Synthesis of DNA-polymer conjugates using RAFT polymerisation

The use of reversible addition–fragmentation chain transfer (RAFT) polymerisation for the production of DNA–polymer conjugates is explored. Chapter 1 gives a general introduction to the field of DNA–polymer conjugates, their potential applications and methods for their synthesis. The need for a general, solutionphase technique for DNA–polymer conjugation is highlighted. In Chapters 2-5, the use of a number of different strategies for the production of DNA–polymer conjugates is described. Amide coupling (Chapter 2) is found to produce the desired products only under very specific reaction conditions. The thiol–alkene Michael addition reaction (Chapter 3) is found to afford DNA–polymer conjugates in aqueous solution with high yield; however, attempts to replicate this using organic solvents are not successful. The inverse electron-demand Diels–Alder reaction between tetrazine and norbornene (Chapter 4) is explored and found to produce DNA–polymer conjugates in high yield in organic solvents; however, the precursor compounds are time-consuming to prepare and so the generality of this approach is limited. Finally, the copper-catalysed azide–alkyne cycloaddition (Chapter 5) is found to be an excellent method for the production of a wide range of DNA–polymer conjugates. Chapter 6 describes the use of the DNA segment of a DNA–polymer conjugate to assemble a discrete three dimensional nanostructure – a DNA tetrahedron – incorporating the temperature-responsive polymer poly(N-isopropylacrylamide). These hybrid structures are found to be able to stabilise the formation of discrete, well-defined polymer nanoparticles at elevated temperatures. Chapter 7 describes the use of a non-covalent interaction (intercalation) to produce DNA– polymer conjugates. The effect of polymer molecular weight and structure on the strength of this interaction are explored. Finally, intercalation is exploited to template the formation of discrete polymer particles on a DNA strand

Efficient DNA-polymer coupling in organic solvents:a survey of amide coupling, Thiol-Ene and Tetrazine-Norbornene chemistries applied to conjugation of Poly(N-Isopropylacrylamide)

A range of chemistries were explored for the efficient covalent conjugation of DNA to poly(N-isopropylacrylamide) (poly(NIPAM)) in organic solvents. Amide coupling and thiol–ene Michael addition were found to be ineffective for the synthesis of the desired products. However, the inverse electron-demand Diels–Alder (DAinv) reaction between tetrazine (Tz) and norbornene (Nb) was found to give DNA–polymer conjugates in good yields (up to 40%) in organic solvents (N,N-dimethylformamide, N,N-dimethylacetamide and N-methyl-2-pyrrolidone), and without the need for a catalyst. Methods for the synthesis of Tz-and Nb- functionalised DNA were developed, along with a post-polymerisation functionalisation strategy for the production of Tz-functionalised polymers

Impact of previous hepatitis B infection on the clinical outcomes from chronic hepatitis C? A population-level analysis

Chronic coinfection with hepatitis C virus (HCV) and hepatitis B virus (HBV) is associated with adverse liver outcomes. The clinical impact of previous HBV infection on liver disease in HCV infection is unknown. We aimed at determining any association of previous HBV infection with liver outcomes using antibodies to the hepatitis B core antigen (HBcAb) positivity as a marker of exposure. The Scottish Hepatitis C Clinical Database containing data for all patients attending HCV clinics in participating health boards was linked to the HBV diagnostic registry and mortality data from Information Services Division, Scotland. Survival analyses with competing risks were constructed for time from the first appointment to decompensated cirrhosis, hepatocellular carcinoma (HCC) and liver‐related mortality. Records of 8513 chronic HCV patients were included in the analyses (87 HBcAb positive and HBV surface antigen [HBsAg] positive, 1577 HBcAb positive and HBsAg negative, and 6849 HBcAb negative). Multivariate cause‐specific proportional hazards models showed previous HBV infection (HBcAb positive and HBsAg negative) significantly increased the risks of decompensated cirrhosis (hazard ratio [HR]: 1.29, 95% CI: 1.01‐1.65) and HCC (HR: 1.64, 95% CI: 1.09‐2.49), but not liver‐related death (HR: 1.02, 95% CI: 0.80‐1.30). This is the largest study to date showing an association between previous HBV infection and certain adverse liver outcomes in HCV infection. Our analyses add significantly to evidence which suggests that HBV infection adversely affects liver health despite apparent clearance. This has important implications for HBV vaccination policy and indications for prioritization of HCV therapy

A new architecture for DNA-templated synthesis in which abasic sites protect reactants from degradation

The synthesis of artificial sequence-defined polymers that match and extend the functionality of proteins is an important goal in materials science. One way of achieving this is to program a sequence of chemical reactions between precursor building blocks by means of attached oligonucleotide adapters. However, hydrolysis of the reactive building blocks has so far limited the length and yield of product that can be obtained using DNA-templated reactions. Here, we report an architecture for DNA-templated synthesis in which reactants are tethered at internal abasic sites on opposite strands of a DNA duplex. We show that an abasic site within a DNA duplex can protect a nearby thioester from degradation, significantly increasing the yield of a DNA-templated reaction. This protective effect has the potential to overcome the challenges associated with programmable sequence-controlled synthesis of long non-natural polymers by extending the lifetime of the reactive building blocks

A New Architecture for DNA‐Templated Synthesis in Which Abasic Sites Protect Reactants from Degradation

The synthesis of artificial sequence‐defined polymers that match and extend the functionality of proteins is an important goal in materials science. One way of achieving this is to program a sequence of chemical reactions between precursor building blocks by means of attached oligonucleotide adapters. However, hydrolysis of the reactive building blocks has so far limited the length and yield of product that can be obtained using DNA‐templated reactions. Here, we report an architecture for DNA‐templated synthesis in which reactants are tethered at internal abasic sites on opposite strands of a DNA duplex. We show that an abasic site within a DNA duplex can protect a nearby thioester from degradation, significantly increasing the yield of a DNA‐templated reaction. This protective effect has the potential to overcome the challenges associated with programmable, sequence‐controlled synthesis of long non‐natural polymers by extending the lifetime of the reactive building blocks

A New Architecture for DNA‐Templated Synthesis in Which Abasic Sites Protect Reactants from Degradation

The synthesis of artificial sequence‐defined polymers that match and extend the functionality of proteins is an important goal in materials science. One way of achieving this is to program a sequence of chemical reactions between precursor building blocks by means of attached oligonucleotide adapters. However, hydrolysis of the reactive building blocks has so far limited the length and yield of product that can be obtained using DNA‐templated reactions. Here, we report an architecture for DNA‐templated synthesis in which reactants are tethered at internal abasic sites on opposite strands of a DNA duplex. We show that an abasic site within a DNA duplex can protect a nearby thioester from degradation, significantly increasing the yield of a DNA‐templated reaction. This protective effect has the potential to overcome the challenges associated with programmable, sequence‐controlled synthesis of long non‐natural polymers by extending the lifetime of the reactive building blocks

Elastomeric polyamide biomaterials with stereochemically tuneable mechanical properties and shape memory

Abstract: Biocompatible polymers are widely used in tissue engineering and biomedical device applications. However, few biomaterials are suitable for use as long-term implants and these examples usually possess limited property scope, can be difficult to process, and are non-responsive to external stimuli. Here, we report a class of easily processable polyamides with stereocontrolled mechanical properties and high-fidelity shape memory behaviour. We synthesise these materials using the efficient nucleophilic thiol-yne reaction between a dipropiolamide and dithiol to yield an α,β − unsaturated carbonyl moiety along the polymer backbone. By rationally exploiting reaction conditions, the alkene stereochemistry is modulated between 35–82% cis content and the stereochemistry dictates the bulk material properties such as tensile strength, modulus, and glass transition. Further access to materials possessing a broader range of thermal and mechanical properties is accomplished by polymerising a variety of commercially available dithiols with the dipropiolamide monomer

Metaphoric coherence: Distinguishing verbal metaphor from `anomaly\u27

Theories and computational models of metaphor comprehension generally circumvent the question of metaphor versus “anomaly” in favor of a treatment of metaphor versus literal language. Making the distinction between metaphoric and “anomalous” expressions is subject to wide variation in judgment, yet humans agree that some potentially metaphoric expressions are much more comprehensible than others. In the context of a program which interprets simple isolated sentences that are potential instances of cross‐modal and other verbal metaphor, I consider some possible coherence criteria which must be satisfied for an expression to be “conceivable” metaphorically. Metaphoric constraints on object nominals are represented as abstracted or extended along with the invariant structural components of the verb meaning in a metaphor. This approach distinguishes what is preserved in metaphoric extension from that which is “violated”, thus referring to both “similarity” and “dissimilarity” views of metaphor. The role and potential limits of represented abstracted properties and constraints is discussed as they relate to the recognition of incoherent semantic combinations and the rejection or adjustment of metaphoric interpretations