 20 amino acids and stop signals during translation of mRNA into protein, but the frequency with which each codon is used varies between organisms. This variation has been thought to be the basis for often poor protein expression when a gene is translated in a heterologous system. John Hunt and colleagues have performed in-depth analysis of protein expression studies to derive a codon-influence metric. When genes are redesigned using this metric, the authors find no effect on their transcription, but much greater translation efficiency. They conclude that
in vivo
mRNA degradation and translation processes are in competition, and using the metric, protein production can be favoured. This approach may facilitate heterologous gene expression in many biotechnical or experimental settings.
Journal Article
Evaluating the small-scale epidemiology of the stony-coral -tissue-loss-disease in the middle Florida Keys
Along the Florida reef tract, stony-coral-tissue-loss disease (SCTLD) has caused extensive mortality of more than 20 scleractinian coral species. The pathogen is unknown, but its epizoology indicates that the disease, facilitated by water currents, has progressed linearly along the tract, affecting reefs at the scale of hundreds of kilometers. To inform ongoing disease mitigation efforts, we examined the small-scale spatial and temporal epidemiology of SCTLD. We established a series of sites in the middle Florida Keys at offshore and inshore locations that had not yet shown signs of SCTLD. We then conducted high-frequency monitoring from February 2018 through September 2019 and documented the onset of SCTLD and its progression through the sites. SCTLD was first observed at one site during early February 2018 and by early March 2018 all sites showed signs of the disease. A dynamic multistate model suggested that disease transmission was independent of coral density and found little evidence of a positive association between a colony showing signs of SCTLD and the condition or distance to its neighboring colonies. The model did, however, indicate that the probability of a colony showing signs of SCTLD increased with increasing colony surface area. These results are consistent with the water-borne transmission of a pathogen that progressed rapidly through the survey area. However, by the end of our survey the progression of SCTLD had slowed, particularly at inshore sites. Many affected colonies no longer exhibited progressive tissue mortality typical of the disease, suggesting the existence of differentially resilient colonies or coral communities, meriting their use for future coral rescue and propagation and disease research. These results are useful for refining ongoing SCTLD mitigation strategies, particularly by determining when disease rates are sufficiently low for direct intervention efforts designed to arrest disease progression on individual coral colonies will be most effective.
Journal Article
The making of place : modern and contemporary gardens
\"From imposing sculptures discovered in woodlands or on hilly trails to community gardens, and along disused rail tracks to ones made on inhospitable seashores, this book offers insights into the history and make-up of contemporary gardens, whether they reflect the priorities of modern society, bring new ideas and materials into the world, or seek the reinvention of ancient cultures. The modern botanical gardens, sculpture parks, campuses, memorial gardens and vernacular gardens examined showcase the differences between cultures and countries around the world, including the United Kingdom, France, Germany, the United States, China and Australia\"--Jacket.
Book
Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form
For cancer cells to survive and proliferate, they must escape normal immune destruction. One mechanism by which this is accomplished is through immune suppression effected by up-regulation of indoleamine 2,3-dioxygenase (IDO1), a heme enzyme that catalyzes the oxidation of tryptophan to N-formylkynurenine. On deformylation, kynurenine and downstream metabolites suppress T cell function. The importance of this immunosuppressive mechanism has spurred intense interest in the development of clinical IDO1 inhibitors. Herein, we describe the mechanism by which a class of compounds effectively and specifically inhibits IDO1 by targeting its apo-form. We show that the in vitro kinetics of inhibition coincide with an unusually high rate of intrinsic enzyme–heme dissociation, especially in the ferric form. X-ray crystal structures of the inhibitor–enzyme complexes show that heme is displaced from the enzyme and blocked from rebinding by these compounds. The results reveal that apo-IDO1 serves as a unique target for inhibition and that heme lability plays an important role in posttranslational regulation.
Journal Article
Genius Loci
From literature to landscape architecture, an expansive, contemplative exploration of the significance of place. For ancient Romans, genius loci was literally \"the genius of the place, \" the presiding divinity who inhabited a site and gave it meaning. While we are less attuned to divinity today, we still sense that a place has significance. In this book, eminent garden historian John Dixon Hunt explores genius loci in many settings, including contemporary land art, the paintings of Paul and John Nash, travel writers such as Henry James, Paul Theroux, and Lawrence Durrell on Provence, Mexico, and Cyprus, and landscape architects who invent new meanings for a site. This book is a nuanced, thoughtful exploration of how places become more significant to us through the myriad ways we see, talk about, and remember them.
eBook
Adaptation for screenwriters
Edgar and Marland make a strong case for adaptation as the fundamental principle of screenwriting, and offers readers a practical framework for achieving it.
Book
Stretchable electronic strips for electronic textiles enabled by 3D helical structure
The development of stretchable electronic devices is a critical area of research for wearable electronics, particularly electronic textiles (e-textiles), where electronic devices embedded in clothing need to stretch and bend with the body. While stretchable electronics technologies exist, none have been widely adopted. This work presents a novel and potentially transformative approach to stretchable electronics using a ubiquitous structure: the helix. A strip of flexible circuitry (‘e-strip’) is twisted to form a helical ribbon, transforming it from flexible to stretchable. A stretchable core—in this case rubber cord—supports the structure, preventing damage from buckling. Existing helical electronics have only extended to stretchable interconnects between circuit modules, and individual components such as printed helical transistors. Fully stretchable circuits have, until now, only been produced in planar form: flat circuits, either using curved geometry to enable them to stretch, or using inherently stretchable elastomer substrates. Helical e-strips can bend along multiple axes, and repeatedly stretch between 30 and 50%, depending on core material and diameter. LED and temperature sensing helical e-strips are demonstrated, along with design rules for helical e-strip fabrication. Widely available materials and standard fabrication processes were prioritized to maximize scalability and accessibility.
Journal Article