The main aim of this thesis was to discover and design new ligands for difficult, under-explored and clinically relevant protein targets. A number of protein-protein interaction complexes (PPIs) are introduced as the target focus for the methods employed and developed herein. This thesis is separated into two sections to independently address both peptides and small molecules as screening agents. The project examines both approaches through comprehensive library design strategies and screening by NMR spectroscopic methods. ATAD2 is the first PPI investigated and was expressed and purified in good yield and was also isotopically labelled with Nitrogen-15 for enhanced sensitivity and orthogonal ligand and protein-observed NMR methods. A known pentapeptide was synthesised by solid-phase peptide synthesis (SPPS) using Fmoc chemistry for target validation and tool compound development. A one-bead one-compound (OBOC) tripeptide library was synthesised by SPPS in good yield and purity, determined using single-bead labelling techniques with a fluorescent dye (TMR) and HPLC analysis. This library contained 3072 unique tripeptides with 12 central non-natural, lysine derivatives flanked by 16 natural L amino acids. The library screening technique was based on using a fluorescently labelled protein and Confocal Nanoscanning to detect binding. However, fluorescent labelling of ATAD2 was unsuccessful due to difficult protein handling conditions, therefore this library was not screened. The advent of small molecule, high affinity inhibitors of this target protein generated by GSK shifted focus to a different PPI target, the ubiquitin conjugating enzyme, UbE2L3. A novel 'on-protein peptide building' approach was introduced with the aim of screening a library of fluorinated dipeptides and extending the most potent via the 'N' and 'C' terminus to increase the affinity. A proof-of-concept tetrapeptide to survivin was synthesised by SPPS by incorporation of a non-natural, fluorinated amino acid in the known tetrapeptide sequence. This fluorinated derivative showed target binding activity by 19F NMR spectroscopy. The tripeptide and dipeptide truncates were synthesised by SPPS and binding was still observable by 19F NMR. This method was extended to screening a library of synthesised fluorinated dipeptides by 19F NMR against UbE2L3. A single dipeptide was identified with low affinity and the dipeptide was extended C and N terminally by SPPS to increase affinity. However, there were no tripeptides identified for this protein using this method. The proof of concept tetrapeptide was a success, therefore further protein targets are required to conclusively assess the viability of the approach. Fragment based screening is then introduced as a second approach to novel ligand discovery. Coupled with cheminformatics analysis and in silico library design, we created an in-house fluorinated fragment library consisting of 109 fluorinated fragments using three parallel methods. Compounds were purchased and quality checked by LCMS, HPLC and 19F-NMR. These fragment libraries were screened in a 19F NMR assay against the UbE2L3 and NusE/NusB protein targets. In a primary mixture screen, two fragment hits were identified against the NusE/NusB PPI and there were no fragment hits identified against the UbE2L3 protein. The two fragments against NusE/NusB were validated using orthogonal ligand-binding NMR methods. A mini-series, consisting of six commercially available analogues, were purchased and two fragment analogues showed increased affinity and were active against E. coli in a bacterial inhibition assay. The dissociation constants of the six active compounds were determined by 15N-HSQC NMR titration experiments and shown to be in 100-500 μM range. The binding sites of each compound were also determined by 15N-HSQC chemical shift mapping. These fragment hits represent a novel chemical scaffold identified against the NusE/NusB PPI and demonstrate the potential druggability of this new, complex target. The use of fluorine as a sensor for binding detection is evaluated by incorporating into both peptides and fragments. Through the use of novel library design strategies, a campaign to discover novel ligands of difficult protein targets is presented.

With the upcoming of the fifth generation of cellular networks there are several perfor- mance requirements that need to be satisfied. This thesis focuses on the topic of mobility which allows users to move through the network using the concept of handovers to switch between base stations. However, the thesis also keeps the energy efficiency in mind and investigates a strategy of reducing the energy consumption. Moving across base stations will inevitably lead to some handover failures, a goal of the system developers is to reduce these, but there exists a tradeoff between too early and too late handover failures. This thesis investigates two approaches of lowering the number of failures by letting the net- work self-optimize parameters in the handover procedure based upon the tradeoff. The first approach includes a parameter adaption to an estimated velocity of the users and the second one making a parameter more granular. Simulating different scenarios in a detailed network simulator shows performance gain by adapting handover parameters to the esti- mated velocity, but gathering more data regarding failures is needed before generalizing the conclusions.

<p>In this thesis, we have analyzed the ex-dividend stock price behavior in the London Stock Exchange to see if the stock prices really drop by the same amount as the dividend on the ex-dividend day. Our sample data covers 80 FTSE100 companies of the London stock exchange for the period 2001 to 2006.</p><p>To answer the research question: Do returns on the London Stock Exchange act in accordance with the efficient market hypothesis on the ex-dividend day? We used a deductive approach and test four hypothesis. The study was carried out by comparing the actual value of the raw price ratio, market adjusted price ratio, raw price drop and market adjusted price drop to their theoretical values. The difference was tested for significance using the one sample t-test.</p><p>The results showed that there are significant differences in the observed figures from their theoretical or expected values. The observed raw price ratio is higher than the expected value of 1, implying that the stock price on the ex-dividend day drops by an amount that is lower than the dividend paid. Similarly, the market adjusted raw price ratio is also higher than the expected value of 1. The raw price drop and market adjusted price drop are lower than the dividend yield, indicating again that the stock price drops by an amount that is lower than the dividend paid.</p><p>Our results indicated that the null hypotheses stated are rejected since the drop in the stock prices is not equal to the amount of the dividend on the ex-dividend day.</p>

<p>Background: We have reason to believe that in fear of doing wrong; most PPM investors are crippled to stay passive. Hence, they are not using the full potential of the PPM systems. Some are lured in to use professional pension saving steward by promises of abnormal return. According to efficient market hypothesis this would be impossible, however, studies have shown that their might exist inherent financial anomalies that by the utilization of historic information can open the window for abnormal return.</p><p>Purpose: The purpose of the study is to draw attention to the problem of using ex ante data to predict ex post returns. Thus, we would have evaluated the practical implication of using ex ante data as a determinant in relation to optimal PPM funds selection, and if possible to provide some simplistic guidelines for the average PPM investor.</p><p>Results: We found a handful of portfolios that gave significant results against their own index; however, when tested against Sverige, rena and Global, Mix bolag the evidence of abnormal return were thin.  From our results, we conclude that their seems to be a persistence effect, as top achievers continued to perform above average in almost all cases, however, one could not profitize on abnormal return other than by chance.  Consequently, historic return can give the investor an aid in optimal portfolio selection. Historic figures concerning standard deviation, expense ratios, and load fees all significantly correlated with return, however, neither seem to give the investor an edge in optimal PPM portfolio selection.</p>

Hand-held devices are among the most successful consumer electronics in modern society. Behind these successful devices, lies a key analog design technique that involves high-performance analog-to-digital conversion combined with very low power consumption. This dissertation presents two different approaches to achieving high power efficiency from a two-step pipelined architecture, which is generally known as one of the most power-consuming analog-to-digital converters. In the first approach, an analog feedback loop of a residue amplifier in a two-step pipelined analog-to-digital converter is reconfigured digitally using a single comparator and an R-2R digital-to-analog converter. This comparator-based structure can reduce power consumption of a conventional two-step pipelined analog-to-digital converter which consists of an opamp-based residue amplifier followed by a second- stage analog-to-digital converter. In addition, this dissertation includes circuit design techniques that provide a digital offset correction for the comparator-based two-step structure, binary-weighted switching for an R-2R digital-to-analog converter, and reference trimming for a flash analog-to-digital converter. A 10-b prototype analog-to-digital converter achieves an FOM of 121 fJ/conversion-step under 0.7-V supply. The second approach provides a way to achieve low power consumption for a high-resolution two-step pipelined analog-to-digital converter. An opamp is designed to consume optimized static power using a quarter-scaled residue gain together with minimized loading capacitance from the proposed second stage. A 14-b prototype analog-to-digital converter achieves an FOM of 31.3 fJ/conversion-step with an ENOB of 11.4 b, which is the lowest FOM in high-resolution analog-to-digital converters having greater than an ENOB of 10 b. Finally, the potential for further power reduction in a two-step pipelined analog-to-digital converter is discussed as a topic for future research. / Graduation date: 2012

A local reconfiguration algorithm (INP) for reliable routing in wireless sensor networks that consist of many static (fixed) energy-constrained nodes is introduced in the dissertation. For routing around crash fault nodes, a communication tree structure connecting sensor nodes to the base station (sink or root) is dynamically reconfigured during information dissemination. Unlike other location based routing approaches, INP does not take any support from a high costing system that gives position information such as GPS. For reconfigurations, INP uses only local relational information in the tree structure among nearby nodes by collaboration between the nodes that does not need global maintenance, so that INP is energy efficient and it scales to large sensor networks. The performance of the algorithm is compared to the single path with repair routing scheme (SWR) that uses a global metric and the modified GRAdient broadcast scheme (GRAB-F) that uses interleaving multiple paths by computation and by simulations. The comparisons demonstrate that using local relative information is mostly enough for reconfigurations, and it consumes less energy and mostly better delivery rates than other algorithms especially in dense environments. For the control observer to know the network health status, two new diagnosis algorithms (Repre and Local) that deal with crash faults for wireless sensor networks are also introduced in the dissertation. The control observer knows not only the static faults found by periodic testing but also the dynamic faults found by a path reconfiguration algorithm like INP that is invoked from evidence during information dissemination. With based on this information, the control observer properly treats the network without lateness. Local algorithm is introduced for providing scalability to reduce communication energy consumption when the network size grows. The performance of these algorithms is computationally compared with other crash faults identification algorithm (WSNDiag). The comparisons demonstrate that maintaining the communication tree with local reconfigurations in Repre and Local needs less energy than making a tree per each diagnosis procedure in WSNDiag. They also demonstrate that providing scalability in Local needs less energy than other approaches.

A local reconfiguration algorithm (INP) for reliable routing in wireless sensor networks that consist of many static (fixed) energy-constrained nodes is introduced in the dissertation. For routing around crash fault nodes, a communication tree structure connecting sensor nodes to the base station (sink or root) is dynamically reconfigured during information dissemination. Unlike other location based routing approaches, INP does not take any support from a high costing system that gives position information such as GPS. For reconfigurations, INP uses only local relational information in the tree structure among nearby nodes by collaboration between the nodes that does not need global maintenance, so that INP is energy efficient and it scales to large sensor networks. The performance of the algorithm is compared to the single path with repair routing scheme (SWR) that uses a global metric and the modified GRAdient broadcast scheme (GRAB-F) that uses interleaving multiple paths by computation and by simulations. The comparisons demonstrate that using local relative information is mostly enough for reconfigurations, and it consumes less energy and mostly better delivery rates than other algorithms especially in dense environments. For the control observer to know the network health status, two new diagnosis algorithms (Repre and Local) that deal with crash faults for wireless sensor networks are also introduced in the dissertation. The control observer knows not only the static faults found by periodic testing but also the dynamic faults found by a path reconfiguration algorithm like INP that is invoked from evidence during information dissemination. With based on this information, the control observer properly treats the network without lateness. Local algorithm is introduced for providing scalability to reduce communication energy consumption when the network size grows. The performance of these algorithms is computationally compared with other crash faults identification algorithm (WSNDiag). The comparisons demonstrate that maintaining the communication tree with local reconfigurations in Repre and Local needs less energy than making a tree per each diagnosis procedure in WSNDiag. They also demonstrate that providing scalability in Local needs less energy than other approaches.

In this thesis, we have analyzed the ex-dividend stock price behavior in the London Stock Exchange to see if the stock prices really drop by the same amount as the dividend on the ex-dividend day. Our sample data covers 80 FTSE100 companies of the London stock exchange for the period 2001 to 2006. To answer the research question: Do returns on the London Stock Exchange act in accordance with the efficient market hypothesis on the ex-dividend day? We used a deductive approach and test four hypothesis. The study was carried out by comparing the actual value of the raw price ratio, market adjusted price ratio, raw price drop and market adjusted price drop to their theoretical values. The difference was tested for significance using the one sample t-test. The results showed that there are significant differences in the observed figures from their theoretical or expected values. The observed raw price ratio is higher than the expected value of 1, implying that the stock price on the ex-dividend day drops by an amount that is lower than the dividend paid. Similarly, the market adjusted raw price ratio is also higher than the expected value of 1. The raw price drop and market adjusted price drop are lower than the dividend yield, indicating again that the stock price drops by an amount that is lower than the dividend paid. Our results indicated that the null hypotheses stated are rejected since the drop in the stock prices is not equal to the amount of the dividend on the ex-dividend day.

Background: We have reason to believe that in fear of doing wrong; most PPM investors are crippled to stay passive. Hence, they are not using the full potential of the PPM systems. Some are lured in to use professional pension saving steward by promises of abnormal return. According to efficient market hypothesis this would be impossible, however, studies have shown that their might exist inherent financial anomalies that by the utilization of historic information can open the window for abnormal return. Purpose: The purpose of the study is to draw attention to the problem of using ex ante data to predict ex post returns. Thus, we would have evaluated the practical implication of using ex ante data as a determinant in relation to optimal PPM funds selection, and if possible to provide some simplistic guidelines for the average PPM investor. Results: We found a handful of portfolios that gave significant results against their own index; however, when tested against Sverige, rena and Global, Mix bolag the evidence of abnormal return were thin.  From our results, we conclude that their seems to be a persistence effect, as top achievers continued to perform above average in almost all cases, however, one could not profitize on abnormal return other than by chance.  Consequently, historic return can give the investor an aid in optimal portfolio selection. Historic figures concerning standard deviation, expense ratios, and load fees all significantly correlated with return, however, neither seem to give the investor an edge in optimal PPM portfolio selection.

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