Proefschrift Universiteit Maastricht. / Met lit. opg. - Met samenvatting in het Nederlands.

Proefschrift Universiteit Maastricht. / Met lit. opg. - Met samenvatting in het Nederlands.

Proefschrift Rijksuniversiteit Limburg, Maastricht. / Met samenvatting in het Engels. - Met lit. opg.

Les prions sont des agrégats amyloïdes infectieux. Le prion [Het-s] de Podospora anserina est un des prions le mieux caractérisé. Le prion [Het-s] est impliqué dans l’incompatibilité végétative – un processus biologique qui a lieu au cours des anastomoses entre des souches génétiquement différentes. Quand une souche [Het-s] fusionne avec une souche exprimant l’allèle alternatif du gène het-s – l’allèle het-S – une réaction de mort cellulaire programmée est déclenchée. Les deux protéines diffèrent de 13 acides aminés et partagent une architecture en deux domaines ; un domaine globulaire en N-terminal nommé HeLo et un domaine PFD (Prion Forming Domain) en C-terminal. Il a été établi qu’en présence des fibres amyloïdes de [Het-s], la protéine HET-S agit en ‘pore-forming’ toxine : la transconformation du PFD de HET-S par les fibres amyloïdes du [Het-s] active le domaine HeLo de HET-S et entraîne la mort cellulaire. Afin de mieux caractériser les propriétés du repliement β-solénoïde du prion [Het-s], nous avons entrepris l’exploration in vivo des relations structure-fonction de ce repliement par une approche d’alanine scanning. Au cours de nos recherches pour des homologues de HET-S/s, nous avons identifié un partenaire fonctionnel de HET-S – une protéine appelée NWD2. NWD2 est une protéine STAND et partage une séquence homologue (3-23) au PFD de HET-S/s. Les protéines STAND, après la reconnaissance d’un ligand, forment des plateformes oligomériques pour transduire le signal. Des analyses génomiques in silico réalisées dans plusieurs génomes fongiques nous ont amené à proposer que la transduction du signal via une protéine STAND à repliement amyloïde est un mécanisme ancien et conservé chez les champignons. Dans ce contexte nous avons identifié deux nouveaux motifs PFD putatifs – σ et PP. En soumettant à l’épreuve notre hypothèse, nous avons d’abord démontré que NWD2 interagit avec HET-S/s en fonction d’un ligand spécifique in vivo et l’interaction est dépendante de la séquence NWD2(3-23) homologue au PFD de HET-S/s. Nous avons ensuite exploré le motif PP associé à un domaine HeLo-like (HELL) dans le génome de Chaetomium globosum. En démontrant la nature amyloïde et prion-like du motif PP ainsi que l’analogie fonctionnelle entre ce motif et le PFD de HET-S/s in vivo nous avons apporté des arguments supplémentaires en faveur de l’implication des repliements amyloïdes dans la transduction du signal chez les champignons filamenteux. / Prions are infectious amyloid aggregates. Podospora anserina’s [Het-s] is one of the best characterized fungal prions with a remarkably high prevalence in wild populations. [Het-s] functions in vegetative incompatibility - a biological process occurring during anastomosis between two genetically incompatible strains. When an [Het-s] prion infected strain fuses with a strain expressing the alternative allelic variant of the het-s locus – het-S – a cell death reaction of the heterokaryon occurs. Differing by 13 amino acids both proteins shares two domain architecture; a globular N-terminal domain called HeLo and a C-terminal Prion Forming Domain (PFD). It has been demonstrated that in presence of [Het-s] amyloid fibers HET-S turns into a pore-forming toxin: transconformation of the HET-S PFD by [Het-s] fibers triggers the refolding of the HET-S HeLo domain, inducing the cell death reaction. In an attempt to better characterize the conserved features of the [Het-s] β-solenoid fold we have used a mutational alanine scanning approach and explored in vivo the existing relations between structure and prion functions of [Het-s]. During our quest for new distant homologues of HET-S/s, we have identified a functional partner of HET-S toxin called NWD2. NWD2 is a STAND protein and shares a homology sequence (3-23) in the HET-S/s PFD. STAND proteins form signal transducing hubs through oligomerization upon ligand recognition. Several in silico analysis in various fungal genomes led us to propose that signal transduction via a STAND protein using an amyloid prion-like fold is a general widespread mechanism in fungi. In that context, we have proposed two novel putative PFD motifs called σ and PP. Testing experimentally our hypothesis, we have first demonstrated that NWD2 interacts with HET-S/s upon ligand recognition in vivo and the interaction is dependant of the NWD2(3-23) region. We have then explored the newly identified putative prion domain PP, associated to a Helo-like domain (termed HELL) from the filamentous fungus Chaetomium globosum. By demonstrating the amyloid, prion-like nature of the PP motif and the functional analogy between PP and HET-S/s PFD domain in vivo, we expose further evidences supporting the implication of amyloid folds in signal transduction in filamentous fungi.

Considerando que os produtos cosméticos são de livre acesso ao consumidor e alguns podem acidentalmente entrar em contato com os olhos, eles devem ser aprovados em testes de irritação ocular. Durante muitos anos, essa avaliação foi feita pelo teste de Draize utilizando animais de experimentação. Entretanto, devido a questões éticas envolvendo o uso desses animais, atualmente há uma busca por métodos alternativos para essa avaliação. Assim, o objetivo deste projeto foi propor uma estratégia para a avaliação do potencial de irritação ocular de alguns ingredientes cosméticos, como os tensoativos, dodecil sulfato de sódio (SDS), lauril éter sulfato de sódio (LESS), cocoilglutamato de sódio (CGS), polissorbato 20, capriloil/caproil metil glucamida (CCMG), cocoamidopropilbetaína (CAB), bem como os silicones, dimeticone e ciclopentasiloxano, utilizados na fabricação de produtos cosméticos para cabelo (shampoos), área dos olhos e rosto (demaquilantes e cremes). Para isso, foram utilizados métodos alternativos à experimentação animal, tais como Hen\'s Egg Test - Chorioallantoic Membrane (HET-CAM) e ensaio de Permeabilidade e Opacidade de Córnea Bovina (BCOP) e análise histopatológica das córneas. O primeiro ensaio avalia os eventos vasculares, hiperemia, hemorragia e coagulação, que a substância teste possa causar na CAM, mimetizando, com isso, a conjuntiva ocular. Já o BCOP avalia as alterações na opacidade e na permeabilidade provocada pela substância teste. A análise histopatológica é uma ferramenta complementar ao ensaio de BCOP, avaliando o grau e a profundidade da lesão ocasionada pela substância teste na córnea bovina. A maioria dos tensoativos foi considerada irritante severo no ensaio de HET-CAM, com exceção do polissorbato 20 (10%) classificado como irritante moderado, enquanto que os silicones não foram irritantes. Já no ensaio de BCOP, a maioria dos tensoativos foi classificada como sem predição, exceto o polissorbato 20 (10%), o CCMG 1,5% e os silicones, os quais foram classificados como não irritantes. Na análise histopatológica, os tensoativos sem predição no BCOP, foram classificados como irritantes severos: SDS 10%, CAB 3% e 1,5% e CCMG 3%; irritantes moderados: LESS 10% e 7%; irritantes leves: SDS 1% e CGS 3%; e não irritantes: CGS 1,5% e CCMG 1,5%. Os silicones não causaram nenhum dano na córnea. Diante dos resultados obtidos no presente trabalho, a seguinte estratégia foi proposta para a avaliação do potencial de irritação ocular de ingredientes cosméticos: em um primeiro nível deve-se utilizar o ensaio de HET-CAM, o qual avalia os eventos vasculares, mimetizando a conjuntiva ocular. Em seguida, no 2º nível, com o ensaio de BCOP, avaliam-se os efeitos do ingrediente sobre a córnea (opacidade e permeabilidade). Se o ingrediente for classificado como irritante severo ou não irritante nos dois ensaios, ele não necessita de mais avaliações. Entretanto, se esse produto apresentar algum potencial irritante no HET-CAM e for classificado como sem predição ou sem categoria no BCOP, deve-se prosseguir para o 3º nível, a avaliação histopatológica. Nessa etapa o ingrediente é avaliado quanto ao grau e a profundidade da lesão que ele provoca na córnea bovina, possibilitando, até mesmo, inferir sobre a reversibilidade da lesão. Portanto, a estratégia proposta para avaliar o potencial de irritação ocular de ingredientes e produtos cosméticos é bastante promissora, pois é possível avaliar os eventuais danos que eles podem causar na conjuntiva ocular e na córnea por diferentes mecanismos toxicológicos, predizendo, assim, a toxicidade ocular desses produtos. / Cosmetic products are freely available to the consumer and may accidentally come into contact with the eyes; thus they must be approved by eye irritation tests. For many years, these evaluations were performed in experimental animals (Draize test). However, due to ethical issues involving the use of animals, there is a search for alternative methods for this evaluation. Thus, the aim of this project was to measure the ocular irritation potential of some cosmetic ingredients, such as sodium dodecyl sulfate (SDS), sodium cocoylglutamate (SCG), polysorbate 20, capryloyl /caproyl methyl glucamide (CCMG), cocoamidopropyl betaine (CAPB), as well as silicones, dimethicone and cyclopentalosiloxane, used to manufacture cosmetic products for hair (shampoos), eye and face area (make-up removers and creams). For that purpose, alternative methods of animal experimentation were used, such as Hen\'s Egg Test - Chorioallantoic Membrane (HET-CAM) and Bovine Corneal Permeability and Opacity (BCOP) test and histopathological analysis of the corneas. The first assay evaluates the vascular events, hyperemia, hemorrhage and coagulation, which a test substance can cause in the CAM, simulating endpoints that occur in ocular conjunctiva. BCOP evaluates alterations in opacity and permeability caused by test substance on the cornea. The histopathological analysis is a complementary tool to BCOP test, evaluating the degree and depth of the lesion caused by the test substance in the bovine cornea. Most of the surfactants were non-irritant on HET-CAM, except polysorbate 20 (10%) that was classified as moderate irritant, while silicones were non-irritant. In the BCOP assay, most surfactants were classified as unpredicted, except polysorbate 20 (10%) and CCMG 1.5%, and silicones, which were classified as no category (non-irritant). In the histopathological analysis, unpredictive surfactants in BCOP were better classified as severe irritants: SDS10%, CAB 3% and 1.5% and CCMG 3%; moderate irritants: LESS 10% and 7%; mild irritants: SDS 1% and CGS 3%; and non-irritant: CGS 1.5% and CCMG 1.5%. Silicones did not cause any damage on the cornea. Considering the results obtained in the present study, the following tiered strategy was proposed for the evaluation of the ocular irritation potential of cosmetic ingredients: the first tier should be the HET-CAM assay, which evaluates the vascular events, simulating the conjunctiva. Then, the second tier, with the BCOP assay, the effects of the ingredient on the cornea (opacity and permeability) are evaluated. If the ingredient is classified as a severe irritant or non-irritant in both tests, it does not require further evaluation. However if that ingredient or product is considered as a potential irritant in HET-CAM and in BCOP, i.e. it is classified as unpredicted or no category, it is necessary to proceed to the third tier, the histopathological evaluation. At this stage, the ingredient is evaluated for the degree and depth of the lesion that it provoked in the bovine cornea, allowing even to infer about the reversibility of the lesion. Finally, the proposed strategy for evaluating the potential of eye irritation is very promising to evaluate ingredients and cosmetic products, since it is possible to evaluate the possible damages that they can cause in the conjunctiva and in the cornea by different toxicological mechanisms, thereby predicting the ocular safety of those products.

Ce mémoire rapporte les études de protéines amyloïdes en interaction avec des membranes modèle afin d’établir une relation structure toxicité. Nous avons choisi différents modèles membranaires (monocouches, bicouches) de composition lipidique et charges différentes et utilisé différentes méthodes physico-chimiques afin de caractériser les interactions des protéines amyloïdes avec les membranes.Nous avons montré l’importance de la contribution électrostatique dans les interactions de la protéine amyloïde HET-s (218-289) et ses mutants avec les membranes modèles.L’ellipsométrie a démontré que les mutants toxiques de HET-s (218-289) (M8, WT.Y1Y2V2) perturbentfortement les monocouches lipidiques à l’interface air-eau. La structure riche en feuillets β antiparallèles des protéines àl’interface air-eau et dans l’interaction avec les monocouches de lipides a été démontrée par la spectroscopie PMIRRAS (Polarization Modulation – Infrared Reflection Absorption Spectroscopy). Nous avons établie que l’interface air-eau peut modifier l’agrégation des protéines amyloïdes. A l’aide de la spectroscopie de fluorescence, la spectroscopie PWR (Plasmon-Waveguided Resonance) et la spectroscopie ATR-FTIR (Attenuated Total Reflection – Fourier Transform Infrared), nous avons mis en évidence que la protéine toxique M8 adopte une structure riche en feuillets β antiparallèles en altérant fortement l’intégrité des bicouches lipidiques. Au contraire, la protéine non toxique WT se structure en feuillets β parallèles dans ces interactions et elle ne perturbe pas l’homogénéité des membranes. La toxicité de la protéine M8 semble liée à son organisation différente et à sa capacité à réorganiser les membranes.Nos résultats confortent également l’hypothèse de la toxicité des oligomères amyloïdes.Une étude sur la fabrication d’une cellule microfluidique pour la séparation de différents types d’autoassemblage afin de les détecter et de les étudier en interaction avec des liposomes par spectroscopie infrarouge est présentée. Une cellule microfluidique de CaF2 de 8 μm d’épaisseur de canaux est obtenue et est utilisée pour la détection d’une protéine de test. / This manuscript reports the studies of amyloid proteins in interaction with membrane models in order to establish their structure-toxicity relationship.Membrane models (monolayer, bilayer) of different charge and lipid composition were used. We used various physico chemical methods to characterize the interaction of these amyloid proteins with membranes.We showed the importance of the electrostatic contribution in the interactions of the amyloid protein HET-s(218-289) and its mutants with model membranes.Ellipsometry showed that the toxic mutants of HET-s (218-289) (M8, WT.Y1Y2V2) strongly disturbed thelipid monolayers at the air-water interface. The structure rich in antiparallel β sheets of auto-assembled proteins at theair-water interface and in interaction with lipid monolayers at the air-water interface has been demonstrated by the PMIRRAS spectroscopy (Polarization Modulation - Infrared Reflection Absorption Spectroscopy). We established that theair-water interface can change the aggregation properties of amyloid proteins.By using fluorescence spectroscopy, PWR spectroscopy (Plasmon Resonance-Waveguided spectroscopy) and ATR-FTIR spectroscopy (Attenuated Total Reflection - Fourier Transform Infrared spectroscopy), we found that thetoxic protein (M8) adopted a structure rich in antiparallel β sheets greatly altered the integrity of lipid bilayers. Incontrast, the protein non-toxic (WT) organized in a structure rich in parallel β sheets in these interactions and it did notdisturb the homogeneity of the membranes. The toxicity of the protein M8 appears to be related to its differentorganization and its ability to rearrange membranes.Our results also support the hypothesis of the toxicity of amyloid oligomers.A study on the fabrication of a microfluidic cell for the separation of different aggregation states of amyloidproteins in order to detect these assemblies and to study their interaction with liposomes by infrared spectroscopy is presented. A CaF2 microfluidic cell with channels of 8 μm of thickness was obtained and was used for the detection of atested protein.

This study focuses on the relation between the picareque genre and the way in which guilt is processed in literature. André Brink’s Inteendeel (On the contrary) was used in this examination and also, for a wider perspective than merely the South African situation, Arthur Japin’s De zwarte met het witte hart (The two hearts of Aquasi Boachi). The possibilities offerd by the picaresque in order to investigate the manifestation of guilt in literary texts were explored with the theories of, inter alia, Wicks, Ricoeur and Todorov. Tracing the origins of the picaresque reveals that this type of text exhibits specific characteristics, e.g. an unethical attitude that is usually imposed on the individual by a society in crisis – “guilt” and a confessional tone are therefore intrinsically part of the picaresque. Using Wicks’s modal-generic approach, the two novels are examined with the purpose of determining their degree of “picaresqueness” to test the validity of the hypothesis, i.e. that the more a text displays picaresque characteristics, the more the issue of guilt would be a central theme to that text. In the two novels relevant to this study, colonial guilt is the main form of guilt examined. / Prof. W. Burger

Under slutet av 1970-talet började det hållas debatter angående den dåliga redovisningskvalitén samt den ökade ekonomiska brottsligheten. I och med detta började debattörer även diskutera revisorns roll och funktion. Detta medförde att man först införde en upplysningsplikt som senare utvecklades till en anmälningsplikt som lagstadgades den 1 januari 1999. Tystnadsplikten som sedan länge varit förankrad i revisorns yrkesroll kom nu i konflikt med den nya lagen. Däribland revisorerna själva, som menade att de inte ville agera som en moralisk polis. Samtidigt menade revisorerna samt olika remissinstanser som FAR och SRS att anmälningsplikten skulle medföra bristfällig information från klienten då de inte skulle vara villiga att utge tillräckligt med information av rädsla för att bli anmälda, vilket därmed skulle medföra svårigheter för revisorn att utföra sitt arbete. Däremot ansåg regeringen att revisorn var det främsta arbetsverktyget i kampen mot ekonomisk brottslighet, då de som enda yrkesgrupp har total insyn i bolagens verksamhet. Samtidigt har revisorns brottsförebyggande roll ifrågasatts på senare tid, då antalet anmälningar som kommer från revisorn varit låg i jämförelse med dem som kommer från konkursförvaltare och skatteförvaltningen. Likväl har anmälningarna från revisorer drastiskt ökat sedan år 2004. Därför har vi i denna studie haft som syfte att undersöka vilka faktorer som påverkar revisorns agerande i tillämpningen av anmälningsplikt och tystnadsplikt. I denna tillämpning uppstår ofta en konflikt av moralisk och etisk natur gentemot klienten. Samtidigt krävs det att revisorn är juridiskt kapabel till att avgöra om ett brott föreligger. Detta beror då på den utbildning denne erhål-lit, vilket enligt tidigare studier inom ämnet skiljer sig åt mellan stora- och små revisionsbyråer. Ju större osäkerhet revisorn känner i fråga om ett brott föreligger desto högre bevisgrad tenderar denne också att kräva. För att undersöka dessa faktorer i förhållande till revisorns agerande inför tillämpningen av anmälningsplikt och tystnadsplikt har vi valt att utföra en kvantitativ studie. Detta har vi gjort med hjälp av en enkätundersökning som riktats till fem stora- och fem små revisionsbyråer med avgränsning till Jönköpings stad. Förutom slutna frågor har vi inkluderat öppna tillämpningsfall direkt tagna ur Ekobrottsmyndighetens rapport- ”revisorns åtgärder vid misstanke om brott”. Resultaten från enkätundersökningen har sedan framställts i stapeldiagram utförda i Excel. För att få en bakgrund till de data vi erhållit behövs en relevant teoretisk referensram. Den främs-ta källan till revisorns åtgärder vid brottsmisstanke finner vi i ABL. Dock har det utvecklats omfattande rättspraxis samt rekvisit för att underlätta revisorns avgörande vid misstanke om brott. Dessutom har EBM givit revisorn vägledning i form av riktlinjer för bevisgrad och mer grund-läggande definitioner av de rekvisit som berör en anmälan eftersom lagen lämnat dessa till god revisorssed att avgöra. Dessutom är det relevant för vår studie att finna hur etik och moral påverkar revisorn i affärssammanhang samt den utbildning denne erhållit angående anmälningsplikt. Vår undersökning visar att nästintill samtliga respondenter erhållit en utbildning om anmälningsplikt men att majoriteten trots detta kräver en betydligt högre bevisgrad än EBMs riktlinjer för att agera på brottsmisstanke. Samtidigt tror vi att revisorn tar på sig en yrkesroll och överlägger allt etiskt ansvar på revisionsbyrån, då kommentarerna till tillämpningsfallen visar att revisorerna skulle valt att agera utan att ta hänsyn till det etiska i situationen. Revisorns agerande påverkas av storleken på revisionsbyrån, då det visar sig att respondenterna från de små revisionsbyråerna haft en större praktisk användning av anmälningsplikten, vilket därtill i vår mening kan bero på den externa utbildning de fått. Samtidigt tror vi att vår undersökning indikerar på att stora revisionsbyråer har en lägre tendens att anmäla sina klienter. Fortfarande visar tillämpningsfallen att respondenterna i stor utsträckning agerar enligt EBMs riktlinjer samt enligt den lagreglering som finns. Därför drar vi den slutsatsen att revisorn fortfarande värnar om tystnadsplikten och helst av allt inte vill bryta den men att anmälningsplikten kommit att bli betydligt mer implementerad i dennes yrkesroll, vilket visas av ett ökat antal anmälningar. / During the end of the 1970s many debates were held concerning the bad quality of accounting and the increase of white collar crimes. Due to this fact many debaters also discussed the role and function of the auditor. This resulted in an introduction of an information duty that later developed into a reporting duty that was bound by law the 1st of January 1999. The professional secrecy which had been a part of the auditors’ occupational role since a long time now came in conflict with the new law. The auditors themselves meant that they did not want to act as moral cops. At the same time the auditors and several body considering proposed legislations, such as FAR and SRS thought that the reporting duty would bring a lack of information from the client since they would not be willing to give out enough information due to the fear of being reported, which thus would complicate the work of the auditor. On the other hand the government regarded the auditors to be the premier tool in the fight against white collar crime, since they as the only occupational group have total insight in the activity of companies. Simultaneously, the auditors’ role as crime preventer has lately been questioned, since the number of reports from auditors has been low in comparison to the number coming from bankruptcy managers and tax managers. Nevertheless the number of reports from the auditors has increased drastically since 2004. Therefore we have with this study aimed to investigate which factors that are affecting the acts of the auditor in the application of reporting duty and professional secrecy. In such an application a conflict of ethical and moral nature often occurs towards the client and the prosecutor. At the same time it is required that the auditor has juridical capabilities to decide whether a crime has been committed or not. This is dependent on the education of the auditor, which according to earlier studies within the field of subject differs between big and small accounting firms. The greater the insecurity the auditor feels in deciding whether a crime has been committed, the higher the rate of proof demanded. In order to investigate these factors in relation to the auditors’ actions towards the application of the reporting duty and the professional secrecy we have chosen to perform a quantitative study. This has been done with the help of a questionnaire that has been handed out to five big and five small accounting firms within the city of Jönköping. Apart from closed questions we have included open cases directly taken from The Authority of Economical Crime’s report- “an auditors vi actions when suspecting a crime”. The result from the questionnaire has then been presented in diagrams made in Excel. In order to get background to the data we have collected we need a relevant theoretical framework. The primer source to the auditors’ measures is found in the Law of joint-stock companies (ABL). However, extensive custom and law terms have been developed to facilitate the auditors’ decision in crime suspicion. Furthermore, The Authority of Economical Crime has given guidance and outlines for the rate of proof and more basic definitions of the law terms that concerns reporting duty since the law leaves it to good auditing custody to decide upon. It is also relevant for our study to look upon how ethics and morals affect the auditor in business contexts and also whether or not the auditors have received education regarding the reporting duty. Our study shows that almost all participants have received education concerning the reporting duty but that the majority despite this demands higher rate of proof than The Authority of Economical Crime outlines before taking actions when suspecting a crime. At the same time we believe that the auditor takes on a role of duty and puts all ethical responsibility on the accounting firm, since the comments from the cases imply that the auditors would act without considering the ethical aspect of the situation. The auditor’s actions is dependent on the size of the accounting firm, since our study has shown that auditors from small accounting firms have had a greater practical use of the reporting duty, which according to us can be a result of the external education they have received. At the same time our study confirms Anderson and Buskas (2006) research which implies that larger firms have lower tendency to report a crime against a client. Still the results from our cases show that participants mostly act according to the outlines conducted by The Authority of Economical Crime and the existing law regulations. Therefore our final conclusions are that the auditor protects the professional secrecy and would rather not violate it but that the reporting duty has lately been considerably more implemented in the auditor occupational role, which is furthermore shown by the increasing number of reports made by auditors’.

<p>Under slutet av 1970-talet började det hållas debatter angående den dåliga redovisningskvalitén samt den ökade ekonomiska brottsligheten. I och med detta började debattörer även diskutera revisorns roll och funktion. Detta medförde att man först införde en upplysningsplikt som senare utvecklades till en anmälningsplikt som lagstadgades den 1 januari 1999. Tystnadsplikten som sedan länge varit förankrad i revisorns yrkesroll kom nu i konflikt med den nya lagen. Däribland revisorerna själva, som menade att de inte ville agera som en moralisk polis. Samtidigt menade revisorerna samt olika remissinstanser som FAR och SRS att anmälningsplikten skulle medföra bristfällig information från klienten då de inte skulle vara villiga att utge tillräckligt med information av rädsla för att bli anmälda, vilket därmed skulle medföra svårigheter för revisorn att utföra sitt arbete. Däremot ansåg regeringen att revisorn var det främsta arbetsverktyget i kampen mot ekonomisk brottslighet, då de som enda yrkesgrupp har total insyn i bolagens verksamhet.</p><p>Samtidigt har revisorns brottsförebyggande roll ifrågasatts på senare tid, då antalet anmälningar som kommer från revisorn varit låg i jämförelse med dem som kommer från konkursförvaltare och skatteförvaltningen. Likväl har anmälningarna från revisorer drastiskt ökat sedan år 2004. Därför har vi i denna studie haft som syfte att undersöka vilka faktorer som påverkar revisorns agerande i tillämpningen av anmälningsplikt och tystnadsplikt. I denna tillämpning uppstår ofta en konflikt av moralisk och etisk natur gentemot klienten. Samtidigt krävs det att revisorn är juridiskt kapabel till att avgöra om ett brott föreligger. Detta beror då på den utbildning denne erhål-lit, vilket enligt tidigare studier inom ämnet skiljer sig åt mellan stora- och små revisionsbyråer. Ju större osäkerhet revisorn känner i fråga om ett brott föreligger desto högre bevisgrad tenderar denne också att kräva.</p><p>För att undersöka dessa faktorer i förhållande till revisorns agerande inför tillämpningen av anmälningsplikt och tystnadsplikt har vi valt att utföra en kvantitativ studie. Detta har vi gjort med hjälp av en enkätundersökning som riktats till fem stora- och fem små revisionsbyråer med avgränsning till Jönköpings stad. Förutom slutna frågor har vi inkluderat öppna tillämpningsfall direkt tagna ur Ekobrottsmyndighetens rapport- ”revisorns åtgärder vid misstanke om brott”. Resultaten från enkätundersökningen har sedan framställts i stapeldiagram utförda i Excel.</p><p>För att få en bakgrund till de data vi erhållit behövs en relevant teoretisk referensram. Den främs-ta källan till revisorns åtgärder vid brottsmisstanke finner vi i ABL. Dock har det utvecklats omfattande rättspraxis samt rekvisit för att underlätta revisorns avgörande vid misstanke om brott. Dessutom har EBM givit revisorn vägledning i form av riktlinjer för bevisgrad och mer grund-läggande definitioner av de rekvisit som berör en anmälan eftersom lagen lämnat dessa till god revisorssed att avgöra. Dessutom är det relevant för vår studie att finna hur etik och moral påverkar revisorn i affärssammanhang samt den utbildning denne erhållit angående anmälningsplikt.</p><p>Vår undersökning visar att nästintill samtliga respondenter erhållit en utbildning om anmälningsplikt men att majoriteten trots detta kräver en betydligt högre bevisgrad än EBMs riktlinjer för att agera på brottsmisstanke. Samtidigt tror vi att revisorn tar på sig en yrkesroll och överlägger allt etiskt ansvar på revisionsbyrån, då kommentarerna till tillämpningsfallen visar att revisorerna skulle valt att agera utan att ta hänsyn till det etiska i situationen. Revisorns agerande påverkas av storleken på revisionsbyrån, då det visar sig att respondenterna från de små revisionsbyråerna haft en större praktisk användning av anmälningsplikten, vilket därtill i vår mening kan bero på den externa utbildning de fått. Samtidigt tror vi att vår undersökning indikerar på att stora revisionsbyråer har en lägre tendens att anmäla sina klienter. Fortfarande visar tillämpningsfallen att respondenterna i stor utsträckning agerar enligt EBMs riktlinjer samt enligt den lagreglering som finns. Därför drar vi den slutsatsen att revisorn fortfarande värnar om tystnadsplikten och helst av allt inte vill bryta den men att anmälningsplikten kommit att bli betydligt mer implementerad i dennes yrkesroll, vilket visas av ett ökat antal anmälningar.</p> / <p>During the end of the 1970s many debates were held concerning the bad quality of accounting and the increase of white collar crimes. Due to this fact many debaters also discussed the role and function of the auditor. This resulted in an introduction of an information duty that later developed into a reporting duty that was bound by law the 1st of January 1999. The professional secrecy which had been a part of the auditors’ occupational role since a long time now came in conflict with the new law. The auditors themselves meant that they did not want to act as moral cops. At the same time the auditors and several body considering proposed legislations, such as FAR and SRS thought that the reporting duty would bring a lack of information from the client since they would not be willing to give out enough information due to the fear of being reported, which thus would complicate the work of the auditor. On the other hand the government regarded the auditors to be the premier tool in the fight against white collar crime, since they as the only occupational group have total insight in the activity of companies.</p><p>Simultaneously, the auditors’ role as crime preventer has lately been questioned, since the number of reports from auditors has been low in comparison to the number coming from bankruptcy managers and tax managers. Nevertheless the number of reports from the auditors has increased drastically since 2004. Therefore we have with this study aimed to investigate which factors that are affecting the acts of the auditor in the application of reporting duty and professional secrecy.</p><p>In such an application a conflict of ethical and moral nature often occurs towards the client and the prosecutor. At the same time it is required that the auditor has juridical capabilities to decide whether a crime has been committed or not. This is dependent on the education of the auditor, which according to earlier studies within the field of subject differs between big and small accounting firms. The greater the insecurity the auditor feels in deciding whether a crime has been committed, the higher the rate of proof demanded.</p><p>In order to investigate these factors in relation to the auditors’ actions towards the application of the reporting duty and the professional secrecy we have chosen to perform a quantitative study. This has been done with the help of a questionnaire that has been handed out to five big and five small accounting firms within the city of Jönköping. Apart from closed questions we have included open cases directly taken from The Authority of Economical Crime’s report- “an auditors vi actions when suspecting a crime”. The result from the questionnaire has then been presented in diagrams made in Excel. In order to get background to the data we have collected we need a relevant theoretical framework. The primer source to the auditors’ measures is found in the Law of joint-stock companies (ABL). However, extensive custom and law terms have been developed to facilitate the auditors’ decision in crime suspicion. Furthermore, The Authority of Economical Crime has given guidance and outlines for the rate of proof and more basic definitions of the law terms that concerns reporting duty since the law leaves it to good auditing custody to decide upon. It is also relevant for our study to look upon how ethics and morals affect the auditor in business contexts and also whether or not the auditors have received education regarding the reporting duty.</p><p>Our study shows that almost all participants have received education concerning the reporting duty but that the majority despite this demands higher rate of proof than The Authority of Economical Crime outlines before taking actions when suspecting a crime. At the same time we believe that the auditor takes on a role of duty and puts all ethical responsibility on the accounting firm, since the comments from the cases imply that the auditors would act without considering the ethical aspect of the situation. The auditor’s actions is dependent on the size of the accounting firm, since our study has shown that auditors from small accounting firms have had a greater practical use of the reporting duty, which according to us can be a result of the external education they have received. At the same time our study confirms Anderson and Buskas (2006) research which implies that larger firms have lower tendency to report a crime against a client. Still the results from our cases show that participants mostly act according to the outlines conducted by</p><p>The Authority of Economical Crime and the existing law regulations. Therefore our final conclusions are that the auditor protects the professional secrecy and would rather not violate it but that the reporting duty has lately been considerably more implemented in the auditor occupational role, which is furthermore shown by the increasing number of reports made by auditors’.</p>

Drosophila telomere maintenance depends on the transposition of three specialized retrotransposons – HeT-A, TART and TAHRE (HTT). Controlling the activation and silencing of these elements is crucial to maintain telomere length homeostasis without compromising genomic instability. In this thesis, I have identified the role of different chromosomal proteins involved in creating the correct chromatin environment to achieve telomere length homeostasis and stability. JIL-1, together with HP1a and Z4, act as a boundary at the telomere-subtelomere frontier. The interplay of these proteins leads to an equilibrium in the activation/repression state of the telomere retrotransposons. Additionally, I have contributed to the finding that the HeT-A Gag protein is a key component targeting different protein complexes to the telomeres and guaranteeing genome stability. I have also been able to demonstrate that the Z4 partners DREF, TRF2 and KEN are also involved in the silencing of HTT, probably by mediating chromatin remodeling. Finally, I have identified a special subtelomere domain at the 4R telomere with different chromatin characteristics and demonstrated that SETDB1, HP1a and POF are involved in the regulation of the telomeric retrotransposons in the 4th chromosome. These results provide important insights to better understand how in Drosophila the telomere retrotransposons are orchestrated to achieve a telomere function analogous to telomerase telomeres in other eukaryotes. / El manteniment dels telòmers de Drosophila depèn de la transposició especialitzada de tres retrotransposons, HeT-A, TART i TAHRE (HTT). El control de l’activació i la repressió d’aquests elements és crucial a l’hora de mantenir la llargada telomèrica sense comprometre l’estabilitat genòmica. En aquesta tesi jo he pogut identificar el paper de diferents proteïnes cromosòmiques involucrades en crear un estat de la cromatina adient per mantenir la longitud i l’estabilitat telomèrica. JIL-1 juntament amb HP1a i Z4 ajuden a crear el llindar entre la frontera dels domini telomèric i subtelomèric. L’actuació conjunta d’aquestes proteïnes aconsegueix un estat d’equilibri activació/repressió dels retrotransposons telomèrics. A més a més, he contribuït a la descoberta de la implicació de la proteïna HeT-A Gag en el reclutament de diferents complexes proteics als telomèrs de Drosophila per poder garantir l’estabilitat telomèrica. També he pogut demostrar que altres membres dels complexes on participa Z4, com ara: DREF, TRF2 i KEN, estan també implicats en el silenciament dels retrotransposons telomèrics segurament per mitjà de la remodelació de la cromatina. Finalment he pogut demostrar que el domini subtelomèric del telòmer 4R, té una estructura cromatínica diferent a la resta dels dominis subtelomèrics dels altres cromosomes i he pogut demostrar que les proteïnes SETDB1, HP1a i POF estan implicades en la regulació de l’HTT del cromosoma 4. Els resultats d’aquesta tesi ajuden de manera substancial a comprendre com els retrotransposons telomèrics estan orquestrats per tal de poder fer una funció anàloga als telòmers de telomerasa en altres eucariotes.