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  • Journal article
    de Bruin A, Friddin MS, Elani Y, Brooks N, Law R, Seddon J, Ces Oet al., 2017,

    A transparent 3D printed device for assembling droplet hydrogel bilayers (DHBs)

    , RSC Advances, Vol: 7, Pages: 47796-47800, ISSN: 2046-2069

    We report a new approach for assembling droplet hydrogel bilayers (DHBs) using a transparent 3D printed device. We characterise the transparency of our platform, confirm bilayer formation using electrical measurements and show that single-channel recordings can be obtained using our reusable rapid prototyped device. This method significantly reduces the cost and infrastructure required to develop devices for DHB assembly and downstream study.

  • Journal article
    Sherlock B, Warren SC, Alexandrov Y, Yu F, Stone J, Knight J, Neil MAA, Paterson C, French PMW, Dunsby CWet al., 2017,

    In vivo multiphoton microscopy using a handheld scanner with lateral and axial motion compensation

    , Journal of Biophotonics, Vol: 11, ISSN: 1864-063X

    This paper reports a handheld multiphoton fluorescence microscope designed for clinical imaging that incorporates axial motion compensation and lateral image stabilization. Spectral domain optical coherence tomography is employed to track the axial position of the skin surface, and lateral motion compensation is realised by imaging the speckle pattern arising from the optical coherence tomography beam illuminating the sample. Our system is able to correct lateral sample velocities of up to ~65 μm s-1. Combined with the use of negative curvature microstructured optical fibre to deliver tunable ultrafast radiation to the handheld multiphoton scanner without the need of a dispersion compensation unit, this instrument has potential for a range of clinical applications. The system is used to compensate for both lateral and axial motion of the sample when imaging human skin in vivo.

  • Conference paper
    Sim S, Sowley H, Kidley N, Barter L, Klug Det al., 2017,

    Investigation of inhibitor-protein interactions in plants & mammalians from EVV 2DIR data

    , 254th National Meeting and Exposition of the American-Chemical-Society (ACS) on Chemistry's Impact on the Global Economy, Publisher: AMER CHEMICAL SOC, ISSN: 0065-7727
  • Journal article
    Cornell CE, McCarthy NLC, Levental KR, Levental I, Brooks NJ, Keller SLet al., 2017,

    Lengths of n-alcohols govern how Lo-Ld mixing temperatures shift in synthetic and cell-derived membranes

    , Biophysical Journal, Vol: 113, Pages: 1-13, ISSN: 1542-0086

    A persistent challenge in membrane biophysics has been to quantitatively predict how membrane physical properties change upon addition of new amphiphiles (e.g., lipids, alcohols, peptides, or proteins) in order to assess whether the changes are large enough to plausibly result in biological ramifications. Because of their roles as general anesthetics, n-alcohols are perhaps the best-studied amphiphiles of this class. When n-alcohols are added to model and cell membranes, changes in membrane parameters tend to be modest. One striking exception is found in the large decrease in liquid-liquid miscibility transition temperatures (Tmix) observed when short-chain n-alcohols are incorporated into giant plasma membrane vesicles (GPMVs). Coexisting liquid-ordered and liquid-disordered phases are observed at temperatures below Tmix in GPMVs as well as in giant unilamellar vesicles (GUVs) composed of ternary mixtures of a lipid with a low melting temperature, a lipid with a high melting temperature, and cholesterol. Here, we find that when GUVs of canonical ternary mixtures are formed in aqueous solutions of short-chain n-alcohols (n ≤ 10), Tmix increases relative to GUVs in water. This shift is in the opposite direction from that reported for cell-derived GPMVs. The increase in Tmix is robust across GUVs of several types of lipids, ratios of lipids, types of short-chain n-alcohols, and concentrations of n-alcohols. However, as chain lengths of n-alcohols increase, nonmonotonic shifts in Tmix are observed. Alcohols with chain lengths of 10–14 carbons decrease Tmix in ternary GUVs of dioleoyl-PC/dipalmitoyl-PC/cholesterol, whereas 16 carbons increase Tmix again. Gray et al. observed a similar influence of the length of n-alcohols on the direction of the shift in Tmix. These results are consistent with a scenario in which the relative partitioning of n-alcohols between liquid-ordered and liquid-disordered phases evolves as the chain length of the n-alcohol increases.

  • Journal article
    Trantidou T, Friddin M, Elani Y, Brooks NJ, Law RV, Seddon JM, Ces Oet al., 2017,

    Engineering compartmentalized biomimetic micro- and nanocontainers

    , ACS Nano, Vol: 11, Pages: 6549-6565, ISSN: 1936-086X

    Compartmentalization of biological content and function is a key architectural feature in biology, where membrane bound micro- and nanocompartments are used for performing a host of highly specialized and tightly regulated biological functions. The benefit of compartmentalization as a design principle is behind its ubiquity in cells and has led to it being a central engineering theme in construction of artificial cell-like systems. In this review, we discuss the attractions of designing compartmentalized membrane-bound constructs and review a range of biomimetic membrane architectures that span length scales, focusing on lipid-based structures but also addressing polymer-based and hybrid approaches. These include nested vesicles, multicompartment vesicles, large-scale vesicle networks, as well as droplet interface bilayers, and double-emulsion multiphase systems (multisomes). We outline key examples of how such structures have been functionalized with biological and synthetic machinery, for example, to manufacture and deliver drugs and metabolic compounds, to replicate intracellular signaling cascades, and to demonstrate collective behaviors as minimal tissue constructs. Particular emphasis is placed on the applications of these architectures and the state-of-the-art microfluidic engineering required to fabricate, functionalize, and precisely assemble them. Finally, we outline the future directions of these technologies and highlight how they could be applied to engineer the next generation of cell models, therapeutic agents, and microreactors, together with the diverse applications in the emerging field of bottom-up synthetic biology.

  • Journal article
    Branch T, Barahona M, Dodson C, Ying Let al., 2017,

    Kinetic analysis reveals the identity of Aβ-metal complex responsible for the initial aggregation of Aβ in the synapse

    , ACS Chemical Neuroscience, Vol: 8, Pages: 1970-1979, ISSN: 1948-7193

    The mechanism of Aβ aggregation in the absence of metal ions is well established, yet the role that Zn2+ and Cu2+, the two most studied metal ions, released during neurotransmission, paly in promoting Aβ aggregation in the vicinity of neuronal synapses remains elusive. Here we report the kinetics of Zn2+ binding to Aβ and Zn2+/Cu2+ binding to Aβ-Cu to form ternary complexes under near physiological conditions (nM Aβ, μM metal ions). We find that these reactions are several orders of magnitude slower than Cu2+ binding to Aβ. Coupled reaction-diffusion simulations of the interactions of synaptically released metal ions with Aβ show that up to a third of Aβ is Cu2+-bound under repetitive metal ion release, while any other Aβ-metal complexes (including Aβ-Zn) are insignificant. We therefore conclude that Zn2+ is unlikely to play an important role in the very early stages (i.e., dimer formation) of Aβ aggregation, contrary to a widely held view in the subject. We propose that targeting the specific interactions between Cu2+ and Aβ may be a viable option in drug development efforts for early stages of AD.

  • Journal article
    Noble E, Kumar S, Gorlitz F, Stain C, Dunsby CW, French PMWet al., 2017,

    In vivo label-free mapping of the effect of a photosystem II inhibiting herbicide in plants using chlorophyll fluorescence lifetime

    , Plant Methods, Vol: 13, ISSN: 1746-4811

    BackgroundIn order to better understand and improve the mode of action of agrochemicals, it is useful to be able to visualize their uptake and distribution in vivo, non-invasively and, ideally, in the field. Here we explore the potential of plant autofluorescence (specifically chlorophyll fluorescence) to provide a readout of herbicide action across the scales utilising multiphoton-excited fluorescence lifetime imaging, wide-field single-photon excited fluorescence lifetime imaging and single point fluorescence lifetime measurements via a fibre-optic probe.ResultsOur studies indicate that changes in chlorophyll fluorescence lifetime can be utilised as an indirect readout of a photosystem II inhibiting herbicide activity in living plant leaves at three different scales: cellular (~μm), single point (~1 mm2) and macroscopic (~8 × 6 mm2 of a leaf). Multiphoton excited fluorescence lifetime imaging of Triticum aestivum leaves indicated that there is an increase in the spatially averaged chlorophyll fluorescence lifetime of leaves treated with Flagon EC—a photosystem II inhibiting herbicide. The untreated leaf exhibited an average lifetime of 560 ± 30 ps while the leaf imaged 2 h post treatment exhibited an increased lifetime of 2000 ± 440 ps in different fields of view. The results from in vivo wide-field single-photon excited fluorescence lifetime imaging excited at 440 nm indicated an increase in chlorophyll fluorescence lifetime from 521 ps in an untreated leaf to 1000 ps, just 3 min after treating the same leaf with Flagon EC, and to 2150 ps after 27 min. In vivo single point fluorescence lifetime measurements demonstrated a similar increase in chlorophyll fluorescence lifetime. Untreated leaf presented a fluorescence lifetime of 435 ps in the 440 nm excited chlorophyll channel, CH4 (620–710 nm). In the first 5 min after treatment, mean fluorescence lifetime is observed to have increased to 1 ns and then to 1.3 ns after 60 min. For

  • Journal article
    Murray JI, Flodén NJ, Bauer A, Fessner ND, Dunklemann DL, Bob-Egbe O, Rzepa HS, Bürgi T, Richardson J, Spivey ACet al., 2017,

    Kinetic Resolution of 2-Substituted Indolines by N -Sulfonylation using an Atropisomeric 4-DMAP- N -oxide Organocatalyst

    , Angewandte Chemie, Vol: 129, Pages: 5854-5858, ISSN: 0044-8249

    The first catalytic kinetic resolution by N‐sulfonylation is described. 2‐Substituted indolines are resolved (s=2.6–19) using an atropisomeric 4‐dimethylaminopyridine‐N‐oxide (4‐DMAP‐N‐oxide) organocatalyst. Use of 2‐isopropyl‐4‐nitrophenylsulfonyl chloride is critical to the stereodiscrimination and enables facile deprotection of the sulfonamide products with thioglycolic acid. A qualitative model that accounts for the stereodiscrimination is proposed.

  • Journal article
    Magness AJ, Squires J, Griffiths B, Khan K, Swain A, Willison K, Cunningham D, Gerlinger M, Klug Det al., 2017,

    Multiplexed single cell protein expression analysis in solid tumours using a miniaturised microfluidic assay

    , Convergent Science Physical Oncology, Vol: 3, ISSN: 2057-1739

    Using patient-derived colorectal cancer xenografts, we demonstrate a practicable workflow for single cell proteomics in clinically relevant samples and thus a potential translational route for single cell proteomics into medical diagnostics. Using a microfluidic antibody capture [MAC] chip we measured the expression of the tumour suppressor protein p53 and of its post-translationally modified form phosphorylated at serine-15. Aberrant expression of these has commonly been found in colorectal cancers and has been widely investigated for prognostic significance. Our results show that the MAC technology is viable for quantitatively assessing protein expression and phosphorylation at the single cell level in microscopic amounts of clinically relevant tumour material. Thus, this could become a useful tool in therapeutic-associated single cell protein analysis. We also found dramatic variability of p53 and phosphorylated p53 quantities between individual cancer cells from the same sample, demonstrating the power of this single cell technology to study functional intratumour heterogeneity.

  • Journal article
    Clulow JA, Storck EM, Lanyon-Hogg T, Kalesh KA, Jones LH, Tate EWet al., 2017,

    Competition-based, quantitative chemical proteomics in breast cancer cells identifies new target profiles for sulforaphane

    , Chemical Communications, Vol: 53, Pages: 5182-5185, ISSN: 1364-548X

    Sulforaphane is a small molecule isothiocyanate which exhibits anticancer potential, yet its biological targets remain poorly understood. Here we employ a competition-based chemical proteomics strategy to profile sulforaphane's targets and identify over 500 targets along with their relative affinities. These targets provide a new set of mediators for sulforaphane's bioactivity, and aid understanding of its complex mode of action.

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