Synthesis of 19F nucleic acid–polymer conjugates as real-time MRI probes of biorecognition

Polymer–DNA conjugates in which one nucleic acid strand contains fluorine-substituted nucleobases have been prepared and characterised. The efficacy of these novel 19F nucleic acid–polymer conjugates as sensitive and selective in vitro reporters of DNA binding events is demonstrated through a number of rapid-acquisition MR sequences. The conjugates respond readily and in a sequence specific manner to external target oligonucleotide sequences by changes in hybridisation. In turn, these structural changes in polymer–nucleotide conjugates translate into responses which are detectable in fluorine relaxation and diffusion switches, and which can be monitored by in vitro Spin Echo and DOSY NMR spectroscopy. Although complementary to conventional FRET methods, the excellent diagnostic properties of fluorine nuclei make this approach a versatile and sensitive probe of molecular structure and conformation in polymeric assemblies

Activating discipline specific thinking with adaptive learning : A digital tool to enhance learning in chemistry

In tertiary science education, students are encouraged to engage in discipline specific thinking, to learn their chosen subject. The challenge for educators is engaging all students equitably, despite their educational backgrounds and depth of discipline specific knowledge. Personalising learning in the context of large-scale tertiary courses can only be achieved by using digital technologies. In the context of chemistry education, this project has investigated how an adaptive learning technology can effectively and consistently engage students in discipline specific thinking, by personalising their learning pathway. Adaptive learning has been integrated into a foundational chemistry subject and through quantitative analysis there is empirical evidence to support the benefit adaptive learning has on outcomes, in both the short and long term. This study shows adaptive learning can equitably meet the needs for all students and can lead to improvements in educational behaviour beyond grades. The evidence supports adaptive learning as one critical tool for chemistry educators, and educators in other disciplines of science, to include in their suite of pedagogical strategies to meet the needs of all their students.</p

Diarylethene Photoswitches and 3D Printing to Fabricate Rewearable Colorimetric UV Sensors for Sun Protection

Despite education campaigns linking sun overexposure and skin cancer, it remains one of the leading preventable cancer diagnoses. Skin cancer risk is correlated with overexposure to UV light in sunlight and can be prevented by avoiding exposure. While sun protection can be achieved using sunscreen and clothing, people must be made aware of their risk to facilitate behavior change. Herein, new rewearable UV sensors which overcome the single-use limitations of other products are presented. These sensors utilize diarylethene photoswitches, which develop a colored appearance upon exposure to UV and are reset to colorless by green light (<10 min). These photoswitches are incorporated into a range of materials, enabling the use of advanced manufacturing to develop highly desirable consumer products. 3D stereolithographic printing is used to prototype sensors, with complex geometries and appealing aesthetics, that can be worn by users. The UV sensitivity of these devices is tuned by incorporating chromophores, meeting the needs of diverse skin types. The colorimetric response allows for direct visual feedback to the user, or quantification using photography, allowing for dosimetry of UV exposure. These new reusable devices aim to reduce people's exposure to UV, while reducing the waste generated by single-use devices.</p

The Macromolecular Design of Poly(styrene-isoprene-styrene) (SIS) Copolymers Defines their Performance in Flexible Electrothermal Composite Heaters

Electric cars are desirable for their environmental and economic benefits yet face limitations in range in cold weather due to the increased energy demands for cabin heating. To provide efficient heating for vehicles, flexible composite electrothermal heaters offer a viable solution owing to their lightweight design, efficiency, and adaptability for use within and beyond vehicle interiors. The current study aims to improve electrothermal heater stability and performance by understanding the impact of the polymer structure on composite properties. We explore how the presence and molecular structure of olefinic bonds within the polyisoprene block of styrenic triblock copolymers affect thermal stability and performance. Composite electrothermal heaters were fabricated by dispersing carbon black (CB) as the heating material in three triblock copolymer matrices, poly(styrene-1,4-isoprene-styrene) (1,4-SIS), poly(styrene-3,4-isoprene-styrene) (3,4-SIS), and its hydrogenated version poly(styrene-ethylene-propylene-styrene) (SEPS). The chemical structure and thermal properties of each copolymer were linked to electrothermal performance measurements of composite heaters to establish structure–function relationships. Notably, 3,4-SIS with 28 wt % CB demonstrated the highest thermal and electrical conductivity, resulting in uniform heat distribution. The outcomes unambiguously demonstrate that the olefinic structure of SIS copolymers enhances the electric and thermal conductivity, leading to enhanced electrothermal performance of prototype heaters compared to that of the hydrogenated copolymer

Strategies to Improve the Potency of Oxazolidinones towards Bacterial Biofilms

Biofilms are part of the natural lifecycle of bacteria and are known to cause chronic infections that are difficult to treat. Most antibiotics are developed and tested against bacteria in the planktonic state and are ineffective against bacterial biofilms. The oxazolidinones, including the last resort drug linezolid, are one of the main classes of synthetic antibiotics progressed to clinical use in the last 50 years. They have a unique mechanism of action and only develop low levels of resistance in the clinical setting. With the aim of providing insight into strategies to design more potent antibiotic compounds with activity against bacterial biofilms, we review the biofilm activity of clinically approved oxazolidinones and report on structural modifications to oxazolidinones and their delivery systems which lead to enhanced anti-biofilm activity.</p

A Versatile Light-Triggered Radical-Releasing Surface Coating Technology

Organic based redox active materials and coatings are increasingly being investigated as solutions for more efficient energy devices, catalysts, sensors, and biomedical technologies. Their advantage is negating the necessity for expensive and unsustainable rare earth metals seen in other redox active materials. Challenges to their wide-spread usage remain, including versatility of coatings on a wide range of substrates, and creating smart devices that can respond to environmental stimuli. A new light responsive radical releasing redox coating has been developed, that can be rapidly and stably applied to a diverse range of substrates including silicon dioxide, plastics, and microparticles. These coatings rapidly cleave upon irradiation with UV-A light to release stable nitroxides from the surface coating. These coatings are developed into microparticle sensors for radical oxygen species, which are able to detect the generation of free radicals in a model system for particulate matter pollution. These new responsive organic redox coatings also offer future potential to function as switchable organic electrodes, and biomedical surface coatings to prevent biofouling and reduce inflammation.</p

Measuring the Interactions and Influence of Amphipathic Copolymers with Lipid Monolayers and Bilayers as Models of Biological Membranes

Amphipathic copolymers are useful materials for nanomedicine, owing to their ability to self-assemble into nanoparticles, act as surfactants for inorganic materials, or for their favorable interactions with lipid membranes. Despite their widespread use, there is still a range of questions about the physicochemical properties that are necessary to drive their interactions at biological interfaces. To fully understand these interactions requires a diverse range of complementary analytical techniques. In this work, a library of neutral amphipathic methacrylate copolymers is synthesized by reversible addition-fragmentation chain-transfer polymerization (RAFT) polymerization, to investigate the effect of polymer composition and nature of the hydrophobic comonomer on interactions with model lipid membranes. These materials are shown to interact with Langmuir lipid monolayers, and neutron reflectometry demonstrates that hydrophobic interactions lead to the polymers intercalating with the monolayers. More complex models of lipid bilayers are studied using an in situ quartz crystal microbalance (QCM) model and shows while the composition and hydrophobic comonomer affect the stability of these interactions, there is no effect on the viscoelasticity of the lipid membranes. The in-depth understanding of these interfacial interactions afforded by this suite of analytical tools will allow for more complex copolymers to be studied, providing a greater understanding of key processes in nanomedicine, such as cellular entry and endosomal escape.</p

In Vitro Activities of Oxazolidinone Antibiotics Alone and in Combination with C-TEMPO against Methicillin-Resistant Staphylococcus aureus Biofilms

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a global health concern. The propensity of MRSA to form biofilms is a significant contributor to its pathogenicity. Strategies to treat biofilms often involve small molecules that disperse the biofilm into planktonic cells. Linezolid and, by extension, theoxazolidinones have been developed to treat infections caused by Gram-positive bacteria such as MRSA. However, the clinical development of these antibiotics has mainly assessed the susceptibility of planktonic cells to the drug. Previous studies evaluating the anti-biofilm activity of theoxazolidinones have mainly focused on the biofilm inhibition of Enterococcus faecalis and methicillin-sensitive Staphylococcus aureus, with only a few studies investigating the activity of oxazolidinones for eradicating established biofilms for these species. Very little is known about the ability of oxazolidinones to eradicate MRSA biofilms. In this work, five oxazolidinones were assessed against MRSA biofilms using a minimum biofilm eradication concentration (MBEC) assay. All oxazolidinones had inherent antibiofilm activity. However, only ranbezolid could completely eradicate MRSA biofilms at clinically relevant concentrations. The susceptibility of the MRSA biofilms to ranbezolid was synergistically enhanced by coadministration with the nitroxide biofilm dispersal agent C-TEMPO. We presume that ranbezolid acts as a dual warhead drug, which combines the mechanism of action of the oxazolidinones with a nitric oxide donor or cytotoxic drug.</p

Simple and Efficient Synthesis of 3-Aryl-2-oxazolidinone Scaffolds Enabling Increased Potency toward Biofilms

Infectious diseases caused by bacterial pathogens are a leading cause of mortality worldwide. In particular, recalcitrant bacterial communities known as biofilms are implicated in persistent and difficult to treat infections. With a diminishing antibiotic pipeline, new treatments are urgently required to combat biofilm infections. An emerging strategy to develop new treatments is the hybridization of antibiotics. The benefit of this approach is the extension of the useful lifetime of existing antibiotics. The oxazolidinones, which include the last resort antibiotic linezolid, are an attractive target for improving antibiofilm efficacy as they present one of the most recently discovered classes of antibiotics. A key step in the synthesis of new 3-aryl-2-oxazolidinone derivatives is the challenging formation of the oxazolidinone ring. Herein we report a direct synthetic route to the piperazinyl functionalized 3-aryl-2-oxazolidinone 17. We also demonstrate an application of these piperazine molecules by functionalizing them with a nitroxide moiety as a strategy to extend the useful lifetime of oxazolidinones and improve their potency against Methicillin-resistant Staphylococcus aureus (MRSA) biofilms. The antimicrobial susceptibility of the linezolid-nitroxide conjugate 11 and its corresponding methoxyamine derivative 12 (a control for biofilm dispersal) was assessed against planktonic cells and biofilms of MRSA. In comparison to linezolid and our lead compound 10 (a piperazinyl oxazolidinone derivative), the linezolid-nitroxide conjugate 11 displayed a minimum inhibitory concentration that was 4-16-fold higher. The opposite effect was seen in biofilms where the linezolid-nitroxide hybrid 11 was >2-fold more effective (160 μg/mL versus >320 μg/mL) in eradicating MRSA biofilms. The methoxyamine derivative 12 performed on par with linezolid. The drug-likeness of the compounds was also assessed, and all compounds were predicted to have good oral bioavailability. Our piperazinyl oxazolidinone derivative 10 was confirmed to be lead-like and would be a good lead candidate for future functionalized oxazolidinones. The modification of antibiotics with a dispersal agent appears to be a promising approach for eradicating MRSA biofilms and overcoming the antibiotic resistance associated with the biofilm mode of growth.</p

Structural elucidation of hydroxy fatty acids by photodissociation mass spectrometry with photolabile derivatives

Rationale: Eicosanoids are short-lived bio-responsive lipids produced locally from oxidation of polyunsaturated fatty acids (FAs) via a cascade of enzymatic or free radical reactions. Alterations in the composition and concentration of eicosanoids are indicative of inflammation responses and there is strong interest in developing analytical methods for the sensitive and selective detection of these lipids in biological mixtures. Most eicosanoids are hydroxy FAs (HFAs), which present a particular analytical challenge due to the presence of regioisomers arising from differing locations of hydroxylation and unsaturation within their structures. Methods: In this study, the recently developed derivatization reagent 1-(3-(aminomethyl)-4-iodophenyl)pyridin-1-ium (4-I-AMPP+) was applied to a representative set of HFAs including bioactive eicosanoids. Photodissociation (PD) mass spectra obtained at 266 nm of 4-I-AMPP+-modified HFAs exhibit abundant product ions arising from photolysis of the aryl–iodide bond within the derivative with subsequent migration of the radical to the hydroxyl group promoting fragmentation of the FA chain and facilitating structural assignment. Results: Representative polyunsaturated HFAs (from the hydroxyeicosatetraenoic acid and hydroxyeicosapentaenoic acid families) were derivatized with 4-I-AMPP+ and subjected to a reversed-phase liquid chromatography workflow that afforded chromatographic resolution of isomers in conjunction with structurally diagnostic PD mass spectra. Conclusions: PD of these complex HFAs was found to be sensitive to the locations of hydroxyl groups and carbon–carbon double bonds, which are structural properties strongly associated with the biosynthetic origins of these lipid mediators.</p