This study addresses the issue of how to convert peptides into drug-like non-peptides while retaining the biological activity at peptide receptors. Angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe, Ang II) was used as a model peptide. Small bioactive peptides are in most cases conformationally flexible molecules. Rigidified peptide analogues or peptidomimetic scaffolds can be introduced into the peptide, to enforce a particular backbone conformation, and thereby locate the side-chains at defined positions in space. The conformationally constrained analogues are of considerable value in determining biologically active conformation(s) of the studied peptide. The strategy applied in this thesis includes identification of non-pharmacophoric amino acid residues, rigidification, conformational analysis and incorporation of turn mimicking scaffolds in Ang II. Several side-chain cyclized (disulfide and methylendithioether) Ang II analogues have been synthesized. The binding studies of the rigidified analogues demonstrated that the compounds designed for the AT1-receptor had affinity for both receptor subtypes, while the compounds designed for the AT2-receptor displayed high selectivity only for this receptor subtype. Conformational evaluation revealed that several of the cyclized Ang II analogues most probably adopt a γ-turn like conformation around Tyr-4 while interacting with the Ang II receptor. Based on this hypothesis, three different γ-turn mimetics replacing amino acid residues 3-5 were designed, synthesized and incorporated into Ang II. One of the synthesized pseudopeptides, incorporating an azepine-containing γ-turn mimetic, exerted high binding affinity and agonistic activity. These results strongly support the theory that Ang II adopts a γ-turn like conformation when activating the AT1 receptor. The other Ang II analogues, incorporating bicyclic and aromatic γ-turn mimetics, did not display any binding to the AT1 receptor.

No description available.

Despite the unfavorable pharmacokinetic properties associated with peptides, they are still of great interest in drug development due to a multitude of interesting biological functions. The development of peptidomimetics strives to maintain or improve the biological activity of a peptide concurrently with removing the unwanted properties. This thesis describes two synthetic approaches to peptidomimetics with particular emphasis on secondary structure mimetics. First the design, synthesis and evaluation of two beta-turn mimetics incorporated in the endorphin Leu-enkephalin is presented. The beta-turn mimetics were stabilized by replacement of the intramolecular hydrogen bond with an ethylene bridge, and the amide bond between Tyr and Gly was replaced with an ether linkage. Linear analogues of the two mimetics were also synthesized. The peptidomimetics and their linear analogues were evaluated in a competitive binding assay at two opiate receptors, my and delta. One of the cyclized beta-turn mimetics was found to be a delta receptor antagonist with an IC50 value of 160 nM. Second a synthetic strategy to a beta-strand mimetic using 2-fluoro-4-iodopyridine as scaffold is described. The synthesis involved a Grignard exchange reaction on the pyridine scaffold using an amino acid derivative as electrophile followed by an SNAr reaction using an amine as nucleophile. The synthesis of a tripeptidomimetic of Leu-Gly-Gly and attempts to introduce chiral building blocks at the C-terminal, as well as studies towards elongated mimetics are presented. Two additional studies deal with the synthesis of two classes of potential thrombin inhibitors based on the pyridine scaffold. The first class contain pyridine as central fragment (P2 residue) substituted with a para-amidinobenzylamine group as P1 residue and various benzoyl groups as P3 residues. Three potential thrombin inhibitors were synthesized and found to be microM inhibitors in an enzymatic assay. In the second class, the pyridine ring serves as P3 residue. This class also lacks a strongly basic group in the P1 position. A small library of eight compounds were synthesized and evaluated in the enzymatic assay. Unfortunately, these compounds lacked inhibitory activity.

The video game is a deeply misunderstood medium, one that is often blamed as a root cause of violence, anti-social behaviour and the laziness of youth. In addition to those who judge video games as corrupting, there are those who note the complexity and instructive power of video games and hope to harness the technology for educational use. This thesis occupies a middle ground between these two poles. I argue that as a distinct textual form, video games are prime sites for encountering power and difference, as well as productive sites through which gamers come to know themselves. Video games are semiotic playing fields that, when theorized as such, call for pedagogical interventions focused on how we teach about the worlds we inhabit both virtual and actual. I end with an explanation of how video games can constructively be theorized as “ethical spaces” for learning about issues of social justice.

The video game is a deeply misunderstood medium, one that is often blamed as a root cause of violence, anti-social behaviour and the laziness of youth. In addition to those who judge video games as corrupting, there are those who note the complexity and instructive power of video games and hope to harness the technology for educational use. This thesis occupies a middle ground between these two poles. I argue that as a distinct textual form, video games are prime sites for encountering power and difference, as well as productive sites through which gamers come to know themselves. Video games are semiotic playing fields that, when theorized as such, call for pedagogical interventions focused on how we teach about the worlds we inhabit both virtual and actual. I end with an explanation of how video games can constructively be theorized as “ethical spaces” for learning about issues of social justice.

The development of an online method for the early detection of a stator turn insulation deterioration is the objective of the research at hand. A high percentage of motor breakdowns is related to the failure of the stator insulation system. Since most of the stator insulation failures originate in the breakdown of the turn-to-turn insulation, the research in this realm is of great significance. Despite the progress that has been made in the field of stator turn fault detection methods, the most popular and the best known ones are still limited to the detection of solid turn faults. The time span between a solid turn fault and the breakdown of the primary insulation system can be as short as a few seconds. Therefore, it is desirable to develop a method capable of detecting the deterioration of the turn insulation as early as possible and prior to the development of a solid turn fault. The different stresses that cause the aging of the insulation and eventually lead to failure are described as well as the various patterns of an insulation failure. A comprehensive literature survey shows the methods presently used for the monitoring of the turn insulation. Up to now no well-tested and reliable online method that can find the deterioration of the turn insulation is available. The most commonly used turn insulation test is the surge test, which, however, is performed only when the motor is out of service and disconnected from the supply. So far no research at all has been conducted on the application of an online surge test. The research at hand examines the applicability of the surge test to an operating machine. Various topologies of online surge testing are examined with regard to their practicability and their limitations. The most practical configuration is chosen for further analysis, implementation and development. Moreover, practical challenges are presented by the non-idealities of the induction machine like the eccentricity of the rotor and the rotor slotting, and have to be taken into account. Two solutions to eliminate the influence of the rotor position on the surge waveform are presented. Even though the basic concepts of online surge testing can be validated experimentally by a machine with a solid turn fault, it is preferable to use a machine with a deteriorated turn insulation. Therefore, a method, which does not require complex and expensive hardware, to experimentally emulate the turn insulation breakdown is implemented. The concepts at any stage of the work are supported by simulations and experimental results. In addition, the theory of surge testing is further developed by giving new definitions of the test's sensitivity, i.e., the frequency sensitivity and the error area ratio (EAR) sensitivity.

Interacting Multiple Model (IMM) estimator is used extensively to estimate trajectories of maneuvering targets in cluttered environment. In the standard tracking methods, it is assumed that movement of target is applicable to a certain model and the target could be monitored via the usage of status predictions of that model. However, targets can make different maneuvering movements. At that time, expression of target dynamic model with only one model can be insufficient. In IMM approach, target dynamic model is expressed with more than one model capsulating all maneuvering movements or with one model with different noise level values. This thesis investigates the tracking of the maneuvering ground targets in cluttered environment via IMM estimator with constant velocity model with low/high process noise, coordinated turn model and move-stop-move model. The selection strategies of models are highlighted and the state errors are calculated to evaluate the performance of IMM estimator.

In the study, it was aimed at determining the discourse patterns of text-based CMC in Second Life in terms of social presence, negotiation of meaning and turn distribution of the students. During the data collection procedure, 54 freshman students participated in the study. Some reading and writing tasks were carried out in Second Life. During the data analysis, the taxonomy adapted by Akayoglu &amp / Altun (2008) was used for negotiation of meaning and the taxonomy prepared by Rourke, Anderson, Garrison and Archer (2001) was used for social presence. Finally, the words uttered by each student were counted and the equality of turn distribution of the students was measured using Gini Coefficient. At the end of the study, it was found that the most frequently used social presence function was &ldquo / expression of emotions&rdquo / and the least frequently used function was &ldquo / quoting from others&rsquo / messages&rdquo / . In terms of negotiation of meaning functions, the most frequently used function was &ldquo / confirmation&rdquo / and the least frequently used function was &ldquo / reply vocabulary&rdquo / . As for the third research question, the numbers of the words uttered by the students were counted and Gini Coefficient was calculated. At the end of this analysis, it was seen that there was equality in all sessions in terms of turn distribution of the students as it was hypothesized in literature. The findings of this study might be helpful for students, educators and researchers who are willing to attend to and design language courses in Second Life. They might better understand the context.

No description available.

beta-Turns in many biologically active peptides are important secondary structural elements which are critical for their biological activities. Hence, it is not surprising that beta-turn based pharmacophore design including beta-turn mimetics has become a central topic in medicinal chemistry in addition to alpha-helix or helical peptides. One of the advantages of such beta-turn mimetics is that they can better control torsion angles of the backbone of peptides and to some degree dihedral angles chi (X). These beta-turn mimicking scaffolds are designed to have a higher avidity for the acceptor by overcoming what otherwise is the inherent entropic cost paid for beta-turn formation upon binding to the acceptor. Among different synthetic strategies to bicyclic structures as beta-turn mimetics, consecutive formation of bicyclic structures using tandem acid-catalyzed N-acyliminium ion cyclization is attractive since this methodology was well established in the synthesis of natural product alkaloids. 1,3,6,8-Substituted tetrahydro-2H-pyrazino[1,2-a]pyrimidine-4,7-diones were designed and synthesized as internal beta-turn mimetics through an acid-catalyzed tandem acyliminium ion cyclization. Its development and synthesis are decribed in Chapter 2 to Chapter 4. Its application toward the development and synthesis of a small molecule ligand for melanocortin receptors is described in Chapter 5. In addition, the development of peptidomimetics for opioid receptors is explained in Chapter 6. On the other hand, a dicarba analogue having opioid receptor agonist, and dicarba analogues for MCRs were synthesized through solid phase synthesis including a ring closing metathesis reaction using Grubbs' catalyst (I) in Chapter 8.