Macrophage polarisation by fatty acids is PPARgamma-dependent

Elevated plasma free fatty acids (FAs) are associated with increased risk of cardiovascular disease. We investigated the effects of the saturated FA palmitate and unsaturated FA oleate on monocyte phenotype and function. Palmitate increased cell surface expression of integrin CD11b and scavenger receptor CD36 in a concentration-dependent manner with some decrease in mitochondrial reducing capacity at high concentration (300µM). Monocytes incubated with palmitate, but not oleate, showed increased uptake of oxidized LDL and increased adhesion to rat aortic endothelium, particularly at bifurcations. The palmitate-induced increase in CD11b and CD36 expression was associated with increased cellular C16 ceramide and sphingomyelin, loss of reduced glutathione, and increased reactive oxygen species (ROS). Increased monocyte surface CD11b and CD36 was inhibited by fumonisin B1, an inhibitor of de novo ceramide synthesis, but not by the superoxide dismutase mimetic MnTBap. In contrast, MnTBap prevented the mitochondrial ROS increase and metabolic inhibition due to 300µM palmitate. This study demonstrates that in viable monocytes, palmitate but not oleate increases expression of surface CD11b and CD36. Palmitate increases monocyte adhesion to the aortic wall and promotes uptake of oxidized LDL and this involves de novo ceramide synthesis. We have also explored whether specific dietary fatty acids drive monocyte to macrophage polarisation via metabolic pathways. Here we show that monocytes pre-incubated with the saturated fatty acid palmitate increase production of inflammatory cytokines such as TNFa and IL-6 in response to a phorbol myristate differentiation trigger. This increases mitochondrial superoxide production, reduces dependency on oxidative phosphorylation through ceramide-dependent inhibition of PPARgamma activity and increases TNFa production, again via a mechanism that requires ceramide production.

Bifurcation and stability in a low-dimensional model for multiple-frequency mode-locked lasers

Recent theoretical investigations have demonstrated that the stability of mode-locked solutions of multiple frequency channels depends on the degree of inhomogeneity in gain saturation. In this article, these results are generalized to determine conditions on each of the system parameters necessary for both the stability and the existence of mode-locked pulse solutions for an arbitrary number of frequency channels. In particular, we find that the parameters governing saturable intensity discrimination and gain inhomogeneity in the laser cavity also determine the position of bifurcations of solution types. These bifurcations are completely characterized in terms of these parameters. In addition to influencing the stability of mode-locked solutions, we determine a balance between cubic gain and quintic loss, which is necessary for the existence of solutions as well. Furthermore, we determine the critical degree of inhomogeneous gain broadening required to support pulses in multiple-frequency channels. © 2010 The American Physical Society.

Strongly localized moving discrete dissipative breather-solitons in Kerr nonlinear media supported by intrinsic gain

We investigate the mobility of nonlinear localized modes in a generalized discrete Ginzburg-Landau-type model, describing a one-dimensional waveguide array in an active Kerr medium with intrinsic, saturable gain and damping. It is shown that exponentially localized, traveling discrete dissipative breather-solitons may exist as stable attractors supported only by intrinsic properties of the medium, i.e., in the absence of any external field or symmetry-breaking perturbations. Through an interplay by the gain and damping effects, the moving soliton may overcome the Peierls-Nabarro barrier, present in the corresponding conservative system, by self-induced time-periodic oscillations of its power (norm) and energy (Hamiltonian), yielding exponential decays to zero with different rates in the forward and backward directions. In certain parameter windows, bistability appears between fast modes with small oscillations and slower, large-oscillation modes. The velocities and the oscillation periods are typically related by lattice commensurability and exhibit period-doubling bifurcations to chaotically "walking" modes under parameter variations. If the model is augmented by intersite Kerr nonlinearity, thereby reducing the Peierls-Nabarro barrier of the conservative system, the existence regime for moving solitons increases considerably, and a richer scenario appears including Hopf bifurcations to incommensurately moving solutions and phase-locking intervals. Stable moving breathers also survive in the presence of weak disorder. © 2014 American Physical Society.

Mode-locked laser pulse sources for wavelength division multiplexing

Recent theoretical investigations have demonstrated that the stability of mode-locked solution of multiple frequency channels depends on the degree of inhomogeneity in gain saturation. In this paper, these results are generalized to determine conditions on each of the system parameters necessary for both the stability and existence of mode-locked pulse solutions for an arbitrary number of frequency channels. In particular, we find that the parameters governing saturable intensity discrimination and gain inhomogeneity in the laser cavity also determine the position of bifurcations of solution types. These bifurcations are completely characterized in terms of these parameters. In addition to influencing the stability of mode-locked solutions, we determine a balance between cubic gain and quintic loss, which is necessary for existence of solutions as well. Furthermore, we determine the critical degree of inhomogeneous gain broadening required to support pulses in multiple frequency channels. © 2010 Copyright SPIE - The International Society for Optical Engineering.

Evaporation maps for ternary non-ideal liquid mixtures

This thesis deals with the evaporation of non-ideal liquid mixtures using a multicomponent mass transfer approach. It develops the concept of evaporation maps as a convenient way of representing the dynamic composition changes of ternary mixtures during an evaporation process. Evaporation maps represent the residual composition of evaporating ternary non-ideal mixtures over the full range of composition, and are analogous to the commonly-used residue curve maps of simple distillation processes. The evaporation process initially considered in this work involves gas-phase limited evaporation from a liquid or wetted-solid surface, over which a gas flows at known conditions. Evaporation may occur into a pure inert gas, or into one pre-loaded with a known fraction of one of the ternary components. To explore multicomponent masstransfer effects, a model is developed that uses an exact solution to the Maxwell-Stefan equations for mass transfer in the gas film, with a lumped approach applied to the liquid phase. Solutions to the evaporation model take the form of trajectories in temperaturecomposition space, which are then projected onto a ternary diagram to form the map. Novel algorithms are developed for computation of pseudo-azeotropes in the evaporating mixture, and for calculation of the multicomponent wet-bulb temperature at a given liquid composition. A numerical continuation method is used to track the bifurcations which occur in the evaporation maps, where the composition of one component of the pre-loaded gas is the bifurcation parameter. The bifurcation diagrams can in principle be used to determine the required gas composition to produce a specific terminal composition in the liquid. A simple homotopy method is developed to track the locations of the various possible pseudo-azeotropes in the mixture. The stability of pseudo-azeotropes in the gas-phase limited case is examined using a linearized analysis of the governing equations. Algorithms for the calculation of separation boundaries in the evaporation maps are developed using an optimization-based method, as well as a method employing eigenvectors derived from the linearized analysis. The flexure of the wet-bulb temperature surface is explored, and it is shown how evaporation trajectories cross ridges and valleys, so that ridges and valleys of the surface do not coincide with separation boundaries. Finally, the assumption of gas-phase limited mass transfer is relaxed, by employing a model that includes diffusion in the liquid phase. A finite-volume method is used to solve the system of partial differential equations that results. The evaporation trajectories for the distributed model reduce to those of the lumped (gas-phase limited) model as the diffusivity in the liquid increases; under the same gas-phase conditions the permissible terminal compositions of the distributed and lumped models are the same.

Dynamics of coupled modes in two-section semiconductor lasers with saturable absorption

Semiconductor lasers have the potential to address a number of critical applications in advanced telecommunications and signal processing. These include applications that require pulsed output that can be obtained from self-pulsing and mode-locked states of two-section devices with saturable absorption. Many modern applications place stringent performance requirements on the laser source, and a thorough understanding of the physical mechanisms underlying these pulsed modes of operation is therefore highly desirable. In this thesis, we present experimental measurements and numerical simulations of a variety of self-pulsation phenomena in two-section semiconductor lasers with saturable absorption. Our theoretical and numerical results will be based on rate equations for the field intensities and the carrier densities in the two sections of the device, and we establish typical parameter ranges and assess the level of agreement with experiment that can be expected from our models. For each of the physical examples that we consider, our model parameters are consistent with the physical net gain and absorption of the studied devices. Following our introductory chapter, the first system that we consider is a two-section Fabry-Pérot laser. This example serves to introduce our method for obtaining model parameters from the measured material dispersion, and it also allows us to present a detailed discussion of the bifurcation structure that governs the appearance of selfpulsations in two-section devices. In the following two chapters, we present two distinct examples of experimental measurements from dual-mode two-section devices. In each case we have found that single mode self-pulsations evolve into complex coupled dualmode states following a characteristic series of bifurcations. We present optical and mode resolved power spectra as well as a series of characteristic intensity time traces illustrating this progression for each example. Using the results from our study of a twosection Fabry-Pérot device as a guide, we find physically appropriate model parameters that provide qualitative agreement with our experimental results. We highlight the role played by material dispersion and the underlying single mode self-pulsing orbits in determining the observed dynamics, and we use numerical continuation methods to provide a global picture of the governing bifurcation structure. In our concluding chapter we summarise our work, and we discuss how the presented results can inform the development of optimised mode-locked lasers for performance applications in integrated optics.

Computer simulations of soft particles in flow

Understanding the dynamics of blood cells is a crucial element to discover biological mechanisms, to develop new efficient drugs, design sophisticated microfluidic devices, for diagnostics. In this work, we focus on the dynamics of red blood cells in microvascular flow. Microvascular blood flow resistance has a strong impact on cardiovascular function and tissue perfusion. The flow resistance in microcirculation is governed by flow behavior of blood through a complex network of vessels, where the distribution of red blood cells across vessel cross-sections may be significantly distorted at vessel bifurcations and junctions. We investigate the development of blood flow and its resistance starting from a dispersed configuration of red blood cells in simulations for different hematocrits, flow rates, vessel diameters, and aggregation interactions between red blood cells. Initially dispersed red blood cells migrate toward the vessel center leading to the formation of a cell-free layer near the wall and to a decrease of the flow resistance. The development of cell-free layer appears to be nearly universal when scaled with a characteristic shear rate of the flow, which allows an estimation of the length of a vessel required for full flow development, $l_c \approx 25D$, with vessel diameter $D$. Thus, the potential effect of red blood cell dispersion at vessel bifurcations and junctions on the flow resistance may be significant in vessels which are shorter or comparable to the length $l_c$. The presence of aggregation interactions between red blood cells lead in general to a reduction of blood flow resistance. The development of the cell-free layer thickness looks similar for both cases with and without aggregation interactions. Although, attractive interactions result in a larger cell-free layer plateau values. However, because the aggregation forces are short-ranged at high enough shear rates ($\bar{\dot{\gamma}} \gtrsim 50~\text{s}^{-1}$) aggregation of red blood cells does not bring a significant change to the blood flow properties. Also, we develop a simple theoretical model which is able to describe the converged cell-free-layer thickness with respect to flow rate assuming steady-state flow. The model is based on the balance between a lift force on red blood cells due to cell-wall hydrodynamic interactions and shear-induced effective pressure due to cell-cell interactions in flow. We expect that these results can also be used to better understand the flow behavior of other suspensions of deformable particles such as vesicles, capsules, and cells. Finally, we investigate segregation phenomena in blood as a two-component suspension under Poiseuille flow, consisting of red blood cells and target cells. The spatial distribution of particles in blood flow is very important. For example, in case of nanoparticle drug delivery, the particles need to come closer to microvessel walls, in order to adhere and bring the drug to a target position within the microvasculature. Here we consider that segregation can be described as a competition between shear-induced diffusion and the lift force that pushes every soft particle in a flow away from the wall. In order to investigate the segregation, on one hand, we have 2D DPD simulations of red blood cells and target cell of different sizes, on the other hand the Fokker-Planck equation for steady state. For the equation we measure force profile, particle distribution and diffusion constant across the channel. We compare simulation results with those from the Fokker-Planck equation and find a very good correspondence between the two approaches. Moreover, we investigate the diffusion behavior of target particles for different hematocrit values and shear rates. Our simulation results indicate that diffusion constant increases with increasing hematocrit and depends linearly on shear rate. The third part of the study describes development of a simulation model of complex vascular geometries. The development of the model is important to reproduce vascular systems of small pieces of tissues which might be gotten from MRI or microscope images. The simulation model of the complex vascular systems might be divided into three parts: modeling the geometry, developing in- and outflow boundary conditions, and simulation domain decomposition for an efficient computation. We have found that for the in- and outflow boundary conditions it is better to use the SDPD fluid than DPD one because of the density fluctuations along the channel of the latter. During the flow in a straight channel, it is difficult to control the density of the DPD fluid. However, the SDPD fluid has not that shortcoming even in more complex channels with many branches and in- and outflows because the force acting on particles is calculated also depending on the local density of the fluid.

Mode locking in a periodically forced "ghostbursting" neuron model

We study a minimal integrate-and-fire based model of a "ghostbursting" neuron under periodic stimulation. These neurons are involved in sensory processing in weakly electric fish. There exist regions in parameter space in which the model neuron is mode-locked to the stimulation. We analyse this locked behavior and examine the bifurcations that define the boundaries of these regions. Due to the discontinuous nature of the flow, some of these bifurcations are nonsmooth. This exact analysis is in excellent agreement with numerical simulations, and can be used to understand the response of such a model neuron to biologically realistic input.

INTEGRATED THRESHOLD-ACTIVATED FEEDBACK MICROSYSTEM FOR REAL-TIME CHARACTERIZATION, SENSING AND TREATMENT OF BACTERIAL BIOFILMS

Biofilms are the primary cause of clinical bacterial infections and are impervious to typical amounts of antibiotics, necessitating very high doses for treatment. Therefore, it is highly desirable to develop new alternate methods of treatment that can complement or replace existing approaches using significantly lower doses of antibiotics. Current standards for studying biofilms are based on end-point studies that are invasive and destroy the biofilm during characterization. This dissertation presents the development of a novel real-time sensing and treatment technology to aid in the non-invasive characterization, monitoring and treatment of bacterial biofilms. The technology is demonstrated through the use of a high-throughput bifurcation based microfluidic reactor that enables simulation of flow conditions similar to indwelling medical devices. The integrated microsystem developed in this work incorporates the advantages of previous in vitro platforms while attempting to overcome some of their limitations. Biofilm formation is extremely sensitive to various growth parameters that cause large variability in biofilms between repeated experiments. In this work we investigate the use of microfluidic bifurcations for the reduction in biofilm growth variance. The microfluidic flow cell designed here spatially sections a single biofilm into multiple channels using microfluidic flow bifurcation. Biofilms grown in the bifurcated device were evaluated and verified for reduced biofilm growth variance using standard techniques like confocal microscopy. This uniformity in biofilm growth allows for reliable comparison and evaluation of new treatments with integrated controls on a single device. Biofilm partitioning was demonstrated using the bifurcation device by exposing three of the four channels to various treatments. We studied a novel bacterial biofilm treatment independent of traditional antibiotics using only small molecule inhibitors of bacterial quorum sensing (analogs) in combination with low electric fields. Studies using the bifurcation-based microfluidic flow cell integrated with real-time transduction methods and macro-scale end-point testing of the combination treatment showed a significant decrease in biomass compared to the untreated controls and well-known treatments such as antibiotics. To understand the possible mechanism of action of electric field-based treatments, fundamental treatment efficacy studies focusing on the effect of the energy of the applied electrical signal were performed. It was shown that the total energy and not the type of the applied electrical signal affects the effectiveness of the treatment. The linear dependence of the treatment efficacy on the applied electrical energy was also demonstrated. The integrated bifurcation-based microfluidic platform is the first microsystem that enables biofilm growth with reduced variance, as well as continuous real-time threshold-activated feedback monitoring and treatment using low electric fields. The sensors detect biofilm growth by monitoring the change in impedance across the interdigitated electrodes. Using the measured impedance change and user inputs provided through a convenient and simple graphical interface, a custom-built MATLAB control module intelligently switches the system into and out of treatment mode. Using this self-governing microsystem, in situ biofilm treatment based on the principles of the bioelectric effect was demonstrated by exposing two of the channels of the integrated bifurcation device to low doses of antibiotics.

A systems approach to cardiovascular health and disease with a focus on aortic wave dynamics

Cardiovascular diseases (CVDs) have reached an epidemic proportion in the US and worldwide with serious consequences in terms of human suffering and economic impact. More than one third of American adults are suffering from CVDs. The total direct and indirect costs of CVDs are more than $500 billion per year. Therefore, there is an urgent need to develop noninvasive diagnostics methods, to design minimally invasive assist devices, and to develop economical and easy-to-use monitoring systems for cardiovascular diseases. In order to achieve these goals, it is necessary to gain a better understanding of the subsystems that constitute the cardiovascular system. The aorta is one of these subsystems whose role in cardiovascular functioning has been underestimated. Traditionally, the aorta and its branches have been viewed as resistive conduits connected to an active pump (left ventricle of the heart). However, this perception fails to explain many observed physiological results. My goal in this thesis is to demonstrate the subtle but important role of the aorta as a system, with focus on the wave dynamics in the aorta.

The operation of a healthy heart is based on an optimized balance between its pumping characteristics and the hemodynamics of the aorta and vascular branches. The delicate balance between the aorta and heart can be impaired due to aging, smoking, or disease. The heart generates pulsatile flow that produces pressure and flow waves as it enters into the compliant aorta. These aortic waves propagate and reflect from reflection sites (bifurcations and tapering). They can act constructively and assist the blood circulation. However, they may act destructively, promoting diseases or initiating sudden cardiac death. These waves also carry information about the diseases of the heart, vascular disease, and coupling of heart and aorta. In order to elucidate the role of the aorta as a dynamic system, the interplay between the dominant wave dynamic parameters is investigated in this study. These parameters are heart rate, aortic compliance (wave speed), and locations of reflection sites. Both computational and experimental approaches have been used in this research. In some cases, the results are further explained using theoretical models.

The main findings of this study are as follows: (i) developing a physiologically realistic outflow boundary condition for blood flow modeling in a compliant vasculature; (ii) demonstrating that pulse pressure as a single index cannot predict the true level of pulsatile workload on the left ventricle; (iii) proving that there is an optimum heart rate in which the pulsatile workload of the heart is minimized and that the optimum heart rate shifts to a higher value as aortic rigidity increases; (iv) introducing a simple bio-inspired device for correction and optimization of aortic wave reflection that reduces the workload on the heart; (v) deriving a non-dimensional number that can predict the optimum wave dynamic state in a mammalian cardiovascular system; (vi) demonstrating that waves can create a pumping effect in the aorta; (vii) introducing a system parameter and a new medical index, Intrinsic Frequency, that can be used for noninvasive diagnosis of heart and vascular diseases; and (viii) proposing a new medical hypothesis for sudden cardiac death in young athletes.

Produção e distribuição da biomassa de Jatropha curcas no Semiárido Brasileiro.

RESUMO: Com o objetivo de avaliar a produção e distribuição da biomassa da parte aérea de diferentes genótipos de pinhão-manso no semiárido brasileiro, foi implantado um experimento na Fazenda Gabriela, localizada no município de Santa Maria da Boa Vista, Pernambuco. O delineamento experimental adotado foi em blocos casualizados, com dez tratamentos (genótipos de pinhão-manso) e três repetições, em parcelas lineares de seis plantas, com bordadura simples e espaçamento de 3,0 x 2,0 m. Foram aplicadas uma adubação correspondente a 150 g de NPK (06:24:12) por cova no plantio e duas adubações de cobertura com 150 g.planta-1 de NPK (10:10:10) aos seis e aos doze meses de idade. As plantas foram irrigadas semanalmente por gotejamento com uma aplicação média de 20 litros de água por planta durante o período de estiagem da região. Aos 24 meses de idade, foi medida a altura total das plantas, o diâmetro médio das bifurcações a 1,30 m da superfície do solo e o número de bifurcações a 0,5 m de altura. Foram feitas 26 colheitas semanais de frutos/sementes. Os frutos foram colhidos maduros, antes de sua queda ao chão, durante sete meses. Os genótipos apresentaram elevada uniformidade agronômica, exceto para a variável número de bifurcações, onde o genótipo 1701 foi superior aos genótipos 1501, 1602, 1703 e 1601. A produção de biomassa dos genótipos em condições irrigadas no semiárido é elevada e a distribuição da biomassa dos genótipos nos diferentes componentes seguiu a ordem decrescente: raiz>frutos>galhos grossos>folhas>casca>galhos finos. ABSTRACT: In order to assess production and distribution of biomass shoots of different genotypes of Jatropha curcas under irrigation in the semiarid region of Pernambuco, Brazil, an experiment was established in Gabriela Farm, in the municipality of Santa Maria da Boa Vista-PE. The experimental design was randomized blocks with ten treatments (genotypes of Jatropha curcas), and three replications in row plots of six plants, with a single border and spacing of 3.0 x 2.0 m. Plants were fertilized with 150 g of NPK (06:24:12) at planting time, and a topdressing with 150 g.planta-1 NPK (10:10:10) applied at six and twelve months of age. The plants were irrigated weekly using a dripping system with an average water application of 20 l.plant-1 during the dry period of the region. At 24 months of age, the overall height of the plants, the average diameter of bifurcations at 1.30m from the soil level and the number of bifurcations at 0.5 m of height were evaluated. Twenty six fruit/ seed harvests were done weekly. Fruits were harvested ripe, before falling on the ground, for seven months. To determine dry biomass, the plants were cut at 0.30 m from soil level. The genotypes showed high agronomic uniformity, except for the variable number of bifurcations, where the genotype 1701 was superior to the genotypes 1501, 1602, 1703 and 1601. Biomass production of genotypes in irrigated conditions in the semiarid region is high and the distribution of biomass followed the decreasing order: root>fruit>thick branches>leaves>bark>thin branches.