Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis

Matrix metalloproteinases (MMPs) are a family of Zn2+-dependent endopeptidases targeting extracellular matrix (ECM) compounds as well as a number of other proteins. Their proteolytic activity acts as an effector mechanism of tissue remodeling in physiologic and pathologic conditions, and as modulator of inflammation. In the context of neuro-inflammatory diseases, MMPs have been implicated in processes such as (a) blood-brain barrier (BBB) and blood-nerve barrier opening, (b) invasion of neural tissue by blood-derived immune cells, (c) shedding of cytokines and cytokine receptors, and (d) direct cellular damage in diseases of the peripheral and central nervous system. This review focuses on the role of MMPs in multiple sclerosis (MS) and bacterial meningitis (BM), two neuro-inflammatory diseases where current therapeutic approaches are insufficient to prevent severe disability in the majority of patients. Inhibition of enzymatic activity may prevent MMP-mediated neuronal damage due to an overactive or deviated immune response in both diseases. Downregulation of MMP release may be the molecular basis for the beneficial effect of IFN-beta and steroids in MS. Instead, synthetic MMP inhibitors offer the possibility to shut off enzymatic activity of already activated MMPs. In animal models of MS and BM, they efficiently attenuated clinical disease symptoms and prevented brain damage due to excessive metalloproteinase activity. However, the required target profile for the therapeutic use of this novel group of compounds in human disease is not yet sufficiently defined and may be different depending on the type and stage of disease. Currently available MMP inhibitors show little target-specificity within the MMP family and may lead to side-effects due to interference with physiological functions of MMPs. Results from human MS and BM indicate that only a restricted number of MMPs specific for each disease is up-regulated. MMP inhibitors with selective target profiles offer the possibility of a more efficient therapy of MS and BM and may enter clinical trials in the near future.

Assessment of Skill and Portability in Regional Marine Biogeochemical Models: Role of Multiple Planktonic Groups

Application of biogeochemical models to the study of marine ecosystems is pervasive, yet objective quantification of these models' performance is rare. Here, 12 lower trophic level models of varying complexity are objectively assessed in two distinct regions (equatorial Pacific and Arabian Sea). Each model was run within an identical one-dimensional physical framework. A consistent variational adjoint implementation assimilating chlorophyll-a, nitrate, export, and primary productivity was applied and the same metrics were used to assess model skill. Experiments were performed in which data were assimilated from each site individually and from both sites simultaneously. A cross-validation experiment was also conducted whereby data were assimilated from one site and the resulting optimal parameters were used to generate a simulation for the second site. When a single pelagic regime is considered, the simplest models fit the data as well as those with multiple phytoplankton functional groups. However, those with multiple phytoplankton functional groups produced lower misfits when the models are required to simulate both regimes using identical parameter values. The cross-validation experiments revealed that as long as only a few key biogeochemical parameters were optimized, the models with greater phytoplankton complexity were generally more portable. Furthermore, models with multiple zooplankton compartments did not necessarily outperform models with single zooplankton compartments, even when zooplankton biomass data are assimilated. Finally, even when different models produced similar least squares model-data misfits, they often did so via very different element flow pathways, highlighting the need for more comprehensive data sets that uniquely constrain these pathways.

Expanded Clinical Spectrum of Multiple Evanescent White Dot Syndrome with Multimodal Imaging

PURPOSE: To evaluate and characterize multiple evanescent white dot syndrome abnormalities with modern multimodal imaging modalities. METHODS: This retrospective cohort study evaluated fundus photography, fluorescein angiography, indocyanine green angiography, optical coherence tomography, enhanced depth imaging optical coherence tomography, short-wavelength autofluorescence, and near-infrared autofluorescence. RESULTS: Thirty-four multiple evanescent white dot syndrome patients with mean age of 28.7 years were studied (range, 14-49 years). Twenty-six patients were women, and eight were men. Initial mean visual acuity was 0.41 logMAR. Final mean visual acuity was 0.03 logMAR. Fluorescein angiography shows a variable number of mid retinal early fluorescent dots distributed in a wreathlike pattern, which correlate to fundus photography, fundus autofluorescence, and indocyanine green angiography. Indocyanine green angiography imaging shows the dots and also hypofluorescent, deeper, and larger spots, which are occasionally confluent, demonstrating a large plaque of deep retinal hypofluorescence. Optical coherence tomography imaging shows multifocal debris centered at and around the ellipsoid layer, corresponding to the location of spots seen with photography, indocyanine green angiography, and fluorescein angiography. Protrusions of the hyperreflectant material from the ellipsoid layer toward the outer nuclear layer correspond to the location of dots seen with photography, indocyanine green angiography, and fluorescein angiography. CONCLUSION: Multimodal imaging analysis of the retina in patients with multiple evanescent white dot syndrome shows additional features that may help in the diagnosis of the disease and in further understanding its etiology. Multiple evanescent white dot syndrome is predominantly a disease of the outer retina, centered at the ellipsoid zone, but also involving the interdigitation zone and the outer nuclear layer.

Perfect imaging of three object points with only two analytic lens surfaces in two dimensions

In this work, a new two-dimensional analytic optics design method is presented that enables the coupling of three ray sets with two lens profiles. This method is particularly promising for optical systems designed for wide field of view and with clearly separated optical surfaces. However, this coupling can only be achieved if different ray sets will use different portions of the second lens profile. Based on a very basic example of a single thick lens, the Simultaneous Multiple Surfaces design method in two dimensions (SMS2D) will help to provide a better understanding of the practical implications on the design process by an increased lens thickness and a wider field of view. Fermat?s principle is used to deduce a set of functional differential equations fully describing the entire optical system. The transformation of these functional differential equations into an algebraic linear system of equations allows the successive calculation of the Taylor series coefficients up to an arbitrary order. The evaluation of the solution space reveals the wide range of possible lens configurations covered by this analytic design method. Ray tracing analysis for calculated 20th order Taylor polynomials demonstrate excellent performance and the versatility of this new analytical optics design concept.

Multiple removal of spent rocket upper stages with an ion beam shepherd

Among the many advantages of the recently proposed ion beam shepherd (IBS) debris removal technique is the capability to deal with multiple targets in a single mission. A preliminary analysis is here conducted in order to estimate the cost in terms of spacecraft mass and total mission time to remove multiple large-size upper stages of the Zenit family. Zenit-2 upper stages are clustered at 71 degrees inclination around 850 km altitude in low Earth orbit. It is found that a removal of two targets per year is feasible with a modest size spacecraft. The most favorable combinations of targets are outlined.

Determination of absorption curves, dissolution profiles and establishment of in vitro-in vivo correlation by in silico methods using GastroPlusTM and DDDPlusTM

The use of computer programs to predict drug absorption in humans and to simulate dissolution profiles has become a valuable tool in the pharmaceutical area. The objective of this study was to use in silico methods through software GastroPlusTM and DDDPlusTM to simulate drug absorption curves and dissolution profiles, and to establish in vitro-in vivo correlations (IVIVCs). The work presented herein is divided into five chapters and includes the drugs ketoprofen, pyrimethamine, metronidazole, fluconazole, carvedilol and doxazosin. In Chapter 1, simulated plasma curves for ketoprofen matrix tablets are presented and IVIVC was established. The use of simulated intrinsic dissolution tests for pyrimethamine and metronidazole as a tool for biopharmaceutics classification is detailed in Chapter 2. In Chapter 3, simulation of plasma curves for fluconazole capsules with different dissolution profiles is demonstrated as a tool for biowaiver. IVIVC studies were also conducted for carvedilol immediate-release tablets from dissolution profiles in Chapter 4. Chapter 5 covers the application of simulated dissolution tests for development of doxazosin extended-release formulations. Simulation of plasma curves and IVIVC using the software GastroPlusTM as well as intrinsic dissolution tests and dissolution profiles using the software DDDPlusTM proved to be a tool of wide application in predicting biopharmaceutical characteristics of drugs and formulations, allowing the reduction of time and costs of experimental laboratory work.

Gesture performance in first- and multiple-episode patients with schizophrenia spectrum disorders

BACKGROUND/AIM Gesturing plays an important role in social behavior and social learning. Deficits are frequent in schizophrenia and may contribute to impaired social functioning. Information about deficits during the course of the disease and presence of severity and patterns of impairment in first-episode patients is missing. Hence, we aimed to investigate gesturing in first- compared to multiple-episode schizophrenia patients and healthy controls. METHODS In 14 first-episode patients, 14 multiple-episode patients and 16 healthy controls matched for age, gender and education, gesturing was assessed by the comprehensive Test of Upper Limb Apraxia. Performance in two domains of gesturing - imitation and pantomime - was recorded on video. Raters of gesture performance were blinded. RESULTS Patients with multiple episodes had severe gestural deficits. For almost all gesture categories, performance was worse in multiple- than in first-episode patients. First-episode patients demonstrated subtle deficits with a comparable pattern. CONCLUSIONS Subjects with multiple psychotic episodes have severe deficits in gesturing, while only mild impairments were found in first-episode patients independent of age, gender, education and negative symptoms. The results indicate that gesturing is impaired at the onset of disease and likely to further deteriorate during its course.

Benefit finding in multiple sclerosis, and associations with positive and negative outcomes

This study examined the direct and stress-buffering effects of benefit finding on positive and negative outcomes. A total of 502 people with multiple sclerosis completed a questionnaire at Time 1 and, 3 months later, at Time 2 (n = 404). Measures of illness were collected at Time 1, and number of problems, stress appraisal, benefit finding, subjective health, and negative (global distress, negative affect) and positive (life satisfaction, positive affect, dyadic adjustment) outcomes were measured at Time 2. Factor analyses showed the Benefit Finding scale to have 2 dimensions: Personal Growth and Family Relations Growth. Hierarchical regressions showed that after controlling for the effects of demographics, illness, problems, and appraisal, benefit finding showed strong direct effects on the positive outcomes. Benefit finding did not have a direct effect on distress, or subjective health but had a weak association with negative affect. Family Relations Growth had a stress-buffering effect on distress.

Structure and dynamics of multiple cationic vectors-siRNA complexation by all-atomic molecular dynamics simulations

Understanding the molecular mechanism of gene condensation is a key component to rationalizing gene delivery phenomena, including functional properties such as the stability of the gene-vector complex and the intracellular release of the gene. In this work, we adopt an atomistic molecular dynamics simulation approach to study the complexation of short strand duplex RNA with four cationic carrier systems of varying charge and surface topology at different charge ratios. At lower charge ratios, polymers bind quite effectively to siRNA, while at high charge ratios, the complexes are saturated and there are free polymers that are unable to associate with RNA. We also observed reduced fluctuations in RNA structures when complexed with multiple polymers in solution as compared to both free siRNA in water and the single polymer complexes. These novel simulations provide a much better understanding of key mechanistic aspects of gene-polycation complexation and thereby advance progress toward rational design of nonviral gene delivery systems.

Analytical approximations to predict performance measures of manufacturing systems with job failures and parallel processing

Parallel processing is prevalent in many manufacturing and service systems. Many manufactured products are built and assembled from several components fabricated in parallel lines. An example of this manufacturing system configuration is observed at a manufacturing facility equipped to assemble and test web servers. Characteristics of a typical web server assembly line are: multiple products, job circulation, and paralleling processing. The primary objective of this research was to develop analytical approximations to predict performance measures of manufacturing systems with job failures and parallel processing. The analytical formulations extend previous queueing models used in assembly manufacturing systems in that they can handle serial and different configurations of paralleling processing with multiple product classes, and job circulation due to random part failures. In addition, appropriate correction terms via regression analysis were added to the approximations in order to minimize the gap in the error between the analytical approximation and the simulation models. Markovian and general type manufacturing systems, with multiple product classes, job circulation due to failures, and fork and join systems to model parallel processing were studied. In the Markovian and general case, the approximations without correction terms performed quite well for one and two product problem instances. However, it was observed that the flow time error increased as the number of products and net traffic intensity increased. Therefore, correction terms for single and fork-join stations were developed via regression analysis to deal with more than two products. The numerical comparisons showed that the approximations perform remarkably well when the corrections factors were used in the approximations. In general, the average flow time error was reduced from 38.19% to 5.59% in the Markovian case, and from 26.39% to 7.23% in the general case. All the equations stated in the analytical formulations were implemented as a set of Matlab scripts. By using this set, operations managers of web server assembly lines, manufacturing or other service systems with similar characteristics can estimate different system performance measures, and make judicious decisions - especially setting delivery due dates, capacity planning, and bottleneck mitigation, among others.

Analytical Approximations to Predict Performance Measures of Manufacturing Systems with Job Failures and Parallel Processing

Parallel processing is prevalent in many manufacturing and service systems. Many manufactured products are built and assembled from several components fabricated in parallel lines. An example of this manufacturing system configuration is observed at a manufacturing facility equipped to assemble and test web servers. Characteristics of a typical web server assembly line are: multiple products, job circulation, and paralleling processing. The primary objective of this research was to develop analytical approximations to predict performance measures of manufacturing systems with job failures and parallel processing. The analytical formulations extend previous queueing models used in assembly manufacturing systems in that they can handle serial and different configurations of paralleling processing with multiple product classes, and job circulation due to random part failures. In addition, appropriate correction terms via regression analysis were added to the approximations in order to minimize the gap in the error between the analytical approximation and the simulation models. Markovian and general type manufacturing systems, with multiple product classes, job circulation due to failures, and fork and join systems to model parallel processing were studied. In the Markovian and general case, the approximations without correction terms performed quite well for one and two product problem instances. However, it was observed that the flow time error increased as the number of products and net traffic intensity increased. Therefore, correction terms for single and fork-join stations were developed via regression analysis to deal with more than two products. The numerical comparisons showed that the approximations perform remarkably well when the corrections factors were used in the approximations. In general, the average flow time error was reduced from 38.19% to 5.59% in the Markovian case, and from 26.39% to 7.23% in the general case. All the equations stated in the analytical formulations were implemented as a set of Matlab scripts. By using this set, operations managers of web server assembly lines, manufacturing or other service systems with similar characteristics can estimate different system performance measures, and make judicious decisions - especially setting delivery due dates, capacity planning, and bottleneck mitigation, among others.

An Efficient Precoder Design for Multiuser MIMO Cognitive Radio Networks with Interference Constraints

We consider a linear precoder design for an underlay cognitive radio multiple-input multiple-output broadcast channel, where the secondary system consisting of a secondary base-station (BS) and a group of secondary users (SUs) is allowed to share the same spectrum with the primary system. All the transceivers are equipped with multiple antennas, each of which has its own maximum power constraint. Assuming zero-forcing method to eliminate the multiuser interference, we study the sum rate maximization problem for the secondary system subject to both per-antenna power constraints at the secondary BS and the interference power constraints at the primary users. The problem of interest differs from the ones studied previously that often assumed a sum power constraint and/or single antenna employed at either both the primary and secondary receivers or the primary receivers. To develop an efficient numerical algorithm, we first invoke the rank relaxation method to transform the considered problem into a convex-concave problem based on a downlink-uplink result. We then propose a barrier interior-point method to solve the resulting saddle point problem. In particular, in each iteration of the proposed method we find the Newton step by solving a system of discrete-time Sylvester equations, which help reduce the complexity significantly, compared to the conventional method. Simulation results are provided to demonstrate fast convergence and effectiveness of the proposed algorithm. 

Simulation als Methode zur Konzipierung vernetzter, getakteter Montagesysteme für variantenreiche Produkte

Die Montage von Produkten in getakteten Fließstraßen als Alternative zu ortsfesten Varianten führt in der Regel zur Verbesserung der logistischen Zielerfüllung. Das volle Potential dieser Organisationsart wird jedoch weitgehend nur für standardisierte Produkte mit hohen Stückzahlen erschlossen. Hindernisse zur Produktion variantenreicher Großerzeugnisse mit volatilen Arbeitsinhalten in einer Fließstraße bestehen vor allem in der Beherrschung der Komplexität in Bezug auf dazu erforderliche flexible Arbeitszeitmodelle, optimierte Produktreihenfolgen sowie operative Taktzeitvariationen. Sollen mehrere Fließstraßen mit differenzierten Produktionsparametern gekoppelt werden, steigt der Anspruch noch einmal erheblich. Bei der Konzipierung und Erprobung geeigneter Organisationsmodelle auf Basis diverser Produktionsszenarien kann auf den Einsatz der Simulationstechnik nicht verzichtet werden.

Discrete-event Simulation and Optimization to Improve the Performance of a Healthcare System

Thesis (Ph.D.)--University of Washington, 2016-08

Simulation of photoinduced processes in organic chromophores: mapping photochemically relevant states for accurate dynamics

The simulation of ultrafast photoinduced processes is a fundamental step towards the understanding of the underlying molecular mechanism and interpretation/prediction of experimental data. Performing a computer simulation of a complex photoinduced process is only possible introducing some approximations but, in order to obtain reliable results, the need to reduce the complexity must balance with the accuracy of the model, which should include all the relevant degrees of freedom and a quantitatively correct description of the electronic states involved in the process. This work presents new computational protocols and strategies for the parameterisation of accurate models for photochemical/photophysical processes based on state-of-the-art multiconfigurational wavefunction-based methods. The required ingredients for a dynamics simulation include potential energy surfaces (PESs) as well as electronic state couplings, which must be mapped across the wide range of geometries visited during the wavepacket/trajectory propagation. The developed procedures allow to obtain solid and extended databases reducing as much as possible the computational cost, thanks to, e.g., specific tuning of the level of theory for different PES regions and/or direct calculation of only the needed components of vectorial quantities (like gradients or nonadiabatic couplings). The presented approaches were applied to three case studies (azobenzene, pyrene, visual rhodopsin), all requiring an accurate parameterisation but for different reasons. The resulting models and simulations allowed to elucidate the mechanism and time scale of the internal conversion, reproducing or even predicting new transient experiments. The general applicability of the developed protocols to systems with different peculiarities and the possibility to parameterise different types of dynamics on an equal footing (classical vs purely quantum) prove that the developed procedures are flexible enough to be tailored for each specific system, and pave the way for exact quantum dynamics with multiple degrees of freedom.