• One-Pot Synthesis of Highly Emissive Dipyridinium Dihydrohelicenes

      Santoro, A.; Lord, Rianne M.; Loughrey, J.J.; McGowan, P.C.; Halcrow, M.A.; Henwood, A.F.; Thomson, C.; Zysman-Colman, E. (2015-05)
      Condensation of a pyridyl-2-carbaldehyde derivative with 2-(bromoethyl)amine hydrobromide gave tetracyclic pyrido[1,2-a]pyrido[1’,2’:3,4]imidazo-[2,1-c]-6,7-dihydropyrazinium dications in excellent yields. Crystal structures and NOE data demonstrated the helical character of the dications, the dihedral angles between the two pyrido groups ranging from 28–458. An intermediate in the synthesis was also characterized. A much brighter emission compared to literature helicenes has been found, with quantum yields as high as 60% in the range of l=460– 600 nm. Preliminary cytotoxicity studies against HT-29 cancer cells demonstrated moderate-to-good activity, with IC50 values 12–30x that of cisplatin.
    • Opioid prescribing for cancer patients in the last year of life: a longitudinal population cohort study

      Ziegler, Lucy; Mulvey, M.; Blenkinsopp, Alison; Petty, Duncan R.; Bennett, M.I. (2015-11)
      We linked UK cancer registry data with the corresponding electronic primary care medical records of 6080 patients who died of cancer over a 7-year period in a large United Kingdom city. We extracted all prescriptions for analgesics issued to each patient in the linked cohort during the 12 months before death and analysed the extent and duration of strong opioid treatment with clinical and patient characteristics. Strong opioids were prescribed for 48% of patients in the last year of life. Median interval between first prescription of a strong opioid and death was 9 weeks (interquartile range 3-23). Strong opioid prescribing was not influenced by cancer type, duration of illness, or gender but was adversely influenced by older age. Compared with patients who died in a hospice, those who died in a hospital were 60% less likely to receive a strong opioid in primary care before admission (relative risk ratio 0.4, CI 0.3-0.5, P < 0.01). The study provides the first detailed analysis of the relatively late onset and short duration of strong opioid treatment in patients with cancer before death in a representative UK cohort. This pattern of prescribing does not match epidemiological data which point to earlier onset of pain. Although persistent undertreatment of cancer pain is well documented, this study suggests that strategies for earlier pain assessment and initiation of strong opioid treatment in community-based patients with cancer could help to improve pain outcomes.
    • Opioid receptor involvement in the adaptation to motion sickness in Suncus murinus.

      Javid, Farideh A.; Naylor, Robert J. (2001)
      The aim of the present study was to investigate an opioid receptor involvement in the adaptation response to motion sickness in Suncus murinus. Different groups of animals were treated intraperitoneally with either saline, morphine (0.1 and 1.0 mg/kg), naloxone (1.0, 10.0 and 5.0 mg/kg) or a combination of naloxone plus morphine in the absence or 30 min prior to a horizontal motion stimulus of I Hz and 40 mm amplitude. For the study of adaptation, different groups received saline on the first trial, and in subsequent trials (every 2 days) they received either saline, naloxone (1.0 and 10.0 mg/kg, ip) or morphine (0.1 mg/kg, ip) 30 min prior to the motion stimulus. Pretreatment with morphine caused a dose-related reduction in emesis induced by a single challenge to a motion stimulus. Pretreatment with naloxone alone did not induce emesis in its own right nor did it modify emesis induced by a single challenge to a motion stimulus. However, pretreatment with naloxone (5.0 mg/kg, ip) revealed an emetic response to morphine (P<.001) (1.0 mg/kg, ip) and antagonised the reduction of motion sickness induced by morphine. In animals that received saline or naloxone (1.0 mg/kg), a motion stimulus inducing emesis decreased the responsiveness of animals to a second and subsequent motion stimulus challenge when applied every 2 days for 11 trials. However, the animals receiving naloxone 10.0 mg/kg prior to the second and subsequent challenges showed no significant reduction in the intensity of emesis compared to the first trial. The data are revealing of an emetic potential of morphine when administered in the presence of a naloxone pretreatment. The administration of naloxone is also revealing of an additional inhibitory opioid system whose activation by endogenous opioid(s) may play a role in the adaptation to motion sickness on repeated challenge in S. murinus.
    • Optical actuation of inorganic/organic interfaces: comparing peptide-azobenzene ligand reconfiguration on gold and silver nanoparticles

      Palafox-Hernandez, J.P.; Lim, C-K.; Tang, Z.; Drew, K.L.M.; Hughes, Zak E.; Li, Y.; Swihart, M.T.; Prasad, P.N.; Knecht, M.R.; Walsh, T.R. (2016-01-13)
      Photoresponsive molecules that incorporate peptides capable of material-specific recognition provide a basis for biomolecule-mediated control of the nucleation, growth, organization, and activation of hybrid inorganic/organic nanostructures. These hybrid molecules interact with the inorganic surface through multiple noncovalent interactions which allow reconfiguration in response to optical stimuli. Here, we quantify the binding of azobenzene-peptide conjugates that exhibit optically triggered cis-trans isomerization on Ag surfaces and compare to their behavior on Au. These results demonstrate differences in binding and switching behavior between the Au and Ag surfaces. These molecules can also produce and stabilize Au and Ag nanoparticles in aqueous media where the biointerface can be reproducibly and reversibly switched by optically triggered azobenzene isomerization. Comparisons of switching rates and reversibility on the nanoparticles reveal differences that depend upon whether the azobenzene is attached at the peptide N- or C-terminus, its isomerization state, and the nanoparticle composition. Our integrated experimental and computational investigation shows that the number of ligand anchor sites strongly influences the nanoparticle size. As predicted by our molecular simulations, weaker contact between the hybrid biomolecules and the Ag surface, with fewer anchor residues compared with Au, gives rise to differences in switching kinetics on Ag versus Au. Our findings provide a pathway toward achieving new remotely actuatable nanomaterials for multiple applications from a single system, which remains difficult to achieve using conventional approaches.
    • Optical control of nanoparticle catalysis influenced by photoswitch positioning in hybrid peptide capping ligands

      Lawrence, R.L.; Hughes, Zak E.; Cendan, V.J.; Liu, Y.; Lim, C.K.; Prasad, P.N.; Swihart, M.T.; Walsh, T.R.; Knecht, M.R. (2018-10)
      Here we present an in-depth analysis of structural factors that modulate peptide-capped nanoparticle catalytic activity via optically driven structural reconfiguration of the biointerface present at the particle surface. Six different sets of peptide-capped Au nanoparticles were prepared, in which an azobenzene photoswitch was incorporated into one of two well-studied peptide sequences with known affinity for Au, each at one of three different positions: The N- or C-terminus, or mid-sequence. Changes in the photoswitch isomerization state induce a reversible structural change in the surface-bound peptide, which modulates the catalytic activity of the material. This control of reactivity is attributed to changes in the amount of accessible metallic surface area available to drive the reaction. This research specifically focuses on the effect of the peptide sequence and photoswitch position in the biomolecule, from which potential target systems for on/off reactivity have been identified. Additionally, trends associated with photoswitch position for a peptide sequence (Pd4) have been identified. Integrating the azobenzene at the N-terminus or central region results in nanocatalysts with greater reactivity in the trans and cis conformations, respectively; however, positioning the photoswitch at the C-terminus gives rise to a unique system that is reactive in the trans conformation and partially deactivated in the cis conformation. These results provide a fundamental basis for new directions in nanoparticle catalyst development to control activity in real time, which could have significant implications in the design of catalysts for multistep reactions using a single catalyst. Additionally, such a fine level of interfacial structural control could prove to be important for applications beyond catalysis, including biosensing, photonics, and energy technologies that are highly dependent on particle surface structures.
    • Optimal edge filters explain human blur detection

      McIlhagga, William H.; May, K.A. (2012)
      Edges are important visual features, providing many cues to the three-dimensional structure of the world. One of these cues is edge blur. Sharp edges tend to be caused by object boundaries, while blurred edges indicate shadows, surface curvature, or defocus due to relative depth. Edge blur also drives accommodation and may be implicated in the correct development of the eye's optical power. Here we use classification image techniques to reveal the mechanisms underlying blur detection in human vision. Observers were shown a sharp and a blurred edge in white noise and had to identify the blurred edge. The resultant smoothed classification image derived from these experiments was similar to a derivative of a Gaussian filter. We also fitted a number of edge detection models (MIRAGE, N(1), and N(3)(+)) and the ideal observer to observer responses, but none performed as well as the classification image. However, observer responses were well fitted by a recently developed optimal edge detector model, coupled with a Bayesian prior on the expected blurs in the stimulus. This model outperformed the classification image when performance was measured by the Akaike Information Criterion. This result strongly suggests that humans use optimal edge detection filters to detect edges and encode their blur.
    • Optimal integration of shading and binocular disparity for depth perception

      Lovell, P.G.; Bloj, Marina; Harris, J.M. (2012)
      We explore the relative utility of shape from shading and binocular disparity for depth perception. Ray-traced images either featured a smooth surface illuminated from above (shading-only) or were defined by small dots (disparity-only). Observers judged which of a pair of smoothly curved convex objects had most depth. The shading cue was around half as reliable as the rich disparity information for depth discrimination. Shading- and disparity-defined cues where combined by placing dots in the stimulus image, superimposed upon the shaded surface, resulting in veridical shading and binocular disparity. Independently varying the depth delivered by each channel allowed creation of conflicting disparity-defined and shading-defined depth. We manipulated the reliability of the disparity information by adding disparity noise. As noise levels in the disparity channel were increased, perceived depths and variances shifted toward those of the now more reliable shading cue. Several different models of cue combination were applied to the data. Perceived depths and variances were well predicted by a classic maximum likelihood estimator (MLE) model of cue integration, for all but one observer. We discuss the extent to which MLE is the most parsimonious model to account for observer performance.
    • Optimisation of intact cell MALDI method for fingerprinting of methicillin-resistant Staphylococcus aureus.

      Jackson, K.A.; Edwards-Jones, V.; Sutton, Chris W.; Fox, A.J. (2005)
      The use of matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectrometry on intact cell microorganisms, Intact Cell MALDI (ICM), has been shown by numerous workers to yield effective species level identification. Early work highlighted the significant effect that variation in culture media, incubation conditions and length of incubation had on the spectra produced. Therefore, in order to achieve reliable and reproducible species level identification and sub-typing of microorganisms from ICM fingerprints, it has been essential to develop standardised methods. For methicillin-resistant Staphylococcus aureus (MRSA), a major nosocomial pathogen, we have developed such a standardised method. In this paper we present the experimental parameters, namely, the incubation period, the number of passages required from lyophilised or stored isolates, the method of deposition of the bacterial cells, the concentration of matrix solution, the drying time of bacterial cells prior to the addition of the matrix solution, the time between preparation of the bacterial/matrix sample and analysis and the MALDI pulsed extraction setting, which were considered during the development of defined methods.
    • Optimisation of the predictive ability of artificial neural network (ANN) models: A comparison of three ANN programs and four classes of training algorithm.

      Rowe, Raymond C.; Plumb, A.P.; York, Peter; Brown, M. (2005)
      The purpose of this study was to determine whether artificial neural network (ANN) programs implementing different backpropagation algorithms and default settings are capable of generating equivalent highly predictive models. Three ANN packages were used: INForm, CAD/Chem and MATLAB. Twenty variants of gradient descent, conjugate gradient, quasi-Newton and Bayesian regularisation algorithms were used to train networks containing a single hidden layer of 3¿12 nodes. All INForm and CAD/Chem models trained satisfactorily for tensile strength, disintegration time and percentage dissolution at 15, 30, 45 and 60 min. Similarly, acceptable training was obtained for MATLAB models using Bayesian regularisation. Training of MATLAB models with other algorithms was erratic. This effect was attributed to a tendency for the MATLAB implementation of the algorithms to attenuate training in local minima of the error surface. Predictive models for tablet capping and friability could not be generated. The most predictive models from each ANN package varied with respect to the optimum network architecture and training algorithm. No significant differences were found in the predictive ability of these models. It is concluded that comparable models are obtainable from different ANN programs provided that both the network architecture and training algorithm are optimised. A broad strategy for optimisation of the predictive ability of an ANN model is proposed.
    • Optimisation of the self-assembly process: production of stable, alginate-based polyelectrolyte nanocomplexes with protamine

      Dul, M.; Paluch, Krzysztof J.; Healy, A.M.; Sasse, A.; Tajber, L. (2017-06)
      The aim of this work was to investigate the possibility of covalent cross-linker-free, polyelectrolyte complex formation at the nanoscale between alginic acid (as sodium alginate, ALG) and protamine (PROT). Optimisation of the self-assembly conditions was performed by varying the type of polymer used, pH of component solutions, mass mixing ratio of the components and the speed and order of component addition on the properties of complexes. Homogenous particles with nanometric sizes resulted when an aqueous dispersion of ALG was rapidly mixed with a solution of PROT. The polyelectrolyte complex between ALG and PROT was confirmed by infrared spectroscopy. To facilitate incorporation of drugs soluble at low pH, pH of ALG dispersion was decreased to 2; however, no nanoparticles (NPs) were formed upon complexation with PROT. Adjusting pH of PROT solution to 3 resulted in the formation of cationic or anionic NPs with a size range 70–300 nm. Colloidal stability of selected alginic acid low/PROT formulations was determined upon storage at room temperature and in liquid media at various pH. Physical stability of NPs correlated with the initial surface charge of particles and was time- and pH-dependent. Generally, better stability was observed for anionic NPs stored as native dispersions and in liquids covering a range of pH.
    • An optimised assay for quantitative, high-throughput analysis of polysialyltransferase activity

      Elkashef, Sara M.; Sutherland, Mark H.; Patterson, Laurence H.; Loadman, Paul M.; Falconer, Robert A. (2016-08-08)
      The polysialyltransferases are biologically important glycosyltransferase enzymes responsible for the biosynthesis of polysialic acid, a carbohydrate polymer that plays a critical role in the progression of several diseases, notably cancer. Having improved the chemical synthesis and purification of the fluorescently-labelled DMB-DP3 acceptor, we report optimisation and validation of a highly sensitive cell-free high-throughput HPLC-based assay for assessment of human polysialyltransferase activity.
    • Optimised patient information materials and recruitment to a study of behavioural activation in older adults: an embedded study within a trial

      Knapp, P.; Gilbody, S.; Holt, J.; Keding, A.; Mitchell, N.; Raynor, D.K.; Silcock, Jonathan; Torgerson, D. (2020-05-21)
      Printed participant information about randomised controlled trials is often long, technical and difficult to navigate. Improving information materials is possible through optimisation and user-testing, and may impact on participant understanding and rates of recruitment. Methods: A study within a trial (SWAT) was undertaken within the CASPER trial. Potential CASPER participants were randomised to receive either the standard trial information or revised information that had been optimised through information design and user testing. Results: A total of 11,531 patients were randomised in the SWAT. Rates of recruitment to the CASPER trial were 2.0% in the optimised information group and 1.9% in the standard information group (odds ratio 1.027; 95% CI 0.79 to 1.33; p=0.202). Conclusions: Participant information that had been optimised through information design and user testing did not result in any change to rate of recruitment to the host trial. Registration: ISRCTN ID ISRCTN02202951; registered on 3 June 2009.
    • Optimising the glaucoma signal/noise ratio by mapping changes in spatial summation with area-modulated perimetric stimuli

      Rountree, Lindsay C.; Mulholland, P.J.; Anderson, R.S.; Garway-Heath, D.F.; Morgan, J.E.; Redmond, T. (2018-02)
      Identification of glaucomatous damage and progression by perimetry are limited by measurement and response variability. This study tested the hypothesis that the glaucoma damage signal/noise ratio is greater with stimuli varying in area, either solely, or simultaneously with contrast, than with conventional stimuli varying in contrast only (Goldmann III, GIII). Thirty glaucoma patients and 20 age-similar healthy controls were tested with the Method of Constant Stimuli (MOCS). One stimulus modulated in area (A), one modulated in contrast within Ricco’s area (CR), one modulated in both area and contrast simultaneously (AC), and the reference stimulus was a GIII, modulating in contrast. Stimuli were presented on a common platform with a common scale (energy). A three-stage protocol minimised artefactual MOCS slope bias that can occur due to differences in psychometric function sampling between conditions. Threshold difference from age-matched normal (total deviation), response variability, and signal/noise ratio were compared between stimuli. Total deviation was greater with, and response variability less dependent on defect depth with A, AC, and CR stimuli, compared with GIII. Both A and AC stimuli showed a significantly greater signal/noise ratio than the GIII, indicating that area-modulated stimuli offer benefits over the GIII for identifying early glaucoma and measuring progression.
    • An optimized force field for crystalline phases of resorcinol.

      Chatchawalsaisin, Jittima; Kendrick, John; Tuble, S.C.; Anwar, Jamshed (Royal Society of Chemistry, 10/03/2008)
      The two known crystalline phases of resorcinol and their phase transitions are of considerable interest. The crystals exhibit pyro- and piezo-electricity and, remarkably, the higher temperature phase is the denser phase. Furthermore, crystals of the phase, by virtue of having a polar axis, have played a crucial role in investigating fundamental issues of crystal growth. We report an optimized force field for the molecular simulation of crystalline phases of resorcinol. The hydroxyl groups of the resorcinol molecule have a torsional degree of freedom and the molecule adopts a different conformation in each of the two phases of resorcinol. The torsional barrier, therefore, was considered to be critical and has been characterized using ab initio methods. Although the atomic partial charges showed some dependence on the molecular conformation, a single set of partial charges was found to be sufficient in describing the electrostatic potential for all conformations. The parameters for the van der Waals interactions were optimized using sensitivity analysis. The proposed force field reproduces not only the static structures but also the stability of the crystalline phases in extended molecular dynamics simulations.
    • Optimized LC-MS/MS quantification method for the detection of piperacillin and application to the development of charged liposaccharides as penetration enhancers

      Violette, A.; Cortes, D.F.; Bergeon, J.A.; Falconer, Robert A.; Toth, I. (2008)
      Piperacillin, a potent ß-lactam antibiotic, is effective in a large variety of Gram+ and Gram¿ bacterial infections but its administration is limited to the parenteral route as it is not absorbed when given orally. In an attempt to overcome this problem, we have synthesized a novel series of charged liposaccharide complexes of piperacillin comprising a sugar moiety derived from d-glucose conjugated to a lipoamino acid residue with varying side-chain length (cationic entity) and the piperacillin anion. A complete multiple reaction monitoring LC¿MS/MS method was developed to detect and characterize the synthesized complexes. The same method was then successfully applied to assess the in vitro apparent permeability values of the charged liposaccharide complexes in Caco-2 monolayers.
    • Optofluidic Sensor: Evaporation Kinetics Detection of Solvents Dissolved with Cd3P2Colloidal Quantum Dots in a Rolled-Up Microtube

      Miao, S.; Chen, D.; Madani, A.; Jorgensen, M.R.; Bolaños Quiñones, V.A.; Ma, L.; Hickey, Stephen G.; Eychmüller, A.; Schmidt, O.G. (2015)
      A method for measuring the evaporation kinetics of pure solvents and solutions containing Cd3P2 quantum dots (QDs) in SiO/SiO2 rolled-up microtube (RUT) resonators is reported. The QDs serve as wavelength-tunable fluorescent sources for the RUT resonator. The first-order kinetic constant (295 K) of the evaporation of toluene embedded in a RUT (D = 9.10 μm) is evaluated (0.055 min−1).
    • Oral anticoagulants for stroke prevention in nonvalvular AF

      Medlinskiene, Kristina; Petty, Duncan R. (2017)
      Warfarin and direct oral anticoagulants (DOACs) have been shown to reduce the risk of stroke in patients with atrial fibrillation, yet many patients are still not being anticoagulated. This article discusses the barriers to the initiation of oral anticoagulants, in particular DOACs, and how these can be overcome.
    • Oral green tea catechin metabolites are incorporated into human skin and protect against UV radiation-induced cutaneous inflammation in association with reduced production of pro-inflammatory eicosanoid 12-hydroxyeicosatetraenoic acid.

      Rhodes, L.E.; Darby, G.; Massey, Karen A.; Clarke, K.A.; Dew, T.P.; Farrar, M.D.; Bennett, S.; Watson, R.E.B.; Williamson, G.; Nicolaou, Anna (2013-09)
      Green tea catechins (GTC) reduce UV radiation (UVR)-induced inflammation in experimental models, but human studies are scarce and their cutaneous bioavailability and mechanism of photoprotection are unknown. We aimed to examine oral GTC cutaneous uptake, ability to protect human skin against erythema induced by a UVR dose range and impact on potent cyclo-oxygenase- and lipoxygenase-produced mediators of UVR inflammation, PGE2 and 12-hydroxyeicosatetraenoic acid (12-HETE), respectively. In an open oral intervention study, sixteen healthy human subjects (phototype I/II) were given low-dose GTC (540 mg) with vitamin C (50 mg) daily for 12 weeks. Pre- and post-supplementation, the buttock skin was exposed to UVR and the resultant erythema quantified. Skin blister fluid and biopsies were taken from the unexposed and the UVR-exposed skin 24 h after a pro-inflammatory UVR challenge (three minimal erythema doses). Urine, skin tissue and fluid were analysed for catechin content and skin fluid for PGE2 and 12-HETE by liquid chromatography coupled to tandem MS. A total of fourteen completing subjects were supplement compliant (twelve female, median 42·5 years, range 29–59 years). Benzoic acid levels were increased in skin fluid post-supplementation (P= 0·03), and methylated gallic acid and several intact catechins and hydroxyphenyl-valerolactones were detected in the skin tissue and fluid. AUC analysis for UVR erythema revealed reduced response post-GTC (P= 0·037). Pre-supplementation, PGE2 and 12-HETE were UVR induced (P= 0·003, 0·0001). After GTC, UVR-induced 12-HETE reduced from mean 64 (sd 42) to 41 (sd 32) pg/μl (P= 0·01), while PGE2 was unaltered. Thus, GTC intake results in the incorporation of catechin metabolites into human skin associated with abrogated UVR-induced 12-HETE; this may contribute to protection against sunburn inflammation and potentially longer-term UVR-mediated damage.
    • Oral Histories: a simple method of assigning chronological age to isotopic values from human dentine collagen

      Beaumont, Julia; Montgomery, Janet (2015-07)
      Background: stable isotope ratios of carbon (δ13C) and nitrogen (δ15N) in bone and dentine collagen have been used for over 30 years to estimate palaeodiet, subsistence strategy, breastfeeding duration and migration within burial populations. Recent developments in dentine microsampling allow improved temporal resolution for dietary patterns. Aim: We propose a simple method which could be applied to human teeth to estimate chronological age represented by dentine microsamples in the direction of tooth growth, allowing comparison of dietary patterns between individuals and populations. The method is tested using profiles from permanent and deciduous teeth of two individuals. Subjects and methods: using a diagrammatic representation of dentine development by approximate age for each human tooth (based on the Queen Mary University of London Atlas) (AlQahtani et al., 2010), we estimate the age represented by each dentine section. Two case studies are shown: comparison of M1 and M2 from a 19th century individual from London, England, and identification of an unknown tooth from an Iron Age female adult from Scotland. Results and conclusions: The isotopic profiles demonstrate that variations in consecutively-forming teeth can be aligned using this method to extend the dietary history of an individual, or identify an unknown tooth by matching the profiles.