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  • Journal article
    Kuimova MK, Mika JT, Thompson AJ, Dent MR, Brooks NJ, Michiels J, Hofkens Jet al., 2016,

    Measuring the viscosity of the Escherichia coli plasma membrane using molecular rotors

    , Biophysical Journal, Vol: 111, Pages: 1528-1540, ISSN: 1542-0086

    The viscosity is a highly important parameter within the cell membrane, affecting the diffusion ofsmall molecules and, hence, controlling the rates of intra-cellular reactions. There is significantinterest in the direct, quantitative assessment of membrane viscosity. Here we report the use offluorescence lifetime imaging microscopy (FLIM) of the molecular rotor BODIPY C10 in themembranes of live Escherichia coli (E. coli) bacteria to permit direct quantification of the viscosity.Using this approach we investigated the viscosity in live E. coli cells, spheroplasts and liposomesmade from E. coli membrane extracts. For live cells and spheroplasts the viscosity was measured atboth room temperature (23o C) and the E. coli growth temperature (37o C), while the membraneextract liposomes were studied over a range of measurement temperatures (5-40o C). At 37o C werecorded a membrane viscosity in live E. coli cells of 950 cP, which is considerably higher than thatpreviously observed in other live cell membranes (e.g., eukaryotic cells, membranes of Bacillusvegetative cells). Interestingly, this indicates that E. coli cells exhibit a high degree of lipid orderingwithin their liquid-phase plasma membranes.

  • Journal article
    Warren SC, Kim Y, Stone JM, Mitchell C, Knight JC, Neil MAA, Paterson C, French PMW, Dunsby CWet al., 2016,

    Adaptive multiphoton endomicroscopy through a dynamically deformed multicore optical fiber using proximal detection

    , Optics Express, Vol: 24, Pages: 21474-21484, ISSN: 1094-4087

    This paper demonstrates multiphoton excited fluorescenceimaging through a polarisation maintaining multicore fiber (PM-MCF)while the fiber is dynamically deformed using all-proximal detection.Single-shot proximal measurement of the relative optical path lengths of allthe cores of the PM-MCF in double pass is achieved using a Mach-Zehnderinterferometer read out by a scientific CMOS camera operating at 416 Hz.A non-linear least squares fitting procedure is then employed to determinethe deformation-induced lateral shift of the excitation spot at the distal tip ofthe PM-MCF. An experimental validation of this approach is presented thatcompares the proximally measured deformation-induced lateral shift infocal spot position to an independent distally measured ground truth. Theproximal measurement of deformation-induced shift in focal spot position isapplied to correct for deformation-induced shifts in focal spot positionduring raster-scanning multiphoton excited fluorescence imaging.

  • Journal article
    Messager L, Burns JR, Kim J, Cecchin D, Hindley J, Pyne ALB, Gaitzsch J, Battaglia G, Howorka Set al., 2016,

    Biomimetic hybrid nanocontainers with selective permeability

    , Angewandte Chemie International Edition, Vol: 55, Pages: 11106-11109, ISSN: 1521-3757

    Chemistry plays a crucial role in creating synthetic analogues of biomacromolecular structures. Of particular scientific and technological interest are biomimetic vesicles that are inspired by natural membrane compartments and organelles but avoid their drawbacks, such as membrane instability and limited control over cargo transport across the boundaries. In this study, completely synthetic vesicles were developed from stable polymeric walls and easy‐to‐engineer membrane DNA nanopores. The hybrid nanocontainers feature selective permeability and permit the transport of organic molecules of 1.5 nm size. Larger enzymes (ca. 5 nm) can be encapsulated and retained within the vesicles yet remain catalytically active. The hybrid structures constitute a new type of enzymatic nanoreactor. The high tunability of the polymeric vesicles and DNA pores will be key in tailoring the nanocontainers for applications in drug delivery, bioimaging, biocatalysis, and cell mimicry.

  • Conference paper
    Walker R, Madej B, Lin C, Dickson C, Skjevik A, Yang L, Gould Iet al., 2016,

    Adventures in the world of lipids: Towards the routine simulation of complex membranes and membrane bound proteins

    , Publisher: AMER CHEMICAL SOC, ISSN: 0065-7727
  • Journal article
    Machta BB, Gray E, Nouri M, McCarthy NLC, Gray EM, Miller AL, Brooks NJ, Veatch SLet al., 2016,

    Conditions that Stabilize Membrane Domains Also Antagonize n-Alcohol Anesthesia

    , Biophysical Journal, Vol: 11, Pages: 537-545, ISSN: 1542-0086

    Diverse molecules induce general anesthesia with potency strongly correlated with both their hydrophobicity and their effects on certain ion channels. We recently observed that several n -alcohol anesthetics inhibit heterogeneity in plasma-membrane-derived vesicles by lowering the critical temperature (Tc) for phase separation. Here, we exploit conditions that stabilize membrane heterogeneity to further test the correlation between the anesthetic potency of n -alcohols and effects on Tc. First, we show that hexadecanol acts oppositely to n -alcohol anesthetics on membrane mixing and antagonizes ethanol-induced anesthesia in a tadpole behavioral assay. Second, we show that two previously described “intoxication reversers” raise Tc and counter ethanol’s effects in vesicles, mimicking the findings of previous electrophysiological and behavioral measurements. Third, we find that elevated hydrostatic pressure, long known to reverse anesthesia, also raises Tc in vesicles with a magnitude that counters the effect of butanol at relevant concentrations and pressures. Taken together, these results demonstrate that ΔTc predicts anesthetic potency for n-alcohols better than hydrophobicity in a range of contexts, supporting a mechanistic role for membrane heterogeneity in general anesthesia.

  • Journal article
    Girvan P, Miyake T, Teng X, Branch T, Ying Let al., 2016,

    Kinetics of the Interactions between Copper and Amyloid-β with FAD Mutations and Phosphorylation at the N-terminus

    , Chembiochem, Vol: 17, Pages: 1732-1737, ISSN: 1439-7633

    Mutations and post-translational modifications of amyloid-β (Aβ) peptide in its N terminus have been shown to increase fibril formation, yet the molecular mechanism is not clear. Here we investigated the kinetics of the interactions of copper with two Aβ peptides containing Familial Alzheimer's disease (FAD) mutations (English (H6R) and Tottori (D7N)), as well as with Aβ peptide phosphorylated at serine 8 (pS8). All three peptides bind to copper with a similar rate as the wild-type (wt). The dissociation rates follow the order pS8>H6R>wt>D7N; the interconversion between the two coordinating species occurs 50 % faster for H6R and pS8, whereas D7N had only a negligible effect. Interestingly, the rate of ternary complex (copper-bridged heterodimer) formation for the modified peptides was significantly faster than that for wt, thus leading us to propose that FAD and sporadic AD might share a kinetic origin for the enhanced oligomerisation of Aβ.

  • Journal article
    Zhao W, Jamshidiha M, Lanyon-Hogg T, Recchi C, Cota E, Tate EWet al., 2016,

    Direct targeting of the Ras GTPase superfamily through structure-based design

    , Current Topics in Medicinal Chemistry, Vol: 16, Pages: 16-29, ISSN: 1873-4294

    The Ras superfamily of small monomeric GTPases includes some of the most prominent cancer targets for which no selective therapeutic agent has yet been successfully developed. The turn of the millennium saw a resurgence of efforts to target these enzymes using new and improved biophysical techniques to overcome the perceived difficulties of insurmountably high affinity for guanosine nucleotides and flat, flexible topology lacking suitable pockets for small molecule inhibitors. Further, recent investigations have begun to probe the dynamic conformational status of GTP-bound Ras, opening up new mechanisms of inhibition. While much of the literature has focused on the oncogenic Ras proteins, particularly K-Ras, these represent only a small minority of therapeutically interesting targets within the superfamily; for example, the Rab GTPases are the largest subfamily of about 70 members, and present an as yet untapped class of potential targets. The present review documents the key methodologies employed to date in structure-guided attempts to drug the Ras GTPases, and forecasts their transferability to other similarly challenging proteins in the superfamily.

  • Journal article
    Kumar S, Lockward N, Ramel M-C, Correia T, Ellis M, Alexandrov Y, Andrews N, Patel R, Bugeon L, Dallman M, Brandner S, Arridge S, Katan M, McGinty J, Frankel P, French PMWet al., 2016,

    Quantitative in vivo optical tomography of cancer progression & vasculature development in adult zebrafish

    , Oncotarget, Vol: 7, Pages: 43939-43948, ISSN: 1949-2553

    We describe a novel approach to study tumour progression and vasculature development in vivo via global 3-D fluorescence imaging of live non-pigmented adult zebrafish utilising angularly multiplexed optical projection tomography with compressive sensing (CS-OPT). This “mesoscopic” imaging method bridges a gap between established ~μm resolution 3-D fluorescence microscopy techniques and ~mm-resolved whole body planar imaging and diffuse tomography. Implementing angular multiplexing with CS-OPT, we demonstrate the in vivo global imaging of an inducible fluorescently labelled genetic model of liver cancer in adult non-pigmented zebrafish that also present fluorescently labelled vasculature. In this disease model, addition of a chemical inducer (doxycycline) drives expression of eGFP tagged oncogenic K-RASV12 in the liver of immune competent animals. We show that our novel in vivo global imaging methodology enables non-invasive quantitative imaging of the development of tumour and vasculature throughout the progression of the disease, which we have validated against established methods of pathology including immunohistochemistry. We have also demonstrated its potential for longitudinal imaging through a study of vascular development in the same zebrafish from early embryo to adulthood. We believe that this instrument, together with its associated analysis and data management tools, constitute a new platform for in vivo cancer studies and drug discovery in zebrafish disease models.

  • Conference paper
    Maioli V, Gorlitz F, Warren S, Kumar S, French PMW, Chennell G, Sardini A, Carling D, Alwes F, Dunsby CWet al., 2016,

    Three-dimensional fluorescence imaging by stage-scanning oblique plane microscopy

    , Conference on Three-Dimensional and Multidimensional Microscopy - Image Acquisition and Processing XXIII, Publisher: SPIE, ISSN: 0277-786X
  • Journal article
    Byrne B, Alguel Y, Scull NJ, Craven G, Armstrong A, Iwata S, Diallinas G, Amillis S, Capaldi S, Cameron AD, Lambrinidis G, Mikros Eet al., 2016,

    Structure of eukaryotic purine/Hþ symporter UapA suggests a role for homodimerization in transport activity

    , Nature Communications, Vol: 7, Pages: 1-9, ISSN: 2041-1723

    The uric acid/xanthine H+ symporter, UapA, is a high-affinity purine transporter from the filamentous fungus Aspergillus nidulans. Here we present the crystal structure of a genetically stabilized version of UapA (UapA-G411VΔ1–11) in complex with xanthine. UapA is formed from two domains, a core domain and a gate domain, similar to the previously solved uracil transporter UraA, which belongs to the same family. The structure shows UapA in an inward-facing conformation with xanthine bound to residues in the core domain. Unlike UraA, which was observed to be a monomer, UapA forms a dimer in the crystals with dimer interactions formed exclusively through the gate domain. Analysis of dominant negative mutants is consistent with dimerization playing a key role in transport. We postulate that UapA uses an elevator transport mechanism likely to be shared with other structurally homologous transporters including anion exchangers and prestin.

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