1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

Multigram synthesis and in vivo efficacy studies of a novel multitarget anti-Alzheimer's compound

We describe the multigram synthesis and in vivo efficacy studies of a donepezil‒huprine hybrid that has been found to display a promising in vitro multitarget profile of interest for the treatment of Alzheimer's disease (AD). Its synthesis features as the key step a novel multigram preparative chromatographic resolution of intermediate racemic huprine Y by chiral HPLC. Administration of this compound to transgenic CL4176 and CL2006 Caenorhabditis elegans strains expressing human Aβ42, here used as simplified animal models of AD, led to a significant protection from the toxicity induced by Aβ42. However, this protective effect was not accompanied, in CL2006 worms, by a reduction of amyloid deposits. Oral administration for 3 months to transgenic APPSL mice, a well-established animal model of AD, improved short-term memory, but did not alter brain levels of Aβ peptides nor cortical and hippocampal amyloid plaque load. Despite the clear protective and cognitive effects of AVCRI104P4, the lack of Aβ lowering effect in vivo might be related to its lower in vitro potency toward Aβ aggregation and formation as compared with its higher anticholinesterase activities. Further lead optimization in this series should thus focus on improving the anti-amyloid/anticholinesterase activity ratio.

Design and manufacture of a microdistillation column

Aim of this thesis was to design and manufacture a microdistillation column. The literature review part of this thesis covers stainless steels, material processing and basics about engineering design and distillation. The main focus, however, is on the experimental part. Experimental part is divided into five distinct sections: First part is where the device is introduced and separated into three parts. Secondly the device is designed part by part. It consists mostly of detail problem solving, since the first drawings had already been drawn and the critical dimensions decided. Third part is the manufacture, which was not fully completed since the final assembly was left out of this thesis. Fourth part is the test welding for the device, and its analysis. Finally some ideas for further studies are presented. The main goal of this thesis was accomplished. The device only lacks some final assembly but otherwise it is complete. One thing that became clear during the process was how difficult it is to produce small and precise steel parts with conventional manufacturing methods. Internal stresses within steel plates and thermal distortions can easily ruin small steel structures. Designing appropriate welding jigs is an important task for even simple devices. Laser material processing is a promising tool for this kind of steel processing because of the flexibility, good cutting quality and also precise and low heat input when welding. Next step in this project is the final assembly and the actual distillation tests. The tests will be carried out at Helsinki University of Technology.

Design and development of the architecture of an agricultural mobile robot

Parameters such as tolerance, scale and agility utilized in data sampling for using in Precision Agriculture required an expressive number of researches and development of techniques and instruments for automation. It is highlighted the employment of methodologies in remote sensing used in coupled to a Geographic Information System (GIS), adapted or developed for agricultural use. Aiming this, the application of Agricultural Mobile Robots is a strong tendency, mainly in the European Union, the USA and Japan. In Brazil, researches are necessary for the development of robotics platforms, serving as a basis for semi-autonomous and autonomous navigation systems. The aim of this work is to describe the project of an experimental platform for data acquisition in field for the study of the spatial variability and development of agricultural robotics technologies to operate in agricultural environments. The proposal is based on a systematization of scientific work to choose the design parameters utilized for the construction of the model. The kinematic study of the mechanical structure was made by the virtual prototyping process, based on modeling and simulating of the tension applied in frame, using the.

Yield of cotton/cowpea and sunflower/cowpea crop rotation systems during the reclamation process of a saline-sodic soil

The objective of this study was to evaluate the use of subsoiling, gypsum and organic matter associated with the cultivation of cotton, sunflower and cowpea in crop rotation, seeking the reclamation and use of a saline-sodic soil. The treatments were arranged in a randomized block design in split plots with four replications, during two crop cycles (2009/2010 and 2010/2011). The plots were formed by the treatments: T1. Subsoiling (S); T2. S + 20 Mg ha-1 of gypsum; T3. S + 40 Mg ha-1 of organic matter; T4. S + 10 Mg ha-1 of gypsum + 20 Mg ha-1 of organic matter; T5. S + 20 Mg ha-1 of gypsum + 40 Mg ha-1 of organic matter and the sub-plots consisted of the cotton-cowpea (C/CP) and sunflower-cowpea (S/CP) crop rotation. The use of gypsum and organic matter contributed to decrease the soil salinity and sodicity. Cotton was not affected by the treatments, while the sunflower crop was favored by the application of amendments only in the second production cycle. Higher yields of cowpea in T5 treatment, during the 2009/2010 cycle, are indicative that higher doses of gypsum and organic matter applied in this treatment accelerate the reclamation process. For other treatments with amendment application there was a beneficial effect for this crop only in the second cycle, when the values of productivity were similar to T5.

Design and validation of stateful composite RESTful web services

A web service is a software system that provides a machine-processable interface to the other machines over the network using different Internet protocols. They are being increasingly used in the industry in order to automate different tasks and offer services to a wider audience. The REST architectural style aims at producing scalable and extensible web services using technologies that play well with the existing tools and infrastructure of the web. It provides a uniform set of operation that can be used to invoke a CRUD interface (create, retrieve, update and delete) of a web service. The stateless behavior of the service interface requires that every request to a resource is independent of the previous ones facilitating scalability. Automated systems, e.g., hotel reservation systems, provide advanced scenarios for stateful services that require a certain sequence of requests that must be followed in order to fulfill the service goals. Designing and developing such services for advanced scenarios with REST constraints require rigorous approaches that are capable of creating web services that can be trusted for their behavior. Systems that can be trusted for their behavior can be termed as dependable systems. This thesis presents an integrated design, analysis and validation approach that facilitates the service developer to create dependable and stateful REST web services. The main contribution of this thesis is that we provide a novel model-driven methodology to design behavioral REST web service interfaces and their compositions. The behavioral interfaces provide information on what methods can be invoked on a service and the pre- and post-conditions of these methods. The methodology uses Unified Modeling Language (UML), as the modeling language, which has a wide user base and has mature tools that are continuously evolving. We have used UML class diagram and UML state machine diagram with additional design constraints to provide resource and behavioral models, respectively, for designing REST web service interfaces. These service design models serve as a specification document and the information presented in them have manifold applications. The service design models also contain information about the time and domain requirements of the service that can help in requirement traceability which is an important part of our approach. Requirement traceability helps in capturing faults in the design models and other elements of software development environment by tracing back and forth the unfulfilled requirements of the service. The information about service actors is also included in the design models which is required for authenticating the service requests by authorized actors since not all types of users have access to all the resources. In addition, following our design approach, the service developer can ensure that the designed web service interfaces will be REST compliant. The second contribution of this thesis is consistency analysis of the behavioral REST interfaces. To overcome the inconsistency problem and design errors in our service models, we have used semantic technologies. The REST interfaces are represented in web ontology language, OWL2, that can be part of the semantic web. These interfaces are used with OWL 2 reasoners to check unsatisfiable concepts which result in implementations that fail. This work is fully automated thanks to the implemented translation tool and the existing OWL 2 reasoners. The third contribution of this thesis is the verification and validation of REST web services. We have used model checking techniques with UPPAAL model checker for this purpose. The timed automata of UML based service design models are generated with our transformation tool that are verified for their basic characteristics like deadlock freedom, liveness, reachability and safety. The implementation of a web service is tested using a black-box testing approach. Test cases are generated from the UPPAAL timed automata and using the online testing tool, UPPAAL TRON, the service implementation is validated at runtime against its specifications. Requirement traceability is also addressed in our validation approach with which we can see what service goals are met and trace back the unfulfilled service goals to detect the faults in the design models. A final contribution of the thesis is an implementation of behavioral REST interfaces and service monitors from the service design models. The partial code generation tool creates code skeletons of REST web services with method pre and post-conditions. The preconditions of methods constrain the user to invoke the stateful REST service under the right conditions and the post condition constraint the service developer to implement the right functionality. The details of the methods can be manually inserted by the developer as required. We do not target complete automation because we focus only on the interface aspects of the web service. The applicability of the approach is demonstrated with a pedagogical example of a hotel room booking service and a relatively complex worked example of holiday booking service taken from the industrial context. The former example presents a simple explanation of the approach and the later worked example shows how stateful and timed web services offering complex scenarios and involving other web services can be constructed using our approach.

Flexible multibody dynamics and intelligent control of a hydraulically driven hybrid redundant robot machine

The assembly and maintenance of the International Thermonuclear Experimental Reactor (ITER) vacuum vessel (VV) is highly challenging since the tasks performed by the robot involve welding, material handling, and machine cutting from inside the VV. The VV is made of stainless steel, which has poor machinability and tends to work harden very rapidly, and all the machining operations need to be carried out from inside of the ITER VV. A general industrial robot cannot be used due to its poor stiffness in the heavy duty machining process, and this will cause many problems, such as poor surface quality, tool damage, low accuracy. Therefore, one of the most suitable options should be a light weight mobile robot which is able to move around inside of the VV and perform different machining tasks by replacing different cutting tools. Reducing the mass of the robot manipulators offers many advantages: reduced material costs, reduced power consumption, the possibility of using smaller actuators, and a higher payload-to-robot weight ratio. Offsetting these advantages, the lighter weight robot is more flexible, which makes it more difficult to control. To achieve good machining surface quality, the tracking of the end effector must be accurate, and an accurate model for a more flexible robot must be constructed. This thesis studies the dynamics and control of a 10 degree-of-freedom (DOF) redundant hybrid robot (4-DOF serial mechanism and 6-DOF 6-UPS hexapod parallel mechanisms) hydraulically driven with flexible rods under the influence of machining forces. Firstly, the flexibility of the bodies is described using the floating frame of reference method (FFRF). A finite element model (FEM) provided the Craig-Bampton (CB) modes needed for the FFRF. A dynamic model of the system of six closed loop mechanisms was assembled using the constrained Lagrange equations and the Lagrange multiplier method. Subsequently, the reaction forces between the parallel and serial parts were used to study the dynamics of the serial robot. A PID control based on position predictions was implemented independently to control the hydraulic cylinders of the robot. Secondly, in machining, to achieve greater end effector trajectory tracking accuracy for surface quality, a robust control of the actuators for the flexible link has to be deduced. This thesis investigates the intelligent control of a hydraulically driven parallel robot part based on the dynamic model and two schemes of intelligent control for a hydraulically driven parallel mechanism based on the dynamic model: (1) a fuzzy-PID self-tuning controller composed of the conventional PID control and with fuzzy logic, and (2) adaptive neuro-fuzzy inference system-PID (ANFIS-PID) self-tuning of the gains of the PID controller, which are implemented independently to control each hydraulic cylinder of the parallel mechanism based on rod length predictions. The serial component of the hybrid robot can be analyzed using the equilibrium of reaction forces at the universal joint connections of the hexa-element. To achieve precise positional control of the end effector for maximum precision machining, the hydraulic cylinder should be controlled to hold the hexa-element. Thirdly, a finite element approach of multibody systems using the Special Euclidean group SE(3) framework is presented for a parallel mechanism with flexible piston rods under the influence of machining forces. The flexibility of the bodies is described using the nonlinear interpolation method with an exponential map. The equations of motion take the form of a differential algebraic equation on a Lie group, which is solved using a Lie group time integration scheme. The method relies on the local description of motions, so that it provides a singularity-free formulation, and no parameterization of the nodal variables needs to be introduced. The flexible slider constraint is formulated using a Lie group and used for modeling a flexible rod sliding inside a cylinder. The dynamic model of the system of six closed loop mechanisms was assembled using Hamilton’s principle and the Lagrange multiplier method. A linearized hydraulic control system based on rod length predictions was implemented independently to control the hydraulic cylinders. Consequently, the results of the simulations demonstrating the behavior of the robot machine are presented for each case study. In conclusion, this thesis studies the dynamic analysis of a special hybrid (serialparallel) robot for the above-mentioned special task involving the ITER and investigates different control algorithms that can significantly improve machining performance. These analyses and results provide valuable insight into the design and control of the parallel robot with flexible rods.

PDM system functions and utilizations analysis to improve efficiency of sheet metal product design and manufacturing

This study will concentrate on Product Data Management (PDM) systems, and sheet metal design features and classification. In this thesis, PDM is seen as an individual system which handles all product-related data and information. The meaning of relevant data is to take the manufacturing process further with fewer errors. The features of sheet metals are giving more information and value to the designed models. The possibility of implementing PDM and sheet metal features recognition are the core of this study. Their integration should make the design process faster and manufacturing-friendly products easier to design. The triangulation method is the basis for this research. The sections of this triangle are: scientific literature review, interview using the Delphi method and the author’s experience and observations. The main key findings of this study are: (1) the area of focus in triangle (the triangle of three different point of views: business, information exchange and technical) depends on the person’s background and their role in the company, (2) the classification in the PDM system (and also in the CAD system) should be done using the materials, tools and machines that are in use in the company and (3) the design process has to be more effective because of the increase of industrial production, sheet metal blank production and the designer’s time spent on actual design and (4) because Design For Manufacture (DFM) integration can be done with CAD-programs, DFM integration with the PDM system should also be possible.

Mechanical design and analysis of modular active magnetic bearing test rig

Tässä työssä on tutkittu modulaarisen aktiivimagneettilaakeroidun koelaitteen mekaanista suunnittelua ja analysointia. Suurnopeusroottorin suunnittelun teoria on esitelty. Lisäksi monia analyyttisiä mallinnusmenetelmiä mekaanisten kuormitusten mallintamiseksi on esitelty. Koska kyseessä on suurnopeussähkökone, roottoridynamiikka ja sen soveltuvuus suunnittelussa on esitelty. Magneettilaakerien rakenteeseen ja toimintaan on tutustuttu osana tätä työtä. Kirjallisuuskatsaus nykyisistä koelaitteista esimerkiksi komponenttien ominaisuuksien tunnistamiseen ja roottoridynamiikan tutkimuksiin on esitelty. Työn rajauksena on konseptisuunnittelu muunneltavalle magneettilaakeroidulle (AMB) koelaitteelle ja suunnitteluprosessin dokumentointi. Muunneltavuuteen päädyttiin, koska se mahdollistaa erilaisten komponenttiasetteluiden testaamisen erilaisille magneettilaakerikokoonpanoille ja roottoreille. Pääpaino tässä työssä on suurnopeus induktiokoneen roottorin suunnittelussa ja mallintamisessa. Modulaaristen toimilaitteiden kuten magneettilaakerien ja induktiosähkömoottorin rakenne on esitelty ja modulaarisen rakenteen käytettävyyden hyödyistä koelaitekäytössä on dokumentoitu. Analyyttisiä ja elementtimenetelmään perustuvia tutkimusmenetelmiä on käytetty tutkittaessa suunniteltua suurnopeusroottoria. Suunnittelun ja analysoinnin tulokset on esitelty ja verrattu keskenään eri mallinnusmenetelmien välillä. Lisäksi johtopäätökset sähkömagneettisten osien liittämisen monimutkaisuudesta ja vaatimuksista roottoriin ja toimilaitteisiin sekä mekaanisten että sähkömagneettisten ominaisuuksien optimoimiseksi on dokumentoitu.

Agent-based management systems for many-core platforms : rigorous design and efficient implementation

Due to various advantages such as flexibility, scalability and updatability, software intensive systems are increasingly embedded in everyday life. The constantly growing number of functions executed by these systems requires a high level of performance from the underlying platform. The main approach to incrementing performance has been the increase of operating frequency of a chip. However, this has led to the problem of power dissipation, which has shifted the focus of research to parallel and distributed computing. Parallel many-core platforms can provide the required level of computational power along with low power consumption. On the one hand, this enables parallel execution of highly intensive applications. With their computational power, these platforms are likely to be used in various application domains: from home use electronics (e.g., video processing) to complex critical control systems. On the other hand, the utilization of the resources has to be efficient in terms of performance and power consumption. However, the high level of on-chip integration results in the increase of the probability of various faults and creation of hotspots leading to thermal problems. Additionally, radiation, which is frequent in space but becomes an issue also at the ground level, can cause transient faults. This can eventually induce a faulty execution of applications. Therefore, it is crucial to develop methods that enable efficient as well as resilient execution of applications. The main objective of the thesis is to propose an approach to design agentbased systems for many-core platforms in a rigorous manner. When designing such a system, we explore and integrate various dynamic reconfiguration mechanisms into agents functionality. The use of these mechanisms enhances resilience of the underlying platform whilst maintaining performance at an acceptable level. The design of the system proceeds according to a formal refinement approach which allows us to ensure correct behaviour of the system with respect to postulated properties. To enable analysis of the proposed system in terms of area overhead as well as performance, we explore an approach, where the developed rigorous models are transformed into a high-level implementation language. Specifically, we investigate methods for deriving fault-free implementations from these models into, e.g., a hardware description language, namely VHDL.

The importance of package design to Japanese consumers: The role of visual and informational elements of package design in decision making

The importance of package design as a marketing tool is growing as the competition in retail environment increases. However, there is a lack of studies on how each element of package design affects consumer decisions in different countries. The objective of this thesis is to study the role of package design to Japanese consumers. The research was conducted through an experiment with a sample of 37 Japanese female participants. They were divided into two groups and were given different tasks: one group had to choose a chocolate for themselves, and the other for a group of friends. The participants were presented with 15 different Finnish chocolate boxes to choose from. The qualitative data was gathered through observation and semi-structured interviews. In addition, data from questionnaires was quantified and all the data was triangulated. The empirical results suggest that visual elements strongly affect the decision making of Japanese consumers. Image was the most important element which acted as both, a visual and an informational aspect in the experiment. Informational elements on the other hand have little effect, especially when the context is written in a foreign language. However, informational elements affected participants who were choosing chocolates for a group of friends. A unique finding was the importance of kawaii (cuteness) to Japanese consumers.

Model-based testing of software systems : functionality and performance

Software is a key component in many of our devices and products that we use every day. Most customers demand not only that their devices should function as expected but also that the software should be of high quality, reliable, fault tolerant, efficient, etc. In short, it is not enough that a calculator gives the correct result of a calculation, we want the result instantly, in the right form, with minimal use of battery, etc. One of the key aspects for succeeding in today's industry is delivering high quality. In most software development projects, high-quality software is achieved by rigorous testing and good quality assurance practices. However, today, customers are asking for these high quality software products at an ever-increasing pace. This leaves the companies with less time for development. Software testing is an expensive activity, because it requires much manual work. Testing, debugging, and verification are estimated to consume 50 to 75 per cent of the total development cost of complex software projects. Further, the most expensive software defects are those which have to be fixed after the product is released. One of the main challenges in software development is reducing the associated cost and time of software testing without sacrificing the quality of the developed software. It is often not enough to only demonstrate that a piece of software is functioning correctly. Usually, many other aspects of the software, such as performance, security, scalability, usability, etc., need also to be verified. Testing these aspects of the software is traditionally referred to as nonfunctional testing. One of the major challenges with non-functional testing is that it is usually carried out at the end of the software development process when most of the functionality is implemented. This is due to the fact that non-functional aspects, such as performance or security, apply to the software as a whole. In this thesis, we study the use of model-based testing. We present approaches to automatically generate tests from behavioral models for solving some of these challenges. We show that model-based testing is not only applicable to functional testing but also to non-functional testing. In its simplest form, performance testing is performed by executing multiple test sequences at once while observing the software in terms of responsiveness and stability, rather than the output. The main contribution of the thesis is a coherent model-based testing approach for testing functional and performance related issues in software systems. We show how we go from system models, expressed in the Unified Modeling Language, to test cases and back to models again. The system requirements are traced throughout the entire testing process. Requirements traceability facilitates finding faults in the design and implementation of the software. In the research field of model-based testing, many new proposed approaches suffer from poor or the lack of tool support. Therefore, the second contribution of this thesis is proper tool support for the proposed approach that is integrated with leading industry tools. We o er independent tools, tools that are integrated with other industry leading tools, and complete tool-chains when necessary. Many model-based testing approaches proposed by the research community suffer from poor empirical validation in an industrial context. In order to demonstrate the applicability of our proposed approach, we apply our research to several systems, including industrial ones.

Development of Measurement Systems in Scientific Research: Case Study

In recent years, technological advancements in microelectronics and sensor technologies have revolutionized the field of electrical engineering. New manufacturing techniques have enabled a higher level of integration that has combined sensors and electronics into compact and inexpensive systems. Previously, the challenge in measurements was to understand the operation of the electronics and sensors, but this has now changed. Nowadays, the challenge in measurement instrumentation lies in mastering the whole system, not just the electronics. To address this issue, this doctoral dissertation studies whether it would be beneficial to consider a measurement system as a whole from the physical phenomena to the digital recording device, where each piece of the measurement system affects the system performance, rather than as a system consisting of small independent parts such as a sensor or an amplifier that could be designed separately. The objective of this doctoral dissertation is to describe in depth the development of the measurement system taking into account the challenges caused by the electrical and mechanical requirements and the measurement environment. The work is done as an empirical case study in two example applications that are both intended for scientific studies. The cases are a light sensitive biological sensor used in imaging and a gas electron multiplier detector for particle physics. The study showed that in these two cases there were a number of different parts of the measurement system that interacted with each other. Without considering these interactions, the reliability of the measurement may be compromised, which may lead to wrong conclusions about the measurement. For this reason it is beneficial to conceptualize the measurement system as a whole from the physical phenomena to the digital recording device where each piece of the measurement system affects the system performance. The results work as examples of how a measurement system can be successfully constructed to support a study of sensors and electronics.

Fiber-reinforced composite fixed dental prostheses: Studies of the materials used as pontics

Fiber-reinforced composite fixed dental prostheses – Studies of the materials used as pontics University of Turku, Faculty of Medicine, Institute of Dentistry, Department of Biomaterials Science, Finnish Doctoral Program in Oral Sciences – FINDOS, Annales Universitatis Turkuensis, Turku, Finland 2015 Fiber-reinforced composites (FRC), a non-metallic biomaterial, represent a suitable alternative in prosthetic dentistry when used as a component of fixed dental prostheses (FDPs). Some drawbacks have been identified in the clinical performance of FRC restorations, such as delamination of the veneering material and fracture of the pontic. Therefore, the current series of studies were performed to investigate the possibilities of enhancing the mechanical and physical properties of FRC FDPs by improving the materials used as pontics, to then heighten their longevity. Four experiments showed the importance of the pontic design and surface treatment in the performance of FRC FDPs. In the first, the load-bearing capacities of inlay-retained FRC FDPs with pontics of various materials and thicknesses were evaluated. Three different pontic materials were assessed with different FRC framework vertical positioning. Thicker pontics showed increased load-bearing capacities, especially ceramic pontics. A second study was completed investigating the influence of the chemical conditioning of the ridge-lap surface of acrylic resin denture teeth on their bonding to a composite resin. Increased shear bond strength demonstrated the positive influence of the pretreatment of the acrylic surfaces, indicating dissolution of the denture surfaces, and suggesting potential penetration of the monomer systems into the surface of denture teeth. A third study analyzed the penetration depth of different monomer systems on the acrylic resin denture teeth surfaces. The possibility of establishing a durable bond between acrylic pontics and FRC frameworks was demonstrated by the ability of monomers to penetrate the surface of acrylic resin denture teeth, measured by a confocal scanning type microscope. A fourth study was designed to evaluate the load-bearing capacities of FRC FDPs using the findings of the previous three studies. In this case, the performance of pre-shaped acrylic resin denture teeth used as pontics with different composite resins as filling materials was evaluated. The filling material influenced the load-bearing capacities, providing more durable FRC FDPs. It can be concluded that the mechanical and physical properties of FRC FDPs can be improved as has been shown in the development of this thesis. The improvements reported then might provide long lasting prosthetic solutions of this kind, positioning them as potentially permanent rehabilitation treatments. Key words: fiber-reinforced composite, fixed dental prostheses, inlay-retained bridges, adhesion, acrylic resin denture teeth, dental material.