arXiv subjects

Edoardo Milotti

Publications and source records attributed to Edoardo Milotti.

33 records · Page 2Linked to original sources

arXiv2009

Numerical integration methods for large-scale biophysical simulations

Simulations of biophysical systems inevitably include steps that correspond to time integrations of ordinary differential equations. These equations are often related to enzyme action in the synthesis and destruction of molecular species, and in the regulation of transport of molecules into and out of the cell or cellular compartments. Enzyme action is almost invariably modeled with the quasi-steady-state Michaelis-Menten formula or its close relative, the Hill formula: this description leads to systems of equations that may be stiff and hard to integrate, and poses unusual computational challenges in simulations where a smooth evolution is interrupted by the discrete events that mark the cells' lives. This is the case of a numerical model (Virtual Biophysics Lab - VBL) that we are developing to simulate the growth of three-dimensional tumor cell aggregates (spheroids). The program must be robust and stable, and must be able to accept frequent changes in the underlying theoretical model: here we study the applicability of known integration methods to this unusual context and we describe the results of numerical tests in situations similar to those found in actual simulations.

physics.bio-ph↗

arXiv2007

Enrico Fermi's view of identical particles

In this paper I discuss Enrico Fermi's view of identical particles, taking a lecture that he gave in 1933 as a starting point. Fermi used his lecture as a basis for a paper that was published in 1934: the paper is in italian and is not easily accessible to a wide audience, and for this reason its translation is also given in a section of the present paper.

physics.hist-ph↗

arXiv2007

Algorithm for anisotropic diffusion in hydrogen-bonded networks

In this paper I describe a specialized algorithm for anisotropic diffusion determined by a field of transition rates. The algorithm can be used to describe some interesting forms of diffusion that occur in the study of proton motion in a network of hydrogen bonds. The algorithm produces data that require a nonstandard method of spectral analysis which is also developed here. Finally, I apply the algorithm to a simple specific example.

cond-mat.soft↗

arXiv2007

Ab initio phenomenological simulation of the growth of large tumor cell populations

In a previous paper we have introduced a phenomenological model of cell metabolism and of the cell cycle to simulate the behavior of large tumor cell populations (Chignola R and Milotti E, Phys. Biol. 2 (2005) 8-22). Here we describe a refined and extended version of the model that includes some of the complex interactions between cells and their surrounding environment. The present version takes into consideration several additional energy-consuming biochemical pathways such as protein and DNA synthesis, the tuning of extracellular pH and of the cell membrane potential. The control of the cell cycle - that was previously modeled by means of ad hoc thresholds - has been directly addressed here by considering checkpoints from proteins that act as targets for phosphorylation on multiple sites. As simulated cells grow, they can now modify the chemical composition of the surrounding environment which in turn acts as a feedback mechanism to tune cell metabolism and hence cell proliferation: in this way we obtain growth curves that match quite well those observed in vitro with human leukemia cell lines. The model is strongly constrained and returns results that can be directly compared with actual experiments, because it uses parameter values in narrow ranges estimated from experimental data, and in perspective we hope to utilize it to develop in silico studies of the growth of very large tumor cell populations (10^6 cells or more) and to support experimental research. In particular, the program is used here to make predictions on the behaviour of cells grown in a glucose-poor medium: these predictions are confirmed by experimental observation.

physics.bio-ph↗

arXiv2007

Dynamical hysteresis in multisite protein modification

Multisite protein modification is a ubiquitous mechanism utilized by cells to control protein functions. We have recently proposed a dynamical description of multisite protein modification which embodies all the essential features of the process (E. Milotti, A. Del Fabbro, C. Dalla Pellegrina, and R. Chignola, Physica A, in press), and we have used this model to analyze the stability and the time-scales of this mechanism. The same model can be used to understand how the system responds to stimuli: here we show that it displays frequency-dependent dynamical hysteresis. This behavior closely parallels -- with the due differences -- what is observed in magnetic systems. By selecting model parameters that span the known biological ranges, we find that the frequency-dependent features cover the band of the observed oscillations of molecular intracellular signals, and this suggests that this mechanism may have an important role in cellular information processing.

physics.bio-ph↗

arXiv2006

New version of PLNoise: a package for exact numerical simulation of power-law noises

In a recent paper I have introduced a package for the exact simulation of power-law noises and other colored noises (E. Milotti, Comput. Phys. Commun. {\bf 175} (2006) 212): in particular the algorithm generates $1/f^α$ noises with $0 < α\leq 2$. Here I extend the algorithm to generate $1/f^α$ noises with $2 < α\leq 4$ (black noises). The method is exact in the sense that it produces a sampled process with a theoretically guaranteed range-limited power-law spectrum for any arbitrary sequence of sampling intervals, i.e., the sampling times may be unevenly spaced.

physics.comp-ph↗

arXiv2006

Dynamics of allosteric action in multisite protein modification

Protein functions in cells may be activated or modified by the attachment of several kinds of chemical groups. While protein phosphorylation, i.e. the attachment of a phosphoryl (PO$_3^-$) group, is the most studied form of protein modification, and is known to regulate the functions of many proteins, protein behavior can also be modified by nitrosylation, acetylation, methylation, etc. A protein can have multiple modification sites, and display some form of transition only when enough sites are modified. In a previous paper we have modeled the generic equilibrium properties of multisite protein modification (R.Chignola, C. Dalla Pellegrina, A. Del Fabbro, E.Milotti, Physica A {\bf 371}, 463 (2006)) and we have shown that it can account both for sharp, robust thresholds and for information transfer between processes with widely separated timescales. Here we use the same concepts to expand that analysis starting from a dynamical description of multisite modification: we give analytical results for the basic dynamics and numerical results in an example where the modification chain is cascaded with a Michaelis-Menten step. We modify the dynamics and analyze an example with realistic phosphorylation/dephosphorylation steps, and give numerical evidence of the independence of the allosteric effect from the details of the attachment-detachment processes. We conclude that multisite protein modification is dynamically equivalent to the classic allosteric effect.

physics.bio-ph↗

arXiv2006

Artifacts with uneven sampling of red noise

The vast majority of sampling systems operate in a standard way: at each tick of a fixed-frequency master clock a digitizer reads out a voltage that corresponds to the value of some physical quantity and translates it into a bit pattern that is either transmitted, stored, or processed right away. Thus signal sampling at evenly spaced time intervals is the rule: however this is not always the case, and uneven sampling is sometimes unavoidable. While periodic or quasi-periodic uneven sampling of a deterministic signal can reasonably be expected to produce artifacts, it is much less obvious that the same happens with noise: here I show that this is indeed the case only for long-memory noise processes, i.e., power-law noises $1/f^α$ with $α> 2$. The resulting artifacts are usually a nuisance although they can be eliminated with a proper processing of the signal samples, but they could also be turned to advantage and used to encode information.

physics.data-an↗

arXiv2006

Fine-grained Delaunay triangulation in a simulation of tumor spheroid growth

The simulation of many-particle systems often requires the detailed knowledge of proximity relations to reduce computational complexity and to provide a basis for specific calculations. Here we describe the basic scheme of a simulator of tumor spheroid growth: the calculation of mechanical interactions between cells and of the concentrations of diffusing chemicals requires a backbone provided by the Delaunay triangulation and the volumes of the associated Voronoi regions. Thus the Delaunay triangulation provides both the proximity relations needed to reduce the computational complexity and the basic structures that are needed to carry out the calculation of the biochemical interactions between cells and with the enviroment. A 3D version of the simulator uses the CGAL library as an essential component for the efficient computation of the Delaunay triangulation and of the Voronoi regions.

physics.bio-ph↗

arXiv2006

Thresholds, long delays and stability from generalized allosteric effect in protein networks

Post-transductional modifications tune the functions of proteins and regulate the collective dynamics of biochemical networks that determine how cells respond to environmental signals. For example, protein phosphorylation and nitrosylation are well-known to play a pivotal role in the intracellular transduction of activation and death signals. A protein can have multiple sites where chemical groups can reversibly attach in processes such as phosphorylation or nitrosylation. A microscopic description of these processes must take into account the intrinsic probabilistic nature of the underlying reactions. We apply combinatorial considerations to standard enzyme kinetics and in this way we extend to the dynamic regime a simplified version of the traditional models on the allosteric regulation of protein functions. We link a generic modification chain to a downstream Michaelis-Menten enzymatic reaction and we demonstrate numerically that this accounts both for thresholds and long time delays in the conversion of the substrate by the enzyme. The proposed mechanism is stable and robust and the higher the number of modification sites, the greater the stability. We show that a high number of modification sites converts a fast reaction into a slow process, and the slowing down depends on the number of sites and may span many orders of magnitude; in this way multisite modification of proteins stands out as a general mechanism that allows the transfer of information from the very short time scales of enzyme reactions (milliseconds) to the long time scale of cell response (hours).

q-bio.CB↗

arXiv2005

A phenomenological approach to the simulation of metabolism and proliferation dynamics of large tumour cell populations

A major goal of modern computational biology is to simulate the collective behaviour of large cell populations starting from the intricate web of molecular interactions occurring at the microscopic level. In this paper we describe a simplified model of cell metabolism, growth and proliferation, suitable for inclusion in a multicell simulator, now under development (Chignola R and Milotti E 2004 Physica A 338 261-6). Nutrients regulate the proliferation dynamics of tumor cells which adapt their behaviour to respond to changes in the biochemical composition of the environment. This modeling of nutrient metabolism and cell cycle at a mesoscopic scale level leads to a continuous flow of information between the two disparate spatiotemporal scales of molecular and cellular dynamics that can be simulated with modern computers and tested experimentally.

physics.bio-ph↗

arXiv2005

Model-based fit procedure for power-law-like spectra

$1/f^α$ noises are ubiquitous and affect many measurements. These noises are both a nuisance and a peculiarity of several physical systems; in dielectrics, glasses and networked liquids it is very common to study this noise to gather useful information. Sometimes it happens that the noise has a power-law shape only in a certain frequency range, and contains other important features, that are however difficult to study because simple fits often fail. Here I propose a model-based fit procedure that performs well on spectra obtained in a molecular dynamics simulation.

physics.data-an↗

arXiv2005

Exact numerical simulation of power-law noises

Many simulations of stochastic processes require colored noises: I describe here an exact numerical method to simulate power-law noises: the method can be extended to more general colored noises, and is exact for all time steps, even when they are unevenly spaced (as may often happen for astronomical data, see e.g. N. R. Lomb, Astrophys. Space Sci. {\bf 39}, 447 (1976)). The algorithm has a well-behaved computational complexity, it produces a nearly perfect Gaussian noise, and its computational efficiency depends on the required degree of noise Gaussianity.

physics.comp-ph↗

arXiv2002

1/f noise: a pedagogical review

This is a pedagogical review of the ubiquitous 1/f^αnoises. The sections include the representation of 1/f^αnoise as a superposition of many relaxation processes; a discussion of the infinitely large fluctuations in the low frequency limit; 1/f^αnoise from diffusion processes; the measured statistical properties of 1/f^αnoises; 1/f^αnoises in self organized criticality; scaling laws in earthquake physics; 1/f noise in deterministic dynamical systems; an example of noise in a biophysical system; the numerical simulation of 1/f^αnoise; 1/f noise literature (including online resources).

physics.class-ph↗

arXiv2000

Quantum Fluctuations of the Gravitational Field and Propagation of Light: a Heuristic Approach

Quantum gravity is quite elusive at the experimental level; thus a lot of interest has been raised by recent searches for quantum gravity effects in the propagation of light from distant sources, like gamma ray bursters and active galactic nuclei, and also in earth-based interferometers, like those used for gravitational wave detection. Here we describe a simple heuristic picture of the quantum fluctuations of the gravitational field that we have proposed recently, and show how to use it to estimate quantum gravity effects in interferometers.

physics.gen-ph↗