Extended versions of the Bourgain-Brezis-Mironescu theorems on the limit as s->1^- of the Gagliardo-Slobodeckij fractional seminorm are established in the Orlicz space setting. Our results hold for fractional Orlicz-Sobolev spaces built upon general Young functions, and complement those of [13], where Young functions satisfying the $\Delta_2$ and the $\nabla_2$ conditions are dealt with. The case of Young functions with an asymptotic linear growth is also considered in connection with the space of functions of bounded variation.

A limitation of current modeling studies in waterborne diseases (one of the leading causesof death worldwide) is that the intrinsic dynamics of the pathogens is poorly addressed, leadingto incomplete, and often, inadequate understanding of the pathogen evolution and its impact ondisease transmission and spread. To overcome these limitations, in this paper, we consider an ODEsmodel with bacterial growth inducing Allee effect. We adopt an adequate functional response tosignificantly express the shape of indirect transmission. The existence and stability of biologicallymeaningful equilibria is investigated through a detailed discussion of both backward and Hopfbifurcations. The sensitivity analysis of the basic reproduction number is performed. Numericalsimulations confirming the obtained results in two different scenarios are shown.

Considerations and analysis of trusted computing in the Cloud Trusted execution technology is increasingly successful in heterogeneous fields aiming at securing the execution of code and access control to premium content, though some criticalities associated with such technologies start becoming apparent. Among other stakeholders, the Cloud Security Alliance, whose mission is to promote the use of best practices for providing security assurance within cloud computing, offers cloud providers and clients with security models and tools that ease security management. This chapter highlights promising technology such as containers and their security aspects. It surveys trusted computing technologies, highlighting the pros and cons of established technologies and novel approaches, as well as the security issues that such approaches introduce ex novo or simply exacerbate. The chapter surveys some relevant, trusted computing environment solutions, such as SGX and containers. It shows how the cloud can make use of the analyzed trusted execution technology to help secure the execution of code and protect access to data.

The transcription factor CCCTC-binding factor (CTCF) modulates pleiotropic functions mostly related to gene expression regulation. The role of CTCF in large scale genome organization is also well established. A unifying model to explain relationships among many CTCF-mediated activities involves direct or indirect interactions with numerous protein cofactors recruited to specific binding sites. The co-association of CTCF with other architectural proteins such as cohesin, chromodomain helicases, and BRG1, further supports the interplay between master regulators of mammalian genome folding. Here, we report a comprehensive LC-MS/MS mapping of the components of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex co-associated with CTCF including subunits belonging to the core, signature, and ATPase modules. We further show that the localization patterns of representative SWI/SNF members significantly overlap with CTCF sites on transcriptionally active chromatin regions. Moreover, we provide evidence of a direct binding of the BRK-BRG1 domain to the zinc finger motifs 4-8 of CTCF, thus, suggesting that these domains mediate the interaction of CTCF with the SWI/SNF complex. These findings provide an updated view of the cooperative nature between CTCF and the SWI/SNF ATP-dependent chromatin remodeling complexes, an important step for understanding how these architectural proteins collaborate to shape the genome.

The code is designed to exploit parallel computing platforms, taking advantage also of the recent AVX-512 instruction set. We focus on LBsoft structure, functionality, parallel implementation, performance and availability, so as to facilitate the access to this computational tool to the research community in the field. We present LBsoft, an open-source software developed mainly to simulate the hydro-dynamics of colloidal systems based on the concurrent coupling between lattice Boltzmann methods for the fluid and discrete particle dynamics for the colloids. Such coupling has been developed before, but, to the best of our knowledge, no detailed discussion of the programming issues to be faced in order to attain efficient implementation on parallel architectures, has ever been presented to date. In this paper, we describe in detail the underlying multi-scale models, their coupling procedure, along side with a description of the relevant input variables, to facilitate third-parties usage.

At variance with other commonly used multigrid methods, mostly oriented to high Reynolds and turbulent flows, the present approach is designed to capture the physics at the smallest scales whenever the lattice Boltzmann alone falls short of providing the correct physical information due to a lack of resolution, as it occurs for example in thin films between interacting bubbles or droplets in microfluidic crystals. In this work we discuss the coupling of two mesoscopic approaches for fluid dynamics, namely the lattice Boltzmann method (LB) and the multiparticle collision dynamics (MPCD) [20] to design a new class of flexible and efficient multiscale schemes based on a dual representation of the fluid observables.

Effective treatment of glioma and other central nervous system (CNS) diseases is hindered by the presence of the blood-brain barrier (BBB). A novel nano-delivery vehicle system composed of PLGA-lysoGM1/DOX micelles was developed to cross the BBB for CNS treatment. We have shown that doxorubicin (DOX) as a model drug encapsulated in PLGA-lysoGM1 micelles can achieve up to 3.8% loading efficiency and 61.6% encapsulation efficiency by the orthogonal test design. Our in vitro experiments demonstrated that PLGA-lysoGM1/DOX micelles had a slow and sustainable drug release under physiological conditions and exhibited a high cellular uptake through the macropinocytosis and the autophagy/lysosomal pathways. In vivo experimental studies in zebrafish and mice confirmed that PLGA-lysoGM1/DOX micelles could cross the BBB and be specifically accumulated in the brain. Moreover, an excellent anti-glioma effect was observed in intracranial glioma-bearing rats. Therefore, PLGA-lysoGM1/DOX micelles not only effectively can cross the BBB, but our results also suggest that they have great potential for anti-glioma therapy and other central nervous system diseases.

We present a mechanistic model of drug release from a multiple emulsion into an external surrounding fluid. We consider a single multilayer droplet where the drug kinetics are described by a pure diffusive process through different liquid shells. The multilayer problem is described by a system of diffusion equations coupled via interlayer conditions imposing continuity of drug concentration and flux. Mass resistance is imposed at the outer boundary through the application of a surfactant at the external surface of the droplet. The two-dimensional problem is solved numerically by finite volume discretization. Concentration profiles and drug release curves are presented for three typical round-shaped (circle, ellipse, and bullet) droplets and the dependency of the solution on the mass transfer coefficient at the surface analyzed. The main result shows a reduced release time for an increased elongation of the droplets.

We use Langevin dynamics simulations to study the mass diffusion problem across two adjacent porous layers of different transport properties. At the interface between the layers, we impose the Kedem-Katchalsky (KK) interfacial boundary condition that is well suited in a general situation. A detailed algorithm for the implementation of the KK interfacial condition in the Langevin dynamics framework is presented. As a case study, we consider a two-layer diffusion model of a drug-eluting stent. The simulation results are compared with those obtained from the solution of the corresponding continuum diffusion equation, and an excellent agreement is shown.

The migration of endothelial cells (ECs) is critical for various processes including vascular wound healing, tumor angiogenesis, and the development of viable endovascular implants. Recent observations (time-lapse imaging over 12hr periods) in our laboratory of ECs cultured on line patterns - surfaces where cellular adhesion is limited to 15 ?m wide lines - have demonstrated the presence of three distinct migration phenotypes: a) running - cells are polarized and migrate continuously and persistently on the adhesive lines with possible directional changes, b) undecided - cells are elongated and exhibit periodic changes in the direction of their polarization and minimal net migration, and c) tumbling-like - cells migrate persistently for a certain amount of time but then stop and round up for a few hours before spreading again and resuming migration. Because EC migration is regulated by intracellular ATP levels and cellular elongation induced ATP release, we hypothesize that the three migration phenotypes on line patterns, which translate into different cell length variations in time, are related to different intracellular ATP profiles. Thus, we have developed a mathematical model to provide a description of the complex interactions between cell length, cytoskeletal (F-actin) organization, and intracellular ATP concentration. To identify the parameters that reproduce the experimental observations, we have implemented an optimization procedure that yields the parameter values that best fit the experimental data on cell lengths. The results show that depending on the parameter values adopted for the simulations, the different ATP profiles can indeed be obtained. Future work will focus on providing experimental evidence for the involvement of intracellular ATP in determining the three types of migration behavior.

The aim of this paper is to solve an inverse problem which regards a mass moving in a bounded domain. We assume that the mass moves following an unknown velocity field and that the evolution of the mass density can be described by a partial differential equation, which is also unknown. The input data of the problems are given by some snapshots of the mass distribution at certain times, while the sought output is the velocity field that drives the mass along its displacement. To this aim, we put in place an algorithm based on the combination of two methods: first, we use the dynamic mode decomposition to create a mathematical model describing the mass transfer; second, we use the notion of Wasserstein distance (also known as earth mover's distance) to reconstruct the underlying velocity field that is responsible for the displacement. Finally, we consider a real-life application: the algorithm is employed to study the travel flows of people in large populated areas using, as input data, density profiles (i.e., the spatial distribution) of people in given areas at different time instants. These kinds of data are provided by the Italian telecommunication company TIM and are derived by mobile phone usage.

The impact of vehicular traffic on society is huge and multifaceted, including economic, social, health and environmental aspects. The problems is complex and hard to model since it requires to consider traffic patterns, air pollutant emissions, and the chemical reactions and dynamics of pollutants in the low atmosphere. This paper aims at exploring a comprehensive simulation tool ranging from vehicular traffic all the way to environmental impact. As first step in this direction, we couple a traffic second-order model, tuned on NGSIM data, with an nitrogen oxides (NO) emission model and a set of equations for some of the main chemical reactions behind ozone (O) production.

In the framework of the exact factorization of the time-dependent electron-nuclear wave function, we investigate the possibility of solving the nuclear time-dependent Schrödinger equation based on trajectories. The nuclear equation is separated in a Hamilton-Jacobi equation for the phase of the wave function, and a continuity equation for its (squared) modulus. For illustrative adiabatic and nonadiabatic one-dimensional models, we implement a procedure to follow the evolution of the nuclear density along the characteristics of the Hamilton-Jacobi equation. Those characteristics are referred to as quantum trajectories, since they are generated via ordinary differential equations similar to Hamilton's equations, but including the so-called quantum potential, and they can be used to reconstruct exactly the quantum-mechanical nuclear wave function, provided infinite initial conditions are propagated in time.

Derivations of the Jarzynski equality (JE) appear to be quite general, and applicable to any particle system, whether deterministic or stochastic, under equally general perturbations of an initial equilibrium state at given temperatureT. At the same time, the definitions of the quantities appearing in the JE, in particular the work, have been questioned. Answers have been given, but a deeper understanding of the range of phenomena to which the JE applies is necessary, both conceptually and in order to interpret the experiments in which it is used. In fact, domains in which the JE is not applicable have been identified. To clarify the issue, we scrutinize the applicability of the JE to a Hamiltonian particle system in a variable volume. We find that, in this case, the standard interpretation of the terms appearing in the JE is not adequate.

Background: Mutations of the mitochondrial protein paraplegin cause hereditary spastic paraplegia type 7 (SPG7), a so-far untreatable degenerative disease of the upper motoneuron with still undefined pathomechanism. The intermittent mitochondrial permeability transition pore (mPTP) opening, called flickering, is an essential process that operates to maintain mitochondrial homeostasis by reducing intra-matrix Ca and reactive oxygen species (ROS) concentration, and is critical for efficient synaptic function. Methods: We use a fluorescence-based approach to measure mPTP flickering in living cells and biochemical and molecular biology techniques to dissect the pathogenic mechanism of SPG7. In the SPG7 animal model we evaluate the potential improvement of the motor defect, neuroinflammation and neurodegeneration by means of an mPTP inducer, the benzodiazepine Bz-423. Findings: We demonstrate that paraplegin is required for efficient transient opening of the mPTP, that is impaired in both SPG7 patients-derived fibroblasts and primary neurons from Spg7 mice. We show that dysregulation of mPTP opening at the pre-synaptic terminal impairs neurotransmitter release leading to ineffective synaptic transmission. Lack of paraplegin impairs mPTP flickering by a mechanism involving increased expression and activity of sirtuin3, which promotes deacetylation of cyclophilin D, thus hampering mPTP opening. Pharmacological treatment with Bz-423, which bypasses the activity of CypD, normalizes synaptic transmission and rescues the motor impairment of the SPG7 mouse model. Interpretation: mPTP targeting opens a new avenue for the potential therapy of this form of spastic paraplegia. Funding: Telethon Foundation grant (TGMGCSBX16TT); Dept. of Defense, US Army, grant W81XWH-18-1-0001

?1-Antitrypsin (AAT) encoded by the SERPINA1 gene is an acute-phase protein synthesized in the liver and secreted into the circulation. Its primary role is to protect lung tissue by inhibiting neutrophil elastase. The Z allele of SERPINA1 encodes a mutant AAT, named ATZ, that changes the protein structure and leads to its misfolding and polymerization, which cause endoplasmic reticulum (ER) stress and liver disease through a gain-of-function toxic mechanism. Hepatic retention of ATZ results in deficiency of one of the most important circulating proteinase inhibitors and predisposes to early-onset emphysema through a loss-of-function mechanism. The pathogenetic mechanisms underlying the liver disease are not completely understood. C/EBP-homologous protein (CHOP), a transcription factor induced by ER stress, was found among the most up-regulated genes in livers of PiZ mice that express ATZ and in human livers of patients homozygous for the Z allele. Compared with controls, juvenile PiZ/Chop -/- mice showed reduced hepatic ATZ and a transcriptional response indicative of decreased ER stress by RNA-Seq analysis. Livers of PiZ/Chop -/- mice also showed reduced SERPINA1 mRNA levels. By chromatin immunoprecipitations and luciferase reporter-based transfection assays, CHOP was found to up-regulate SERPINA1 cooperating with c-JUN, which was previously shown to up-regulate SERPINA1, thus aggravating hepatic accumulation of ATZ. Increased CHOP levels were detected in diseased livers of children homozygous for the Z allele. In summary, CHOP and c-JUN up-regulate SERPINA1 transcription and play an important role in hepatic disease by increasing the burden of proteotoxic ATZ, particularly in the pediatric population.

Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease. To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the IGROV-CP20 ovarian carcinoma cells, whose resistance significantly relies on ATP7B. Using a synthetic lethality approach, we identified and validated three hits (Tranilast, Telmisartan, and Amphotericin B) that reduced cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these comprised key Pt-transporting proteins, including ATOX1, whose suppression affected ability of ATP7B to traffic in response to cisplatin. In summary, our findings reveal Tranilast, Telmisartan, and Amphotericin B as effective drugs that selectively promote cisplatin toxicity in Pt-resistant ovarian cancer cells and underscore the efficiency of HTS strategy for identification of biosafe compounds, which might be rapidly repurposed to overcome resistance of tumors to Pt-based chemotherapy.

We study the formation of singularities for the problem {u(t) = [phi(u)](xx) + epsilon[psi(u)](txx) in Omega x (0, T) phi(u) + epsilon[psi(u)](t) = 0 in partial derivative Omega x(0, T) u = u(0) >= 0 in Omega x {0}, where epsilon and Tare positive constants, Omega a bounded interval, u(0) a nonnegative Radon measure on Omega, phi a nonmonotone and nonnegative function with phi(0) = phi(infinity) = 0, and psi an increasing bounded function. We show that if u(0) is a bounded or continuous function, singularities may appear spontaneously. The class of singularities which can arise in finite time is remarkably large, and includes infinitely many Dirac masses and singular continuous measures.

We consider a mathematical model describing population dynamics of normal and abnormal cell densities with contact inhibition of cell growth from a theoretical point of view. In the first part of this paper, we discuss the global existence of a solution satisfying the segregation property in one space dimension for general initial data. Here, the term segregation property means that the different types of cells keep spatially segregated when the initial densities are segregated. The second part is devoted to singular limit problems for solutions of the PDE system and traveling wave solutions, respectively. Actually, the contact inhibition model considered in this paper possesses quite similar properties to those of the Fisher-KPP equation. In particular, the limit problems reveal a relation between the contact inhibition model and the Fisher-KPP equation.

We prove existence and uniqueness for a class of signed Radon measure-valued entropy solutions of the Cauchy problem for a first order scalar hyperbolic conservation law in one space dimension. The initial data of the problem is a finite superposition of Dirac masses, whereas the flux is Lipschitz continuous and bounded. The solution class is determined by an additional condition which is needed to prove uniqueness.