Development of simple and efficient synthetic strategies for production of fine chemicals of pharmaceutical relevance : metal-mediated allylation combined with applied catalysis

Den snart 200 år gamla vetenskapsgrenen organisk synteskemi har starkt bidragit till moderna samhällens välfärd. Ett av flaggskeppen för den organiska synteskemin är utvecklingen och produktionen av nya läkemedel och speciellt de aktiva substanserna däri. Därmed är det viktigt att utveckla nya syntesmetoder, som kan tillämpas vid framställningen av farmaceutiskt relevanta målstrukturer. I detta sammanhang är den ultimata målsättningen dock inte endast en lyckad syntes av målmolekylen, utan det är allt viktigare att utveckla syntesrutter som uppfyller kriterierna för den hållbara utvecklingen. Ett av de centralaste verktygen som en organisk kemist har till förfogande i detta sammanhang är katalys, eller mera specifikt möjligheten att tillämpa olika katalytiska reaktioner vid framställning av komplexa målstrukturer. De motsvarande industriella processerna karakteriseras av hög effektivitet och minimerad avfallsproduktion, vilket naturligtvis gynnar den kemiska industrin samtidigt som de negativa miljöeffekterna minskas avsevärt. I denna doktorsavhandling har nya syntesrutter för produktion av finkemikalier med farmaceutisk relevans utvecklats genom att kombinera förhållandevis enkla transformationer till nya reaktionssekvenser. Alla reaktionssekvenser som diskuteras i denna avhandling påbörjades med en metallförmedlad allylering av utvalda aldehyder eller aldiminer. De erhållna produkterna innehållende en kol-koldubbelbindning med en närliggande hydroxyl- eller aminogrupp modifierades sedan vidare genom att tillämpa välkända katalytiska reaktioner. Alla syntetiserade molekyler som presenteras i denna avhandling karakteriseras som finkemikalier med hög potential vid farmaceutiska tillämpningar. Utöver detta tillämpades en mängd olika katalytiska reaktioner framgångsrikt vid syntes av dessa molekyler, vilket i sin tur förstärker betydelsen för de katalytiska verktygen i organiska kemins verktygslåda.

Generalized Differential Evolution for Global Multi-Objective Optimization with Constraints

The objective of this thesis work is to develop and study the Differential Evolution Algorithm for multi-objective optimization with constraints. Differential Evolution is an evolutionary algorithm that has gained in popularity because of its simplicity and good observed performance. Multi-objective evolutionary algorithms have become popular since they are able to produce a set of compromise solutions during the search process to approximate the Pareto-optimal front. The starting point for this thesis was an idea how Differential Evolution, with simple changes, could be extended for optimization with multiple constraints and objectives. This approach is implemented, experimentally studied, and further developed in the work. Development and study concentrates on the multi-objective optimization aspect. The main outcomes of the work are versions of a method called Generalized Differential Evolution. The versions aim to improve the performance of the method in multi-objective optimization. A diversity preservation technique that is effective and efficient compared to previous diversity preservation techniques is developed. The thesis also studies the influence of control parameters of Differential Evolution in multi-objective optimization. Proposals for initial control parameter value selection are given. Overall, the work contributes to the diversity preservation of solutions in multi-objective optimization.

Tuotannonohjausmuodon vaihtaminen tilausohjautuvasta varasto-ohjautuvaan

Diplomityössä tutkitaan tuotannonohjausmuodon vaihtamista tilausohjautuvasta varasto-ohjautuvaan. Tavoitteena on löytää kohdeyritykselle kustannustehokkain vaihtoehto tuotannonohjaukseen. Tutkimuksessa analysoidaan yrityksen tuotantoprosessi nykytila-analyysilla toiminnan tehokkuuden arvioimiseksi ja tuotannon pullonkaulojen löytämiseksi. Asiakastilauksen kytkentäpisteet ja taloudelliset tuotantoeräkoot määritellään yrityksen valmistamille tuotteille. Työn tuloksissa käydään tuotannon tunnuslukujen avulla läpi tuotannon tehokkuuden kehittymistä projektin aikana. Varasto-ohjautuva tuotannonohjausmuoto osoittautui kannattavimmaksi ohjausmuodoksi tarkasteltavana ajankohtana. Toimitusvarmuus ja kapasiteetin käyttöaste parantuivat ohjausmuodon vaihtamisen myötä. Asetuskustannuksia saatiin vähennettyä ja tuotantoprosessia kehitettyä. Tuotannon läpimenoaikojen lyhennyttyä tilausohjautuvuutta tulee tarkastella uudestaan.

Maahanmuuttajien kotoutumiskoulutuksen moduulimallin ulkoinen arviointi : Hieman hiomalla timantiksi

Kainuun ELY-keskus järjestää yhteistyössä alueen TE-toimistojen kanssa maahanmuuttajien kotoutumiskoulutusta moduulimuotoisena. Kotoutumiskoulutusta järjestetään aikuisille, kotoutumislain piirissä oleville maahanmuuttajille. Koulutus on pääsääntöisesti työvoimapoliittista koulutusta ja sen tarkoituksena on kehittää maahanmuuttajien suomen- tai ruotsinkielentaitoa sekä yhteiskunnan tuntemusta. Tämä raportti on Kainuun ELY-keskuksen hallinnoiman Kansainvälinen työvoima -projektin (ESR) toimeksiannosta tehtävän ulkoisen arvioinnin loppuraportti. Kotoutumiskoulutuksen moduulimallin ulkoisella arvioinnilla tähdätään mallin kehittämiseen ja sitä kautta maahanmuuttajien kotoutumisen ja myös työllistymismahdollisuuksien parantamiseen. Ulkoisen arvioinnin tavoitteena on moduulimallin kehittäminen tuloksellisempaan ja tehokkaampaan suuntaan siten, että se paremmin palvelee maahanmuuttajien kotoutumistavoitteita.

Strategic outsourcing of R&D: The location-specific advantages of India to the pharmaceutical industry

Companies are increasingly under pressure to be more efficient both in terms of costs and overall performance and thus, they seek new ways to develop their products and innovate. For pharmaceutical industry it can take several decades to launch a new drug to the markets. Since pharmaceutical industry is one of the most research-intensive industries, is outsourcing one way to enhance the R&D processes of such companies. It is said that outsourcing to offshore locations is vastly more challenging and complicated than any other exporting activity or inter-company relationship that has evoked a lot of discussion. By outsourcing strategically, companies must also thoroughly focus on transaction costs and core competences. Today, the suppliers are looked for beyond national boundaries and furthermore, the location of the outsourcing activity must also be thoroughly considered. Consequently, the purpose of this study is to analyze what is known of strategic outsourcing of pharmaceutical R&D to India. In order to meet the purpose of the study, this study tries to answer three sub-questions set to it: first, what is strategic outsourcing, second, why pharmaceutical companies utilize strategic outsourcing of R&D and last, why pharmaceutical companies select India as the location for outsourcing their R&D. The study is a qualitative study. The purpose of the study was approached by a literature review with systematic elements and sub-questions were analyzed through different relevant theories, such as theory of transaction costs, core competences and location advantages. Applicable academic journal articles were comprehensively included in the study. The data was collected from electronic journal article databases using key words and almost only peer-reviewed, as new as possible articles were included. Also both the reference list of the included articles and article recommendations from professionals generated more articles for inclusion. The data was analyzed through thematization that resulted in themes that illuminate the purpose of the study and sub-questions. As an outcome of the analysis, each of the theory chapters in the study represents one sub-question. The literature used in this study revealed that strategic outsourcing of R&D is increasingly used in pharmaceutical industry and the major motives to practice it has to do with lowering costs, accessing skilled labor, resources and knowledge and enhancing their quality while speeding up the introduction of new drugs. Mainly for the above-mentioned motives India is frequently chosen as the target location for pharma outsourcers. Still, the literature is somewhat incomplete in this complex phenomenon and more research is needed.

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.

Performance and scalability of isolated DC-DC converter topologies in low voltage, high current applications

Fuel cells are a promising alternative for clean and efficient energy production. A fuel cell is probably the most demanding of all distributed generation power sources. It resembles a solar cell in many ways, but sets strict limits to current ripple, common mode voltages and load variations. The typically low output voltage from the fuel cell stack needs to be boosted to a higher voltage level for grid interfacing. Due to the high electrical efficiency of the fuel cell, there is a need for high efficiency power converters, and in the case of low voltage, high current and galvanic isolation, the implementation of such converters is not a trivial task. This thesis presents galvanically isolated DC-DC converter topologies that have favorable characteristics for fuel cell usage and reviews the topologies from the viewpoint of electrical efficiency and cost efficiency. The focus is on evaluating the design issues when considering a single converter module having large current stresses. The dominating loss mechanism in low voltage, high current applications is conduction losses. In the case of MOSFETs, the conduction losses can be efficiently reduced by paralleling, but in the case of diodes, the effectiveness of paralleling depends strongly on the semiconductor material, diode parameters and output configuration. The transformer winding losses can be a major source of losses if the windings are not optimized according to the topology and the operating conditions. Transformer prototyping can be expensive and time consuming, and thus it is preferable to utilize various calculation methods during the design process in order to evaluate the performance of the transformer. This thesis reviews calculation methods for solid wire, litz wire and copper foil winding losses, and in order to evaluate the applicability of the methods, the calculations are compared against measurements and FEM simulations. By selecting a proper calculation method for each winding type, the winding losses can be predicted quite accurately before actually constructing the transformer. The transformer leakage inductance, the amount of which can also be calculated with reasonable accuracy, has a significant impact on the semiconductor switching losses. Therefore, the leakage inductance effects should also be taken into account when considering the overall efficiency of the converter. It is demonstrated in this thesis that although there are some distinctive differences in the loss distributions between the converter topologies, the differences in the overall efficiency can remain within a range of a few percentage points. However, the optimization effort required in order to achieve the high efficiencies is quite different in each topology. In the presence of practical constraints such as manufacturing complexity or cost, the question of topology selection can become crucial.

Measuring effects of strategic utilization of social media in business-to-business marketing: Case Greenlux Finland Oy

Utilization of social media is increasingly common in B2B marketing. Social media is an efficient and cheap marketing and communication channel available for everyone, and thus extremely attractive marketing medium. The more companies get involved in social media the more failures are reported. It is not enough for a company to just be present in social media. Succeeding on it requires hard work, investing time and money, and ability to measure and to monitor performance. With an increasing number of companies failing in utilizing social media, together with lack of research on strategic utilization of social media focusing on B2B marketing, measuring, and monitoring create a purpose for this research. The aim of this research is to discover methods for measuring and monitoring effects of strategic utilization of social media in B2B marketing. Most relevant financial and non-financial indicators are discussed, and the methods by which these can be monitored and measured. In addition, effects of strategic utilization of social media on the case company are measured and analyzed. The research methodology used in this research is a participatory action research, which includes elements of both qualitative and quantitative research methods. The case company examined in the research provides a unique opportunity to follow through all phases of strategic utilization of social media for B2B marketing purposes concluding real effects of social media to the case company, and thus gain a deep understanding about this new marketing medium in the perspective of B2B marketing. Duration of the research period is seven months. During this time, information is collected, measured, and analyzed. Case company does not have any other marketing activities simultaneously which makes it possible to examine social media apart from effects of other visible marketing activities. Effects of strategic utilization of social media can be monitored and measured in many ways. Methods that should be used depend on goals set for social media. Fundamental nature of social media requires multidimensional assessment, and thus effects should be measured, and monitored considering both financial and non-financial indicators. The results implicates that effects of strategic utilization of social media are relatively wide ranged. According to the findings, social media affects positively on brand, number of web page visitors, visitor behavior, and on distribution of awareness. According to investment calculations social media is a legitimate investment for case company. Results also implicate that by using social media case company gains conversation, arouses interest, gets attention, and creates interactivity. In addition and as a side note, winter holiday season appears to have a great effect on social media activity of B2B companies’ representatives.

Rapid and sensitive detection of Bordetella bronchiseptica by loop-mediated isothermal amplification (LAMP)

Bordetella bronchiseptica causes acute and chronic respiratory infections in diverse animal species and occasionally in humans. In this study, we described the establishment of a simple, sensitive and cost-efficient loop-mediated isothermal amplification (LAMP) assay for the detection of B. bronchiseptica. A set of primers towards a 235 bp region within the flagellum gene of B. bronchiseptica was designed with online software.. The specificity of the LAMP assay was examined by using 6 porcine pathogens and 100 nasal swabs collected from healthy pigs and suspect infected pigs. The results indicated that positive reactions were confirmed for all B. bronchiseptica and no cross-reactivity was observed from other non-B. bronchiseptica. In sensitivity evaluations, the technique successfully detected a serial dilutions of extracted B. bronchiseptica DNA with a detection limit of 9 copies, which was 10 times more sensitive than that of PCR. Compared with conventional PCR, the higher sensitivity of LAMP method and no need for the complex instrumentation make this LAMP assay a promising alternative for the diagnosis of B. bronchiseptica in rural areas and developing countries where there lacks of complex laboratory services.

On Energy Efficient Computing Platforms

In accordance with the Moore's law, the increasing number of on-chip integrated transistors has enabled modern computing platforms with not only higher processing power but also more affordable prices. As a result, these platforms, including portable devices, work stations and data centres, are becoming an inevitable part of the human society. However, with the demand for portability and raising cost of power, energy efficiency has emerged to be a major concern for modern computing platforms. As the complexity of on-chip systems increases, Network-on-Chip (NoC) has been proved as an efficient communication architecture which can further improve system performances and scalability while reducing the design cost. Therefore, in this thesis, we study and propose energy optimization approaches based on NoC architecture, with special focuses on the following aspects. As the architectural trend of future computing platforms, 3D systems have many bene ts including higher integration density, smaller footprint, heterogeneous integration, etc. Moreover, 3D technology can signi cantly improve the network communication and effectively avoid long wirings, and therefore, provide higher system performance and energy efficiency. With the dynamic nature of on-chip communication in large scale NoC based systems, run-time system optimization is of crucial importance in order to achieve higher system reliability and essentially energy efficiency. In this thesis, we propose an agent based system design approach where agents are on-chip components which monitor and control system parameters such as supply voltage, operating frequency, etc. With this approach, we have analysed the implementation alternatives for dynamic voltage and frequency scaling and power gating techniques at different granularity, which reduce both dynamic and leakage energy consumption. Topologies, being one of the key factors for NoCs, are also explored for energy saving purpose. A Honeycomb NoC architecture is proposed in this thesis with turn-model based deadlock-free routing algorithms. Our analysis and simulation based evaluation show that Honeycomb NoCs outperform their Mesh based counterparts in terms of network cost, system performance as well as energy efficiency.

Regulation of self-renewal and detection of karyotypic changes of pluripotent human embryonic stem cells

Human embryonic stem cells are pluripotent cells capable of renewing themselves and differentiating to specialized cell types. Because of their unique regenerative potential, pluripotent cells offer new opportunities for disease modeling, development of regenerative therapies, and treating diseases. Before pluripotent cells can be used in any therapeutic applications, there are numerous challenges to overcome. For instance, the key regulators of pluripotency need to be clarified. In addition, long term culture of pluripotent cells is associated with the accumulation of karyotypic abnormalities, which is a concern regarding the safe use of the cells for therapeutic purposes. The goal of the work presented in this thesis was to identify new factors involved in the maintenance of pluripotency, and to further characterize molecular mechanisms of selected candidate genes. Furthermore, we aimed to set up a new method for analyzing genomic integrity of pluripotent cells. The experimental design applied in this study involved a wide range of molecular biology, genome-wide, and computational techniques to study the pluripotency of stem cells and the functions of the target genes. In collaboration with instrument and reagent company Perkin Elmer, KaryoliteTM BoBsTM was implemented for detecting karyotypic changes of pluripotent cells. Novel genes were identified that are highly and specifically expressed in hES cells. Of these genes, L1TD1 and POLR3G were chosen for further investigation. The results revealed that both of these factors are vital for the maintenance of pluripotency and self-renewal of the hESCs. KaryoliteTM BoBsTM was validated as a novel method to detect karyotypic abnormalities in pluripotent stem cells. The results presented in this thesis offer significant new information on the regulatory networks associated with pluripotency. The results will facilitate in understanding developmental and cancer biology, as well as creating stem cell based applications. KaryoliteTM BoBsTM provides rapid, high-throughput, and cost-efficient tool for screening of human pluripotent cell cultures.

Fast pyrolysis in circulating fluidized bed: feasibility study

Today the limitedness of fossil fuel resources is clearly realized. For this reason there is a strong focus throughout the world on shifting from fossil fuel based energy system to biofuel based energy system. In this respect Finland with its proven excellent forestry capabilities has a great potential to accomplish this goal. It is regarded that one of the most efficient ways of wood biomass utilization is to use it as a feedstock for fast pyrolysis process. By means of this process solid biomass is converted into liquid fuel called bio-oil which can be burnt at power plants, used for hydrogen generation through a catalytic steam reforming process and as a source of valuable chemical compounds. Nowadays different configurations of this process have found their applications in several pilot plants worldwide. However the circulating fluidized bed configuration is regarded as the one with the highest potential to be commercialized. In the current Master’s Thesis a feasibility study of circulating fluidized bed fast pyrolysis process utilizing Scots pine logs as a raw material was conducted. The production capacity of the process is 100 000 tonne/year of bio-oil. The feasibility study is divided into two phases: a process design phase and economic feasibility analysis phase. The process design phase consists of mass and heat balance calculations, equipment sizing, estimation of pressure drops in the pipelines and development of plant layout. This phase resulted in creation of process flow diagrams, equipment list and Microsoft Excel spreadsheet that calculates the process mass and heat balances depending on the bio-oil production capacity which can be set by a user. These documents are presented in the current report as appendices. In the economic feasibility analysis phase there were at first calculated investment and operating costs of the process. Then using these costs there was calculated the price of bio-oil which is required to reach the values of internal rate of return of 5%, 10%, 20%, 30%, 40%, and 50%.

Design and testing of an armature-reaction-compensated permanent magnet synchronous generator for island operation

At present, permanent magnet synchronous generators (PMSGs) are of great interest. Since they do not have electrical excitation losses, the highly efficient, lightweight and compact PMSGs equipped with damper windings work perfectly when connected to a network. However, in island operation, the generator (or parallel generators) alone is responsible for the building up of the network and maintaining its voltage and reactive power level. Thus, in island operation, a PMSG faces very tight constraints, which are difficult to meet, because the flux produced by the permanent magnets (PMs) is constant and the voltage of the generator cannot be controlled. Traditional electrically excited synchronous generators (EESGs) can easily meet these constraints, because the field winding current is controllable. The main drawback of the conventional EESG is the relatively high excitation loss. This doctoral thesis presents a study of an alternative solution termed as a hybrid excitation synchronous generator (HESG). HESGs are a special class of electrical machines, where the total rotor current linkage is produced by the simultaneous action of two different excitation sources: the electrical and permanent magnet (PM) excitation. An overview of the existing HESGs is given. Several HESGs are introduced and compared with the conventional EESG from technical and economic points of view. In the study, the armature-reaction-compensated permanent magnet synchronous generator with alternated current linkages (ARC-PMSG with ACL) showed a better performance than the other options. Therefore, this machine type is studied in more detail. An electromagnetic design and a thermal analysis are presented. To verify the operation principle and the electromagnetic design, a down-sized prototype of 69 kVA apparent power was built. The experimental results are demonstrated and compared with the predicted ones. A prerequisite for an ARC-PMSG with ACL is an even number of pole pairs (p = 2, 4, 6, …) in the machine. Naturally, the HESG technology is not limited to even-pole-pair machines. However, the analysis of machines with p = 3, 5, 7, … becomes more complicated, especially if analytical tools are used, and is outside the scope of this thesis. The contribution of this study is to propose a solution where an ARC-PMSG replaces an EESG in electrical power generation while meeting all the requirements set for generators given for instance by ship classification societies, particularly as regards island operation. The maximum power level when applying the technology studied here is mainly limited by the economy of the machine. The larger the machine is, the smaller is the efficiency benefit. However, it seems that machines up to ten megawatts of power could benefit from the technology. However, in low-power applications, for instance in the 500 kW range, the efficiency increase can be significant.