Service level agreements-driven management of distributed applications in cloud computing environments

Advancements in cloud computing have enabled the proliferation of distributed applications, which require management and control of multiple services. However, without an efficient mechanism for scaling services in response to changing workload conditions, such as number of connected users, application performance might suffer, leading to violations of Service Level Agreements (SLA) and possible inefficient use of hardware resources. Combining dynamic application requirements with the increased use of virtualised computing resources creates a challenging resource Management context for application and cloud-infrastructure owners. In such complex environments, business entities use SLAs as a means for specifying quantitative and qualitative requirements of services. There are several challenges in running distributed enterprise applications in cloud environments, ranging from the instantiation of service VMs in the correct order using an adequate quantity of computing resources, to adapting the number of running services in response to varying external loads, such as number of users. The application owner is interested in finding the optimum amount of computing and network resources to use for ensuring that the performance requirements of all her/his applications are met. She/he is also interested in appropriately scaling the distributed services so that application performance guarantees are maintained even under dynamic workload conditions. Similarly, the infrastructure Providers are interested in optimally provisioning the virtual resources onto the available physical infrastructure so that her/his operational costs are minimized, while maximizing the performance of tenants’ applications. Motivated by the complexities associated with the management and scaling of distributed applications, while satisfying multiple objectives (related to both consumers and providers of cloud resources), this thesis proposes a cloud resource management platform able to dynamically provision and coordinate the various lifecycle actions on both virtual and physical cloud resources using semantically enriched SLAs. The system focuses on dynamic sizing (scaling) of virtual infrastructures composed of virtual machines (VM) bounded application services. We describe several algorithms for adapting the number of VMs allocated to the distributed application in response to changing workload conditions, based on SLA-defined performance guarantees. We also present a framework for dynamic composition of scaling rules for distributed service, which used benchmark-generated application Monitoring traces. We show how these scaling rules can be combined and included into semantic SLAs for controlling allocation of services. We also provide a detailed description of the multi-objective infrastructure resource allocation problem and various approaches to satisfying this problem. We present a resource management system based on a genetic algorithm, which performs allocation of virtual resources, while considering the optimization of multiple criteria. We prove that our approach significantly outperforms reactive VM-scaling algorithms as well as heuristic-based VM-allocation approaches.

A simplified spectral approachfor impedance-based damage identification of frp-strengthened rc beams

Hoy en día, el refuerzo y reparación de estructuras de hormigón armado mediante el pegado de bandas de polímeros reforzados con fibras (FRP) se emplea cada vez con más frecuencia a causa de sus numerosas ventajas. Sin embargo, las vigas reforzadas con esta técnica pueden experimentar un modo de fallo frágil a causa del despegue repentino de la banda de FRP a partir de una fisura intermedia. A pesar de su importancia, el número de trabajos que abordan el estudio de este mecanismo de fallo y su monitorización es muy limitado. Por ello, el desarrollo de metodologías capaces de monitorizar a largo plazo la adherencia de este refuerzo a las estructuras de hormigón e identificar cuándo se inicia el despegue de la banda constituyen un importante desafío a abordar. El principal objetivo de esta tesis es la implementación de una metodología fiable y efectiva, capaz de detectar el despegue de una banda de FRP en una viga de hormigón armado a partir de una fisura intermedia. Para alcanzar este objetivo se ha implementado un procedimiento de calibración numérica a partir de ensayos experimentales. Para ello, en primer lugar, se ha desarrollado un modelo numérico unidimensional simple y no costoso representativo del comportamiento de este tipo vigas de hormigón reforzadas con FRP, basado en un modelo de fisura discreta para el hormigón y el método de elementos espectrales. La formación progresiva de fisuras a flexion y el consiguiente despegue en la interface entre el hormigón y el FRP se formulan mediante la introducción de un nuevo elemento capaz de representar ambos fenómenos simultáneamente sin afectar al procedimiento numérico. Además, con el modelo propuesto, se puede obtener de una forma sencilla la respuesta dinámica en altas frecuencias de este tipo de estructuras, lo cual puede hacer muy útil su uso como herramienta de diagnosis y detección del despegue en su fase inicial mediante una monitorización de la variación de las características dinámicas locales de la estructura. Un método de evaluación no destructivo muy prometedor para la monitorización local de las estructuras es el método de la impedancia usando sensores-actuadores piezoeléctricos (PZT). La impedancia eléctrica de los sensores PZT se puede relacionar con la impedancia mecánica de las estructuras donde se encuentran adheridos Ya que la impedancia mecánica de una estructura se verá afectada por su deterioro, se pueden implementar indicadores de daño mediante una comparación del espectro de admitancia (inversa de la impedancia) a lo largo de distintas etapas durante el periodo de servicio de una estructura. Cualquier cambio en el espectro se podría interpretar como una variación en la integridad de la estructura. La impedancia eléctrica se mide a altas frecuencias con lo cual esta metodología debería ser muy sensible a la detección de estados de daño incipiente local, tal como se desea en la aplicación de este trabajo. Se ha implementado un elemento espectral PZT-FRP como extensión del modelo previamente desarrollado, con el objetivo de poder calcular numéricamente la impedancia eléctrica de sensores PZT adheridos a bandas de FRP sobre una viga de hormigón armado. El modelo, combinado con medidas experimentales captadas mediante sensores PZT, se implementa en el marco de una metodología de calibración de modelos para detectar cuantitativamente el despegue en la interfase entre una banda de FRP y una viga de hormigón. El procedimiento de optimización se resuelve empleando el método del enjambre cooperativo con un algoritmo bagging. Los resultados muestran una gran aproximación en la estimación del daño para el problema propuesto. Adicionalmente, se ha desarrollado también un método adaptativo para el mallado de elementos espectrales con el objetivo de localizar las zonas dañadas a partir de los resultados experimentales, el cual contribuye a aumentar la robustez y efectividad del método propuesto a la hora de identificar daños incipientes en su aparición inicial. Finalmente, se ha llevado a cabo un procedimiento de optimización multi-objetivo para detectar el despegue inicial en una viga de hormigón a escala real reforzada con FRP a partir de las impedancias captadas con una red de sensores PZT instrumentada a lo largo de la longitud de la viga. Cada sensor aporta los datos para definir cada una de las funciones objetivo que definen el procedimiento. Combinando el modelo previo de elementos espectrales con un algoritmo PSO multi-objetivo el procedimiento de detección de daño resultante proporciona resultados satisfactorios considerando la escala de la estructura y todas las incertidumbres características ligadas a este proceso. Los resultados obtenidos prueban la viabilidad y capacidad de los métodos antes mencionados y también su potencial en aplicaciones reales. Abstract Nowadays, the external bonding of fibre reinforced polymer (FRP) plates or sheets is increasingly used for the strengthening and retrofitting of reinforced concrete (RC) structures due to its numerous advantages. However, this kind of strengthening often leads to brittle failure modes being the most dominant failure mode the debonding induced by an intermediate crack (IC). In spite of its importance, the number of studies regarding the IC debonding mechanism and bond health monitoring is very limited. Methodologies able to monitor the long-term efficiency of bonding and successfully identify the initiation of FRP debonding constitute a challenge to be met. The main purpose of this thesisis the implementation of a reliable and effective methodology of damage identification able to detect intermediate crack debonding in FRP-strengthened RC beams. To achieve this goal, a model updating procedure based on numerical simulations and experimental tests has been implemented. For it, firstly, a simple and non-expensive one-dimensional model based on the discrete crack approach for concrete and the spectral element method has been developed. The progressive formation of flexural cracks and subsequent concrete-FRP interfacial debonding is formulated by the introduction of a new element able to represent both phenomena simultaneously without perturbing the numerical procedure. Furthermore, with the proposed model, high frequency dynamic response for these kinds of structures can also be obtained in a very simple and non-expensive way, which makes this procedure very useful as a tool for diagnoses and detection of debonding in its initial stage by monitoring the change in local dynamic characteristics. One very promising active non-destructive evaluation method for local monitoring is impedance-based structural health monitoring(SHM)using piezoelectric ceramic (PZT) sensor-actuators. The electrical impedance of the PZT can be directly related to the mechanical impedance of the host structural component where the PZT transducers are attached. Since the structural mechanical impedance will be affected by the presence of structural damage, comparisons of admittance (inverse of impedance) spectra at various times during the service period of the structure can be used as damage indicator. Any change in the spectra might be an indication of a change in the structural integrity. The electrical impedance is measured at high frequencies with which this methodology appears to be very sensitive to incipient damage in structural systems as desired for our application. Abonded-PZT-FRP spectral beam element approach based on an extension of the previous discrete crack approach is implemented in the calculation of the electrical impedance of the PZT transducer bonded to the FRP plates of a RC beam. This approach in conjunction with the experimental measurements of PZT actuator-sensors mounted on the structure is used to present an updating methodology to quantitatively detect interfacial debonding between a FRP strip and the host RC structure. The updating procedure is solved by using an ensemble particle swarm optimization approach with abagging algorithm, and the results demonstrate a big improvement for the performance and accuracy of the damage detection in the proposed problem. Additionally, an adaptive strategy of spectral element mesh has been also developed to detect damage location with experimental results, which shows the robustness and effectiveness of the proposed method to identify initial and incipient damages at its early stage. Lastly, multi-objective optimization has been carried out to detect debonding damage in a real scale FRP-strengthened RC beam by using impedance signatures. A net of PZT sensors is distributed along the beam to construct impedance-based multiple objectives under gradually induced damage scenario. By combining the spectral element model presented previously and an ensemble multi-objective PSO algorithm, the implemented damage detection process yields satisfactory predictions considering the scale and uncertainties of the structure. The obtained results prove the feasibility and capability of the aforementioned methods and also their potentials in real engineering applications.

Influencia de las restricciones medioambientales en el sector eléctrico

El objetivo de esta tesis es la caracterización de la generación térmica representativa de la existente en la realidad, para posteriormente proceder a su modelización y simulación integrándolas en una red eléctrica tipo y llevar a cabo estudios de optimización multiobjetivo económico medioambiental. Para ello, en primera instancia se analiza el contexto energético y eléctrico actual, y más concretamente el peninsular, en el que habiendo desaparecido las centrales de fuelóleo, sólo quedan ciclos combinados y centrales de carbón de distinto rango. Seguidamente se lleva a cabo un análisis de los principales impactos medioambientales de las centrales eléctricas basadas en combustión, representados sobre todo por sus emisiones de CO2, SO2 y NOx, de las medidas de control y mitigación de las mismas y de la normativa que les aplica. A continuación, a partir de las características de los combustibles y de la información de los consumos específicos, se caracterizan los grupos térmicos frente a las funciones relevantes que definen su comportamiento energético, económico y medioambiental, en términos de funciones de salida horarias dependiendo de la carga. Se tiene en cuenta la posibilidad de desnitrificación y desulfuración. Dado que las funciones objetivo son múltiples, y que están en conflicto unas con otras, se ha optado por usar métodos multiobjetivo que son capaces de identificar el contorno de puntos óptimos o frente de Pareto, en los que tomando una solución no existe otra que lo mejore en alguna de las funciones objetivo sin empeorarlo en otra. Se analizaron varios métodos de optimización multiobjetivo y se seleccionó el de las ε constraint, capaz de encontrar frentes no convexos y cuya optimalidad estricta se puede comprobar. Se integró una representación equilibrada de centrales de antracita, hulla nacional e importada, lignito y ciclos combinados en la red tipo IEEE-57, en la que se puede trabajar con siete centrales sin distorsionar demasiado las potencias nominales reales de los grupos, y se programó en Matlab la resolución de flujos óptimos de carga en alterna con el método multiobjetivo integrado. Se identifican los frentes de Pareto de las combinaciones de coste y cada uno de los tres tipos de emisión, y también el de los cuatro objetivos juntos, obteniendo los resultados de costes óptimos del sistema para todo el rango de emisiones. Se valora cuánto le cuesta al sistema reducir una tonelada adicional de cualquier tipo de emisión a base de desplazarse a combinaciones de generación más limpias. Los puntos encontrados aseguran que bajo unas determinadas emisiones no pueden ser mejorados económicamente, o que atendiendo a ese coste no se puede reducir más allá el sistema en lo relativo a emisiones. También se indica cómo usar los frentes de Pareto para trazar estrategias óptimas de producción ante cambios horarios de carga. ABSTRACT The aim of this thesis is the characterization of electrical generation based on combustion processes representative of the actual power plants, for the latter modelling and simulation of an electrical grid and the development of economic- environmental multiobjective optimization studies. In this line, the first step taken is the analysis of the current energetic and electrical framework, focused on the peninsular one, where the fuel power plants have been shut down, and the only ones remaining are coal units of different types and combined cycle. Then it is carried out an analysis of the main environmental impacts of the thermal power plants, represented basically by the emissions of CO2, SO2 y NOx, their control and reduction measures and the applicable regulations. Next, based on the combustibles properties and the information about the units heat rates, the different power plants are characterized in relation to the outstanding functions that define their energy, economic and environmental behaviour, in terms of hourly output functions depending on their load. Optional denitrification and desulfurization is considered. Given that there are multiple objectives, and that they go in conflictive directions, it has been decided the use of multiobjective techniques, that have the ability of identifying the optimal points set, which is called the Pareto front, where taken a solution there will be no other point that can beat the former in an objective without worsening it in another objective. Several multiobjective optimization methods were analysed and pondered, selecting the ε constraint technique, which is able to find no convex fronts and it is opened to be tested to prove the strict Pareto optimality of the obtained solutions. A balanced representation of the thermal power plants, formed by anthracite, lignite, bituminous national and imported coals and combined cycle, was integrated in the IEEE-57 network case. This system was selected because it deals with a total power that will admit seven units without distorting significantly the actual size of the power plants. Next, an AC optimal power flow with the multiobjective method implemented in the routines was programmed. The Pareto fronts of the combination of operative costs with each of the three emissions functions were found, and also the front of all of them together. The optimal production costs of the system for all the emissions range were obtained. It is also evaluated the cost of reducing an additional emission ton of any of the emissions when the optimal production mix is displaced towards cleaner points. The obtained solutions assure that under a determined level of emissions they cannot be improved economically or, in the other way, at a determined cost it cannot be found points of lesser emissions. The Pareto fronts are also applied for the search of optimal strategic paths to follow the hourly load changes.

The role of nutrients for improving seedling quality in drylands

Forest plantations have been extensively used to combat desertification. In drylands, harsh climate conditions and unfertile soils often preclude seedling establishment. The improvement in seedling quality by manipulating nutrient availability could contribute to increase planting success. However, morpho-functional traits defining optimum seedling quality in drylands, and the fertilization schemes to achieve them, are still under discussion. Several studies suggest that well fertilized seedlings may perform better than nutrient limited seedlings in these environments. However, recent works have shown opposite results. In this review, we discuss the concept of seedling quality in drylands based on an evaluation of the effects of nutrient manipulation on seedling morpho-functional traits and field performance. According to existing data, we hypothesize that nutrient-limited small seedlings may be better adapted to arid environments and unfavorable microsites, where access to water is uncertain and a conservative water use strategy may be advantageous. In contrast, in dry sub-humid areas, areas with deep soils, protected from excess radiation, and areas where irrigation is feasible, well-fertilized big seedlings with high root growth potential may have more chances of success. We discuss this theory in the context of the multiple objectives of dryland restoration and the environmental constrains posed by these areas, and identify knowledge gaps that should be targeted to test our hypothesis.

Trade-offs between timber production and biodiversity in rainforest plantations: Emerging issues and an ecological perspective

During the past two centuries there have been three major paradigm shifts in the management of Australian rainforests and the use of their timbers: from felling native forests towards growing plantations; from viewing forests and plantations as mainly providers of timber to viewing them as sources of multiple benefits (e.g. timber, biodiversity, carbon sequestration, catchment protection, recreation, regional economic development); and from timber plantations being developed mainly by government on public land towards those established by private citizens, companies, or joint venture arrangements, on previously-cleared freehold land. Rainforest timber plantations are increasingly established for varied reasons, and with multiple objectives. Landholders are increasingly interested in the biodiversity values of their plantations. However, there are few guidelines on the changes to plantation design and management that would augment biodiversity outcomes, or on the extent to which this might require a sacrifice of production. [Abstract extract]

Temperature management for heterogeneous multi-core FPGAs using adaptive evolutionary multi-objective approaches

Heterogeneous multi-core FPGAs contain different types of cores, which can improve efficiency when used with an effective online task scheduler. However, it is not easy to find the right cores for tasks when there are multiple objectives or dozens of cores. Inappropriate scheduling may cause hot spots which decrease the reliability of the chip. Given that, our research builds a simulating platform to evaluate all kinds of scheduling algorithms on a variety of architectures. On this platform, we provide an online scheduler which uses multi-objective evolutionary algorithm (EA). Comparing the EA and current algorithms such as Predictive Dynamic Thermal Management (PDTM) and Adaptive Temperature Threshold Dynamic Thermal Management (ATDTM), we find some drawbacks in previous work. First, current algorithms are overly dependent on manually set constant parameters. Second, those algorithms neglect optimization for heterogeneous architectures. Third, they use single-objective methods, or use linear weighting method to convert a multi-objective optimization into a single-objective optimization. Unlike other algorithms, the EA is adaptive and does not require resetting parameters when workloads switch from one to another. EAs also improve performance when used on heterogeneous architecture. A efficient Pareto front can be obtained with EAs for the purpose of multiple objectives.

Otimização do controle do diagrama de radiação de radares de varredura para rastreio de foguetes usando o método GAMMC para o Caso Planar (GAMMC-P)

Launching centers are designed for scientific and commercial activities with aerospace vehicles. Rockets Tracking Systems (RTS) are part of the infrastructure of these centers and they are responsible for collecting and processing the data trajectory of vehicles. Generally, Parabolic Reflector Radars (PRRs) are used in RTS. However, it is possible to use radars with antenna arrays, or Phased Arrays (PAs), so called Phased Arrays Radars (PARs). Thus, the excitation signal of each radiating element of the array can be adjusted to perform electronic control of the radiation pattern in order to improve functionality and maintenance of the system. Therefore, in the implementation and reuse projects of PARs, modeling is subject to various combinations of excitation signals, producing a complex optimization problem due to the large number of available solutions. In this case, it is possible to use offline optimization methods, such as Genetic Algorithms (GAs), to calculate the problem solutions, which are stored for online applications. Hence, the Genetic Algorithm with Maximum-Minimum Crossover (GAMMC) optimization method was used to develop the GAMMC-P algorithm that optimizes the modeling step of radiation pattern control from planar PAs. Compared with a conventional crossover GA, the GAMMC has a different approach from the conventional one, because it performs the crossover of the fittest individuals with the least fit individuals in order to enhance the genetic diversity. Thus, the GAMMC prevents premature convergence, increases population fitness and reduces the processing time. Therefore, the GAMMC-P uses a reconfigurable algorithm with multiple objectives, different coding and genetic operator MMC. The test results show that GAMMC-P reached the proposed requirements for different operating conditions of a planar RAV.

Stakeholder-led science: engaging resource managers to identify science needs for long-term management of floodplain conservation lands

Floodplains pose challenges to managers of conservation lands because of constantly changing interactions with their rivers. Although scientific knowledge and understanding of the dynamics and drivers of river-floodplain systems can provide guidance to floodplain managers, the scientific process often occurs in isolation from management. Further, communication barriers between scientists and managers can be obstacles to appropriate application of scientific knowledge. With the coproduction of science in mind, our objectives were the following: (1) to document management priorities of floodplain conservation lands, and (2) identify science needs required to better manage the identified management priorities under nonstationary conditions, i.e., climate change, through stakeholder queries and interactions. We conducted an online survey with 80 resource managers of floodplain conservation lands along the Upper and Middle Mississippi River and Lower Missouri River, USA, to evaluate management priority, management intensity, and available scientific information for management objectives and conservation targets. Management objectives with the least information available relative to priority included controlling invasive species, maintaining respectful relationships with neighbors, and managing native, nongame species. Conservation targets with the least information available to manage relative to management priority included pollinators, marsh birds, reptiles, and shore birds. A follow-up workshop and survey focused on clarifying science needs to achieve management objectives under nonstationary conditions. Managers agreed that metrics of inundation, including depth and extent of inundation, and frequency, duration, and timing of inundation would be the most useful metrics for management of floodplain conservation lands with multiple objectives. This assessment provides guidance for developing relevant and accessible science products to inform management of highly dynamic floodplain environments. Although the problems facing managers of these lands are complex, products focused on a small suite of inundation metrics were determined to be the most useful to guide the decision making process.

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

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

Avaliação da interação entre aflatoxina M1 e B1 com a fração proteica do leite

Dissertação composta por 02 artigos.

Managing Fisheries in the context of an integrated policy: the importance of spatial issues

A variety of conservation policies now frame the management of fishing activity and so do also the spatial planning of different sectorial activities. These framework policies are additional to classical fishery management. There is a risk that the policies applying on the marine system are not coherent from a fisheries point of view. The spatial management of fishing activity at regional scale has the potential to meet multiple management objectives, on a habitat basis. Here we consider how to integrate multiple objectives of different policies into integrated ocean management scenarios. In the EU, European Directives and the CFP are now implementing the ecosystem approach to the management of human activity at sea. In this context, we further identify three research needs: • Develop Management Strategy Evaluation (MSE) for multiple-objective and multiple-sector spatial management schemes • Improve knowledge on and evaluation of functional habitats • Develop spatially-explicit end-to-end models with appropriate complexity for spatial MSE The contribution is based on the results of a workshop of the EraNet COFASP.

Compliance verification of virtual Phasor Measuring Unit using Ip-DFT algorithm according to the IEEE-60255-118-1(2018).

With the increase in load demand for various sectors, protection and safety of the network are key factors that have to be taken into consideration over the electric grid and distribution network. A phasor Measuring unit is an Intelligent electronics device that collects the data in the form of a real-time synchrophasor with a precise time tag using GPS (Global positioning system) and transfers the data to the grid command to monitor and assess the data. The measurements made by PMU have to be very precise to protect the relays and measuring equipment according to the IEEE 60255-118-1(2018). As a device PMU is very expensive to research and develop new functionalities there is a need to find an alternative to working with. Hence many open source virtual libraries are available to replicate the exact function of PMU in the virtual environment(Software) to continue the research on multiple objectives, providing the very least error results when verified. In this thesis, I executed performance and compliance verification of the virtual PMU which was developed using the I-DFT (Interpolated Discrete Fourier transforms) C-class algorithm in MATLAB. In this thesis, a test environment has been developed in MATLAB and tested the virtually developed PMU on both steady state and dynamic state for verifying the latest standard compliance(IEEE-60255-118-1).

Objectives for multiple-species conservation planning

The first step in conservation planning is to identify objectives. Most stated objectives for conservation, such as to maximize biodiversity outcomes, are too vague to be useful within a decision-making framework. One way to clarify the issue is to define objectives in terms of the risk of extinction for multiple species. Although the assessment of extinction risk for single species is common, few researchers have formulated an objective function that combines the extinction risks of multiple species. We sought to translate the broad goal of maximizing the viability of species into explicit objectives for use in a decision-theoretic approach to conservation planning. We formulated several objective functions based on extinction risk across many species and illustrated the differences between these objectives with simple examples. Each objective function was the mathematical representation of an approach to conservation and emphasized different levels of threat Our objectives included minimizing the joint probability of one or more extinctions, minimizing the expected number of extinctions, and minimizing the increase in risk of extinction from the best-case scenario. With objective functions based on joint probabilities of extinction across species, any correlations in extinction probabilities bad to be known or the resultant decisions were potentially misleading. Additive objectives, such as the expected number of extinctions, did not produce the same anomalies. We demonstrated that the choice of objective function is central to the decision-making process because alternative objective functions can lead to a different ranking of management options. Therefore, decision makers need to think carefully in selecting and defining their conservation goals.

Allelic Variation Investigation of the Estrogen Receptor Within an Australian Multiple Sclerosis Population

Multiple Sclerosis (MS) is a central nervous system (CNS) chronic inflammatory demyelinating disease leading to various neurological disabilities. The disorder is more prevalent for women with a ratio of 3:2 female to male. Objectives: To investigate variation within the estrogen receptor 1 (ESR1) polymorphism gene in an Australian MS case-control population using two intragenic restriction fragment length polymorphisms; the G594A located in exon 8 detected with the BtgI restriction enzyme and T938C located in intron 1, detected with PvuII. One hundred and ten Australian MS patients were studied, with patients classified clinically as Relapsing Remitting MS (RR-MS), Secondary Progressive MS (SP-MS) or Primary Progressive MS (PP-MS). Also, 110 age, sex and ethnicity matched controls were investigated as a comparative group. No significant difference in the allelic distribution frequency was found between the case and control groups for the ESR1 PvuII (P = 0.50) and Btg1 (P = 0.45) marker. Our results do not support a role for these two ESR1 markers in multiple sclerosis susceptibility, however other markers within ESR1 should not be excluded for potential involvement in the disorder.

Essential Role of CCR2 in Neutrophil Tissue Infiltration and Multiple Organ Dysfunction in Sepsis

Rationale Sepsis is defined as a systemic inflammatory response to infection, which in its severe form is associated with multiple organ dysfunction syndrome (MODS). The precise mechanisms by Which MODS develops remain unclear. Neutrophils have a pivotal role in the defense against infections; however, overwhelming activation of neutrophils is known to elicit tissue damage. Objectives: We investigated the role of the chemokine receptor CCR2 in driving neutrophil infiltration and eliciting tissue damage in remote organs during sepsis. Methods: Sepsis was induced in wild-type mice treated with CCR2 antagonist (RS504393) or CCR2(-/-) mice by cecal ligation and puncture (CLP) model. Neutrophil infiltration into the organs was measured by myeloperoxidase activity and fluorescence-activated cell sorter. CCR2 expression and chemotaxis were determined in neutrophils stimulated with Toll-like receptor agonists or isolated from septic mice and patients. Measurements and Main Results: CCR2 expression and responsiveness to its ligands was induced in circulating neutrophils during CLP-induced sepsis by a mechanism dependent on Toll-like receptor/nuclear factor-kappa B pathway. Genetic or pharmacologic inhibition of CCR2 protected mice from CLP-induced mortality. This protection was associated with lower infiltration of neutrophils into the lungs, heart, and kidneys and reduced serum biochemical indicators of organ injury and dysfunction. Importantly, neutrophils from septic patients express high levels of CCR2, and the severity of patient illness correlated positively with increasing neutrophil chemotaxis to CCR2 ligands. Conclusions: Collectively, these data identify CCR2 as a key receptor that drives the inappropriate infiltration of neutrophils into remote organs during sepsis. Therefore, CCR2 blockade is a novel potential therapeutic target for treatment of sepsis-induced MODS.