Protein Kinase C and Anaplastic Lymphoma Kinase Targeted Compounds

The protein kinases (PKs) belong to the largest single family of enzymes, phosphotransferases, which catalyze the phosphorylation of other enzymes and proteins and function primarily in signal transduction. Consequently, PKs regulate cell mechanisms such as growth, differentiation, and proliferation. Dysfunction of these cellular mechanisms may lead to cancer, a major predicament in health care. Even though there is a range of clinically available cancer-fighting drugs, increasing number of cancer cases and setbacks such as drug resistance, constantly keep cancer research active. At the commencement of this study an isophthalic acid derivative had been suggested to bind to the regulatory domain of protein kinase C (PKC). In order to investigate the biological effects and structure-activity relationships (SARs) of this new chemical entity, a library of compounds was synthesized. The best compounds induced apoptosis in human leukemia HL-60 cells and were not cytotoxic in Swiss 3T3 fibroblasts. In addition, the best apoptosis inducers were neither cytotoxic nor mutagenic. Furthermore, results from binding affinity assays of PKC isoforms revealed the pharmacophores of these isophthalic acid derivatives. The best inhibition constants of the tested compounds were measured to 210 nM for PKCα and to 530 nM for PKCδ. Among natural compounds targeting the regulatory domain of PKC, the target of bistramide A has been a matter of debate. It was initially found to activate PKCδ; however, actin was recently reported as the main target. In order to clarify and to further study the biological effects of bistramide A, the total syntheses of the natural compound and two isomers were performed. Biological assays of the compounds revealed accumulation of 4n polyploid cells as the primary mode of action and the compounds showed similar overall antiproliferative activities. However, each compound showed a distinct distribution of antimitotic effect presumably via actin binding, proapoptotic effect presumably via PKCδ, and pro-differentiation effect as evidenced by CD11b expression. Furthermore, it was shown that the antimitotic and proapoptotic effects of bistramide A were not secondary effects of actin binding but independent effects. The third aim in this study was to synthesize a library of a new class of urea-based type II inhibitors targeted at the kinase domain of anaplastic lymphoma kinase (ALK). The best compounds in this library showed IC50 values as low as 390 nM for ALK while the initial low cellular activities were successfully increased even by more than 70 times for NPM-ALK- positive BaF3 cells. More importantly, selective antiproliferative activity on ALK-positive cell lines was achieved; while the best compound affected the BaF3 and SU-DHL-1 cells with IC50 values of 0.5 and 0.8 μM, respectively, they were less toxic to the NPM-ALK-negative human leukemic cells U937 (IC50 = 3.2 μM) and BaF3 parental cells (IC50 = 5.4 μM). Furthermore, SAR studies of the synthesized compounds revealed functional groups and positions of the scaffold, which enhanced the enzymatic and cellular activities.

Late-industrial sawmill customers.

The methods of secondary wood processing are assumed to evolve over time and to affect the requirements set for the wood material and its suppliers. The study aimed at analysing the industrial operating modes applied by joinery and furniture manufacturers as sawnwood users. Industrial operating mode was defined as a pattern of important decisions and actions taken by a company which describes the company's level of adjustment in the late-industrial transition. A non-probabilistic sample of 127 companies was interviewed, including companies from Denmark, Germany, the Netherlands, and Finland. Fifty-two of the firms were furniture manufacturers and the other 75 were producing windows and doors. Variables related to business philosophy, production operations, and supplier choice criteria were measured and used as a basis for a customer typology; variables related to wood usage and perceived sawmill performance were measured to be used to profile the customer types. Factor analysis was used to determine the latent dimensions of industrial operating mode. Canonical correlations analysis was applied in developing the final base for classifying the observations. Non-hierarchical cluster analysis was employed to build a five-group typology of secondary wood processing firms; these ranged from traditional mass producers to late-industrial flexible manufacturers. There is a clear connection between the amount of late-industrial elements in a company and the share of special and customised sawnwood it uses. Those joinery or furniture manufacturers that are more late-industrial also are likely to use more component-type wood material and to appreciate customer-oriented technical precision. The results show that the change is towards the use of late-industrial sawnwood materials and late-industrial supplier relationships.

A modell of socially optimal hydro reservoir usage - yelding socially optimal outcomes in nordic electricity markets

An extensive electricity transmission network facilitates electricity trading between Finland, Sweden, Norway and Denmark. Currently most of the area's power generation is traded at NordPool, where the trading volumes have steadily increased since the early 1990's, when the exchange was founded. The Nordic electricity is expected to follow the current trend and further integrate with the other European electricity markets. Hydro power is the source for roughly a half of the supply in the Nordic electricity market and most of the hydro is generated in Norway. The dominating role of hydro power distinguishes the Nordic electricity market from most of the other market places. Production of hydro power varies mainly due to hydro reservoirs and demand for electricity. Hydro reservoirs are affected by water inflows that differ each year. The hydro reservoirs explain remarkably the behaviour of the Nordic electricity markets. Therefore among others, Kauppi and Liski (2008) have developed a model that analyzes the behaviour of the markets using hydro reservoirs as explanatory factors. Their model includes, for example, welfare loss due to socially suboptimal hydro reservoir usage, socially optimal electricity price, hydro reservoir storage and thermal reservoir storage; that are referred as outcomes. However, the model does not explain the real market condition but rather an ideal situation. In the model the market is controlled by one agent, i.e. one agent controls all the power generation reserves; it is referred to as a socially optimal strategy. Article by Kauppi and Liski (2008) includes an assumption where an individual agent has a certain fraction of market power, e.g. 20 % or 30 %. In order to maintain the focus of this thesis, this part of their paper is omitted. The goal of this thesis is two-fold. Firstly we expand the results from the socially optimal strategy for years 2006-08, as the earlier study finishes in 2005. The second objective is to improve on the methods from the previous study. This thesis results several outcomes (SPOT-price and welfare loss, etc.) due to socially optimal actions. Welfare loss is interesting as it describes the inefficiency of the market. SPOT-price is an important output for the market participants as it often has an effect on end users' electricity bills. Another function is to modify and try to improve the model by means of using more accurate input data, e.g. by considering pollution trade rights effect on input data. After modifications to the model, new welfare losses are calculated and compared with the same results before the modifications. The hydro reservoir has the higher explanatory significance in the model followed by thermal power. In Nordic markets, thermal power reserves are mostly nuclear power and other thermal sources (coal, natural gas, oil, peat). It can be argued that hydro and thermal reservoirs determine electricity supply. Roughly speaking, the model takes into account electricity demand and supply, and several parameters related to them (water inflow, oil price, etc.), yielding finally the socially optimal outcomes. The author of this thesis is not aware of any similar model being tested before. There have been some other studies that are close to the Kauppi and Liski (2008) model, but those have a somewhat different focus. For example, a specific feature in the model is the focus on long-run capacity usage that differs from the previous studies on short-run market power. The closest study to the model is from California's wholesale electricity markets that, however, uses different methodology. Work is constructed as follows.

An empirical evaluation of a framework for design for variety and novelty

The objective of this paper is to empirically evaluate a framework for designing – GEMS of SAPPhIRE as req-sol – to check if it supports design for variety and novelty. A set of observational studies is designed where three teams of two designers each, solve three different design problems in the following order: without any support, using the framework, and using a combination of the framework and a catalogue. Results from the studies reveal that both variety and novelty of the concept space increases with the use of the framework or the framework and the catalogue. However, the number of concepts and the time taken by the designers decreases with the use of the framework and, the framework and the catalogue. Based on the results and the interview sessions with the designers, an interactive framework for designing to be supported on a computer is proposed as future work.

Computational representations for multi state design tasks and enumeration of mechanical device behaviour

The role of a computer emerged from modeling and analyzing concepts (ideas) to generate concepts. Research into methods for supporting conceptual design using automated synthesis had attracted much attention in the past decades. To find out how designers synthesize solution concepts for multi-state mechanical devices, ten experimental studies were conducted. Observations from these empirical studies would be used as the basis to develop knowledge involved in the multi-state design synthesis process. In this paper, we propose a computational representation for expressing the multi-state design task and for enumerating multi-state behaviors of kinematic pairs and mechanisms. This computational representation would be used to formulate computational methods for the synthesis process to develop a system for supporting design synthesis of multiple state mechanical devices by generating a comprehensive variety of solution alternatives.

Analysing modifica-tions in the synthesis of multiple state mechanical devices using configuration space and topology graphs

Automated synthesis of mechanical designs is an important step towards the development of an intelligent CAD system. Research into methods for supporting conceptual design using automated synthesis has attracted much attention in the past decades. In our research, ten experimental studies are conducted to find out how designers synthesize solution concepts for multi-state mechanical devices. The designers are asked to think aloud, while carrying out the synthesis. These design synthesis processes are video recorded. It has been found that modification of kinematic pairs and mechanisms is the major activity carried out by all the designers. This paper presents an analysis of these synthesis processes using configuration space and topology graph to identify and classify the types of modifications that take place. Understanding of these modification processes and the context in which they happened is crucial to develop a system for supporting design synthesis of multiple state mechanical devices that is capable of creating a comprehensive variety of solution alternatives.

BIOCARDS AND LEVEL OF ABSTRACTION

Biocards are formal descriptions of biological phenomena and their underlying functional principles. They are used in bioinspired design to document search results and to communicate the findings for use in the further design process. The present study explored the effect of abstraction level used in biocards. This was done in two workshops conducted with design students in Denmark and India. Students were given a design assignment and instructions for how to perform the BID ideation work. Half of the students were given biocards with abstract descriptions while the other half got biocards with concrete descriptions. The novelty of found solutions was evaluated by the students by rating novelty of each solution on a scale from 1 to 5. Mean values for abstract descriptions were 0,3 higher than for concrete descriptions indicating that more innovative solutions were found when students used biocards with abstract descriptions compared to concrete descriptions. The difference in mean value is significant with a confidence level better than 1%. It seems likely that more abstract descriptions in biocards helps avoiding design fixation in biomimetic design work.