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Biological implications of the hypervariable VNTR region in the carboxyl ester lipase (CEL) gene
Get PDFKarboksylester-lipase (CEL) er eit fordøyingsenzym som hovudsakleg blir uttrykt i bukspyttkjertelen. CEL-genet inneheld ein region med repeterte DNA-sekvensar i det siste eksonet, også kalla ein VNTR-region. Repetisjonslengder mellom tre og 23 har vore observerte. Sjukdommar som er assosierte med CEL, er ofte knytte til endringar i VNTR-regionen. Enkeltbase-insersjonar i CEL VNTR resulterer i eit prematurt stoppkodon og trunkert protein, men det vore uklart om slike variantar er patogene. CEL-HYB1 er ein kopinummer-variant av CEL, der VNTR-sekvensen stammar frå det nærliggande pseudogenet CELP. CEL-HYB1 er ein etablert risikofaktor for kronisk betennelse i bukspyttkjertelen (pankreatitt) via såkalla protein-misfolding, og denne varianten er fem gongar overrepresentert i europeiske kohortar med pankreatitt pasientar.
I Artikkel I studerte vi frekvensen av enkeltbase-insersjonar i CEL sin VNTR-region i ein kohort av pasientar med bukspyttkjertelkreft. Vi fann ingen skilnad i frekvens samanlikna med ei kontrollgruppe. Vi analyserte også celler som uttrykte ulike insersjonsvariantar av CEL for å undersøke eigenskapane til desse variantane. Vi konkluderte med at fleirtalet av slike variantar er godarta, men at insersjon i den proksimale enden av VNTR-sekvensen kan ha eit patogent potensial. Overraskande nok fann vi også at insersjonsvariantar av CEL kan oppstå spontant i bukspyttkjertelvevet.
I Artikkel II etablerte vi ein musemodell for CEL-HYB1 ved å bytte ut musenes Cel VNTR med VNTR-regionen frå det humane CEL-HYB1 allelet. Cel-HYB1-musene utvikla kronisk pankreatitt spontant med kjenneteikn som atrofi, inflammasjon, fibrose og feittvev i bukspyttkjertelen. Den nye muse-stamma er såleis ein vellukka modell for korleis kronisk pankreatitt oppstår med bakgrunn i protein-misfolding.
I Artikkel III undersøkte vi mus som bar både det humane sjukdomsallelet CEL-HYB1 og det vanlegaste normale humane VNTR-allelet med 16 repetisjonar (Cel-16R/HYB1). Denne gen-kombinasjonen hadde ingen auka effekt på sjukdomsfenotypen til bukspyttkjertelen. Vi gav difor Cel-HYB1-musene ein feittrik diett som ein ekstra risikofaktor for å akselerere sjukdomsutviklinga. Cel-HYB1-musene som gjekk på denne dietten synte ein litt sterkare eksokrin fenotype medan den endokrine funksjonen var upåverka. Vi gjorde også innleiande studiar av det samla proteinuttrykket i pankreasvev frå Cel-HYB1-musene med mål om å skjøne meir av sjukdomsmekanismen.
Oppsummert så har vi vist at insersjons-variantar av CEL er godarta med mogleg unntak av variantar der insersjonen sit i den proksimale VNTR-delen. Vidare har vi etablert ein Cel-HYB1-basert musemodell for kronisk pankreatitt og funne at overvekt kan akselerere sjukdomsutviklinga i Cel-HYB1-mus.Carboxyl ester lipase (CEL) is a digestive enzyme that is mainly expressed in the acinar cells of the pancreas. The CEL gene consists of 11 exons where the last exon contains a GC-rich variable number tandem repeat (VNTR) region which makes the gene highly polymorphic. Repeat lengths between three and 23 repeats have been observed. Pathogenicity associated with the CEL gene is mainly related to alterations in the VNTR region. Single-base insertions within the VNTR result in a premature stop codon and a truncated CEL protein. Pathogenic effects of these variants remain to be identified. CEL- HYB1 is a copy number variant of CEL, where the VNTR region originates from the nearby pseudogene CELP. CEL-HYB1 is an established risk factor for chronic pancreatitis (CP) via the misfolding pathway, and the variant is fivefold overrepresented among European CP patients.
In Paper I, we investigated the allele frequency of CEL insertion variants in a cohort of patients with pancreatic neoplastic disorders and found that the frequency was similar to that in a population-based control group. Next, we assessed the properties of different insertion variants in a cellular model system. We concluded that most insertions variants are benign and that variants with insertion in the proximal part of the VNTR may have a pathogenic potential. Finally, we made the intriguing observation that CEL insertion variants can arise somatically within pancreatic tissue.
In Paper II, we created a Cel-HYB1 knock-in mouse by exchanging the mouse Cel VNTR with the human CEL-HYB1 VNTR region. The mice developed spontaneous CP with histological features like atrophy, inflammation, fibrosis and fatty replacement of the pancreatic parenchyma. The new mouse strain was therefore a successful animal model for CP caused by protein misfolding.
In Paper III, we created a compound heterozygous mouse carrying both the human CEL-HYB1 allele and the most common human VNTR allele with 16 repeats (Cel -16R/HYB1). This genetic constellation directly recapitulates the situation in human CEL-HYB1 carriers but did not enhance the pancreatic phenotype in mice. Therefore, we challenged Cel-HYB1 mice with a high-fat diet (HFD) as an additional factor to accelerate disease development. Cel-HYB1 mice fed HFD presented with a somewhat more severe exocrine phenotype, but the endocrine function remained similar to control animals fed HFD. In this paper, we also performed initial proteome analyses of exocrine and endocrine pancreatic tissue from the Cel-HYB1 mice to elucidate the pathogenic mechanism of CEL-HYB1-induced CP.
In summary, we have shown that CEL insertion variants are benign, except for a pathogenic potential of insertions in proximal VNTR repeats. Moreover, we have established a Cel-HYB1 mouse model for CP and demonstrated that obesity can accelerate the exocrine phenotype of Cel-HYB1 mice.Doktorgradsavhandlin
Å se hele barnet - flerspråklige barns språkutvikling og behov for støtte i barnehagen: en kvalitativ studie av fagperosner med spesialpedagogisk kompetanse og deres erfaringer rundt arbeidet med flerspråklige barn
Get PDFMasteroppgave i spesialpedagogikkSPED395MAPS-PEDMAPS-SPE
Glacial, and shallow geological processes in the Southern Norwegian North Sea since the Last Glacial Maximum
No full textThe shallow geology in the Southern Norwegian North Sea has undergone significant changes since the Last Glacial Maximum (LGM). These changes have influenced the composition of shallow sediments and the present-day seabed conditions, both relevant for offshore infrastructure development. This study aims to investigate the glacial and shallow geological processes since the LGM, as well as the geomorphological setting within and northeast of the Sørlige Nordsjø II region, extending towards the Norwegian Channel. The investigations are based on an integrated method, using multibeam bathymetry, high-resolution shallow seismic, sediment core analyses, radiocarbon dating, and geotechnical tests. The shallow geology of the area is divided into Holocene- (Unit 1), deglaciation to palaeovalley infill- (Unit 2), and pre-LGM (Unit 3) deposits. Radiocarbon dates indicate initial marine inundation of a palaeovalley from ~14 cal. ka BP, suggesting an earlier inundation of the Southern Norwegian North Sea than previously assumed. Several moraine features, including a larger structure associated with the Tampen re-advance, are revealed in the bathymetric, and seismic data. Areas with sand waves of various dimensions have been revealed on the seabed, complicating potential infrastructure placement. They also suggest active seabed sediment transport, as evidenced by several lobes of Holocene sand observed in seismic data. A moraine landscape is also identified, with one of the moraines linked to the Tampen re-advance. These findings contribute to a better understanding of the present-day seabed geomorphology, the shallow geology, and the processes of glacial retreat and marine inundation following the LGM in the study area.Masteroppgave i geovitenskapGEOV399MAMN-GEO
Agents of Modernization: Airline Companies, the Rise of Civil Aviation, and the Making of Modern Society in Norway, 1945-65
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Voices of a Borderland: Liminality and Rituality in Anna Starobinets’ novel Lisi Brody
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Perovskite Solar Cells: Materials, Fabrication, and Characterization
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Crime, Enlightenment, and Punishment Bureaucratic and Scientific Change in Habsburg Austria, 1750s–1820s
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Reeling in Emissions: Evaluating Emission Control Policies in Icelandic Fisheries Through System Dynamics
Get PDFAs part of its commitment to the Paris Agreement, the Icelandic government has proposed energy transition-related policies to reduce greenhouse gas emissions in the fisheries sector. However, scholarship tackling the complexity of energy transition for the Icelandic fishing fleet – and indeed for most fishing fleets worldwide – is currently missing. A system dynamics model running from 2008 to 2050 is built in this thesis, with the aim of understanding and exploring the endogenous dynamics of the Icelandic fishing fleet energy use and its greenhouse gas emissions. The model simulates a business-as-usual scenario, and two additional climate change scenarios to reflect the potential change in fish populations in Icelandic waters and how that affects the industry. In addition, two government-suggested policies are introduced in the model: (1) Biodiesel as an intermediary, where biodiesel is used as drop-in fuel in the vessels to make them immediately cut a certain percentage of their emissions, and (2) transition towards alternative energy, where the vessels taken out of commission are replaced by vessels that run on alternative energy, gradually decreasing emissions gradually as more fossil-fuelled vessels get replaced. The results show that the two policies have bigger effects in the scenarios with high amounts of fish than with low amounts of fish. This is due to as there are increased emissions in high fish scenarios, there is more room for emissions decrease. Biodiesel as an intermediary works better as a short-term policy option as it cuts a certain percentage off emissions in fossil-fuelled vessels, while transition towards alternative energy works as a long-term policy option due to the gradual decrease in annual emissions as more fossil-fuelled vessels get replaced by vessels using alternative energy. This thesis shows that the transition towards alternative energy is a gradual process that does not happen overnight, and that as vessel turnover increases, the transition process accelerates. Additionally, it indicates that feedback within the system structure and delays are both crucial for a better forecasting of the energy transition progress. Future research in the time needed to implement the proper infrastructure for each policy option could shed light on the time frame of when different policies could be implemented.Masteroppgave i systemdynamikkGEO-SD351INTL-KMDMASV-SYSDYINTL-MNINTL-HFINTL-MEDINTL-PSYKINTL-JUSINTL-S
Elastic Seismic Imaging and Probabilistic AVO Inversion: Application to CO2 Storage at Sleipner
Get PDFIn order to reduce the effect of global warming, carbon capture and storage (CCS) is considered to be important as it reduces the amount of CO2 in the atmosphere. Geophysical monitoring is essential for safe storage of CO2. This requires accurate seismic inversion techniques so that the subsurface can be mapped in detail. However, the inverted model is not unique. Therefore, estimating the uncertainty of the model can be valuable. As a result, the development of probabilistic seismic inversion techniques is a key part of CCS. In this thesis, I present and compare inversion techniques. A deterministic and two probabilistic inversion techniques are applied to amplitude versus offset (AVO) data. The probabilistic inversion techniques are gradient-based and Ensemble Smoother for Multiple Data Assimilation (ES-MDA). In addition to these methods, I use elastic imaging using the block-diagonal of the Hessian and then compare these different methods. These inversion techniques are applied to two elastic models, where the reservoir consists of alternating thin layers of CO2-saturated sandstone and shale. The first model is 1D, and the second model is 2D, with the reservoir layers being slight anticlines. These models mimic CO2 storage at Sleipner in the North Sea. ES-MDA gives the most accurate inversion results for the 1D model. However, imaging is more useful for the 2D model and to obtain large-scale realistic models of the subsurface. Imaging is, therefore, preferred over AVO inversion for reservoir characterization and CO2 monitoring.Masteroppgave i geovitenskapGEOV399MAMN-GEO