33 research outputs found

    H-Bond Self-Assembly: Folding versus Duplex Formation

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    Linear oligomers equipped with complementary H-bond donor (D) and acceptor (A) sites can interact via intermolecular H-bonds to form duplexes or fold via intramolecular H-bonds. These competing equilibria have been quantified using NMR titration and dilution experiments for seven systems featuring different recognition sites and backbones. For all seven architectures, duplex formation is observed for homo-sequence 2-mers (AA·DD) where there are no competing folding equilibria. The corresponding hetero-sequence AD 2-mers also form duplexes, but the observed self-association constants are strongly affected by folding equilibria in the monomeric states. When the backbone is flexible (five or more rotatable bonds separating the recognition sites), intramolecular H-bonding is favored, and the folded state is highly populated. For these systems, the stability of the AD·AD duplex is 1-2 orders of magnitude lower than that of the corresponding AA·DD duplex. However, for three architectures which have more rigid backbones (fewer than five rotatable bonds), intramolecular interactions are not observed, and folding does not compete with duplex formation. These systems are promising candidates for the development of longer, mixed-sequence synthetic information molecules that show sequence-selective duplex formation.We thank the Engineering and Physical Sciences Research Council (EP/J008044/2) and European Research Council (ERC-2012-AdG 320539-duplex) for funding

    Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

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    We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2

    Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

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    Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

    Controlled mutation in the replication of synthetic oligomers.

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    Replication of sequence information with mutation is the molecular basis for the evolution of functional biopolymers. Covalent template-directed synthesis has been used to replicate sequence information in synthetic oligomers, and the covalent base-pairs used in these systems provide an opportunity to manipulate the outcome of the information transfer process through the use of traceless linkers. Two new types of covalent base-pair have been used to introduce mutation in the replication of an oligotriazole, where information is encoded as the sequence of benzoic acid and phenol monomer units. When a benzoic acid-benzoic acid base-pairing system was used, a direct copy of a benzoic acid homo-oligomer template was obtained. When a phenol-benzoic acid base-pairing system was used, a reciprocal copy, the phenol homo-oligomer, was obtained. The two base-pairing systems are isosteric, so they can be used interchangeably, allowing direct and reciprocal copying to take place simultaneously on the same template strand. As a result, it was possible to introduce mutations in the replication process by spiking the monomer used for direct copying with the monomer used for reciprocal copying. The mutation rate is determined precisely by the relative proportions of the two monomers. The ability to introduce mutation at a controlled rate is a key step in the development of synthetic systems capable of evolution, which requires replication with variation

    Homochiral oligomers with highly flexible backbones form stable H-bonded duplexes.

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    Two homochiral building blocks featuring a protected thiol, an alkene and a H-bond recognition unit (phenol or phosphine oxide) have been prepared. Iterative photochemical thiol-ene coupling reactions were used to synthesize oligomers containing 1-4 phosphine oxide and 1-4 phenol recognition sites. Length-complementary H-bond donor and H-bond acceptor oligomers were found to form stable duplexes in toluene. NMR titrations and thermal denaturation experiments show that the association constant and the enthalpy of duplex formation increase significantly for every additional H-bonding unit added to the chain. There is an order of magnitude increase in stability for each additional H-bonding interaction at room temperature indicating that all of the H-bonding sites are fully bound to their complements in the duplexes. The backbone of the thiol-ene duplexes is a highly flexible alkane chain, but this conformational flexibility does not have a negative impact on binding affinity. The average effective molarity for the intramolecular H-bonding interactions that zip up the duplexes is 18 mM. This value is somewhat higher than the EM of 14 mM found for a related family of duplexes, which have the same recognition units but a more rigid backbone prepared using reductive amination chemistry. The flexible thiol-ene AAAA·DDDD duplex is an order of magnitude more stable than the rigid reductive amination AAAA·DDDD duplex. The backbone of the thiol-ene system retains much of its conformational flexibility in the duplex, and these results show that highly flexible molecules can make very stable complexes, provided there is no significant restriction of degrees of freedom on complexation.Engineering and Physical Sciences Research Council, European Research Counci
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