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  • Journal article
    Craven G, Affron D, Allen C, Matthies S, Greener J, Morgan R, Tate E, Armstrong A, Mann Det al., 2018,

    High-throughput kinetic analysis for target-directed covalent ligand discovery

    , Angewandte Chemie International Edition, Vol: 57, Pages: 5257-5261, ISSN: 1433-7851

    Cysteine-­reactive small molecules are used as chemical probes of biological systems and as medicines. Identifying high-­quality covalent ligands requires comprehensive kinetic analysis to distinguish selective binders from pan-­reactive compounds. Here we describe quantitative irreversible tethering(qIT), a general method for screening cysteine-­reactive small moleculesbased upon the maximization of kinetic selectivity. We apply this method prospectively to discover covalent fragments that target the clinically important cell cycle regulator Cdk2. Crystal structures of the inhibitor complexes validate the approach and guide further optimization. The power of this technique is highlighted by the identification of a Cdk2-­selective allosteric (type IV) kinase inhibitor whose novel mode-­of-­action could be exploited therapeutically.

  • Journal article
    Loftus C, Saeed M, Davis D, Dunlop IEet al., 2018,

    Activation of human Natural Killer cells by graphene oxide-templated antibody nanoclusters

    , Nano Letters, Vol: 18, Pages: 3282-3289, ISSN: 1530-6984

    An emerging new paradigm is that immune cell activation is controlled by transient interactions between supramolecular assemblies of receptors and ligands. Current immunotherapy biologic pharmaceuticals that activate or desensitize NK cells are, however, individual molecules that do not replicate this nanoscale organization of proteins. Here, we use nanoscale graphene oxide (NGO) as a template to generate soluble nanoscale clusters of Natural Killer cell-activating antibodies. We control nanocluster size and molecular number to mimic reported values for cell surface proteins. These NGO-templated molecular nanoclusters, used to stimulate NK cells via the CD16 receptor, successfully induced cellular activation, indicated by degranulation of cytolytic granules and IFN-γ secretion. Importantly, activation significantly exceeded that induced by the same antibodies applied as a solution of individual molecules. These results demonstrate that future immunotherapies could be enhanced by assembling immunomodulatory drugs into nanoclusters and establish NGO-templating as a candidate technology.

  • Journal article
    Cadinu P, Campolo G, Pud S, Yang W, Edel J, Dekker C, Ivanov Aet al., 2018,

    Double barrel nanopores as a new tool for controlling single-molecule transport

    , Nano Letters, Vol: 18, Pages: 2738-2745, ISSN: 1530-6984

    The ability to control the motion of single biomolecules is key to improving a wide range of biophysical and diagnostic applications. Solid-state nanopores are a promising tool capable of solving this task. However, molecular control and the possibility of slow readouts of long polymer molecules are still limited due to fast analyte transport and low signal-to-noise ratios. Here, we report on a novel approach of actively controlling analyte transport by using a double-nanopore architecture where two nanopores are separated by only a ∼ 20 nm gap. The nanopores can be addressed individually, allowing for two unique modes of operation: (i) pore-to-pore transfer, which can be controlled at near 100% efficiency, and (ii) DNA molecules bridging between the two nanopores, which enables detection with an enhanced temporal resolution (e.g., an increase of more than 2 orders of magnitude in the dwell time) without compromising the signal quality. The simplicity of fabrication and operation of the double-barrel architecture opens a wide range of applications for high-resolution readout of biological molecules.

  • Conference paper
    Wang S, Gould I, 2018,

    All-atom molecular dynamics of an ion-channel formed by viral protein U in lipid bilayers

    , 255th National Meeting and Exposition of the American-Chemical-Society (ACS) - Nexus of Food, Energy, and Water, Publisher: AMER CHEMICAL SOC, ISSN: 0065-7727
  • Journal article
    Hindley JW, Elani Y, McGilvery CM, Ali S, Bevan CL, Law R, Ces Oet al., 2018,

    Light-triggered enzymatic reactions in nested vesicle reactors

    , Nature Communications, Vol: 9, ISSN: 2041-1723

    Cell-sized vesicles have tremendous potential both as miniaturised pL reaction vessels and in bottom-up synthetic biology as chassis for artificial cells. In both these areas the introduction of light-responsive modules affords increased functionality, for example, to initiate enzymatic reactions in the vesicle interior with spatiotemporal control. Here we report a system composed of nested vesicles where the inner compartments act as phototransducers, responding to ultraviolet irradiation through diacetylene polymerisation-induced pore formation to initiate enzymatic reactions. The controlled release and hydrolysis of a fluorogenic β-galactosidase substrate in the external compartment is demonstrated, where the rate of reaction can be modulated by varying ultraviolet exposure time. Such cell-like nested microreactor structures could be utilised in fields from biocatalysis through to drug delivery.

  • Journal article
    Elani Y, Trantidou T, Wylie D, Dekker L, Polizzi K, Law R, Ces Oet al., 2018,

    Constructing vesicle-based artificial cells with embedded living cells as organelle-like modules

    , Scientific Reports, Vol: 8, ISSN: 2045-2322

    There is increasing interest in constructing artificial cells by functionalisinglipid vesicles with biological and synthetic machinery. Due to their reduced complexity and lack of evolved biochemical pathways, the capabilities of artificial cells are limitedin comparison to their biologicalcounterparts. We show that encapsulating living cells in vesicles provides a means for artificial cells to leverage cellular biochemistry, with the encapsulated cells serving organelle-like functions as living modules inside a larger syntheticcell assembly. Using microfluidic technologies to construct such hybrid systems, we demonstrate that the vesicle host and the encapsulated cell operate in concert. The external architecture of the vesicle shields the cell from toxic surroundings, whilethe cellacts as a bioreactor module that processes encapsulated feedstock which is further processedby a synthetic enzymatic cascadeco-encapsulated in the vesicle.

  • Journal article
    Kim Y, Warren S, Favero F, Stone J, Clegg J, Neil M, Paterson C, Knight J, French P, Dunsby CWet al., 2018,

    Semi-random multicore fibre design for adaptive multiphoton endoscopy

    , Optics Express, Vol: 26, Pages: 3661-3673, ISSN: 1094-4087

    This paper reports the development, modelling and application of a semi-random multicore fibre (MCF) design for adaptive multiphoton endoscopy. The MCF was constructed from 55 sub-units, each comprising 7 single mode cores, in a hexagonally close-packed lattice where each sub-unit had a random angular orientation. The resulting fibre had 385 single mode cores and was double-clad for proximal detection of multiphoton excited fluorescence. The random orientation of each sub-unit in the fibre reduces the symmetry of the positions of the cores in the MCF, reducing the intensity of higher diffracted orders away from the central focal spot formed at the distal tip of the fibre and increasing the maximum size of object that can be imaged. The performance of the MCF was demonstrated by imaging fluorescently labelled beads with both distal and proximal fluorescence detection and pollen grains with distal fluorescence detection. We estimate that the number of independent resolution elements in the final image – measured as the half-maximum area of the two-photon point spread function divided by the area imaged – to be ~3200.

  • Conference paper
    Marston SB, Messer AE, Eiros-Zamora J, Gould I, Papadaki M, Choudry A, Sheehan Aet al., 2018,

    The Molecular Defects in Ca2+ Regulation due to Mutations that Cause Hypertrophic Cardiomyopathy can be Reversed by Small Molecules that Bind to Troponin

    , 62nd Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 37A-37A, ISSN: 0006-3495
  • Conference paper
    Tahirbegi B, Magness AJ, Boillat A, Willison KR, Klug DR, Knopfel T, Ying Let al., 2018,

    Probing synaptic amyloid-beta aggregation promoted by copper release

    , 62nd Annual Meeting of the Biophysical-Society, Publisher: Biophysical Society, Pages: 430A-430A, ISSN: 0006-3495

    Whether or not the metal ions released during synaptic transmission induce amyloid-beta oligomer formation in the vicinity of synapses is a central question pertinent to the molecular mechanism of Alzheimer's disease. Recently, through a combination of experimental kinetics studies and coupled reaction-diffusion simulations, we predicted that Cu(II) rather than Zn(II) plays an important role in the very early stages (i.e., dimer formation) of Aβ aggregation in the synapse. Single molecule photobleaching analysis is a powerful tool to determine the stoichiometry of amyloid-beta oligomers which enables us to examine the time course of small amyloid-beta oligomer formation in solution, immobilised to a solid-phase substrate or artificial lipid membrane, and in live neurons in the presence of Cu(II). Preliminary results indicate that small amyloid-beta oligomers can be locked in their oligomeric state without dissociation on a poly-lysine coated surface and that Cu(II) increases the diversity and abundance of amyloid-beta oligomers.

  • Journal article
    Barlow NE, Bolognesi G, Haylock S, Flemming AJ, Brooks NJ, Barter LMC, Ces Oet al., 2017,

    Rheological Droplet Interface Bilayers (rheo-DIBs): Probing the Unstirred Water Layer Effect on Membrane Permeability via Spinning Disk Induced Shear Stress

    , Scientific Reports, Vol: 7, ISSN: 2045-2322

    A new rheological droplet interface bilayer (rheo-DIB) device is presented as a tool to apply shear stress on biological lipid membranes. Despite their exciting potential for affecting high-throughput membrane translocation studies, permeability assays conducted using DIBs have neglected the effect of the unstirred water layer (UWL). However as demonstrated in this study, neglecting this phenomenon can cause significant underestimates in membrane permeability measurements which in turn limits their ability to predict key processes such as drug translocation rates across lipid membranes. With the use of the rheo-DIB chip, the effective bilayer permeability can be modulated by applying shear stress to the droplet interfaces, inducing flow parallel to the DIB membranes. By analysing the relation between the effective membrane permeability and the applied stress, both the intrinsic membrane permeability and UWL thickness can be determined for the first time using this model membrane approach, thereby unlocking the potential of DIBs for undertaking diffusion assays. The results are also validated with numerical simulations.

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