The role of Malt1 proteolytic activity in T cell activation and lymphoma development

Abstract Long term contact with pathogens induces an adaptive immune response, which is mainly mediated by T and B cells. Antigen-induced activation of T and B cells is an important event, since it facilitates the transition of harmless, low proliferative lymphocytes into powerful and fast expanding cells, which can, if deregulated, be extremely harmful and dangerous for the human body. One of the most important events during lymphocyte activation is the induction of NF-xB activity, a transcription factor that controls not only cytokine secretion, but also lymphocyte proliferation and survival. Recent discoveries identified the CBM complex as the central regulator of NF-xB activity in lymphocytes. The CBM complex consists of the three proteins Carma1, Bcl10 and Malt1, in which Carma1 serves as recruitment platform of the complex and Bcl10 as an adaptor to recruit Malt1 to this platform. But exactly how Malt1 activates NF-x6 is still poorly understood. We discovered that Malt1 is a protease, which cleaves its interaction partner Bcl10 upon T and B cell stimulation. We mapped the Bcl10 cleavage site by single point mutations as well as by a proteomics approach, and used this knowledge to design a fluorogenic Malt1 reporter peptide. With this tool were we able to the first time demonstrate proteolytic activity of Malt1 in vitro, using recombinant Malt1, and in stimulated T cells. Based on similarities to a metacaspase, we designed a Malt1inhibitor, which allowed unto investigate the role of Malt1 activity in T cells. Malt1-inhibited T cells showed a clear defect in NF-xB activity, resulting in impaired IL-2 cytokine secretion levels. We also found a new unexpected role for Bcl10; the blockade of Bcl10 cleavage resulted in a strongly impaired capability of stimulated T cells to adhere to the extracellular matrix protein fibronectin. Because of the central position of the C8M complex, it is not surprising that different lymphomas show abnormal expressions of Carma1, Bcl10 and Malt1. We investigated the role of Malt1 proteolytic activity in the most aggressive subtype of diffuse large B cell lymphomas called ABC, which was described to depend on the expression of Carmal, and frequently carries oncogenic Carmal mutations. We found constitutive high Malt1 activity in all tested ABC cell lines visualized by detection of cleavage products of Malt1 substrates. With the use of the Malt1-inhibitor, we could demonstrate that Malt-inhibition in those cells had two effects. First, the tumor cell proliferation was decreased, most likely because of lower autocrine stimulation by cytokines. Second, we could sensitize the ABC cells towards cell death, which is most likely caused by reduced expression of prosurvival NF-xB target gens. Taken together, we identified Malt1 as a protease in T and B cells, demonstrated its importance for NF-xB signaling and its deregulation in a subtype of diffuse large B cell lymphoma. This could allow the development of a new generation of immunomodulatory and anti-cancer drugs. Résumé Un contact prolongé avec des pathogènes provoque une réponse immunitaire adaptative qui dépend principalement des cellules T et 8. L'activation des lymphocytes T et B, suite à la reconnaissance d'un antigène, est un événement important puisqu'il facilite la transition pour ces cellules d'un état de prolifération limitée et inoffensive à une prolifération soutenue et rapide. Lorsque ce mécanisme est déréglé ìl peut devenir extrêmement nuisible et dangereux pour le corps humain. Un des événement les plus importants lors de l'activation des lymphocytes est l'induction du facteur de transcription NFxB, qui organise la sécrétion de cytokines ainsi que la prolifération et la survie des lymphocytes. Le complexe CBM, composé des trois protéines Carmai, Bc110 et Malt1, a été récemment identifié comme un régulateur central de l'activité de NF-x8 dans les lymphocytes. Carma1 sert de plateforme de recrutement pour ce complexe alors que Bc110 permet d'amener Malt1 dans cette plateforme. Cependant, le rôle exact de Malt1 dans l'activation de NF-tcB reste encore mal compris. Nous avons découvert que Malt1 est une protéase qui clive son partenaire d'interaction BcI10 après stimulation des cellules T et B. Nous avons identifié le site de clivage de BcI10 par une série de mutations ponctuelles ainsi que par une approche protéomique, ce qui nous a permis de fabriquer un peptide reporteur fluorogénique pour mesurer l'activité de Malt1. Grâce à cet outil, nous avons démontré pour la première fois l'activité protéolytique de Malt1 in vitro à l'aide de protéines Malt1 recombinantes ainsi que dans des cellules T stimulées. La ressemblance de Malt1 avec une métacaspase nous a permis de synthétiser un inhibiteur de Malt1 et d'étudier ainsi le rôle de l'activité de Malt1 dans les cellules T. L'inhibition de Malt1 dans les cellules T a révélé un net défaut de l'activité de NF-x8, ayant pour effet une sécrétion réduite de la cytokine IL-2. Nous avons également découvert un rôle inattendu pour Bcl10: en effet, bloquer le clivage de Bcl10 diminue fortement la capacité d'adhésion des cellules T stimulées à la protéine fïbronectine, un composant de la matrice extracellulaire. En raison de la position centrale du complexe CBM, il n'est pas étonnant que le niveau d'expression de Carmai, Bcl10 et Malt1 soit anormal dans plusieurs types de lymphomes. Nous avons examiné le rôle de l'activité protéolytique de Malt1 dans le sous-type le plus agressif des lymphomes B diffus à grandes cellules, appelé sous-type ABC. Ce sous-type de lymphomes dépend de l'expression de Carmai et présente souvent des mutations oncogéniques de Carma1. Nous avons démontré que l'activité de Malt1 était constitutivement élevée dans toutes les lignées cellulaires de type ABC testées, en mettant en évidence la présence de produits de clivage de différents substrats de Malt1. Enfin, l'utilisation de l'inhibiteur de Malt1 nous a permis de démontrer que l'inhibition de Malt1 avait deux effets. Premièrement, une diminution de la prolifération des cellules tumorales, probablement dûe à leur stimulation autocrine par des cytokines fortement réduite. Deuxièmement, une sensibilisation des cellules de type ABC à ia mort cellulaire, vraisemblablement causée par l'expression diminuée de gènes de survie dépendants de NF-tcB. En résumé, nous avons identifié Malt1 comme une protéase dans les cellules T et B, nous avons mis en évidence son importance pour l'activation de NF-xB ainsi que les conséquences du dérèglement de l'activité de Malt1 dans un sous-type de lymphome B diffus à larges cellules. Notre étude ouvre ainsi la voie au développement d'une nouvelle génération de médicaments immunomodulateurs et anti-cancéreux.

Development of an Economic Dust Palliative for Limestone Surfaced Secondary Roads, HR-297, 1990

This research project was directed at laboratory and field evaluation of sodium montmorillonite clay (bentonite) as a dust palliative for limestone surfaced secondary roads. It had been postulated that the electrically charged surfaces of the clay particles could interact with the charged surfaces of the limestone and act as a bonding agent to agglomerate fine (-#200) particulates and also to band the fine particulates to larger (+#200) limestone particles. Laboratory testing using soda ash dispersed bentonite treatment of limestone fines indicated significant improvement of compressive strength and slaking characteristics. It was recommended that the project proceed to field trials and test roads were constructed in Dallas and Adair counties in Iowa. Soda ash dispersed bentonite solutions can be field mixed and applied with conventional spray distribution equipment. A maximum of 1.5% bentonite(by weight of aggregate)can be applied at one time. Higher applications would have to be staged allowing the excess moisture to evaporate between applications. Construction of higher application treatments can be accomplished by adding dry bentonite to the surfacing material and then by dry road mixing. The soda ash water solution can then be spray applied and the treated surfacing material wet mixed by motor graders to a consistency of 3 to 4 inch slump concrete. Two motor graders working in tandem can provide rapid mixing for both methods of construction. Calcium and magnesium chloride treatments are 2 to 3 times more effective in dust reduction in the short term (3-4 months) but are prone to washboarding and potholing due to maintenance restrictions. Bentonite treatment at the 2-3% level is estimated to provide a 30-40% dust reduction over the long term(18-24 months). Normal maintenance blading operations can be used on bentonite treated areas. Vehicle braking characteristics are not adversely affected up to the 3.0% treatment level. The bentonite appears to be functioning as a banding agent to bind small particulates to larger particles and is acting to agglomerate fine particles of limestone. This bonding capability appears recoverable from environmental effects of winter, and from alternating wet and dry periods. The bentonite appears to be able to interact with new applications of limestone maintenance material and maintains a dust reduction capability. Soda ash dispersed bentonite treatment is approximately 10 times more cost effective per percent dust reduction than conventional chloride treatments with respect to time. However,the disadvantage is that there is not the initial dramatic reduction in dust generation as with the chloride treatment. Although dust is reduced 30-40% after treatment there is still dust being generated and the traveling public or residents may not perceive the reduction.

Institutional trust - development of the construct and the scale

Organisatorisen luottamuksen tutkimuksessa luottamus nähdään yleensä henkilöiden välisenä ilmiönä kuten työntekijän luottamuksena työtovereihin, esimieheen tai lähimpään johtoon. Organisatorisessa luottamuksessa on kuitenkin myös ei-henkilöityvä ulottuvuus, ns. institutionaalinen luottamus. Tähän mennessä vain muutamat tutkijat ovat omissa tutkimuksissaan käyttäneet myös institutionaalista luottamusta osana organisatorista luottamusta. Tämän työn tavoitteena on kehittää institutionaalisen luottamuksen käsitettä sekä mittari sen havainnoimiseksi organisaatioympäristössä. Kehitysprosessi koostui kolmesta vaiheesta. Ensimmäisessä vaiheessa kehitettiin mittariin tulevia väittämiä sekä arvioitiin sisällön validiteetti. Toinen vaihe käsitti aineiston keruun, väittämien karsimisen sekä vaihtoehtoisten mallien vertailun. Kolmannessa vaiheessa arvioitiin rakennevaliditeetti sekä reliabiliteetti. Työn empiirinen osatoteutettiin internet-kyselynä aikuisopiskelijoiden keskuudessa. Aineiston analysoinnissa käytettiin pääkomponenttianalyysiä sekä konfirmatorista faktorianalyysiä. Institutionaalinen luottamus muodostuu kahdesta ulottuvuudesta: kyvykkyys ja oikeudenmukaisuus. Kyvykkyys muodostuu viidestä alakomponentista: operatiivisen toiminnan organisointi, organisaation pysyvyys, kyvykkyys liiketoiminnan ja ihmisten johtamisessa, teknologinen luotettavuus sekä kilpailukyky. Oikeudenmukaisuus puolestaan muodostuu HRM-käytännöistä, organisaatiossa vallitsevasta reilun pelin hengestä sekä kommunikaatiosta. Lopullinen mittari kyvykkyydelle käsittää 18 väittämää ja oikeudenmukaisuudelle 13 väittämää. Työssä kehitetty mittari mahdollistaa organisatorisen luottamuksen entistä paremman ja luotettavamman mittaamisen. Tutkijan tietämyksen mukaan tämä onensimmäinen kokonaisvaltainen mittari institutionaalisen luottamuksen mittaamiseksi.

Applying the principles of life cycle assessment and costing in process modeling to examine profit-making capability

Static process simulation has traditionally been used to model complex processes for various purposes. However, the use of static processsimulators for the preparation of holistic examinations aiming at improving profit-making capability requires a lot of work because the production of results requires the assessment of the applicability of detailed data which may be irrelevant to the objective. The relevant data for the total assessment gets buried byirrelevant data. Furthermore, the models do not include an examination of the maintenance or risk management, and economic examination is often an extra property added to them which can be performed with a spreadsheet program. A process model applicable to holistic economic examinations has been developed in this work. The model is based on the life cycle profit philosophy developed by Hagberg and Henriksson in 1996. The construction of the model has utilized life cycle assessment and life cycle costing methodologies with a view to developing, above all, a model which would be applicable to the economic examinations of complete wholes and which would require the need for information focusing on aspects essential to the objectives. Life cycle assessment and costing differ from each other in terms of the modeling principles, but the features of bothmethodologies can be used in the development of economic process modeling. Methods applicable to the modeling of complex processes can be examined from the viewpoint of life cycle methodologies, because they involve the collection and management of large corpuses of information and the production of information for the needs of decision-makers as well. The results of the study shows that on the basis of the principles of life cycle modeling, a process model can be created which may be used to produce holistic efficiency examinations on the profit-making capability of the production line, with fewer resources thanwith traditional methods. The calculations of the model are based to the maximum extent on the information system of the factory, which means that the accuracyof the results can be improved by developing information systems so that they can provide the best information for this kind of examinations.

Modeling and measuring organizational renewal capability

Globalization and new information technologies mean that organizations have to face world-wide competition in rapidly transforming, unpredictable environments, and thus the ability to constantly generate novel and improved products, services and processes has become quintessential for organizational success. Performance in turbulent environments is, above all, influenced by the organization's capability for renewal. Renewal capability consists of the ability of the organization to replicate, adapt, develop and change its assets, capabilities and strategies. An organization with a high renewal capability can sustain its current success factors while at the same time building new strengths for the future. This capability does not only mean that the organization is able to respond to today's challenges and to keep up with the changes in its environment, but also that it can actas a forerunner by creating innovations, both at the tactical and strategic levels of operation and thereby change the rules of the market. However, even though it is widely agreed that the dynamic capability for continuous learning, development and renewal is a major source of competitive advantage, there is no widely shared view on how organizational renewal capability should be defined, and the field is characterized by a plethora of concepts and definitions. Furthermore,there is a lack of methods for systematically assessing organizational renewal capability. The dissertation aims to bridge these gaps in the existing research by constructing an integrative theoretical framework for organizational renewal capability and by presenting a method for modeling and measuring this capability. The viability of the measurement tool is demonstrated in several contexts, andthe framework is also applied to assess renewal in inter-organizational networks. In this dissertation, organizational renewal capability is examined by drawing on three complimentary theoretical perspectives: knowledge management, strategic management and intellectual capital. The knowledge management perspective considers knowledge as inherently social and activity-based, and focuses on the organizational processes associated with its application and development. Within this framework, organizational renewal capability is understood as the capacity for flexible knowledge integration and creation. The strategic management perspective, on the other hand, approaches knowledge in organizations from the standpoint of its implications for the creation of competitive advantage. In this approach, organizational renewal is framed as the dynamic capability of firms. The intellectual capital perspective is focused on exploring how intangible assets can be measured, reported and communicated. From this vantage point, renewal capability is comprehended as the dynamic dimension of intellectual capital, which consists of the capability to maintain, modify and create knowledge assets. Each of the perspectives significantly contributes to the understanding of organizationalrenewal capability, and the integrative approach presented in this dissertationcontributes to the individual perspectives as well as to the understanding of organizational renewal capability as a whole.

Influence of software development process quality on product quality

Ohjelmistojen tärkeys nykypäivän yhteiskunnalle kasvaa jatkuvasti. Monia ohjelmistoprojekteja vaivaavat ongelmat aikataulussa pysymisestä, korkean tuottavuuden ylläpitämisestä ja riittävän korkeasta laadusta. Ohjelmistokehitysprosessien parantamisessa on naiden ongelmien minimoimiseksi tehty suuria investointeja. Investointien syynä on ollut olettamus ohjelmistokehityksen kapasiteetin suora riippuvuus tuotteen laadusta. Tämän tutkimuksen tarkoituksena oli tutkia Ohjelmistokehitysprosessien parantamisen mahdollisuuksia. Olemassaolevat ohjelmistokehityksen ja Ohjelmistokehitysprosessin parantamisen mallit, tekniikat ja metodologiat esiteltiin. Esiteltyjen mallien, tekniikoiden ja metodologioiden soveltuvuus analysoitiin ja suositus mallien käytöstä annettiin.

Development and validation of a method for the analysis of tetracyclines in chicken-muscle by liquid chromatography-electrospray-mass spectrometry in tandem (LC-ESI-MS/MS)

A LC-ESI-MS/MS method was developed and validated according to the European Union decision 2002/657/EC, for the determination of tetracyclines (TCs) in chicken-muscle since Europe is one of the main markets for Brazilian products. Linearity of r > 0.9979, limits of quantification in the range of 7.0-35.0 ng/g, average recoveries of 89.38 - 106.27%, within-day and between-day precision were adequate for all TCs. The decision limit and the detection capability were 93.00-106.46 ng/g and 95.84-114.38 ng/g, respectively. This method is suitable for application in surveillance programmes of residues of TCs in chicken-muscle samples.

Diagnosing and developing knowledge management capability –Knowledge management capability in UPM-Kymmene Wood Oy

The purpose of this case study is to clarify how KM (knowledge management) capability is constructed through six different activities and to explore how this capability can be diagnosed and developed in the three case organizations. The study examines the knowledge management capability of the three factories in UPM-Kymmene Wood Oy, a major Finnish plywood producer. Forest industry is usually considered to be quite hierarchical. The importance of leveraging employee skills and knowledge has been recognized in all types of organizations – including those that mainly deal with tangible resources. However, the largest part of empirical knowledge management literature examines KM in so called knowledge-intensive or knowledge-based organizations. This study extends existing literature by providing an in depth case study into assessment and development of KM activities in these three organizations with little awareness of the KM discourse. This subject is analyzed through literature review, theoretical analysis and empirical research in the case organizations. The study also presents a structured method for evaluating KM activities of a company and for diagnosing the main weaknesses that should be developed in order to achieve KM excellence. The results help in understanding how knowledge management capability is constructed and provide insight into developing and exploiting it within an organization.

The value of digitalization of services in the new service development

The purpose of this thesis is to study factors that have an impact on the company’s capabilities to identify and analyze the value of digitalization of services during the early stages of service development process and evaluate them from the perspective of a case company. The research problem was defined: “How digitalization of services affects delivering the services of the future?” The research method of this thesis was based on the qualitative case study which aimed to study both company’s and customer’s set of values. The study included a literature review and a development study. The empirical research part consisted of analyzing three existing services, specifying a new digital service concept and its feasibility analysis as part of a business requirement phase. To understand the set of values, 10 stakeholder interviews were conducted and earlier customer surveys were utilized, and additionally, a number of meetings were conducted with the case company representatives to develop service concept, and evaluate the findings. The impact of the early stages of service development process discovered to reflect directly in the capabilities of the case company to identify and create customer value were related to the themes presented in the literature review. In order to specify the value achieved from the digitalization the following areas of strategic background elements were deepened during the study: Innovations, customer understanding and business service. Based on the findings, the study aims to enhance the case company’s capability to identify and evaluate the impact of the digitalization in delivering services of the future. Recognizing the value of digital service before the beginning of the development project is important to the businesses of both customer and provider. By exploring the various levels of digitalization one can get the overall picture of the value gained from utilizing digital opportunities. From the development perspective, the process of reviewing and discovering the most promising opportunities and solutions is the key step in order to deliver superior services. Ultimately, a company should understand the value outcome determination of the individual services as well as their digital counterparts.

Enhancing the development of military capabilities by a systems approach

The political environment of security and defence has changed radically in the Western industrialised world since the Cold War. As a response to these changes, since the beginning of the twenty-first century, most Western countries have adopted a ‘capabilities-based approach’ to developing and operating their armed forces. More responsive and versatile military capabilities must be developed to meet the contemporary challenges. The systems approach is seen as a beneficial means of overcoming traps in resolving complex real -world issues by conventional thinking. The main objectives of this dissertation are to explore and assess the means to enhance the development of military capabilities both in concept development and experimentation (CD&E) and in national defence materiel collaboration issues. This research provides a unique perspective, a systems approach, to the development areas of concern in resolving complex real-world issues. This dissertation seeks to increase the understanding of the military capability concept both as a whole and with in its life cycle. The dissertation follows the generic functionalist systems methodology by Jackson. The methodology applies a comprehensive set of constitutive rules to examine the research objectives. This dissertation makes contribution to current studies about military capability. It presents two interdepen dent conceptual capability models: the comprehensive capability meta-model (CCMM) and the holistic capability life cycle model (HCLCM). These models holistically and systematically complement the existing, but still evolving, understanding of military capability and its life cycle. In addition, this dissertation contributes to the scientific discussion of defence procurement in its broad meaning by introducing the holistic model about the national defence materiel collaboration between the defence forces, defence industry and academia. The model connects the key collaborative mechanisms, which currently work in isolation from each other, and take into consideration the unique needs of each partner. This dissertation contributes empirical evidence regarding the benefits of enterprise architectures (EA) to CD&E. The EA approach may add value to traditional concept development by increasing the clarity, consistency and completeness of the concept. The most important use considered for EA in CD&E is that it enables further utilisation of the concept created in the case project.

On the development of an unstructured grid solver for inert and reactive high speed flow simulations

An unstructured grid Euler solver for reactive compressible flow applications is presented. The method is implemented in a cell centered, finite volume context for unstructured triangular grids. Three different schemes for spatial discretization are implemented and analyzed. Time march is implemented in a time-split fashion with independent integrators for the flow and chemistry equations. The capability implemented is tested for inert flows in a hypersonic inlet and for inert and reactive supersonic flows over a 2-D wedge. The results of the different schemes are compared with each other and with independent calculations using a structured grid code. The strengths and the possible weaknesses of the proposed methods are discussed.

Development and characterization of thin printed films for gas sensing applications

The monitoring and control of hydrogen sulfide (H2S) level is of great interest for a wide range of application areas including food quality control, defense and antiterrorist applications and air quality monitoring e.g. in mines. H2S is a very poisonous and flammable gas. Exposure to low concentrations of H2S can result in eye irritation, a sore throat and cough, shortness of breath, and fluid retention in the lungs. These symptoms usually disappear in a few weeks. Long-term, low-level exposure may result in fatigue, loss of appetite, headache, irritability, poor memory, and dizziness. Higher concentrations of 700 - 800 ppm tend to be fatal. H2S has a characteristic smell of rotten egg. However, because of temporary paralysis of olfactory nerves, the smelling capability at concentrations higher than 100 ppm is severely compromised. In addition, volatile H2S is one of the main products during the spoilage of poultry meat in anaerobic conditions. Currently, no commercial H2S sensor is available which can operate under anaerobic conditions and can be easily integrated in the food packaging. This thesis presents a step-wise progress in the development of printed H2S gas sensors. Efforts were made in the formulation, characterization and optimization of functional printable inks and coating pastes based on composites of a polymer and a metal salt as well as a composite of a metal salt and an organic acid. Different processing techniques including inkjet printing, flexographic printing, screen printing and spray coating were utilized in the fabrication of H2S sensors. The dispersions were characterized by measuring turbidity, surface tension, viscosity and particle size. The sensing films were characterized using X-ray photoelectron spectroscopy, X-ray diffraction, atomic force microscopy and an electrical multimeter. Thin and thick printed or coated films were developed for gas sensing applications with the aim of monitoring the H2S concentrations in real life applications. Initially, a H2S gas sensor based on a composite of polyaniline and metal salt was developed. Both aqueous and solvent-based dispersions were developed and characterized. These dispersions were then utilized in the fabrication of roll-to-roll printed H2S gas sensors. However, the humidity background, long term instability and comparatively lower detection limit made these sensors less favourable for real practical applications. To overcome these problems, copper acetate based sensors were developed for H2S gas sensing. Stable inks with excellent printability were developed by tuning the surface tension, viscosity and particle size. This enabled the formation of inkjet-printed high quality copper acetate films with excellent sensitivity towards H2S. Furthermore, these sensors showed negligible humidity effects and improved selectivity, response time, lower limit of detection and coefficient of variation. The lower limit of detection of copper acetate based sensors was further improved to sub-ppm level by incorporation of catalytic gold nano-particles and subsequent plasma treatment of the sensing film. These sensors were further integrated in an inexpensive wirelessly readable RLC-circuit (where R is resistor, L is inductor and C is capacitor). The performance of these sensors towards biogenic H2S produced during the spoilage of poultry meat in the modified atmosphere package was also demonstrated in this thesis. This serves as a proof of concept that these sensors can be utilized in real life applications.

Dependency of military capabilities on technological development

Our goal is to get better understanding of different kind of dependencies behind the high-level capability areas. The models are suitable for investigating present state capabilities or future developments of capabilities in the context of technology forecasting. Three levels are necessary for a model describing effects of technologies on military capabilities. These levels are capability areas, systems and technologies. The contribution of this paper is to present one possible model for interdependencies between technologies. Modelling interdependencies between technologies is the last building block in constructing a quantitative model for technological forecasting including necessary levels of abstraction. This study supplements our previous research and as a result we present a model for the whole process of capability modelling. As in our earlier studies, capability is defined as the probability of a successful task or operation or proper functioning of a system. In order to obtain numerical data to demonstrate our model, we conducted a questionnaire to a group of defence technology researchers where interdependencies between seven representative technologies were inquired. Because of a small number of participants in questionnaires and general uncertainties concerning subjective evaluations, only rough conclusions can be made from the numerical results

Sen and Nussbaum: Agency and Capability- Expansion1

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Development and Evaluation of Blind Identification Techniques for Nonlinear Systems

Identification and Control of Non‐linear dynamical systems are challenging problems to the control engineers.The topic is equally relevant in communication,weather prediction ,bio medical systems and even in social systems,where nonlinearity is an integral part of the system behavior.Most of the real world systems are nonlinear in nature and wide applications are there for nonlinear system identification/modeling.The basic approach in analyzing the nonlinear systems is to build a model from known behavior manifest in the form of system output.The problem of modeling boils down to computing a suitably parameterized model,representing the process.The parameters of the model are adjusted to optimize a performanace function,based on error between the given process output and identified process/model output.While the linear system identification is well established with many classical approaches,most of those methods cannot be directly applied for nonlinear system identification.The problem becomes more complex if the system is completely unknown but only the output time series is available.Blind recognition problem is the direct consequence of such a situation.The thesis concentrates on such problems.Capability of Artificial Neural Networks to approximate many nonlinear input-output maps makes it predominantly suitable for building a function for the identification of nonlinear systems,where only the time series is available.The literature is rich with a variety of algorithms to train the Neural Network model.A comprehensive study of the computation of the model parameters,using the different algorithms and the comparison among them to choose the best technique is still a demanding requirement from practical system designers,which is not available in a concise form in the literature.The thesis is thus an attempt to develop and evaluate some of the well known algorithms and propose some new techniques,in the context of Blind recognition of nonlinear systems.It also attempts to establish the relative merits and demerits of the different approaches.comprehensiveness is achieved in utilizing the benefits of well known evaluation techniques from statistics. The study concludes by providing the results of implementation of the currently available and modified versions and newly introduced techniques for nonlinear blind system modeling followed by a comparison of their performance.It is expected that,such comprehensive study and the comparison process can be of great relevance in many fields including chemical,electrical,biological,financial and weather data analysis.Further the results reported would be of immense help for practical system designers and analysts in selecting the most appropriate method based on the goodness of the model for the particular context.