Applications of AFM in pharmaceutical sciences

Atomic force microscopy (AFM) is a high-resolution imaging technique that uses a small probe (tip and cantilever) to provide topographical information on surfaces in air or in liquid media. By pushing the tip into the surface or by pulling it away, nanomechanical data such as compliance (stiffness, Young’s Modulus) or adhesion, respectively, may be obtained and can also be presented visually in the form of maps displayed alongside topography images. This chapter outlines the principles of operation of AFM, describing some of the important imaging modes and then focuses on the use of the technique for pharmaceutical research. Areas include tablet coating and dissolution, crystal growth and polymorphism, particles and fibres, nanomedicine, nanotoxicology, drug-protein and protein-protein interactions, live cells, bacterial biofilms and viruses. Specific examples include mapping of ligand-receptor binding on cell surfaces, studies of protein-protein interactions to provide kinetic information and the potential of AFM to be used as an early diagnostic tool for cancer and other diseases. Many of these reported investigations are from 2011-2014, both from the literature and a few selected studies from the authors’ laboratories

Fluorescence Analysis for Multi-Site Aluminum Binding to Natural Organic Matter

Natural organic matter (NOM) samples isolated from different water sources in Norway were compared using their fluorescence properties. Fluorescence surfaces were observed at pH 4.36 and deconvoluted using SIMPLISMA (Windig and Guilment 1991). There were a total of seven different fluorophores observed for these samples and each sampling site had between four and six ofthe fluorescent components. These components were observed to bind Al during titrations at the same pH. Multiresponse titration curves were fit using the method of Smith and Kramer (1998) and most of the binding strengths are similar to values for Suwannee River fulvic acid (1ogK’ between 4.8 and 5.5), but there are strong sites (IogK’ = 7) and weak sites (1ogK’ between 3 and 4) also observed. Results depended on the isolation method used; reverse osmosis and low pressure evaporation yielded different values but with no consistent trends

Efficient Aggregation of Panel Qualitative Survey Data

Qualitative business survey data are used widely to provide indicators of economic activity ahead of the publication of official data. Traditional indicators exploit only aggregate survey information, namely the proportions of respondents who report “up” and “down”. This paper examines disaggregate or firm-level survey responses. It considers how the responses of the individual firms should be quantified and combined if the aim is to produce an early indication of official output data. Having linked firms’ categorical responses to official data using ordered discrete choice models, the paper proposes a statistically efficient means of combining the disparate estimates of aggregate output growth which can be constructed from the responses of individual firms. An application to firm-level survey data from the Confederation of British Industry shows that the proposed indicator can provide early estimates of output growth more accurately than traditional indicators.Survey Data; Indicators; Quantification; Forecasting; Forecast Combination

Comprehensive simulations of superhumps

(Abridged) We use 3D SPH calculations with higher resolution, as well as with more realistic viscosity and sound-speed prescriptions than previous work to examine the eccentric instability which underlies the superhump phenomenon in semi-detached binaries. We illustrate the importance of the two-armed spiral mode in the generation of superhumps. Differential motions in the fluid disc cause converging flows which lead to strong spiral shocks once each superhump cycle. The dissipation associated with these shocks powers the superhump. We compare 2D and 3D results, and conclude that 3D simulations are necessary to faithfully simulate the disc dynamics. We ran our simulations for unprecedented durations, so that an eccentric equilibrium is established except at high mass ratios where the growth rate of the instability is very low. Our improved simulations give a closer match to the observed relationship between superhump period excess and binary mass ratio than previous numerical work. The observed black hole X-ray transient superhumpers appear to have systematically lower disc precession rates than the cataclysmic variables. This could be due to higher disc temperatures and thicknesses. The modulation in total viscous dissipation on the superhump period is overwhelmingly from the region of the disc within the 3:1 resonance radius. As the eccentric instability develops, the viscous torques are enhanced, and the disc consequently adjusts to a new equilibrium state, as suggested in the thermal-tidal instability model. We quantify this enhancement in the viscosity, which is ~10 per cent for q=0.08. We characterise the eccentricity distributions in our accretion discs, and show that the entire body of the disc partakes in the eccentricity.Comment: 18 pages (mn2e LaTeX), 14 figures, 5 tables, Accepted for publication in MNRA

Development and application of a self-referencing glucose microsensor for the measurement of glucose consumption by pancreatic ?-cells

Glucose gradients generated by an artificial source and ?-cells were measured using an enzyme-based glucose microsensor, 8-?m tip diameter, as a self-referencing electrode. The technique is based on a difference measurement between two locations in a gradient and thus allows us to obtain real-time flux values with minimal impact of sensor drift or noise. Flux values were derived by incorporation of the measured differential current into Fick's first equation. In an artificial glucose gradient, a flux detection limit of 8.2 ± 0.4 pmol·cm-2·s-1 (mean ± SEM, n = 7) with a sensor sensitivity of 7.0 ± 0.4 pA/mM (mean ± SEM, n = 16) was demonstrated. Under biological conditions, the glucose sensor showed no oxygen dependence with 5 mM glucose in the bulk medium. The addition of catalase to the bulk medium was shown to ameliorate surface-dependent flux distortion close to specimens, suggesting an underlying local accumulation of hydrogen peroxide. Glucose flux from ?-cell clusters, measured in the presence of 5 mM glucose, was 61.7 ± 9.5 fmol·nL-1·s-1 (mean ± SEM, n = 9) and could be pharmacologically modulated. Glucose consumption in response to FCCP (1 ?M) transiently increased, subsequently decreasing to below basal by 93 ± 16 and 56 ± 6%, respectively (mean ± SEM, n = 5). Consumption was decreased after the application of 10 ?M rotenone by 74 ± 5% (mean ± SEM, n = 4). These results demonstrate that an enzyme-based amperometric microsensor can be applied in the self-referencing mode. Further, in obtaining glucose flux measurements from small clusters of cells, these are the first recordings of the real-time dynamic of glucose movements in a biological microenvironment. <br/