The long-term external financing of a corporation is satisfied through the bond market where issues of index-linked bonds, which are discussed in this thesis, is one alternative. (Finnerty&Emery 2001) An index- linked bond is a debt instrument where the investor is guaranteed the principal and premium amount in real terms. As the bonds cash flows are indexed to the inflation this implies that the issuer of an index-linked bond assumes an inflation risk. Purpose: The purpose of this thesis is to describe and examine corporate motives for choosing index-linked bonds as way of financing their business. Realization: Primary data was collected through interviews with corporate issuers of non-swapped index-linked bonds. Results: From our research it has been acknowledged that both internal and external factors determine the decision to issue index-linked bonds. The most important internal reason for the issuance was that this type of financing implies matching advantages, which helps lowering the companies’ risks. This is achieved by balancing the size and time of the cash inflows with the cash out- flows. Of the external factors we found that it is primary the financing cost that is of interest. The cost savings are primarily achieved because of the lower liquidity premium demanded when using index-linked bonds as a way of financing the business. We believe that this depends partly on the character of the investors and on market imperfections.

The main purpose of this thesis is to examine how Lean is applied at the Akademiska hospital in Uppsala, Sweden. Lean is regarded as a solution for many issues connected to healthcare. We consider it interesting to examine to what extent Lean is applicable to healthcare in regard with that Lean is initially created for the production industry. We have conducted interviews with leaders and employees at the head division and at four different departments to see if there exists a difference in how they work Lean. From our study we can see that Lean is manifested differently at the departments based on which typology of technology they belong to and how the leaders communicate Lean to its employees. We hope that this study has clarified both difficulties and opportunities with implementing Lean at a hospital. Suggestions for further studies would be to examine what implications there could be with combining Lean with other management philosophies.

Programmed cell death (apoptosis) is the most common mechanism of cell death in eukaryotes. The ability of cancer cells to evade and inhibit apoptosis has become a hallmark feature of cancer. This is accomplished through a family of proteins known as the inhibitor of apoptosis proteins (IAPs). X-Linked inhibitor of apoptosis protein (XIAP) is one of the best characterized IAPs. XIAP suppresses apoptosis by forming complexes with cysteine-aspartic proteases (caspase), through one of its baculovirus IAP repeat (BIR) domains. Its activity is endogenously antagonized by a second mitochondria derived activator of caspase (Smac). The anti-apoptotic behaviour of XIAP and the critical role it plays in the apoptotic program makes the Smac-XIAP interaction an important drug target. To this end, our laboratory is interested in synthesizing biologically related Smac mimetics which can induce apoptosis in a MDA-MB-231 cell line. Efforts have focused on (1) understanding BIR domain binding sites which allow for this interaction, and (2) the design and synthesis of molecules which are much more effective at inducing apoptosis compared to other well known analogues. Through the synthesis and evaluation of various divalent Smac mimetics we have been able to support the hypothesis that the likely binding site on XIAP is the BIR3 domain. As well, through the synthesis of a library of novel compounds, as described in the thesis, we have been able to assess the nature of the linker which joins the two tetrapeptide units. In our effort to understand which domains Smac binds with, various divalent analogues were synthesized containing MeAVPI-linker-IPVMeA (forward-reverse) and MeAVPI-linker-MeAVPI (forward-forward) sequence, which incorporated linkers with varying degrees of flexibility. We hypothesized that the forward-forward divalent mimetics would have decreased activity compared to the peptides synthesized in a forward-reverse fashion. Lastly, information gathered from structure activity relationship (SAR) studies have shown that substituting the lysine (P2) and isoleucine residues (P4) in the AVPI protein can create more potent inducers of apoptosis than its native AVPI sequence. As one of the most potent Smac mimetic that has been previously made known contains an alkyne bridge at P2 and a large hydrophobic moiety at P4, we hypothesized that similar Smac mimetics containing a propargyl glycine residue at P2 and a bulky hydrophobic moiety at P4 will be much more potent in inducing apoptosis.

Programmed cell death (apoptosis) is the most common mechanism of cell death in eukaryotes. The ability of cancer cells to evade and inhibit apoptosis has become a hallmark feature of cancer. This is accomplished through a family of proteins known as the inhibitor of apoptosis proteins (IAPs). X-Linked inhibitor of apoptosis protein (XIAP) is one of the best characterized IAPs. XIAP suppresses apoptosis by forming complexes with cysteine-aspartic proteases (caspase), through one of its baculovirus IAP repeat (BIR) domains. Its activity is endogenously antagonized by a second mitochondria derived activator of caspase (Smac). The anti-apoptotic behaviour of XIAP and the critical role it plays in the apoptotic program makes the Smac-XIAP interaction an important drug target. To this end, our laboratory is interested in synthesizing biologically related Smac mimetics which can induce apoptosis in a MDA-MB-231 cell line. Efforts have focused on (1) understanding BIR domain binding sites which allow for this interaction, and (2) the design and synthesis of molecules which are much more effective at inducing apoptosis compared to other well known analogues. Through the synthesis and evaluation of various divalent Smac mimetics we have been able to support the hypothesis that the likely binding site on XIAP is the BIR3 domain. As well, through the synthesis of a library of novel compounds, as described in the thesis, we have been able to assess the nature of the linker which joins the two tetrapeptide units. In our effort to understand which domains Smac binds with, various divalent analogues were synthesized containing MeAVPI-linker-IPVMeA (forward-reverse) and MeAVPI-linker-MeAVPI (forward-forward) sequence, which incorporated linkers with varying degrees of flexibility. We hypothesized that the forward-forward divalent mimetics would have decreased activity compared to the peptides synthesized in a forward-reverse fashion. Lastly, information gathered from structure activity relationship (SAR) studies have shown that substituting the lysine (P2) and isoleucine residues (P4) in the AVPI protein can create more potent inducers of apoptosis than its native AVPI sequence. As one of the most potent Smac mimetic that has been previously made known contains an alkyne bridge at P2 and a large hydrophobic moiety at P4, we hypothesized that similar Smac mimetics containing a propargyl glycine residue at P2 and a bulky hydrophobic moiety at P4 will be much more potent in inducing apoptosis.

In previous research on pricing mortality-linked securities, the no-arbitrage approach is often used. However, this method, which takes market prices as given, is difficult to implement in today's embryonic market where there are few traded securities. In particular, with limited market price data, identifying a risk neutral measure requires strong assumptions. In this thesis, we approach the pricing problem from a different angle by considering economic methods. We propose pricing approaches in both competitive market and non-competitive market. In the competitive market, we treat the pricing work as a Walrasian tâtonnement process, in which prices are determined through a gradual calibration of supply and demand. Such a pricing framework provides with us a pair of supply and demand curves. From these curves we can tell if there will be any trade between the counterparties, and if there will, at what price the mortality-linked security will be traded. This method does not require the market prices of other mortality-linked securities as input. This can spare us from the problems associated with the lack of market price data. We extend the pricing framework to incorporate population basis risk, which arises when a pension plan relies on standardized instruments to hedge its longevity risk exposure. This extension allows us to obtain the price and trading quantity of mortality-linked securities in the presence of population basis risk. The resulting supply and demand curves help us understand how population basis risk would affect the behaviors of agents. We apply the method to a hypothetical longevity bond, using real mortality data from different populations. Our illustrations show that, interestingly, population basis risk can affect the price of a mortality-linked security in different directions, depending on the properties of the populations involved. We have also examined the impact of transitory mortality jumps on trading in a competitive market. Mortality dynamics are subject to jumps, which are due to events such as the Spanish flu in 1918. Such jumps can have a significant impact on prices of mortality-linked securities, and therefore should be taken into account in modeling. Although several single-population mortality models with jump effects have been developed, they are not adequate for trades in which population basis risk exists. We first develop a two-population mortality model with transitory jump effects, and then we use the proposed mortality model to examine how mortality jumps may affect the supply and demand of mortality-linked securities. Finally, we model the pricing process in a non-competitive market as a bargaining game. Nash's bargaining solution is applied to obtain a unique trading contract. With no requirement of a competitive market, this approach is more appropriate for the current mortality-linked security market. We compare this approach with the other proposed pricing method. It is found that both pricing methods lead to Pareto optimal outcomes.

In the biopharmaceutical industry, identification of glycans in a glycoprotein is a regulatory requirement and is a part of the characterization of the protein. Glycans are constructed of several monosaccharides linked together. N-linked glycans, which have been studied in this project, are attached to the nitrogen atom in asparagine. A method for separating N-linked glycans by high performance anion exchange chromatography had already been developed at the department. To develop a method for identification of the N-glycans by mass spectrometry, a desalting method on porous graphitic carbon (PGC) columns was used and optimized resulting in the eluents A (0,05% TFA in ACN:water 5:95 v/v) and B (0,05% TFA in ACN:water 50:50 v/v). Also the sample introduction on the mass spectrometer was optimized and resulted in a sensitive on-line liquid chromatography mass spectrometry (LC-MS) approach which gave mass spectrometric peaks with high signal to noise ratios and with high mass accuracy. The developed procedure was then successfully used on glycans cleaved from a glycoprotein separated by high performance anion exchange chromatography with pulsed amperometric detector.

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ABSTRACT PREPARATION OF CROSS-LINKED TYROSINASE AGGREGATES Aytar, Burcu Selin M.S., Department of Chemical Engineering Supervisor: Prof. Dr. Ufuk Bakir June 2006, 82 pages The aim of this study was to prepare cross-linked enzyme aggregate (CLEA) from crude mushroom (Agaricus bisporus) extract. However, the optimization of CLEA production was performed by using pure tyrosinase. Important parameters were determined as protein, ammonium sulfate and glutaraldehyde concentrations, CLEA particle size, and cross-linking temperature and period. On the other hand, the order of ammonium sulfate and glutaraldehyde addition did not affect the yield of CLEA. Optimum CLEA preparation conditions were 60 % ammonium sulfate saturation, 2 % (v/v) glutaraldehyde, and 3 hour cross-linking reaction at room temperature. Particle size of the CLEAs should be reduced by mechanical stirring to eliminate mass transfer limitations. Under these circumstances, 100 % recovery was obtained from both pure and crude tyrosinases. Optimum temperature and the activation energy for catechol oxidation were determined as 34 oC and 16.9 kcal/mol for CLEAs, whereas, 32 oC and 12.5 kcal/mol for the free enzyme. Furthermore, the thermostability of CLEAs was significantly higher than the free enzyme. CLEAs, prepared from crude mushroom extract, retained 72 % of its maximum activity in eight months storage at 4 oC. Moreover, changing the storage temperature from 4 oC to room temperature did not decrease CLEAs stabilities.

The main object of the presented study was investigation of the use of cross-linked enzyme (tyrosinase) aggregates (CLTA) obtained from crude mushroom extract for a rapid phenolic content analysis in wines. In addition, a comparison of phenolic characteristics of Turkish red wines was performed. Reproducible and reliable results in total phenolic measurement were obtained with CLTAs similar to pure tyrosinase and tyrosinase obtained from crude mushroom extract. Measurement of total phenolic content is possible both in standard solutions and in complex matrices, such as wine. In a very short time period, 10 seconds, phenolics content in red and white wines produced from grapes of Turkey were investigated by using CLTAs. Results were consistent when compared to a well known phenolic measurement method, Folin-Ciocalteau. CLTAs exhibited very high operational stability and retained more than 90% of its activity after 30th use. Moreover, it showed good shelf-life stability for about 2 months storage by maintaining 90% of its maximum activity. So, use of CLTAs prepared from crude mushroom extract is an effective, fast and cheap alternative in total phenolics measurements in wines. Moreover, a novel catalase phenoloxidase (CATPO) produced by a fungal microorganism, Scytalidium thermophilum, was studied to check its capabilities in phenolics measurements. This novel catalase phenol oxidase showed similarly good results, exhibiting widesubstrate selectivity.

名古屋大学博士学位論文 学位の種類 : 博士(医学)(論文) 学位授与年月日:平成9年2月28日 森脇崇之氏の博士論文として提出された