<p>G protein-coupled receptors (GPCR) are integral membrane proteins with seven α-helices that translate a remarkable diversity of signals into cellular responses. The superfamily of GPCRs is among the largest and most diverse protein families in vertebrates. </p><p>We have searched the human genome for GPCRs and show that the family includes approximately 800 proteins, which can divided into five main families; <i>Glutamate</i>, <i>Rhodopsin</i>, <i>Adhesion</i>, <i>Frizzled/Taste2</i> and <i>Secretin</i>. This study represents one of the first overall road maps of the GPCR family in a mammalian genome. Moreover, we identified eight novel members of the human <i>Adhesion</i> family which are characterized by long N-termini with various domains. We also investigated the GPCR repertoire of the chicken genome, where we manually verified a total of 557 chicken GPCRs. We detected several specific expansions and deletions that may reflect some of the functional differences between human and chicken.</p><p>Substantial effort has been made over the years to find compounds that can bind and activate the melanocortin 4 receptor (MC4R). This receptor is involved in food intake and is thus an important target for antiobesity drugs. We used site-directed mutagenesis to insert micromolar affinity binding sites for zinc between transmembrane (TM) regions 2 and 3. We generated a molecular model of the human MC4R which suggests that a rotation of TM3 is important for activation of the MC4R. </p><p>Furthermore, we present seven new vertebrate prolactin releasing hormone receptors (PRLHRs) and show that they form two separate subtypes, PRLHR1 and PRLHR2. We performed a pharmacological characterization of the human PRLHR which showed that the receptor can bind neuropeptide Y (NPY) related ligands. We propose that an ancestral PRLH peptide has coevolved with a redundant NPY binding receptor, which then became PRLHR. This suggests how gene duplication events can lead to novel peptide ligand/receptor interactions and hence spur the evolution of new physiological functions. </p>

<p>Solid organ transplantation is today an established form of treatment for end-stage organ disease. Monitoring of graft function and pharmacological therapy constitutes a maze of clinical observations and histological evaluations of biopsy specimens; with the biopsy results playing a decisive role. The aims of this doctoral research were to investigate the feasibility of detecting acute rejection of transplanted organs and monitoring the effect of anti-rejection treatment, with the use of ultrasmall superparamagnetic iron oxide particles (USPIO) and magnetic resonance (MR) imaging with a clinical MR scanner.</p><p>Allogeneic and syngeneic heterotopic heart transplantations were performed in rats. Three different-sized USPIO were given to one allogeneic and one syngeneic group. The change in MR signal intensity (SI) over time was measured. An increase in SI was interpreted as damage to micro vessels due to the pronounced inflammatory reaction caused by acute rejection, which led to leakage of USPIO into the tissue. A decrease in SI was interpreted as normal vascular structure, since USPIO normally remains in the intravascular space. The same method, using one of the previously tested USPIO, was used in a treatment study in which acute rejection in transplanted rats was induced and subsequently treated. An attempt was also made to detect presence of macrophages in an acutely rejecting graft, since this cell type plays an important role in the acute rejection process; this was done by testing the ability of macrophages to phagocytose the UPSIO compound.</p><p>In permeability studies with MR imaging all three USPIO tested discriminated between rejecting and non-rejecting grafts without any overlap of the groups. Factors that contributed to the ability to distinguish between grafts were the size and half-life of the particle. We were also able to monitor effects of anti-rejection treatment by studying the vascular permeability of USPIO and MR imaging. We did not succeed in detecting macrophages in the rejecting grafts with USPIO and MR imaging.</p><p>This thesis presents a novel approach to detection of acute rejection of transplanted organs and to monitoring the effects of anti-rejection treatment using different USPIO contrast agents and MR imaging in a clinical MR scanner.</p>

<p>Myocardial infarction (MI) causes high morbidity and mortality worldwide and for effective prevention and treatment MIs have to be adequately detected. </p><p>The existence of clinically unrecognized MIs (UMIs) has been known for the past hundred years, but an ultimate tool for their detection has not yet been found. Using persistent Q waves on electrocardiography as a sign of MI, it has been estimated that UMIs constitute at least ¼ of all MIs and have mortality rates similar to those of recognized MIs (RMIs). These estimates are misleading, however, since persistent Q waves do not necessarily represent MIs.</p><p>The late enhancement technique in magnetic resonance imaging (LE MRI) has been developed over the past decade and accurately determines myocardial viability. The aim of this research was to investigate the prevalence and impact of UMI and RMI in a population-based sample of 70-year-olds, assessed with MRI.</p><p>Cardiac function and viability were examined with MRI in 259 randomly selected 70-year-old subjects (127 women, 132 men) participating in a larger population-based study (PIVUS). Information on other parameters of cardiovascular disease was obtained and related to the findings.</p><p>Three methods for segmentation of the left ventricular mass were used in the first 100 subjects; these differed in accuracy and led to differences in systolic function values. In the subsequent 159 examinations one of the segmentation methods was used. </p><p>The viability images were assessable in 248 subjects (123 women, 125 men). Among these, the prevalence of UMI, 19.8%, definitely exceeded the expectations and UMIs constituted 4/5 of all MIs. The prevalence of RMI was 4.4%. MRI-detected UMIs differed from RMIs in several respects; they were smaller, frequently located inferolaterally, did not appear to be associated with atherosclerosis, and displayed increased collagen turnover. The pathogenesis of these UMIs remains to be investigated, but our observations suggest that they are caused by ischemia. Subjects with UMI showed increased cardiac morbidity, a decreased ejection fraction and an increased left ventricular mass, indicating an increased cardiovascular risk.</p><p>It is thus important to detect these UMIs, and this is adequately achieved by LE MRI. However, to decide upon prevention and treatment of these UMIs we need to know more about their pathogenesis and prognosis.</p>

Bakgrund: Under de senaste åren har samhället blivit alltmer kunskapsintensivt och som ett resultat av detta har den projektverksamhet som bedrivs i företag tilltagit. Denna utveckling har ändrat förutsättningarna för att använda sig av belöningar som ett styrmedel och det är därför av yttersta vikt att dagens företag anpassar sina belöningssystem efter de ändrade förutsättningarna. Syfte: Syftet med denna uppsats är att undersöka hur företag agerar vid belöning av anställda som arbetar i forsknings- och utvecklingsprojekt. Syftet är vidare att analysera eventuella olikheter företag emellan som kan förklara skillnader i deras agerande. Genomförande: Uppsatsen är baserad på sju intervjuer genomförda med personer som arbetar med belöning av anställda i forsknings- och utvecklingsprojekt. Dessa har genomförts på fem fallföretag. Resultat: Studien har visat att företag många gånger agerar relativt likartat vid belöning av anställda som arbetar i forsknings- och utvecklingsprojekt. De belöningar som utfaller är främst beroende av prestation, den anställde utvärderas vanligtvis av en person utanför projektet och de belöningsformer som används är såväl finansiella som icke-finansiella. Vissa skillnader föreligger dock mellan företags agerande och två ytterligheter har identifierats. Dessa skillnader menar vi är starkt kopplade till den verksamhet som bedrivs samt till den omfattning som de anställda arbetar i projektform.

Inom både skatterätten och redovisningsrätten finns begreppen pågående arbete och forskning och utveckling. Pågående arbete är uppdrag som ett företag utför för en annan persons räkning som är oavslutade vid räkenskapsårets utgång. De båda begreppen regleras olika både i skatterätten och i redovisningsrätten, varför gränsdragningen mellan forskning och utveckling och pågående arbete får betydelse för företag som arbetar på uppdrag av kunder samtidigt som man bedriver forsknings- och utvecklingsarbete. Syftet med den här uppsatsen är främst att analysera gränsdragningen mellan de skatterättsliga reglerna om forskning och utveckling och pågående arbete. Denna analys syftar till att komma fram till om det finns en skatterättslig gråzon inom vilken ett företag har möjlighet att välja om de vill hänföra en utgift till pågående arbete eller till forskning och utveckling. Även frågan om denna eventuella skatterättsliga gråzons gränser diskuteras. Utöver en analys av själva gränsdragningsproblematiken innehåller uppsatsen även en grundlig analys av själva begreppen pågående arbete och forskning och utveckling, samt en diskussion kring frågan om ett företags incitament att redovisa en utgift som pågående arbete respektive som forskning och utveckling. Min slutsats är att det finns en skatterättslig gråzon inom vilken ett företag har möjlighet att välja om de vill hänföra en utgift till pågående arbete eller till forskning och utveckling. Jag har även kommit till slutsatsen att det finns regler som sätter gränserna för denna skatterättslig gråzons omfattning.

Den 7 juni 2002 antogs EG-förordningen 1606/2002, vilken innebär en förpliktelse för noterade europeiska företag att fr o m räkenskapsåret 2005 upprätta sin koncernredovisning enligt International Accounting Standards (IAS). Förordningen ger även medlemsstaterna möjligheten att tillåta eller kräva en tillämpning av IAS även i juridisk person, d v s i årsredovisningen. Syftet med uppsatsen är att, med utgångspunkt i sambandet mellan redovisning och beskattning, analysera vilka konsekvenser förordningen kan komma att medföra för företagsbeskattningen i Sverige. För det första diskuteras hur beskattningen kan komma att påverkas om tillämpningen av förordningen begränsas till koncernnivå. För det andra diskuteras förordningens effekter i en situation där den även görs tillämplig i juridisk person, och därmed också direkt påverkar beskattningsunderlaget. För att konkretisera effekterna av en tillämpning av IAS i juridisk person undersöks slutligen ett område där svenska och internationella normer idag skiljer sig åt; utgifter för forskning och utveckling.

Frågan om hur företag skall behandla sina utgifter för Forskning och utveckling (FoU)skattemässigt är av stor betydelse eftersom det kan leda till stora skattekonsekvenser för företagen. Huvudfrågorna vid den skattemässiga behandlingen av ett företags utgifter och inkomster är de om omfång och periodisering. Även klassificeringen av en utgift är många gånger av största betydelse i en utredning. Eftersom FoU är ett vitt begrepp som kan omfatta verksamheter av olika typer och med olika resultat kan många avgränsningsfrågor tänkas uppkomma. Syftet med uppsatsen är att utreda hur företags utgifter för forskning och utveckling skall periodiseras skattemässigt. Som en del av periodiseringsfrågan måste även klassificeringar av utgifter göras. Syftet är därför även att analysera vad som utgör FoU och vilka avgränsningsproblem som kan uppkomma.

Eukaryotic gene transcription plays a regulatory role in mammalian developmental processes. It has been shown that transcriptional control is an important mechanism for specification of neurotransmitter phenotypes. In the mammalian central nervous system, the transcription factor AP-2 family is one of the critical regulatory factors for neural gene expression and neuronal development. It has been shown that several genes in the monoaminergic systems have AP-2 binding sites in regulatory regions, suggesting a regulatory role of AP-2 also in the adult brain. Brainstem monoamines are implicated in the expression of personality traits and imbalances in these systems may give rise to psychiatric disorders. The gene encoding AP-2β includes a polymorphic region consisting of a tetranucleotide repeat of [CAAA]4-5 in intron 2. Studies on AP-2β genotype in relation to personality and platelet MAO activity, a trait-dependant marker for personality, are presented in this thesis. Furthermore, correlations between brainstem levels of AP-2α and AP-2β and monoamine turnover in projection areas in rat forebrain are reported. These results strengthen the notion that the AP-2 family is important regulators of the monoaminergic systems in the adult brain. Furthermore, two studies are presented in this thesis with analyses indicating a role for AP-2 in the molecular mechanism of antidepressant drugs. Altogether, this thesis presents data supporting our notion that the transcription factor AP-2 family is involved in the regulation of the monoaminergic systems both pre- and postnatally, and, therefore, might be involved in the pathophysiology of neuropsychiatric disorders.

Plasma activity of the enzyme semicarbazide-sensitive amine oxidase (SSAO; EC.1.4.3.6) has been reported to be high in disorders such as diabetes mellitus, chronic congestive heart failure and liver cirrhosis. Little is known of how the activity is regulated and, consequently, the cause for these findings is not well understood. Due to the early occurrence of increased enzyme activity in diabetes, in conjunction with the production of highly cytotoxic substances in SSAO-catalysed reactions, it has been speculated that there could be a causal relationship between high SSAO activity and vascular damage. Aminoacetone and methylamine are the best currently known endogenous substrates for human SSAO and the resulting aldehyde-products are methylglyoxal and formaldehyde, respectively. Both of these aldehydes have been shown to be implicated in the formation of advanced glycation end products (AGEs). This thesis is based on studies exploring the regulation of SSAO activity and its possible involvement in the development of vascular damage. The results further strengthen the connection between high SSAO activity and the occurrence of vascular damage, since type 2 diabetic patients with retinopathy were found to have higher plasma activities of SSAO and lower urinary concentrations of methylamine than patients with uncomplicated diabetes. From studies on mice, it was also found that an SSAO inhibitor potently reduces the incorporation of methylamine-metabolite in the tissues. By quantifying SSAO-gene expression in alloxan-induced diabetes, increased transcription could be ruled out as a cause for the increased enzyme activity, thereby opening up for the possibility that the activity is regulated post-translationally. In fact, increased enzyme activity in adipose tissue was accompanied by decreased mRNA-levels, suggesting that the gene expression could be negatively controlled by the enzyme activity.

Oligopeptides can be used to carry cytotoxic agents in cancer chemotherapy, using tumour-associated proteins as the molecular target for selectivity. During the seventies and eighties Peptichemio, a cocktail of six alkylating oligopeptides carrying m-L-sarcolysin, was investigated in a wide variety of human malignancies. Positive clinical results were suggested to result from rapid and effective DNA-crosslinking following uptake in neoplastic cells, but also from antimetabolic properties of the drug. Although m-L-sarcolysin never reached widespread clinical use, the well established para-isomer melphalan still, after nearly fifty years, has a place in cancer chemotherapy. The present study was undertaken to synthesise the melphalan containing analogue of the tripeptide P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester, the main contributor to Peptichemio’s activity) and similar compounds, preferably dipeptides. The new compounds compared favourably with melphalan, m-L-sarcolysin and P2, considering their potency in vitro. Structure activity relationship analysis showed that the activity of melphalan dipeptides depended on the amino acid composition, sequence and end group modifications, but only to a minor degree on lipophilicity. Results suggested that the dipeptides, to exert their full cytotoxic activity, had to interact with specific biomolecules such as dipeptide transporters or peptidases. Although no active transport could be demonstrated the influence of peptide hydrolysis was obvious, thereby suggesting a rationale for increased activity as well as potential tumour selectivity in comparison with melphalan. Preliminary in vivo studies in mice supported the results, despite equal alkylating capacity the dipeptide J1 (melphalanyl-p-L-fluorophenylalanine ethyl ester) and the tripeptide J3 (L-prolyl-melphalanyl-p-L-fluorophenylalanine ethyl ester) were more active than was melphalan on human tumour cells implanted in test animals although all drugs produced expected side effects, notably leukopenia, of similar magnitude. In conclusion, oligopeptide derivatives of melphalan seem to provide improved cytotoxic activity and therapeutic index. Further development of such oligopeptides for clinical use seems worthwhile.