Study of ligand-based virtual screening tools in computer-aided drug design

Virtual screening is a central technique in drug discovery today. Millions of molecules can be tested in silico with the aim to only select the most promising and test them experimentally. The topic of this thesis is ligand-based virtual screening tools which take existing active molecules as starting point for finding new drug candidates. One goal of this thesis was to build a model that gives the probability that two molecules are biologically similar as function of one or more chemical similarity scores. Another important goal was to evaluate how well different ligand-based virtual screening tools are able to distinguish active molecules from inactives. One more criterion set for the virtual screening tools was their applicability in scaffold-hopping, i.e. finding new active chemotypes. In the first part of the work, a link was defined between the abstract chemical similarity score given by a screening tool and the probability that the two molecules are biologically similar. These results help to decide objectively which virtual screening hits to test experimentally. The work also resulted in a new type of data fusion method when using two or more tools. In the second part, five ligand-based virtual screening tools were evaluated and their performance was found to be generally poor. Three reasons for this were proposed: false negatives in the benchmark sets, active molecules that do not share the binding mode, and activity cliffs. In the third part of the study, a novel visualization and quantification method is presented for evaluation of the scaffold-hopping ability of virtual screening tools.

Computational studies for the design of process equipment with complex geometries

This study combines several projects related to the flows in vessels with complex shapes representing different chemical apparata. Three major cases were studied. The first one is a two-phase plate reactor with a complex structure of intersecting micro channels engraved on one plate which is covered by another plain plate. The second case is a tubular microreactor, consisting of two subcases. The first subcase is a multi-channel two-component commercial micromixer (slit interdigital) used to mix two liquid reagents before they enter the reactor. The second subcase is a micro-tube, where the distribution of the heat generated by the reaction was studied. The third case is a conventionally packed column. However, flow, reactions or mass transfer were not modeled. Instead, the research focused on how to describe mathematically the realistic geometry of the column packing, which is rather random and can not be created using conventional computeraided design or engineering (CAD/CAE) methods. Several modeling approaches were used to describe the performance of the processes in the considered vessels. Computational fluid dynamics (CFD) was used to describe the details of the flow in the plate microreactor and micromixer. A space-averaged mass transfer model based on Fick’s law was used to describe the exchange of the species through the gas-liquid interface in the microreactor. This model utilized data, namely the values of the interfacial area, obtained by the corresponding CFD model. A common heat transfer model was used to find the heat distribution in the micro-tube. To generate the column packing, an additional multibody dynamic model was implemented. Auxiliary simulation was carried out to determine the position and orientation of every packing element in the column. This data was then exported into a CAD system to generate desirable geometry, which could further be used for CFD simulations. The results demonstrated that the CFD model of the microreactor could predict the flow pattern well enough and agreed with experiments. The mass transfer model allowed to estimate the mass transfer coefficient. Modeling for the second case showed that the flow in the micromixer and the heat transfer in the tube could be excluded from the larger model which describes the chemical kinetics in the reactor. Results of the third case demonstrated that the auxiliary simulation could successfully generate complex random packing not only for the column but also for other similar cases.

Permanent magnet synchronous motor for industrial inverter applications - analysis and design

During the latest few years the need for new motor types has grown, since both high efficiency and an accurate dynamic performance are demanded in industrial applications. For this reason, new effective control systems such as direct torque control (DTC) have been developed. Permanent magnet synchronous motors (PMSM) are well suitable for new adjustable speed AC inverter drives, because their efficiency and power factor are not depending on the pole pair number and speed to the same extent as it is the case in induction motors. Therefore, an induction motor (IM) with a mechanical gearbox can often be replaced with a direct PM motor drive. Space as well as costs will be saved, because the efficiency increases and the cost of maintenance decreases as well. This thesis deals with design criterion, analytical calculation and analysis of the permanent magnet synchronous motor for both sinusoidal air-gap flux density and rectangular air-gapflux density. It is examined how the air-gap flux, flux densities, inductances and torque can be estimated analytically for salient pole and non-salient pole motors. It has been sought by means of analytical calculations for the ultimate construction for machines rotating at relative low 300 rpm to 600 rpm speeds, which are suitable speeds e.g. in Pulp&Paper industry. The calculations are verified by using Finite Element calculations and by measuring of prototype motor. The prototype motor is a 45 kW, 600 rpm PMSM with buried V-magnets, which is a very appropriate construction for high torque motors with a high performance. With the purposebuilt prototype machine it is possible not only to verify the analytical calculations but also to show whether the 600 rpm PMSM can replace the 1500 rpm IM with a gear. It can also be tested if the outer dimensions of the PMSM may be the same as for the IM and if the PMSM in this case can produce a 2.5 fold torque, in consequence of which it may be possible to achieve the same power. The thesis also considers the question how to design a permanent magnet synchronous motor for relatively low speed applications that require a high motor torqueand efficiency as well as bearable costs of permanent magnet materials. It is shown how a selection of different parameters affects the motor properties. Key words: Permanent magnet synchronous motor, PMSM, surface magnets, buried magnets

Business Process Modeling in Software Requirements Engineering for Small and Medium Software Projects

Vaatimusmäärittelyn tavoitteena on luoda halutun järjestelmän kokonaisen, yhtenäisen vaatimusluettelon vaatimusten määrittämiseksi käsitteellisellä tasolla. Liiketoimintaprosessien mallintaminen on varsin hyödyllinen vaatimusmäärittelyn varhaisissa vaiheissa. Tämä työ tutkii liiketoimintaprosessien mallintamista tietojärjestelmien kehittämistä varten. Nykyään on olemassa erilaisia liiketoimintaprosessien mallintamiseen tarkoitettuja tekniikoita. Tämä työ tarkastaa liiketoimintaprosessien mallintamisen periaatteet ja näkökohdat sekä eri mallinnustekniikoita. Uusi menetelmä, joka on suunniteltu erityisesti pienille ja keskisuurille ohjelmistoprojekteille, on kehitetty prosessinäkökohtien ja UML-kaavioiden perusteella.

High-Speed Solid-Rotor Induction Machine – Electromagnetic Calculation and Design

Within the latest decade high-speed motor technology has been increasingly commonly applied within the range of medium and large power. More particularly, applications like such involved with gas movement and compression seem to be the most important area in which high-speed machines are used. In manufacturing the induction motor rotor core of one single piece of steel it is possible to achieve an extremely rigid rotor construction for the high-speed motor. In a mechanical sense, the solid rotor may be the best possible rotor construction. Unfortunately, the electromagnetic properties of a solid rotor are poorer than the properties of the traditional laminated rotor of an induction motor. This thesis analyses methods for improving the electromagnetic properties of a solid-rotor induction machine. The slip of the solid rotor is reduced notably if the solid rotor is axially slitted. The slitting patterns of the solid rotor are examined. It is shown how the slitting parameters affect the produced torque. Methods for decreasing the harmonic eddy currents on the surface of the rotor are also examined. The motivation for this is to improve the efficiency of the motor to reach the efficiency standard of a laminated rotor induction motor. To carry out these research tasks the finite element analysis is used. An analytical calculation of solid rotors based on the multi-layer transfer-matrix method is developed especially for the calculation of axially slitted solid rotors equipped with wellconducting end rings. The calculation results are verified by using the finite element analysis and laboratory measurements. The prototype motors of 250 – 300 kW and 140 Hz were tested to verify the results. Utilization factor data are given for several other prototypes the largest of which delivers 1000 kW at 12000 min-1.

Exploration and Design of Power-Efficient Networked Many-Core Systems

Multiprocessing is a promising solution to meet the requirements of near future applications. To get full benefit from parallel processing, a manycore system needs efficient, on-chip communication architecture. Networkon- Chip (NoC) is a general purpose communication concept that offers highthroughput, reduced power consumption, and keeps complexity in check by a regular composition of basic building blocks. This thesis presents power efficient communication approaches for networked many-core systems. We address a range of issues being important for designing power-efficient manycore systems at two different levels: the network-level and the router-level. From the network-level point of view, exploiting state-of-the-art concepts such as Globally Asynchronous Locally Synchronous (GALS), Voltage/ Frequency Island (VFI), and 3D Networks-on-Chip approaches may be a solution to the excessive power consumption demanded by today’s and future many-core systems. To this end, a low-cost 3D NoC architecture, based on high-speed GALS-based vertical channels, is proposed to mitigate high peak temperatures, power densities, and area footprints of vertical interconnects in 3D ICs. To further exploit the beneficial feature of a negligible inter-layer distance of 3D ICs, we propose a novel hybridization scheme for inter-layer communication. In addition, an efficient adaptive routing algorithm is presented which enables congestion-aware and reliable communication for the hybridized NoC architecture. An integrated monitoring and management platform on top of this architecture is also developed in order to implement more scalable power optimization techniques. From the router-level perspective, four design styles for implementing power-efficient reconfigurable interfaces in VFI-based NoC systems are proposed. To enhance the utilization of virtual channel buffers and to manage their power consumption, a partial virtual channel sharing method for NoC routers is devised and implemented. Extensive experiments with synthetic and real benchmarks show significant power savings and mitigated hotspots with similar performance compared to latest NoC architectures. The thesis concludes that careful codesigned elements from different network levels enable considerable power savings for many-core systems.

Working fluid selection and design of small-scale waste heat recovery systems based on organic Rankine cycles

Demand for the use of energy systems, entailing high efficiency as well as availability to harness renewable energy sources, is a key issue in order to tackling the threat of global warming and saving natural resources. Organic Rankine cycle (ORC) technology has been identified as one of the most promising technologies in recovering low-grade heat sources and in harnessing renewable energy sources that cannot be efficiently utilized by means of more conventional power systems. The ORC is based on the working principle of Rankine process, but an organic working fluid is adopted in the cycle instead of steam. This thesis presents numerical and experimental results of the study on the design of small-scale ORCs. Two main applications were selected for the thesis: waste heat re- covery from small-scale diesel engines concentrating on the utilization of the exhaust gas heat and waste heat recovery in large industrial-scale engine power plants considering the utilization of both the high and low temperature heat sources. The main objective of this work was to identify suitable working fluid candidates and to study the process and turbine design methods that can be applied when power plants based on the use of non-conventional working fluids are considered. The computational work included the use of thermodynamic analysis methods and turbine design methods that were based on the use of highly accurate fluid properties. In addition, the design and loss mechanisms in supersonic ORC turbines were studied by means of computational fluid dynamics. The results indicated that the design of ORC is highly influenced by the selection of the working fluid and cycle operational conditions. The results for the turbine designs in- dicated that the working fluid selection should not be based only on the thermodynamic analysis, but requires also considerations on the turbine design. The turbines tend to be fast rotating, entailing small blade heights at the turbine rotor inlet and highly supersonic flow in the turbine flow passages, especially when power systems with low power outputs are designed. The results indicated that the ORC is a potential solution in utilizing waste heat streams both at high and low temperatures and both in micro and larger scale appli- cations.

Advanced analysis and design methods for preparative chromatographic separation processes

Preparative liquid chromatography is one of the most selective separation techniques in the fine chemical, pharmaceutical, and food industries. Several process concepts have been developed and applied for improving the performance of classical batch chromatography. The most powerful approaches include various single-column recycling schemes, counter-current and cross-current multi-column setups, and hybrid processes where chromatography is coupled with other unit operations such as crystallization, chemical reactor, and/or solvent removal unit. To fully utilize the potential of stand-alone and integrated chromatographic processes, efficient methods for selecting the best process alternative as well as optimal operating conditions are needed. In this thesis, a unified method is developed for analysis and design of the following singlecolumn fixed bed processes and corresponding cross-current schemes: (1) batch chromatography, (2) batch chromatography with an integrated solvent removal unit, (3) mixed-recycle steady state recycling chromatography (SSR), and (4) mixed-recycle steady state recycling chromatography with solvent removal from fresh feed, recycle fraction, or column feed (SSR–SR). The method is based on the equilibrium theory of chromatography with an assumption of negligible mass transfer resistance and axial dispersion. The design criteria are given in general, dimensionless form that is formally analogous to that applied widely in the so called triangle theory of counter-current multi-column chromatography. Analytical design equations are derived for binary systems that follow competitive Langmuir adsorption isotherm model. For this purpose, the existing analytic solution of the ideal model of chromatography for binary Langmuir mixtures is completed by deriving missing explicit equations for the height and location of the pure first component shock in the case of a small feed pulse. It is thus shown that the entire chromatographic cycle at the column outlet can be expressed in closed-form. The developed design method allows predicting the feasible range of operating parameters that lead to desired product purities. It can be applied for the calculation of first estimates of optimal operating conditions, the analysis of process robustness, and the early-stage evaluation of different process alternatives. The design method is utilized to analyse the possibility to enhance the performance of conventional SSR chromatography by integrating it with a solvent removal unit. It is shown that the amount of fresh feed processed during a chromatographic cycle and thus the productivity of SSR process can be improved by removing solvent. The maximum solvent removal capacity depends on the location of the solvent removal unit and the physical solvent removal constraints, such as solubility, viscosity, and/or osmotic pressure limits. Usually, the most flexible option is to remove solvent from the column feed. Applicability of the equilibrium design for real, non-ideal separation problems is evaluated by means of numerical simulations. Due to assumption of infinite column efficiency, the developed design method is most applicable for high performance systems where thermodynamic effects are predominant, while significant deviations are observed under highly non-ideal conditions. The findings based on the equilibrium theory are applied to develop a shortcut approach for the design of chromatographic separation processes under strongly non-ideal conditions with significant dispersive effects. The method is based on a simple procedure applied to a single conventional chromatogram. Applicability of the approach for the design of batch and counter-current simulated moving bed processes is evaluated with case studies. It is shown that the shortcut approach works the better the higher the column efficiency and the lower the purity constraints are.

Review of water electrolysis technologies and design of renewable hydrogen production systems

An electric system based on renewable energy faces challenges concerning the storage and utilization of energy due to the intermittent and seasonal nature of renewable energy sources. Wind and solar photovoltaic power productions are variable and difficult to predict, and thus electricity storage will be needed in the case of basic power production. Hydrogen’s energetic potential lies in its ability and versatility to store chemical energy, to serve as an energy carrier and as feedstock for various industries. Hydrogen is also used e.g. in the production of biofuels. The amount of energy produced during hydrogen combustion is higher than any other fuel’s on a mass basis with a higher-heating-value of 39.4 kWh/kg. However, even though hydrogen is the most abundant element in the universe, on Earth most hydrogen exists in molecular forms such as water. Therefore, hydrogen must be produced and there are various methods to do so. Today, the majority hydrogen comes from fossil fuels, mainly from steam methane reforming, and only about 4 % of global hydrogen comes from water electrolysis. Combination of electrolytic production of hydrogen from water and supply of renewable energy is attracting more interest due to the sustainability and the increased flexibility of the resulting energy system. The preferred option for intermittent hydrogen storage is pressurization in tanks since at ambient conditions the volumetric energy density of hydrogen is low, and pressurized tanks are efficient and affordable when the cycling rate is high. Pressurized hydrogen enables energy storage in larger capacities compared to battery technologies and additionally the energy can be stored for longer periods of time, on a time scale of months. In this thesis, the thermodynamics and electrochemistry associated with water electrolysis are described. The main water electrolysis technologies are presented with state-of-the-art specifications. Finally, a Power-to-Hydrogen infrastructure design for Lappeenranta University of Technology is presented. Laboratory setup for water electrolysis is specified and factors affecting its commissioning in Finland are presented.

Application of Computational Fluid Dynamics in Modeling Blood Flow in Human Thoracic Aorta

The aim of this study was to simulate blood flow in thoracic human aorta and understand the role of flow dynamics in the initialization and localization of atherosclerotic plaque in human thoracic aorta. The blood flow dynamics in idealized and realistic models of human thoracic aorta were numerically simulated in three idealized and two realistic thoracic aorta models. The idealized models of thoracic aorta were reconstructed with measurements available from literature, and the realistic models of thoracic aorta were constructed by image processing Computed Tomographic (CT) images. The CT images were made available by South Karelia Central Hospital in Lappeenranta. The reconstruction of thoracic aorta consisted of operations, such as contrast adjustment, image segmentations, and 3D surface rendering. Additional design operations were performed to make the aorta model compatible for the numerical method based computer code. The image processing and design operations were performed with specialized medical image processing software. Pulsatile pressure and velocity boundary conditions were deployed as inlet boundary conditions. The blood flow was assumed homogeneous and incompressible. The blood was assumed to be a Newtonian fluid. The simulations with idealized models of thoracic aorta were carried out with Finite Element Method based computer code, while the simulations with realistic models of thoracic aorta were carried out with Finite Volume Method based computer code. Simulations were carried out for four cardiac cycles. The distribution of flow, pressure and Wall Shear Stress (WSS) observed during the fourth cardiac cycle were extensively analyzed. The aim of carrying out the simulations with idealized model was to get an estimate of flow dynamics in a realistic aorta model. The motive behind the choice of three aorta models with distinct features was to understand the dependence of flow dynamics on aorta anatomy. Highly disturbed and nonuniform distribution of velocity and WSS was observed in aortic arch, near brachiocephalic, left common artery, and left subclavian artery. On the other hand, the WSS profiles at the roots of branches show significant differences with geometry variation of aorta and branches. The comparison of instantaneous WSS profiles revealed that the model with straight branching arteries had relatively lower WSS compared to that in the aorta model with curved branches. In addition to this, significant differences were observed in the spatial and temporal profiles of WSS, flow, and pressure. The study with idealized model was extended to study blood flow in thoracic aorta under the effects of hypertension and hypotension. One of the idealized aorta models was modified along with the boundary conditions to mimic the thoracic aorta under the effects of hypertension and hypotension. The results of simulations with realistic models extracted from CT scans demonstrated more realistic flow dynamics than that in the idealized models. During systole, the velocity in ascending aorta was skewed towards the outer wall of aortic arch. The flow develops secondary flow patterns as it moves downstream towards aortic arch. Unlike idealized models, the distribution of flow was nonplanar and heavily guided by the artery anatomy. Flow cavitation was observed in the aorta model which was imaged giving longer branches. This could not be properly observed in the model with imaging containing a shorter length for aortic branches. The flow circulation was also observed in the inner wall of the aortic arch. However, during the diastole, the flow profiles were almost flat and regular due the acceleration of flow at the inlet. The flow profiles were weakly turbulent during the flow reversal. The complex flow patterns caused a non-uniform distribution of WSS. High WSS was distributed at the junction of branches and aortic arch. Low WSS was distributed at the proximal part of the junction, while intermedium WSS was distributed in the distal part of the junction. The pulsatile nature of the inflow caused oscillating WSS at the branch entry region and inner curvature of aortic arch. Based on the WSS distribution in the realistic model, one of the aorta models was altered to induce artificial atherosclerotic plaque at the branch entry region and inner curvature of aortic arch. Atherosclerotic plaque causing 50% blockage of lumen was introduced in brachiocephalic artery, common carotid artery, left subclavian artery, and aortic arch. The aim of this part of the study was first to study the effect of stenosis on flow and WSS distribution, understand the effect of shape of atherosclerotic plaque on flow and WSS distribution, and finally to investigate the effect of lumen blockage severity on flow and WSS distributions. The results revealed that the distribution of WSS is significantly affected by plaque with mere 50% stenosis. The asymmetric shape of stenosis causes higher WSS in branching arteries than in the cases with symmetric plaque. The flow dynamics within thoracic aorta models has been extensively studied and reported here. The effects of pressure and arterial anatomy on the flow dynamic were investigated. The distribution of complex flow and WSS is correlated with the localization of atherosclerosis. With the available results we can conclude that the thoracic aorta, with complex anatomy is the most vulnerable artery for the localization and development of atherosclerosis. The flow dynamics and arterial anatomy play a role in the localization of atherosclerosis. The patient specific image based models can be used to diagnose the locations in the aorta vulnerable to the development of arterial diseases such as atherosclerosis.

Näkökulmia 3D-tulostuksen opetukseen ja koulutukseen

Additive manufacturing, or 3D printing, is globally one of most interesting area in developing of manufacturing technologies. This technology is suitable for fabrication off industrial products and it interests actors in fields of computer sciences, economics, medical sciences and design&arts. Additive manufacturing is often referred as third industrial revolution: first revolution was invention of steam engines in 18th century and second was industrial revolution started by Henry Ford in 1920s. Companies should be able to test suitability of their products for additive manufacturing and 3D printing but also how much better products could be when products are totally re-designed so that all potential of this new technology can be utilized. This is where education has its importance; new generations who enter working life should be educated to know of additive manufacturing and 3D printing, its advantages but also of it limits. There has to be also possibility to educate industry and people already working there, so that industrial implementation could be done successfully. This is especially very valid for Finland. Education is strongly needed so that Finnish industry can maintain its competence in global markets. Role of education is extremely important when a new technology is industrially implemented. Additive manufacturing and 3D printing offers freedom to design new products, production and generally ways of doing things. Development, planning and execution of education for additive manufacturing and 3D printing is challenging as this area develops very fast. New innovations are coming almost every month. Planning of education for additive manufacturing and 3D printing requires collection pieces of data from various of sources. Additive manufacturing and 3D printing industry and its development has to be followed frequently, and material for additive manufacturing and 3D printing has to be renewed frequently.

Tuning the design procedures for laser processed microwave mechanics

This research has been focused at the development of a tuned systematic design methodology, which gives the best performance in a computer aided environment and utilises a cross-technological approach, specially tested with and for laser processed microwave mechanics. A tuned design process scheme is also presented. Because of the currently large production volumes of microwave and radio frequency mechanics even slight improvements of design methodologies or manufacturing technologies would give reasonable possibilities for cost reduction. The typical number of required iteration cycles could be reduced to one fifth of normal. The research area dealing with the methodologies is divided firstly into a function-oriented, a performance-oriented or a manufacturability-oriented product design. Alternatively various approaches can be developed for a customer-oriented, a quality-oriented, a cost-oriented or an organisation-oriented design. However, the real need for improvements is between these two extremes. This means that the effective methodology for the designers should not be too limited (like in the performance-oriented design) or too general (like in the organisation-oriented design), but it should, include the context of the design environment. This is the area where the current research is focused. To test the developed tuned design methodology for laser processing (TDMLP) and the tuned optimising algorithm for laser processing (TOLP), seven different industrial product applications for microwave mechanics have been designed, CAD-modelled and manufactured by using laser in small production series. To verify that the performance of these products meets the required level and to ensure the objectiveness ofthe results extensive laboratory tests were used for all designed prototypes. As an example a Ku-band horn antenna can be laser processed from steel in 2 minutes at the same time obtaining a comparable electrical performance of classical aluminium units or the residual resistance of a laser joint in steel could be limited to 72 milliohmia.

Evolutionary computing in search-based software engineering

This master’s thesis aims to study and represent from literature how evolutionary algorithms are used to solve different search and optimisation problems in the area of software engineering. Evolutionary algorithms are methods, which imitate the natural evolution process. An artificial evolution process evaluates fitness of each individual, which are solution candidates. The next population of candidate solutions is formed by using the good properties of the current population by applying different mutation and crossover operations. Different kinds of evolutionary algorithm applications related to software engineering were searched in the literature. Applications were classified and represented. Also the necessary basics about evolutionary algorithms were presented. It was concluded, that majority of evolutionary algorithm applications related to software engineering were about software design or testing. For example, there were applications about classifying software production data, project scheduling, static task scheduling related to parallel computing, allocating modules to subsystems, N-version programming, test data generation and generating an integration test order. Many applications were experimental testing rather than ready for real production use. There were also some Computer Aided Software Engineering tools based on evolutionary algorithms.