G protein-coupled receptors (GPCRs) are signal mediators that have a prominent role in the regulation of physiological processes and they make up the targets for 30-45% of all drugs. Papers I and II describe the discovery of new human GPCRs belonging to the Rhodopsin family, a family which contains many common drug targets. The new receptors have only weak relationships to previously known GPCRs. However, they have been evolutionary conserved in several species and most of them display distinct expression patterns. In paper III we identified new human GPCRs belonging to the Adhesion family, which is characterised by very long N-termini containing conserved domains. The different compositions of conserved domains as well as the expression patterns suggest that the Adhesions can have several different functions. In paper IV we revealed remarkable species variations in the repertoires of Trace Amine-Associated Receptors (TAARs), which are relatives of the biogenic amine receptors. The human, mouse and rat TAAR genes are located in only one locus and are therefore most likely the result of gene tandem duplications. 47 of the 57 zebrafish TAARs were mapped to nine different loci on six chromosomes containing from 1 to 27 genes each. This study suggests that the TAARs arose through several different mechanisms involving tetraploidisation, block duplications, and local duplication events. Papers V and VI are overall analyses of the repertoires of GPCRs in humans, mice and rats; which contain approximately 800, 1800 and 1900 members, respectively. The repertoires were compared to distinguish between species-specific and common (orthologous) members, something which is important for example when predicting drug effects from experiments in rodents. The Glutamate, Adhesion, Frizzled and Secretin families show no or very little variation between human and rodents, whereas the repertoires of olfactory, vomeronasal and Taste2 receptors display large differences between all three species.

The G-protein coupled receptors (GPCRs) comprise the largest family of receptors in humans and other vertebrates. They are embedded in the cell membrane and are activated by many different signaling molecules. Activation modulates cellular signal transduction pathways and influences many physiological processes. Therefore the GPCRs are important as targets for numerous drugs. The receptors for NPY (neuropeptide Y) belong to GPCRs of Class A (rhodopsin-like). NPY and its related peptides PYY and PP are involved in the regulation of appetite, blood pressure and many other processes. They share a common structure and interact with the receptors Y1, Y2, Y4 and Y5 in mammals, and, in addition, Y7 and Y8 in amphibians and bony fishes. This thesis is focused on the human Y2 receptor, known to reduce appetite, by investigating the importance of thirteen amino acid residues for ligand binding. Mutagenesis followed by functional expression and receptor binding was conducted. During the course of this work several new GPCR crystal structures have been resolved, thereby improving the receptor modeling in papers I-III. The major finding is that even though the Y1 and Y2 receptors have evolved from a common ancestor, their points of ligand interaction differ and have thus changed during evolution. In general, the positions investigated resulted in milder changes in the ligands’ affinities for Y2 compared to Y1. These findings were incorporated in the design of new Y1 and Y2 receptor models, leading to improved understanding of how such divergent receptors, sharing only 30 percent sequence identity, can still interact with the same ligands. Notably, several of the mutations introduced in Y2 resulted in increased affinity. A novel NPY receptor gene named Y2-2 was identified in the genomes of zebrafish and medaka. This brings the number of zebrafish NPY receptors to seven. The binding characteristics of zebrafish Y2-2 differed from zebrafish Y2 mainly in the interaction with NPY13-36 and the antagonist BIIE0246. In conclusion, these results increase our understanding of ligand interactions with GPCRs and will be useful for refinement of ligand-receptor models for future development of receptor subtype-selective drugs.

Excitation of the low frequency vibrational modes of a submerged vessel can generate significant radiated noise levels. Vibrational modes of a submarine hull are excited from the transmission of fluctuating forces through the shaft and thrust bearings due to the propeller rotating in an unsteady fluid. The focus of this work is to investigate the structural and acoustic responses of a submarine hull under axial excitation. The submarine hull is modelled as a cylindrical shell with internal bulkheads and ring stiffeners. The cylindrical shell is closed by truncated conical shells, which in turn are closed at each end using circular plates. The entire structure is submerged in a heavy fluid medium. The structural responses of the submerged vessel are calculated by solving the cylindrical shell equations of motion using a wave approach and the conical shell equations with a power series solution. The displacement normal to the surface of the structure in contact with the fluid medium was calculated by assembling the boundary/continuity matrix. The far field radiated sound pressure was then calculated by means of the Helmholtz integral. Results from the analytical model are compared with computational results from a fully coupled finite element/boundary element model. The individual and combined effects of the various influencing factors, corresponding to the ring stiffeners, bulkheads, conical end closures and fluid loading, on the structural and acoustic responses are characterised by examining the contribution by the circumferential modes. It is shown that equally spaced internal bulkheads generate a periodic structure thus creating a grouping effect for the higher circumferential modes, but do not have strong influence on the sound radiation. Stiffeners are found to have an important effect on both the dynamic and acoustic responses of the hull. The contribution of the conical end closures on the radiated sound pressure for the lowest circumferential mode numbers is also clearly observed. This work shows the importance of the bending modes when evaluating the sound pressure radiated by a submarine under harmonic excitation from the propulsion system.

Excitation of the low frequency vibrational modes of a submerged vessel can generate significant radiated noise levels. Vibrational modes of a submarine hull are excited from the transmission of fluctuating forces through the shaft and thrust bearings due to the propeller rotating in an unsteady fluid. The focus of this work is to investigate the structural and acoustic responses of a submarine hull under axial excitation. The submarine hull is modelled as a cylindrical shell with internal bulkheads and ring stiffeners. The cylindrical shell is closed by truncated conical shells, which in turn are closed at each end using circular plates. The entire structure is submerged in a heavy fluid medium. The structural responses of the submerged vessel are calculated by solving the cylindrical shell equations of motion using a wave approach and the conical shell equations with a power series solution. The displacement normal to the surface of the structure in contact with the fluid medium was calculated by assembling the boundary/continuity matrix. The far field radiated sound pressure was then calculated by means of the Helmholtz integral. Results from the analytical model are compared with computational results from a fully coupled finite element/boundary element model. The individual and combined effects of the various influencing factors, corresponding to the ring stiffeners, bulkheads, conical end closures and fluid loading, on the structural and acoustic responses are characterised by examining the contribution by the circumferential modes. It is shown that equally spaced internal bulkheads generate a periodic structure thus creating a grouping effect for the higher circumferential modes, but do not have strong influence on the sound radiation. Stiffeners are found to have an important effect on both the dynamic and acoustic responses of the hull. The contribution of the conical end closures on the radiated sound pressure for the lowest circumferential mode numbers is also clearly observed. This work shows the importance of the bending modes when evaluating the sound pressure radiated by a submarine under harmonic excitation from the propulsion system.

Thesis (Ph. D.)--University of Texas at Austin, 2007. / Vita. Includes bibliographical references.

Thesis (Ph.D.)--University of Melbourne, School of Earth Sciences, 2006. / Typescript. Includes bibliographical references (leaves 179-193).

Thesis (Ph.D.)--University of Nebraska-Lincoln, 2007. / Title from title screen (site viewed July 22, 2008). PDF text: viii, 127 p. : ill. (some col.) ; 2 Mb. UMI publication number: AAT 3296996. Includes bibliographical references. Also available in microfilm and microfiche formats.

Stuttgart, Univ., Diss., 2008.

Thesis (Ph. D.)--Oregon State University, 1993. / Typescript (photocopy). Includes bibliographical references (leaves 102-110). Also available on the World Wide Web.

Thesis (Ph.D.)--University of Tennessee Health Science Center, 2008. / Title from title page screen (viewed on November 5, 2008). Research advisor: Jie Zheng, Ph.D. Document formatted into pages (xiii, 140 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 105-116).