The conceptualization of immunological self is amongst the most important theories of modern biology, representing a sort of theoretical guideline for experimental immunologists, in order to understand how host constituents are ignored by the immune system (IS). A consistent advancement in this field has been represented by the danger/damage theory and its subsequent refinements, which at present represents the most comprehensive conceptualization of immunological self. Here, we present the new hypothesis of "liquid self," which integrates and extends the danger/damage theory. The main novelty of the liquid self hypothesis lies in the full integration of the immune response mechanisms into the host body's ecosystems, i.e., in adding the temporal, as well as the geographical/evolutionary and environmental, dimensions, which we suggested to call "immunological biography." Our hypothesis takes into account the important biological changes occurring with time (age) in the IS (including immunosenescence and inflammaging), as well as changes in the organismal context related to nutrition, lifestyle, and geography (populations). We argue that such temporal and geographical dimensions impinge upon, and continuously reshape, the antigenicity of physical entities (molecules, cells, bacteria, viruses), making them switching between "self" and "non-self" states in a dynamical, "liquid" fashion. Particular attention is devoted to oral tolerance and gut microbiota, as well as to a new potential source of unexpected self epitopes produced by proteasome splicing. Finally, our framework allows the set up of a variety of testable predictions, the most straightforward suggesting that the immune responses to defined molecules representing potentials antigens will be quantitatively and qualitatively quite different according to the immuno-biographical background of the host. © 2014 Grignolio, Mishto, Faria, Garagnani, Franceschi and Tieri.

A model of drug release from an eluting stent to the arterial wall is presented. The coating layer is described as a porous reservoir where the drug is initially loaded in a polymer-encapsulated solid phase, and is then released both to the coating and to the tissue of the arterial wall in a free phase. The wall is treated as a heterogeneous porous medium and the drug transfer through it is modeled by a non-homogeneous set of coupled partial differential equations that describe a convection-diffusion-reaction process. Change of phases due to drug dissolution in the coating and binding-unbinding reactions in the arterial wall are addressed. Numerical results show a strong coupling of the release kinetics in the polymer and the drug dynamics in the wall, and this coupling depends on the physico-chemical drug properties, the microstructure of the polymeric stent coating and the properties of the arterial wall.

We introduce a classification method (cumulative discriminant analysis) of the discriminant analysis type to discriminate between cloudy and clear-sky satellite observations in the thermal infrared. The tool is intended for the high-spectral-resolution infrared sounder (IRS) planned for the geostationary METEOSAT (Meteorological Satellite) Third Generation platform and uses IASI (Infrared Atmospheric Sounding Interferometer) data as a proxy. The cumulative discriminant analysis does not introduce biases intrinsic with the approximation of the probability density functions and is flexible enough to adapt to different strategies to optimize the cloud mask. The methodology is based on nine statistics computed from IASI spectral radiances, which exploit the high spectral resolution of the instrument and which effectively summarize information contained within the IASI spectrum. A principal component analysis prior step is also introduced, which makes the problem more consistent with the statistical assumptions of the methodology. An initial assessment of the scheme is performed based on global and regional IASI real data sets and cloud masks obtained from AVHRR (Advanced Very High Resolution Radiometer) and SEVIRI (Spinning Enhanced Visible and Infrared Imager) imagers. The agreement with these independent cloud masks is generally well above 80 %, except at high latitudes in the winter seasons.

In non-parametric regression analysis the advantage of frames with respect to classical orthonormal bases is that they can furnish an efficient representation of a more broad class of functions. For example, fast oscillating functions as audio, speech, sonar, radar, EEG and stock market are much more well represented by a frame, with similar oscillating characteristic, than by a classical orthonormal basis. In this respect, a new frame based shrinkage estimator is derived as the Empirical Regularized version of the optimal Shrinkage estimator generalized to the frame operator. An analytic expression of it is furnished leading to an efficient implementation. Results on standard and real test functions are shown. © 2014 Elsevier B.V. All rights reserved.

Gene therapy is a promising approach for treating a wide range of human pathologies such as genetic disorders as well as diseases acquired over time. Viral and non-viral vectors are used to convey sequences of genes that can be expressed for therapeutic purposes. Plasmid DNA is receiving considerable attention for intramuscular gene transfer due to its safety, simplicity and low cost of production. Nevertheless, strategies to improve DNA uptake into the nucleus of cells for its expression are required. Cytoskeleton plays an important role in the intracellular trafficking. The mechanism regulating this process must be elucidated. Here, we propose a new methodological approach based on the coupling of biology assays and predictive mathematical models, in order to clarify the mechanism of the DNA uptake and its expression into the cells. Once these processes are better clarified, we will be able to propose more efficient therapeutic gene transfer protocols for the treatment of human patients.

A new partial differential model for monitoring and detecting copper corrosion products (mainly brochantite and cuprite) is proposed to provide predictive tools suitable for describing the evolution of damage induced on bronze specimens by sulfur dioxide (SO2) pollution. This model is characterized by the movement of a double free boundary. Numerical simulations show a nice agreement with experimental result. (C) 2014 Elsevier Inc. All rights reserved.

Various molecular pharmacokinetic-pharmacodynamic (PK-PD) models have been proposed in the last decades to represent and predict drug effects in anticancer chemotherapies. Most of these models are cell population based since clearly measurable effects of drugs can be seen much more easily on populations of cells, healthy and tumour, than in individual cells. The actual targets of drugs are, however, cells themselves. The drugs in use either disrupt genome integrity by causing DNA strand breaks, and consequently initiate programmed cell death, or block cell proliferation mainly by inhibiting factors that enable cells to proceed from one cell cycle phase to the next through checkpoints in the cell division cycle. DNA damage caused by cytotoxic drugs (and also cytostatic drugs at high concentrations) activates, among others, the p53 protein-modulated signalling pathways that directly or indirectly force the cell to make a decision between survival and death. The paper aims to become the first-step in a larger scale enterprise that should bridge the gap between intracellular and population PK-PD models, providing oncologists with a rationale to predict and optimise the effects of anticancer drugs in the clinic. So far, it only sticks at describing p53 activation and regulation in single cells following their exposure to DNA damaging stress agents. We show that p53 oscillations that have been observed in individual cells can be reconstructed and predicted by compartmentalising cellular events occurring after DNA damage, either in the nucleus or in the cytoplasm, and by describing network interactions, using ordinary differential equations (ODEs), between the ATM, p53, Mdm2 and Wip1 proteins, in each compartment, nucleus or cytoplasm, and between the two compartments. This article is part of a Special Issue entitled: Computational Proteomics, Systems Biology 82 Clinical Implications. (C) 2013 Elsevier B.V. All rights reserved.

The intracellular signalling network of the p53 protein plays important roles in genome protection and the control of cell cycle phase transitions. Recently observed oscillatory behaviour in single cells under stress conditions has inspired several research groups to simulate and study the dynamics of the protein with the aim of gaining a proper understanding of the physiological meanings of the oscillations. We propose compartmental ODE and PDE models of p53 activation and regulation in single cells following DNA damage and we show that the p53 oscillations can be retrieved by plainly involving p53-Mdm2 and ATM-p53-Wip1 negative feedbacks, which are sufficient for oscillations experimentally, with no further need to introduce any delays into the protein responses and without considering additional positive feedback.

The complex differentiation process of the CD4+ T helper lymphocytes shapes the form and the range of the immune response to different antigenic challenges. Few mathematical and computational models have addressed this key phenomenon. We here present a multiscale approach in which two different levels of description, i.e. a gene regulatory network model and an agent-based simulator for cell population dynamics, are integrated into a single immune system model. We illustrate how such model integration allows bridging a gap between gene level information and cell level population, and how the model is able to describe a coherent immunological behaviour when challenged with different stimuli.

Background: Non-codingRNAs(ncRNAs)areemergingaskeyregulatorsofmanycellularprocessesinboth physiological and pathological states. Moreover, the constant discovery of new non-coding RNA species suggests that the study of their complex functions is still in its very early stages. This variegated class of RNA species encompasses the well-known microRNAs (miRNAs) and the most recently acknowledged long non-coding RNAs (lncRNAs). Interestingly, in the last couple of years, a few studies have shown that some lncRNAs can act as miRNA sponges, i.e. as competing endogenous RNAs (ceRNAs), able to reduce the amount of miRNAs available to target messenger RNAs (mRNAs). Results: WeproposeacomputationalapproachtoexploretheabilityoflncRNAstoactasceRNAsbyprotecting mRNAs from miRNA repression. A seed match analysis was performed to validate the underlying regression model. We built normal and cancer networks of miRNA-mediated sponge interactions (MMI-networks) using breast cancer expression data provided by The Cancer Genome Atlas. Conclusions: OurstudyhighlightsamarkedrewiringintheceRNAprogrambetweennormalandpathological breast tissue, documented by its "on/off" switch from normal to cancer, and vice-versa. This mutually exclusive activation confers an interesting character to ceRNAs as potential oncosuppressive, or oncogenic, protagonists in cancer. At the heart of this phenomenon is the lncRNA PVT1, as illustrated by both the width of its antagonist mRNAs in normal-MMI-network, and the relevance of the latter in breast cancer. Interestingly, PVT1 revealed a net binding preference towards the mir-200 family as the bone of contention with its rival mRNAs.

Duchenne muscular dystrophy (DMD) is a genetic disease that results in the death of affected boys by early adulthood. The genetic defect responsible for DMD has been known for over 25 years, yet at present there is neither cure nor effective treatment for DMD. During early disease onset, the mdx mouse has been validated as an animal model for DMD and use of this model has led to valuable but incomplete insights into the disease process. For example, immune cells are thought to be responsible for a significant portion of muscle cell death in the mdx mouse; however, the role and time course of the immune response in the dystrophic process have not been well described. In this paper we constructed a simple mathematical model to investigate the role of the immune response in muscle degeneration and subsequent regeneration in the mdx mouse model of Duchenne muscular dystrophy. Our model suggests that the immune response contributes substantially to the muscle degeneration and regeneration processes. Furthermore, the analysis of the model predicts that the immune system response oscillates throughout the life of the mice, and the damaged fibers are never completely cleared. © 2014 Abdul Salam Jarrah et al.

It is coming nowadays more clear that in order to obtain a unified description of the different mechanisms governing the behavior and causality relations among the various parts of a living system, the development of comprehensive computational and mathematical models at different space and time scales is required. This is one of the most formidable challenges of modern biology characterized by the availability of huge amount of high throughput measurements. In this paper we draw attention to the importance of multiscale modeling in the framework of studies of biological systems in general and of the immune system in particular.

A Godunov scheme is derived for two-dimensional scalar conservation laws without or with source terms following ideas originally proposed by Boukadida and LeRoux [Math. Comput., 63 (1994), pp. 541-553] in the context of a staggered Lax-Friedrichs scheme. In both situations, the numerical fluxes are obtained at each interface of a uniform Cartesian computational grid just by means of the "external waves" involved in the entropy solution of the elementary two-dimensional (2D) Riemann problems; in particular, all the wave-interaction phenomena are overlooked. This restriction of the wave pattern suffices for deriving the exact numerical fluxes of the staggered Lax-Friedrichs scheme, but it furnishes only an approximation for the Godunov scheme: we show that under convenient assumptions, these flux functions are smooth and the resulting discretization process is stable under nearly optimal CFL restriction. A well-balanced extension is presented, relying on the Curl-free component of the Helmholtz decomposition of the source term. Several numerical tests against exact 2D solutions are performed for convex, nonconvex, and inhomogeneous equations and the time-evolution of the L1 truncation error is displayed.

When numerically simulating a kinetic model of an n+nn+ semiconductor device, obtaining a constant macroscopic current at steady state is still a challenging task. Part of the difficulty comes from the multiscale, discontinuous nature of both p|n junctions, which create spikes in the electric field and enclose a channel where corresponding depletion layers glue together. The kinetic formalism furnishes a model holding inside the whole domain, but at the price of strongly varying parameters. By concentrating both the electric acceleration and the linear collision terms at each interface of a Cartesian computational grid, we can treat them by means of a Godunov scheme involving two types of scattering matrices. Combining both these mechanisms into a global Smatrix can be achieved thanks to "Redheffer's star-product." Assuming that the resulting S-matrix is stochastic permits us to prove maximum principles under a mild CFL restriction. Numerical illustrations of collisional Landau damping and various n+nn+ devices are provided on coarse grids.

The numerical approximation of one-dimensional relativistic Dirac wave equations is considered within the recent framework consisting in deriving local scattering matrices at each interface of the uniform Cartesian computational grid. For a Courant number equal to unity, it is rigorously shown that such a discretization preserves exactly the (Formula presented.) norm despite being explicit in time. This construction is well-suited for particles for which the reference velocity is of the order of (Formula presented.), the speed of light. Moreover, when (Formula presented.) diverges, that is to say, for slow particles (the characteristic scale of the motion is non-relativistic), Dirac equations are naturally written so as to let a "diffusive limit" emerge numerically, like for discrete 2-velocity kinetic models. It is shown that an asymptotic-preserving scheme can be deduced from the aforementioned well-balanced one, with the following properties: it yields unconditionally a classical Schrödinger equation for free particles, but it handles the more intricate case with an external potential only conditionally (the grid should be such that (Formula presented.)). Such a stringent restriction on the computational grid can be circumvented easily in order to derive a seemingly original Schrödinger scheme still containing tiny relativistic features. Numerical tests (on both linear and nonlinear equations) are displayed. © 2014 Springer Science+Business Media Dordrecht.

Nel febbraio del 2010 nei pressi dell'abitato di Maierato, in provincia di Vibo Valentia, si è verificata una frana profonda, evoluta in colata veloce, che ha determinato una condizione di grave emergenza. Le attività di studio e indagine condotte nell'ambito dell'Ordinanza della Presidenza del Consiglio dei Ministri n. 3862/2010 ed i successivi approfondimenti, hanno evidenziato la presenza di un'antica frana nella parte sud dell'abitato, in località Vonace. In particolare, lo studio geologico-strutturale e geomorfologico ha evidenziato che si tratta di un antico scorrimento in blocco, costituito da calcare evaporitico messiniano, con movimento lungo una superficie a basso angolo, localizzata all'interno delle sottostanti marne emipelagiche tortoniano-messiniane, prossima al contatto stratigrafico tra le due unità. L'antica scarpata di frana è attualmente modellata ed il blocco di calcare evaporitico traslato si trova nella parte bassa del versante. Su base geologico-geomorfologica non sussistono elementi riconducibili ad una riattivazione dello scorrimento in blocco e un'analoga indicazione si desume dall'analisi di sensitività delle condizioni di stabilità condotta con riferimento al modello geotecnico preliminare. I tempi e le risorse necessari per continuare gli approfondimenti di studio, e la presenza in località Vonace di elementi geologico-strutturali simili a quelli riscontrati nel versante coinvolto dalla frana del febbraio 2010, suggeriscono l'opportunità di utilizzare il monitoraggio per il controllo dell'area e per individuare variazioni significative di grandezze correlabili alle condizioni di instabilità. Nella nota è pertanto illustrata una sperimentazione che vede l'utilizzo di un monitoraggio che considera l'integrazione dei dati acquisiti da misure GPS, inclinometriche e da Ground-Based SAR (GBSAR). In particolare, l'analisi delle misure eseguite fornisce indicazioni circa lo stato di attività della frana antica considerata. Le indicazioni desunte dalla sperimentazione condotta forniscono gli elementi per precisare la strategia di monitoraggio integrato, con tecniche tradizionali e tecnologie innovative, finalizzata al controllo nel medio-lungo termine delle condizioni di movimento ed alla mitigazione del rischio da frana in località Vonace. I risultati ottenuti indirizzano, inoltre, la prosecuzione degli approfondimenti di studio in corso.

The paper deals with the numerical solution of a nonstandard Sturm-Liouville boundary value problem on the half line where the coefficients of the differential terms depend on the unknown function by means of a scalar integral operator. By using a finite difference discretization, a truncated quadrature rule and an iterative procedure, we construct a numerical method, whose convergence is proved. The order of convergence and the truncation at infinity are also discussed. Finally, some numerical tests are given to show the performance of the method. © 2013 Elsevier B.V. All rights reserved.

Tidal interactions have a significant influence on the late dynamics of compact binary systems, which constitute the prime targets of the upcoming network of gravitational-wave detectors. We refine the theoretical description of tidal interactions (hitherto known only to the second post-Newtonian level) by extending our recently developed analytic self-force formalism, for extreme-mass-ratio binary systems, to the computation of several tidal invariants. Specifically, we compute, to linear order in the mass ratio and to the 7.5th post-Newtonian order, the following tidal invariants: the square and the cube of the gravitoelectric quadrupolar tidal tensor, the square of the gravitomagnetic quadrupolar tidal tensor, and the square of the gravitoelectric octupolar tidal tensor. Our high-accuracy analytic results are compared to recent numerical self-force tidal data by Dolan et al. [arXiv:1406.4890 [Phys. Rev. D (to be published)]?], and, notably, provide an analytic understanding of the light ring asymptotic behavior found by them. We transcribe our kinematical tidal-invariant results in the more dynamically significant effective one-body description of the tidal interaction energy. By combining, in a synergetic manner, analytical and numerical results, we provide simple, accurate analytic representations of the global, strong-field behavior of the gravitoelectric quadrupolar tidal factor. A striking finding is that the linear-in-mass-ratio piece in the latter tidal factor changes sign in the strong-field domain, to become negative (while its previously known second post-Newtonian approximant was always positive). We, however, argue that this will be more than compensated by a probable fast growth, in the strong-field domain, of the nonlinear-in-mass-ratio contributions in the tidal factor.