Skodras, A. and Marcelli, G. (2015). Computer-Generated Ovaries to Assist Follicle Counting Experiments. PLOS ONE [Online] 10. Available at: http://dx.doi.org/10.1371/journal.pone.0120242.
Precise estimation of the number of follicles in ovaries is of key importance in the field of reproductive biology, both from a developmental point of view, where follicle numbers are determined at specific time points, as well as from a therapeutic perspective, determining the adverse effects of environmental toxins and cancer chemotherapeutics on the reproductive system. The two main factors affecting follicle number estimates are the sampling method and the variation in follicle numbers within animals of the same strain, due to biological variability. This study aims at assessing the effect of these two factors, when estimating ovarian follicle numbers of neonatal mice. We developed computer algorithms, which generate models of neonatal mouse ovaries (simulated ovaries), with characteristics derived from experimental measurements already available in the published literature. The simulated ovaries are used to reproduce in-silico counting experiments based on unbiased stereological techniques; the proposed approach provides the necessary number of ovaries and sampling frequency to be used in the experiments given a specific biological variability and a desirable degree of accuracy. The simulated ovary is a novel, versatile tool which can be used in the planning phase of experiments to estimate the expected number of animals and workload, ensuring appropriate statistical power of the resulting measurements. Moreover, the idea of the simulated ovary can be applied to other organs made up of large numbers of individual functional units.
Fraternali, F. and Marcelli, G. (2012). A Multiscale Approach to the Elastic Moduli of Biomembrane. Biomechanics and Modeling in Mechanobiology [Online] 11:1097-1108. Available at: http://dx.doi.org/10.1007/s10237-012-0376-9.
We develop equilibrium fluctuation formulae for the isothermal elastic moduli of discrete biomembrane models at different scales. We account for the coupling of large stretching and bending strains of triangulated network models endowed with harmonic and dihedral angle potentials, on the basis of the discrete-continuum approach presented in Schmidt and Fraternali (J Mech Phys Solids 60:172–180, 2012). We test the proposed equilibrium fluctuation formulae with reference to a coarse-grained molecular dynamics model of the red blood cell (RBC) membrane (Marcelli et al. in Biophys J 89:2473–2480, 2005; Hale et al. in Soft Matter 5:3603–3606, 2009), employing a local maximum-entropy regularization of the fluctuating configurations (Fraternali et al. in J Comput Phys 231:528–540, 2012). We obtain information about membrane stiffening/softening due to stretching, curvature, and microscopic undulations of the RBC model. We detect local dependence of the elastic moduli over the RBC membrane, establishing comparisons between the present theory and different approaches available in the literature.
Fraternali, F., Lorenz, C. and Marcelli, G. (2012). On the estimation of the curvatures and bending rigidity of membrane networks via a local maximum-entropy approach. Journal of Computational Physics [Online] 231:528-540. Available at: http://dx.doi.org/10.1016/j.jcp.2011.09.017.
We present a meshfree method for the curvature estimation of membrane networks based on the local maximum entropy approach recently presented in . A continuum regularization of the network is carried out by balancing the maximization of the information entropy corresponding to the nodal data, with the minimization of the total width of the shape functions. The accuracy and convergence properties of the given curvature prediction procedure are assessed through numerical applications to benchmark problems, which include coarse grained molecular dynamics simulations of the fluctuations of red blood cell membranes  and . We also provide an energetic discrete-to-continuum approach to the prediction of the zero-temperature bending rigidity of membrane networks, which is based on the integration of the local curvature estimates. The local maximum entropy approach is easily applicable to the continuum regularization of fluctuating membranes, and the prediction of membrane and bending elasticities of molecular dynamics models.
Marcelli, G. and Patel, B. (2010). Understanding Changes in Uptake and Release of Serotonin from Gastrointestinal Tissue using a Novel Electroanalytical Approach. Analyst [Online] 135:2340-2347. Available at: http://dx.doi.org/10.1039/c0an00260g.
Serotonin (5-HT) is well known to be a key neurotransmitter within the gastrointestinal (GI) tract, where it is responsible for influencing motility. Obtaining dynamic information about the neurotransmission process (specifically the release and reuptake of 5-HT) requires the development of new approaches to measure the extracellular 5-HT concentration profile. In this work constant-potential amperometry has been utilised at +650 mV vs. Ag|AgCl to measure in vitro the overflow of 5-HT. Steady-state levels of 5-HT have been observed, due to continuous mechanical stimulation of the tissue from the experimental protocol. Measurements are conducted at varying tissue–electrode distances in the range of 5 to 1100 µm. The difference in the current from the bulk media and that from each tissue–electrode distance is obtained, and the natural log of this current is plotted versus the tissue–electrode distance. The linear fit to the log of the current is derived, and its intercept, I0, with the vertical axis and its slope are calculated. The reciprocal of the slope, indicated as slope?1, is used as a marker of reuptake. The ratio between intercept, I0, and the reciprocal of the slope, I0/slope?1, is a measure of the flux at the tissue surface and it can be used as a marker for the 5-HT release rate. Current measurements for ileum and colon tissue indicated a significantly higher reuptake rate in the colon, showed by a lower slope?1. In addition, the ratio, I0/slope?1, indicated that the colon has a higher 5-HT flux compared to the ileum. Following the application of the serotonin selective reuptake inhibitor (SSRI), fluoxetine, both tissues showed a higher value of slope?1, as the reuptake process is blocked preventing clearance of 5-HT. No differences were observed in the ratio, I0/slope?1, in the ileum, but a decrease was observed in the colon. These results indicate that ileum and colon are characterised by different reuptake and release processes. The new approach we propose provides pivotal information on the variations in the signalling mechanism, where steady state levels are observed and can be a vital tool to study differences between normal and diseased tissue and also the efficacy of pharmacological agents.
da Silva-Buttkus, P., Marcelli, G., Franks, S., Stark, J. and Hardy, K. (2009). Inferring Biological Mechanisms from Spatial Analysis: Prediction of a Local Inhibitor in the Ovary. Proceedings of the National Academy of Sciences [Online] 106:456-461. Available at: http://dx.doi.org/10.1073/pnas.0810012106.
Female mammals are born with a lifetime's supply of oocytes individually enveloped in flattened epithelial cells to form primordial follicles. It is not clear how sufficient primordial follicles are maintained to sustain the reproductive lifespan, while providing an adequate supply of mature oocytes for ovulation. Locally produced growth factors are thought to be critical regulators of early follicle growth, but knowledge of their identity and source remains incomplete. Here, we have used a simple approach of spatial analysis of structures in histological tissue sections to identify likely sources of such regulatory molecules, narrowing the field for future screening for candidate growth factors or antagonists. We have quantified the relative spatial positions of primordial (resting) follicles and growing follicles in mice on days 4, 8, and 12 after birth, and calculated interfollicular distances. Follicles were significantly less likely to have started growing if they had 1 or more primordial follicles close by (within 10 ?m), predicting that primordial follicles inhibit each other. This approach allows us to hypothesize that primordial follicles produce a diffusible inhibitor that prevents neighboring primordial follicles from growing. Such an approach has wide applicability within many branches of developmental and cell biology for studying spatial signaling within tissues and cells.
Hale, J., Marcelli, G., Parker, K., Winlove, C. and Petrov, P. (2009). Red Blood Cell Thermal Fluctuations: Comparison Between Experiment and Molecular Dynamics Simulations. Soft Matter [Online] 5:3603-3606. Available at: http://dx.doi.org/10.1039/b910422d.
We outline a new method of analysis of thermal shape fluctuations of red blood cells, based on comparison between experiments and coarse-grained molecular dynamics simulations. The fluctuations of 2D equatorial contours of red blood cells are recorded experimentally using fast phase-contrast video microscopy, from which the fluctuation spectrum is calculated. The spectrum is compared to the corresponding contour fluctuation spectrum obtained from a finite-temperature particle-dynamics simulation, modelling a cell with bending and shear elasticity and conserved volume and surface area. We demonstrate that the simulation correctly describes the mean cell shape as well as the membrane thermal fluctuations, returning physically sound values for the relevant membrane elastic moduli.
Marcelli, G. (2007). Boundary homogenization for spherical surfaces randomly covered with nonoverlapping partially absorbing disks. The Journal of chemical physics [Online] 127:176101. Available at: http://scitation.aip.org/content/aip/journal/jcp/127/17/10.1063/1.2780867.
A common signaling mechanism used by cells involves producing soluble extracellular ligands, which diffuse and bind to specific receptors covering the cell surface. This mechanism can be modeled with point particles (ligands) diffusing in a medium containing reflective spheres (cells) randomly covered by non over lapping partially absorbing disks (receptors). In order to simplify the modeling, it is desirable to replace the patchy cell surface with a spherical surface where absorption is uniform. In this Note, we use a Brownian dynamics model to test an approximating formula reported by Berezhkovkii et al. [J. Chem. Phys.121, 11390 (2004)] designed for boundary homogenization problems. We also use the model to solve the more general problem of diffusion to reactive spherical sinks.
Hale, J., Marcelli, G., Parker, K., Winlove, C. and Petrov, P. (2007). Advanced red blood cell thermal fluctuation analysis: a new method to quantify membrane elasticity. European Biophysics Journal [Online] 36:51-248. Available at: http://dx.doi.org/10.1007/s00249-007-0178-7.
We propose a new experimental technique for red blood cell thermal
fluctuation analysis, which makes it possible to quantify the
cell membrane elastic moduli. The method is based on the comparison
of the mean-square fluctuations in the shape of cell equatorial
contours as observed using phase contrast microscopy to the equivalent
fluctuation spectrum acquired in a coarse grained molecular
dynamics simulation. The simulation is based on a network of virtual
particles which interact via a harmonic potential and a dihedral
angle potential and are subject to a constant volume and area constraints,
which gives rise to finite values for the membrane bending
and shear elastic moduli. Using this method, the elastic properties
of individual red blood cells can be measured and their changes can
be easily monitored in response to changing environmental conditions
(temperature, solute concentration, osmotic pressure changes).
We also present evidence of increased bending rigidity in red blood
cells from diabetic individuals.
Marcelli, G., Parker, K. and Winlove, C. (2005). Thermal Fluctuations of Red Blood Cell Membrane via a Constant-Area Particle-Dynamics Model. Biophysical Journal [Online] 89:2473-2480. Available at: http://doi.org/10.1529/biophysj.104.056168.
We describe a model of the mechanical properties of the cell plasma membrane using a finite-temperature particle-dynamics simulation of the whole cell, in which a two-dimensional network of virtual particles embedded in a three-dimensional closed surface represents the membrane. The particles interact via harmonic potential and dihedral angle potential and are subject to a constant area constraint. The evolution of the positions of the particles yields the equilibrium state of the membrane and allows determination of the membrane thermal fluctuations and the elastic moduli. We show that time-averaging of the cell-model configurations allows quantitative comparison with experimental data on membrane fluctuations and elastic moduli of the red blood cell.
Marcelli, G., Todd, B. and Sadus, R. (2004). Erratum: On the relationship between two-body and three-body interactions from nonequilibrium molecular dynamics simulation. The Journal of Chemical Physics [Online] 120:3043-3043. Available at: http://dx.doi.org/10.1063/1.1639901.
This article contains errata applying to the following content:
On the relationship between two-body and three-body interactions from nonequilibrium molecular dynamics simulation
Marcelli, G. and Tenenbaum, A. (2003). Quantumlike short-time behavior of a classical crystal. Physical review. E, Statistical, nonlinear, and soft matter physics [Online] 68:41112. Available at: http://dx.doi.org/10.1103/PhysRevE.68.041112.
We have performed a molecular-dynamics simulation of a face-centered-cubic Lennard-Jones crystal, and studied its relaxation toward equilibrium and its microcanonical equilibrium dynamics through the computation of the normal modes. At low temperature, the weak interaction among normal modes yields a very slow relaxation of the fluctuation of the kinetic energy; this requires a new formulation of the measure of the microcanonical specific heat at constant volume. This specific heat turns out to depend on the time of observation; for times of the order of 20 ps, its values are much nearer to the quantum ones than to the value 3R predicted by the classical Dulong and Petit law. For longer observation times, the classical specific heat progressively approaches 3R over most of the temperature range of the solid crystal, with the exception of the lowest temperature range, where it still drops to values close to zero. The time dependence of the specific heat of the crystal is similar to the behavior found in a supercooled liquid near the glass transition.
Cubero, D., Marcelli, G. and Quirke, N. (2002). Electronic states of excess electrons in polyethylene. IEEE Annual Report Conference on Electrical Insulation and Dielectric Phenomena [Online]:430-433. Available at: http://www.dx.doi.org/10.1109/CEIDP.2002.1048826.
We compare and contrast preliminary semiclassical results for the electronic states associated with excess electrons in explicit molecular models of crystalline polyethylene and an alkane crystal C<sub>27</sub>H<sub>56</sub>. In addition we consider the low energy states in models of amorphous polyethylene and in voids in amorphous polyethylene. From our results it is clear that alkane crystals are not representative of crystalline polyethylene although they are often so considered. In amorphous polyethylene the ground state is estimated to be at -0.27 &plusmn; 0.1 eV with the electron localised on a nanometre scale in regions of relatively low density. A nanometer void in the amorphous region lowers the ground state to -0.45 &plusmn; 0.1 eV. With respect to realistic models of the crystalline regions of polyethylene such states constitute electron traps of the order of 1.0 eV and are therefore likely to play an important role in determining electron transport in polyethylene.
Marcelli, G., Meunie, M. and Quirke, N. (2002). Electronic Traps in Polymer Insulators: I (V) characteristics. IEEE Annual Report Conference on Electrical Insulation and Dielectric Phenomena [Online]:40-43. Available at: http://dx.doi.org/10.1109/CEIDP.2002.1048731.
We present three methods to estimate current-voltage characteristics of insulators starting from a description of the electronic traps in the dielectric. The methods are: (1) analytic and numerical solutions of the Kubo equation, (2) computation of local electron mobilities from a multiple trapping electron transport code (TrAM, Transport in Amorphous Materials) which includes trap filling effects and macroscopic integration of the Poisson's and current-field equations, using local electron mobility data from TrAM and (3) direct incorporation of the local field in TrAM removing the need for the assumption of space charge limited conduction. We compare our model results with experimental studies of the current-voltage curve of cross-linked polyethylene.
Anta, J., Marcelli, G., Meunier, M. and Quirke, N. (2002). Models of electron trapping and transport in polyethylene: Current--voltage characteristics. Journal of Applied Physics [Online] 92:1002-1008. Available at: http://dx.doi.org/10.1063/1.1489714.
We present a unified method to estimate current–voltage characteristics of insulators starting from
ab initio electronic calculations of the properties of the dielectric material. The method consists of
three stages: 1) computation of trap energy distributions for excess electrons by means of density
functional theory, 2) computation of local electron mobilities from a multiple trapping electron
transport model which includes trap filling effects and 3) macroscopic integration of the Poisson
and current–field equations, using local electron mobility data from stage 2) to predict the current–
voltage characteristics for a material of a given width. The only input to this procedure is the
chemical composition of the insulating material. We compare our model results with experimental
studies of the current–voltage curve of cross-linked polyethylene.
Marcelli, G., Todd, B. and Sadus, R. (2001). The strain rate dependence of shear viscosity, pressure and energy from two-body and three-body interactions. Fluid Phase Equilibria [Online] 183-18:371-379. Available at: http://www.dx.doi.org/10.1016/S0378-3812(01)00449-6.
Non-equilibrium molecular dynamics simulations (NEMD) are reported for the shear viscosity of xenon using
accurate two- and three-body potentials. The hydrostatic pressure and energy are observed to vary proportionally
with the square of the strain rate. This is in contrast to the non-analytic three-halves power dependence on strain
rate predicted by mode-coupling theory. This result is attributed solely to the two-body potential. The main effect
of the three-body potential is to alter the magnitude of the pressure, energy and viscosity profiles.
Vogt, P., Liapine, R., Kirchner, B., Dyson, A., Huber, H., Marcelli, G. and Sadus, R. (2001). Molecular simulation of the vapour - liquid phase coexistence of neon and argon using ab initio potentials. Physical Chemistry Chemical Physics [Online] 3:1297-1302. Available at: http://www.dx.doi.org/10.1039/B008061F.
Gibbs ensemble simulations using ab initio intermolecular potentials are reported for the vapour--liquid phase coexistence of neon and argon. For neon two different quantum chemical ab initio potentials of well-known quality are used to investigate the effect of the quality of pair interactions. In addition calculations are also reported for neon using a potential that includes three-body interactions. For argon, simulations are compared with results obtained from NPH-ensemble molecular dynamics simulations. It is found that the results of a perfect pair potential must occur outside the experimental temperature--density phase envelope. Therefore, if a perfect pair potential is used, many-body interactions and quantum effects must be considered to obtain good agreement with experiment.
Marcelli, G., Todd, B. and Sadus, R. (2001). Analytic dependence of the pressure and energy of an atomic fluid under shear. Physical review. E, Statistical, nonlinear, and soft matter physics [Online] 63:21204. Available at: http://dx.doi.org/10.1103/PhysRevE.63.021204.
Nonequilibrium molecular dynamics simulations are reported at different strain rates (gamma;) for a shearing atomic fluid interacting via accurate two- and three-body potentials. We report that the hydrostatic pressure has a strain-rate dependence of gamma;(2), in contrast to the gamma;(3/2) dependence predicted by mode-coupling theory. Our results indicate that the pressure and energy of real fluids may display an analytic dependence on the strain rate. This is in contrast to previous work using either Lennard-Jones or Weeks-Chandler-Anderson potentials that had shown a gamma;(3/2) dependence of pressure and energy.
Ge, J., Marcelli, G., Todd, B. and Sadus, R. (2001). Energy and pressure of shearing fluids at different state points. Physical review. E, Statistical, nonlinear, and soft matter physics [Online] 64:21201. Available at: http://www.dx.doi.org/10.1103/PhysRevE.64.021201.
Nonequilibrium molecular dynamics simulations are reported at different strain rates (gamma) and thermodynamic state points for a shearing atomic fluid interacting via a Lennard-Jones potential. Our simulations are performed at the Lennard-Jones triple point, a point midway between the triple point and the critical point, and a high point closer to the critical temperature. We find that, for the mid-point and high point, the energy and hydrostatic pressures have strain-rate dependencies of gamma(2), in contrast to the gamma(3/2) dependencies predicted by mode coupling theory. This analytical dependence is consistent with a Taylor series expansion of these quantities as powers of the strain rate tensor. Only at the triple point does the pressure and energy display a nonanalytical dependence on gamma(3/2).
Marcelli, G., Todd, B. and Sadus, R. (2001). On the relationship between two-body and three-body interactions from nonequilibrium molecular dynamics simulation. The Journal of Chemical Physics [Online] 115:9410. Available at: http://dx.doi.org/10.1063/1.1413971.
Nonequilibrium molecular dynamics (NEMD) simulations are performed for argon at different strain rates using accurate two-body and three-body intermolecular potentials. The contributions of two- and three-body interactions to the configurational energy of argon at different strain rates are reported. The NEMD data indicate that there is the same simple relationship between two- and three-body interactions as reported previously Marcelli and Sadus, J. Chem. Phys. 112, 6382 (2000) from equilibrium Monte Carlo simulations. The relationship is largely independent of strain rate. NEMD calculations using this relationship for shear viscosity at different strain rates indicate good agreement with full two-body+three-body calculations. This means that the effect of three-body interactions on transport properties might be achieved in a conventional two-body NEMD simulation without incurring the computational penalty of three-body calculations.
Marcelli, G. and Sadus, R. (2001). Three-body interactions and the phase equilibria of mixtures. HIGH TEMPERATURES HIGH PRESSURES [Online] 33:111-118. Available at: http://dx.doi.org/10.1068/htwu244.
Gibbs ensemble Monte-Carlo simulations are reported for the vapour-liquid phase
coexistence of the binary argon - krypton mixture. The calculations employ accurate two-body
potentials in addition to contributions from three-body dispersion resulting from third-order
triple-dipole interactions. The calculations are in good overall agreement with experiment. The
composition of coexisting vapour and liquid phases is relatively unaffected by three-body interactions.
In contrast, three-body interactions affect substantially the density of the liquid phase.
Marcelli, G. and Sadus, R. (2000). A link between the two-body and three-body interaction energies of fluids from molecular simulation. The Journal of Chemical Physics [Online] 112:6382-6385. Available at: http://dx.doi.org/10.1063/1.481199.
Molecular simulation data are reported that indicate that there is a simple empirical relationship
between two-body and three-body interaction energies. The significance of this relationship is that
three-body interactions can be estimated accurately from two-body interactions without incurring
the computational penalty of three-body calculations. The relationship is tested by performing Gibbs
ensemble simulations for the vapor–liquid equilibria of argon. The results are in good agreement
with calculations that explicitly evaluate all three-body interactions.
Marcelli, G. and Sadus, R. (1999). Molecular simulation of the phase behavior of noble gases using accurate two-body and three-body intermolecular potentials. The Journal of Chemical Physics [Online] 111:1533. Available at: http://dx.doi.org/10.1063/1.479412.
Gibbs ensemble Monte Carlo simulations are reported for the vapor- liquid phase coexistence of argon, krypton, and xenon. The calculations employ accurate two-body potentials in addition to contributions from three-body dispersion interactions resulting from third-order triple-dipole, dipole-dipole-quadrupole, dipole- quadrupole-quadrupole, quadrupole-quadrupole-quadrupole, and fourth- order triple- dipole terms. It is shown that vapor-liquid equilibria are affected substantially by three-body interactions. The addition of three-body interactions results in good overall agreement of theory with experimental data. In particular, the subcritical liquid- phase densities are predicted accurately. (C) 1999 American Institute of Physics. S0021- 9606(99)50728-9.