We propose a novel in silico model for computing drug release from multi-layer capsules. The diffusion problem in such heterogeneous layer-by-layer composite medium is described by a system of coupled partial differential equations, which we solve analytically using separation of variables. In addition to the conventional partitioning and mass transfer interlayer conditions, we consider a surface finite mass transfer resistance, which corresponds to the case of a coated capsule. The drug concentration in the core and through all the layers, as well as in the external release medium, is given in terms of a Fourier series that we compute numerically to describe and characterize the drug release mechanism.

The nucleotides ATP and ADP regulate many aspects of endothelial cell (EC) biology, including intracellular calcium concentrations, focal adhesion activation, cytoskeletal organization, and cellular motility. In vivo, ECs are constantly under flow, and the concentration of ATP/ADP on the EC surface is determined by the combined effects of nucleotide convective and diffusive transport as well as hydrolysis by ectonucleotidases on the EC surface. In addition, experiments have demonstrated that flow induces ATP release from the cells. Previous computational models have incorporated the above effects and thus described nucleotide concentration at the EC surface. However, it remains unclear what physical processes are responsible for nucleotide regulation. While some EC responses to flow have been shown to be directly driven by shear stress, others appear to also involve a non-negligible contribution of transport. In the present work, we develop a mathematical model and perform numerical simulations to investigate the relative contributions of shear stress and transport to nucleotide concentration at the EC surface. Because in vitro experiments are performed by using confluent cells in some cases and subconfluent cells in other cases, we also investigate the effect of cell density on the results. The outcomes of the simulations demonstrate a complex interplay between shear stress and transport such that transport has a significant contribution at certain shear stress values but not at others. The effect of transport on nucleotide concentration increases with cell density. The present findings enhance our understanding of the mechanisms that govern the regulation at the EC surface under flow. The implications of these findings for downstream responses such as cellular motility merit future investigation.

We present a general mechanistic model of mass diffusion for a composite sphere placed in a large ambient medium. The multi-layer problem is described by a system of diffusion equations coupled via interlayer boundary conditions such as those imposing a finite mass resistance at the extemal surface of the sphere. While the work is applicable to the generic problem of heat or mass transfer in a multi-layer sphere, the analysis and results are presented in the context of drug kinetics for desorbing and absorbing spherical microcapsules. We derive an analytical solution for the concentration in the sphere and in the surrounding medium that avoids any artificial truncation at a finite distance. The closed-form solution in each concentric layer is expressed in terms of a suitably-defined inverse Laplace transform that can be evaluated numerically. Concentration profiles and drug mass curves in the spherical layers and in the external environment are presented and the dependency of the solution on the mass transfer coefficient at the surface of the sphere analyzed.

In this study, we designed a novel drug-eluting coating for vascular implants consisting of a core coating of the anti-proliferative drug docetaxel ( DTX) and a shell coating of the platelet glycoprotein IIb/IIIa receptor monoclonal antibody SZ-21. The core/shell structure was sprayed onto the surface of 316L stainless steel stents using a coaxial electrospray process with the aim of creating a coating that exhibited a differential release of the two drugs. The prepared stents displayed a uniform coating consisting of nano/micro particles. In vitro drug release experiments were performed, and we demonstrated that a biphasic mathematical model was capable of capturing the data, indicating that the release of the two drugs conformed to a diffusion-controlled release system. We demonstrated that our coating was capable of inhibiting the adhesion and activation of platelets, as well as the proliferation and migration of smooth muscle cells ( SMCs), indicating its good biocompatibility and anti-proliferation qualities. In an in vivo porcine coronary artery model, the SZ-21/DTX drug-loaded hydrophobic core/hydrophilic shell particle coating stents were observed to promote re-endothelialization and inhibit neointimal hyperplasia. This core/shell particle-coated stent may serve as part of a new strategy for the differential release of different functional drugs to sequentially target thrombosis and in-stent restenosis during the vascular repair process and ensure rapid re-endothelialization in the field of cardiovascular disease.

The topic of controlled drug release has received much attention in recent years, for example in the design of tablets and in local drug delivery devices such as stents, transdermal patches and orthopaedic implants. In recent years, we have developed a series of models for such devices to describe drug release from a polymeric platform and transport in surrounding biological tissues. These works have culminated in the development of a mathematical model that demonstrates agreement with in-vivo drug release and tissue uptake data, for the case of a drug-eluting stent. If, on the one hand, these fully coupled models are indeed necessary to understand the spatio-temporal drug concentration in the surrounding environment, on the other hand it is clear that device manufacturers cannot intervene on the underlying biology. What they can control, however, are the properties of the polymeric platform to ensure the desired drug release profile is achieved. Indeed, the release profile is known to be a key predictor of device performance. Therefore, in the present work we focus instead primarily on the properties of the drug-containing coating. We consider two particular aspects of the drug coating design. Firstly, the delivery of two therapeutic agents, what we refer to as dual drug delivery. Depending on the particular application in question, it may be desirable for the drugs to be released at similar rates, or perhaps one of the drugs released rapidly with the other being eluted over a longer period of time. In the case of drug-eluting stents, for example, devices which release an anti-proliferative and a 'pro-healing' drug have been proposed, whilst a combination of the two has also been suggested. Secondly, motivated by today's advances in micro and nanotechnology, we propose variable porosity multi-layer coatings as an additional means of controlling the dual drug delivery. In this talk we present our mathematical model of dual drug delivery from a durable polymer coated device. We demonstrate how the release rate of each drug may in principle be controlled by varying the underlying microstructure of polymer coating or by changing the initial loading configuration of the two drugs . Our results show the role of the relevant material parameters used to tailor the release curves to a given application.

Many drugs currently on the market or in development are poorly water-soluble. This presents a serious challenge to the pharmaceutical industry because orally delivered drugs that are poorly soluble tend to pass through the gastrointestinal tract before they can fully dissolve, leading to poor drug bioavailability. One strategy to improve drug solubility is to use a solid dispersion. A solid dispersion typically consists of a hydrophobic drug embedded in a hydrophilic polymer matrix. When the dispersion dissolves in the stomach, drug-polymer interactions maintain the drug at supersaturated levels, thereby accelerating drug dissolution. Unfortunately, despite extensive research, the dissolution behaviour of solid dispersions is only partially understood. This makes the design of successful solid dispersions a somewhat hit and miss affair. Clearly, the construction of reliable mathematical models that capture the key interactions between the drug, polymer and solvent molecules in a dissolving solid dispersion would greatly assist with their rational design. In this presentation, we develop mathematical models describing the storage and dissolution of solid dispersions. The models consist of coupled systems of nonlinear partial differential equations. We then analyze in detail a particular problem describing a solid dispersion in storage. The drug-polymer interaction in the dispersion is modelled using Flory-Huggins theory , and we use the model to identify regimes in the model parameter space that lead to stable, metastable and unstable storage behaviour (phase separation).We illustrate the various phenomena arising using numerical simulations.

We propose a novel in-silico model for computing drug release from multi-layer capsules. The diffusion problem in such heterogeneous layer-by-layer composite medium is described by a system of coupled partial differential equations, which we solve analytically using separation of variables. In addition to the conventional partitioning and mass transfer interlayer conditions, we consider also the case of finite mass transfer resistance, which corresponds to the case of a coated capsule. The drug concentration in the core and through all layers, as well as in the external release medium, is given in terms of a Fourier series that we compute numerically to describe pharmacokinetics and to characterize the drug release mechanism.

Observational data from the European Space Agency astrometric mission Gaia determining the positions of celestial objects within an accuracy of a few microarcseconds will be soon fully available. Other satellite-based space missions are currently planned to significantly improve such precision in the next years. The data reduction process needs high-precision general relativistic models, allowing one to solve the inverse ray-tracing problem in the gravitational field of the Solar System up to the requested level of accuracy and leading then to the estimate of astrometric parameters. Besides a satisfactory description of the background field due to the planets (which should include their multipolar structure), one should consider also other effects which may induce modifications to the light propagation. For instance, the interaction of the light signal with the superposed gravitational field of a gravitational wave emitted by a distant source would cause a shift in the apparent positions of the stars. We compute here the main astrometric observables needed for data reduction of satellite-based missions in the presence of a passing plane gravitational wave. We also take into account the effect of the mass quadrupole moment of the planets, improving previous results obtained for Gaia.

Background & Aims: Acute liver failure is a rapidly progressive deterioration of hepatic function resulting in high mortality and morbidity. Metabolic enzymes can translocate to the nucleus to regulate histone acetylation and gene expression. Methods: Levels and activities of pyruvate dehydrogenase complex (PDHC) and lactate dehydrogenase (LDH) were evaluated in nuclear fractions of livers of mice exposed to various hepatotoxins including CD95-antibody, ?-amanitin, and acetaminophen. Whole-genome gene expression profiling by RNA-seq was performed in livers of mice with acute liver failure and analyzed by gene ontology enrichment analysis. Cell viability was evaluated in cell lines knocked-down for PDHA1 or LDH-A and in cells incubated with the LDH inhibitor galloflavin after treatment with CD95-antibody. We evaluated whether the histone acetyltransferase inhibitor garcinol or galloflavin could reduce liver damage in mice with acute liver failure. Results: Levels and activities of PDHC and LDH were increased in nuclear fractions of livers of mice with acute liver failure. The increase of nuclear PDHC and LDH was associated with increased concentrations of acetyl-CoA and lactate in nuclear fractions, and histone H3 hyper-acetylation. Gene expression in livers of mice with acute liver failure suggested that increased histone H3 acetylation induces the expression of genes related to damage response. Reduced histone acetylation by the histone acetyltransferase inhibitor garcinol decreased liver damage and improved survival in mice with acute liver failure. Knock-down of PDHC or LDH improved viability in cells exposed to a pro-apoptotic stimulus. Treatment with the LDH inhibitor galloflavin that was also found to inhibit PDHC, reduced hepatic necrosis, apoptosis, and expression of pro-inflammatory cytokines in mice with acute liver failure. Mice treated with galloflavin also showed a dose-response increase in survival. Conclusion: PDHC and LDH translocate to the nucleus, leading to increased nuclear concentrations of acetyl-CoA and lactate. This results in histone H3 hyper-acetylation and expression of damage response genes. Inhibition of PDHC and LDH reduces liver damage and improves survival in mice with acute liver failure. Thus, PDHC and LDH are targets for therapy of acute liver failure. Lay summary: Acute liver failure is a rapidly progressive deterioration of liver function resulting in high mortality. In experimental mouse models of acute liver failure, we found that two metabolic enzymes, namely pyruvate dehydrogenase complex and lactic dehydrogenase, translocate to the nucleus resulting in detrimental gene expression. Treatment with an inhibitor of these two enzymes was found to reduce liver damage and to improve survival.

The dynamics of a quasi two-dimensional isotropic droplet in a cholesteric liquid crystal medium under symmetric shear flow is studied by lattice Boltzmann simulations. We consider a geometry in which the flow direction is along the axis of the cholesteric, as this setup exhibits a significant viscoelastic response to external stress. We find that the dynamics depends on the magnitude of the shear rate, the anchoring strength of the liquid crystal at the droplet interface and the chirality. While low shear rate and weak interface anchoring the system shows a non-Newtonian behavior, a Newtonian-like response is observed at high shear rate and strong interface anchoring. This is investigated both by estimating the secondary flow profile, namely a flow emerging along the out-of-plane direction (absent in fully-Newtonian fluids, such as water) and by monitoring defect formation and dynamics, which significantly alter the rheological response of the system.

We investigate numerically, by a hybrid lattice Boltzmann method, the morphology and the dynamics of an emulsion made of a polar active gel, contractile or extensile, and an isotropic passive fluid. We focus on the case of a highly off-symmetric ratio between the active and passive components. In absence of any activity we observe an hexatic-ordered droplets phase, with some defects in the layout. We study how the morphology of the system is affected by activity both in the contractile and extensile case. In the extensile case a small amount of activity favors the elimination of defects in the array of droplets, while at higher activities, first aster-like rotating droplets appear, and then a disordered pattern occurs. In the contractile case, at sufficiently high values of activity, elongated structures are formed. Energy and enstrophy behavior mark the transitions between the different regimes.

An overview of recent Virtualization Technologies impact on Cloud Security, including Advantages, Issues, and Perspectives

We propose a stochastic model in evolutionary game theory where individuals (or subpopulations) can mutate changing their strategies randomly (but rarely) and explore the external environment. This environment affects the selective pressure by modifying the payoff arising from the interactions between strategies. We derive a Fokker-Planck integro-differential equation and provide Monte Carlo simulations for the Hawks vs Doves game. In particular we show that, in some cases, taking into account the external environment favors the persistence of the low-fitness strategy.

We are concerned with a priori estimates, in rearrangement form, for weak solutions to fully anisotropic, nonlinear elliptic equations with lower-order terms whose prototype is \begin{equation*} \left\{ \begin{array} [c]{lll} -\hbox{\rm div} \; (a(x, u, \nabla u)) + b(u)=f(x) & \qquad\hbox{\rm in\ } \Omega \\ u=0 & \qquad\text{on}\;\partial\Omega. \end{array} \right. \end{equation*} Here, $\Omega$ is an open bounded set in $\mathbb{R}^{N}$, with $N\geq2$, $a(x, \eta, \xi)$ is a Carath\'{e}odory function fulfilling \begin{equation*} a(x,\eta,\xi)\cdot\xi\geq\Phi\left( \xi\right) \qquad \text{ for } \left( \eta,\xi\right) \in\mathbb{R}\times\mathbb{R}^{N}, \; \text{ for a. e. } x\in\Omega, \end{equation*} where $\Phi :\mathbb{R}^{N}\rightarrow\left[ 0,+\infty\right[ $ is an $N-$dimensional Young function, and $b:\mathbb{R}\rightarrow\mathbb{R}$ is a continuous and strictly increasing function such that $b\left( 0\right)=0$. Finally, $f:\Omega \rightarrow\mathbb{R}$ is a nonnegative measurable function enjoying suitable integrability conditions.

Purpose: We studied microRNAs as potential biomarkers for Pompe disease. Methods: We analyzed microRNA expression by small RNA-seq in tissues from the disease murine model at two different ages (3 and 9 months), and in plasma from Pompe patients. Results: In the mouse model we found 211 microRNAs that were differentially expressed in gastrocnemii and 66 in heart, with a different pattern of expression at different ages. In a preliminary analysis in plasma from six patients 55 microRNAs were differentially expressed. Sixteen of these microRNAs were common to those dysregulated in mouse tissues. These microRNAs are known to modulate the expression of genes involved in relevant pathways for Pompe disease pathophysiology (autophagy, muscle regeneration, muscle atrophy). One of these microRNAs, miR-133a, was selected for further quantitative real-time polymerase chain reaction analysis in plasma samples from 52 patients, obtained from seven Italian and Dutch biobanks. miR-133a levels were significantly higher in Pompe disease patients than in controls and correlated with phenotype severity, with higher levels in infantile compared with late-onset patients. In three infantile patients miR-133a decreased after start of enzyme replacement therapy and evidence of clinical improvement. Conclusion: Circulating microRNAs may represent additional biomarkers of Pompe disease severity and of response to therapy.

Retinal gene therapy based on adeno-associated viral (AAV) vectors is safe and efficient in humans. The low intrinsic DNA transfer capacity of AAV has been expanded by dual vectors where a large expression cassette is split in two halves independently packaged in two AAV vectors. Dual AAV transduction efficiency, however, is greatly reduced compared to that obtained with a single vector. As AAV intracellular trafficking and processing are negatively affected by phosphorylation, this study set to identify kinase inhibitors that can increase dual AAV vector transduction. By high-throughput screening of a kinase inhibitors library, three compounds were identified that increase AAV transduction in vitro, one of which has a higher effect on dual than on single AAV vectors. Importantly, the transduction enhancement is exerted on various AAV serotypes and is not transgene dependent. As kinase inhibitors are promiscuous, siRNA-mediated silencing of targeted kinases was performed, and AURKA and B, PLK1, and PTK2 were among those involved in the increase of AAV transduction levels. The study shows that kinase inhibitor administration reduces AAV serotype 2 (AAV2) capsid phosphorylation and increases the activity of DNA-repair pathways involved in AAV DNA processing. Importantly, the kinase inhibitor PF-00562271 improves dual AAV8 transduction in photoreceptors following sub-retinal delivery in mice. The study identifies kinase inhibitors that increase dual and single AAV transduction by modulating AAV entry and post-entry steps.

MASCOT2018 is the 15th edition of the IMACS/ISGG workshop focused on methods and tools for the complete cycle of numerical modelling and simulation, from the development of theoretically well based models and methods to the deep investigation of crucial applications, from geometry and model construction to its implementation, from data analysis and powerful design of computational tools, with advanced capabilities. Aim of the workshop is the presentation and discussion of innovative technologies dealing with all aspects of computational processes. We recall, but without limiting to them, methodologies for effective grid generation, advanced approximation methods, identification and application of efficient PDE numerical solution algorithms, the development of powerful tools for image processing and scientific visualization. The workshop would bring together developers and users of computational methods and software tools to go deeper into advantages of new methodologies, discuss applications and results, illustrate educational approaches, identify new needs and innovative development directions in a growing variety of problems in applied mathematics