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"Fletcher, Stephen"
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A Perspective on RNAi-Based Biopesticides
Sustainable agriculture relies on practices and technologies that combine effectiveness with a minimal environmental footprint. RNA interference (RNAi), a eukaryotic process in which transcript expression is reduced in a sequence-specific manner, can be co-opted for the control of plant pests and pathogens in a topical application system. Double-stranded RNA (dsRNA), the key trigger molecule of RNAi, has been shown to provide protection without the need for integration of dsRNA-expressing constructs as transgenes. Consequently, development of RNA-based biopesticides is gaining momentum as a narrow-spectrum alternative to chemical-based control measures, with pests and pathogens targeted with accuracy and specificity. Limitations for a commercially viable product to overcome include stable delivery of the topically applied dsRNA and extension of the duration of protection. In addition to the research focus on delivery of dsRNA, development of regulatory frameworks, risk identification, and establishing avoidance and mitigation strategies is key to widespread deployment of topical RNAi technologies. Once in place, these measures will provide the crop protection industry with the certainty necessary to expend resources on the development of innovative dsRNA-based products. Readily evident risks to human health appear minimal, with multiple barriers to uptake and a long history of consumption of dsRNA from plant material. Unintended impacts to the environment are expected to be most apparent in species closely related to the target. Holistic design practices, which incorporate bioinformatics-based dsRNA selection along with experimental testing, represent important techniques for elimination of adverse impacts.
Journal Article
Transmission of chirality through space and across length scales
This Review charts how chiral information can be relayed across length scales in nanomaterials and beyond.
Chirality is a fundamental property and vital to chemistry, biology, physics and materials science. The ability to use asymmetry to operate molecular-level machines or macroscopically functional devices, or to give novel properties to materials, may address key challenges at the heart of the physical sciences. However, how chirality at one length scale can be translated to asymmetry at a different scale is largely not well understood. In this Review, we discuss systems where chiral information is translated across length scales and through space. A variety of synthetic systems involve the transmission of chiral information between the molecular-, meso- and macroscales. We show how fundamental stereochemical principles may be used to design and understand nanoscale chiral phenomena and highlight important recent advances relevant to nanotechnology. The survey reveals that while the study of stereochemistry on the nanoscale is a rich and dynamic area, our understanding of how to control and harness it and dial-up specific properties is still in its infancy. The long-term goal of controlling nanoscale chirality promises to be an exciting journey, revealing insight into biological mechanisms and providing new technologies based on dynamic physical properties.
Journal Article
A chemically fuelled self-replicator
The continuous consumption of chemical energy powers biological systems so that they can operate functional supramolecular structures. A goal of modern science is to understand how simple chemical mixtures may transition from non-living components to truly emergent systems and the production of new lifelike materials and machines. In this work a replicator can be maintained out-of-equilibrium by the continuous consumption of chemical energy. The system is driven by the autocatalytic formation of a metastable surfactant whose breakdown products are converted back into building blocks by a chemical fuel. The consumption of fuel allows the high-energy replicators to persist at a steady state, much like a simple metabolic cycle. Thermodynamically-driven reactions effect a unidirectional substrate flux as the system tries to regain equilibrium. The metastable replicator persists at a higher concentration than achieved even transiently in a closed system, and its concentration is responsive to the rate of fuel supply.
Understanding how simple chemical mixtures transition into truly emergent systems is essential to create new lifelike materials. Here, the authors show a self-replicating system that can be maintained out-of-equilibrium by an oxidant fuel in analogy to simple metabolic cycles.
Journal Article
Bundles Prevent Surgical Site Infections After Colorectal Surgery: Meta-analysis and Systematic Review
Introduction
Colorectal surgeries (CRS) have one of the highest rates of surgical site infections (SSIs) with rates 15 to >30%. Prevention “bundles” or sets of evidence-based interventions are structured ways to improve patient outcomes. The aim sof this study is to evaluate CRS SSI prevention bundles, bundle components, and implementation and compliance strategies.
Methods
A meta-analysis of studies with pre- and post-implementation data was conducted to assess the impact of bundles on SSI rates (superficial, deep, and organ/space). Subgroup analysis of bundle components identified optimal bundle designs.
Results
Thirty-five studies (51,413 patients) were identified and 23 (17,557 patients) were included in the meta-analysis. A SSI risk reduction of 40% (
p
< 0.001) was noted with 44% for superficial SSI (
p
< 0.001) and 34% for organ/space (
p
= 0.048). Bundles with sterile closure trays (58.6 vs 33.1%), MBP with oral antibiotics (55.4 vs 31.8%), and pre-closure glove changes (56.9 vs 28.5%) had significantly greater SSI risk reduction.
Conclusion
Bundles can effectively reduce the risk of SSIs after CRS, by fostering a cohesive environment, standardization, and reduction in operative variance. If implemented successfully and complied with, bundles can become vital to improving patients’ surgical quality of care.
Journal Article
Asymmetric Suzuki-Miyaura coupling of heterocycles via Rhodium-catalysed allylic arylation of racemates
Using asymmetric catalysis to simultaneously form carbon–carbon bonds and generate single isomer products is strategically important. Suzuki-Miyaura cross-coupling is widely used in the academic and industrial sectors to synthesize drugs, agrochemicals and biologically active and advanced materials. However, widely applicable enantioselective Suzuki-Miyaura variations to provide 3D molecules remain elusive. Here we report a rhodium-catalysed asymmetric Suzuki-Miyaura reaction with important partners including aryls, vinyls, heteroaromatics and heterocycles. The method can be used to couple two heterocyclic species so the highly enantioenriched products have a wide array of cores. We show that pyridine boronic acids are unsuitable, but they can be halogen-modified at the 2-position to undergo reaction, and this halogen can then be removed or used to facilitate further reactions. The method is used to synthesize isoanabasine, preclamol, and niraparib—an anticancer agent in several clinical trials. We anticipate this method will be a useful tool in drug synthesis and discovery.
Asymmetric Suzuki-Miyaura procedures often have difficulty incorporating heterocyclic reagents, despite the importance of these in the pharmaceutical industry. Here the authors report a rhodium catalysed cross-coupling that tolerates a wide variety of nucleophiles including a range of heterocycles.
Journal Article
Rhodium-catalysed asymmetric allylic arylation of racemic halides with arylboronic acids
C
s
p
2
−
C
s
p
2
cross-coupling reactions between arylboronic acid and aryl halides are widely used in both academia and industry and are strategically important in the development of new agrochemicals and pharmaceuticals.
C
s
p
2
−
C
s
p
3
cross-coupling reactions have been developed, but enantioselective variations are rare and simply retaining the stereochemistry is a problem. Here we report a highly enantioselective
C
s
p
2
−
C
s
p
3
bond-forming method that couples arylboronic acids to racemic allyl chlorides. Both enantiomers of a cyclic chloride are converted into a single enantiomer of product via a dynamic kinetic asymmetric transformation. This Rh-catalysed method uses readily available and inexpensive building blocks and is mild and broadly applicable. For electron-deficient, electron-rich or
ortho
-substituted boronic acids better results are obtained with racemic allyl bromides. Oxygen substitution in the allyl halide is tolerated and the products can be functionalized to provide diverse building blocks. The approach fills a significant gap in the methods for catalytic asymmetric synthesis.
Cross-couplings between boronic acids and halides are a mainstay of synthetic organic chemistry but enantioselective
C
s
p
2
−
C
s
p
3
couplings are rare, and simply retaining the stereochemistry of the starting material is problematic. Now, it is shown that racemic allylic halides can converted to single enantiomer products by a rhodium(
I
)-catalysed asymmetric allylic arylation using arylboronic acids
Journal Article
A transient self-assembling self-replicator
Developing physical models of complex dynamic systems showing emergent behaviour is key to informing on persistence and replication in biology, how living matter emerges from chemistry, and how to design systems with new properties. Herein we report a fully synthetic small molecule system in which a surfactant replicator is formed from two phase-separated reactants using an alkene metathesis catalyst. The replicator self-assembles into aggregates, which catalyse their own formation, and is thermodynamically unstable. Rather than replicating until the reactants are fully consumed, the metastable replicator is depleted in a second metathesis reaction, and closed system equilibrium is eventually reached. Mechanistic experiments suggest phase separation is responsible for both replicator formation and destruction.
Understanding self-replication and persistence in an out-of-equilibrium state is key to designing systems with new properties mimicking “living systems”. Here, the authors developed a synthetic small molecule system in which a transient surfactant replicator is responsible for both an autocatalytic aggregation pathway and a destructive pathway.
Journal Article
Chelation enables selectivity control in enantioconvergent Suzuki–Miyaura cross-couplings on acyclic allylic systems
Asymmetric Suzuki–Miyaura cross-couplings with aryl boronic acids and allylic electrophiles are a powerful method to convert racemic mixtures into enantioenriched products. Currently, enantioconvergent allylic arylations are limited to substrates that are symmetrical about the allylic unit, and the absence of strategies to control regio-,
E
/
Z
- and enantioselectivity in acyclic allylic systems is a major restriction. Here, using a system capable of either conjugate addition or allylic arylation, we have discovered the structural features and experimental conditions that allow an acyclic system to undergo chemo- and regioselective, enantioconvergent allylic Suzuki–Miyaura-type arylation. A wide variety of boronic acid coupling partners can be used, and both alkyl and aromatic substituents are tolerated on the allylic unit so that a wide variety of structures can be obtained. Preliminary mechanistic studies reveal that the chelating ability of the ester group is crucial to obtaining high regio- and enantioselectivity. Using this method, we were able to synthesize the natural products (
S
)-curcumene and (
S
)-4,7-dimethyl-1-tetralone and the clinically used antidepressant sertraline (Zoloft).
Achieving selectivity control in allylic arylations is a long-standing challenge in catalysis. Now a rhodium-catalysed system demonstrates chemo-, regio- and enantioselectivity, enabling Suzuki–Miyaura-type arylation with racemic, non-symmetrical, acyclic allylic systems; chelation is speculated to facilitate oxidative addition and enable both enantiomers of the starting material to converge onto a single product.
Journal Article
An autonomously oscillating supramolecular self-replicator
A key goal of chemistry is to develop synthetic systems that mimic biology, such as self-assembling, self-replicating models of minimal life forms. Oscillations are often observed in complex biological networks, but oscillating, self-replicating species are unknown, and how to control autonomous supramolecular-level oscillating systems is also not yet established. Here we show how a population of self-assembling self-replicators can autonomously oscillate, so that simple micellar species repeatedly appear and disappear in time. The interplay of molecular and supramolecular events is key to observing oscillations: the repeated formation and disappearance of compartments is connected to a reaction network where molecular-level species are formed and broken down. The dynamic behaviour of our system across different length scales offers the opportunities for mass transport, as we demonstrate via reversible dye uptake. We believe these findings will inspire new biomimetic systems and may unlock nanotechnology systems such as (supra)molecular pumps, where compartment formation is controlled in time and space.
Oscillations are widespread throughout the natural world and a number of fascinating inorganic oscillating reactions are known—but the formation and control of oscillating, self-replicating synthetic systems has remained challenging. Now, it has been shown that chemically fuelled oscillations within a network of organic replicators can drive supramolecular assembly and disassembly.
Journal Article