Genetic variation of tight junction structures in intestinal inflammation

The epithelial barrier facing the external environment in the gastrointestinal (GI) tract is comprised of several components, including the tight junction (TJ) structures observed for the first time in 1963. TJ structures, which are multiprotein complexes composed of transmembrane proteins and a diverse spectrum of intracellular components, create a primary barrier to diffusion of ions, solutes, and water and they concomitantly prevent permeation of pro-inflammatory factors, such as pathogens, toxins, and antigens. Recent studies suggested that disturbance of epithelial integrity is associated with intestinal inflammatory conditions, such as inflammatory bowel disease (IBD), graft-versus-host disease (GVHD), celiac disease, but also diabetes. The general aim of this thesis was to identify novel genetic variants related to the development of intestinal inflammation with a specific focus on the TJ structures, yielding implications for epithelial integrity and paracellular permeability. Using a case-control study approach (Swedish cases and controls) in paper I, potential associations were investigated between IBD and three selected genetic markers in the genetic region of CLDN1, CLDN2, and CLDN4 (one marker per gene). The strongest association was observed between Crohn’s disease (CD) and the single nucleotide polymorphism (SNP) marker in the genetic region of CLDN2. The same SNP markers were further investigated using a family-based approach in non-Swedish families, but none of the identified associations from the Swedish case-control approach were confirmed. MORC4 which is located in the same genetic region as CLDN2 was also included in the investigation. A significant association was observed between a nonsynonymous SNP in MORC4 and CD in the Swedish case-control cohort. Similarities between IBD and GVHD include intestinal barrier defects and genetic contributions. GVHD is considered to be multifactorial, where the human leucocyte antigen (HLA) acts as a cornerstone; however, non-HLA genes have been identified in association with the outcome after stem cell transplantation (SCT). By using a casecontrol approach the relationship between non-HLA polymorphisms and emergence of GVHD as well as overall mortality after SCT was analyzed in paper II. The markers of MORC4, CD14, TLR4, and NOD2 were found to associate with the outcome (overall mortality) after SCT. The SNP marker of CD14 was the only analyzed marker that associated with acute GVHD. In paper III, the associations between IBD and several TJ genes that encode proteins reported to interact with each other were analyzed in a Swedish population. The strongest associations were observed between IBD and SNP markers in the membraneassociated guanylate kinase inverted genes MAGI2 and MAGI3. The MAGI3 SNP was also associated with ileal MAGI3 expression level in the non-inflamed non-IBD subgroup. Furthermore, no overlap between the expression levels of PTEN in inflamed colonic mucosa from patients with CD and those in the non-inflamed mucosa was detected, suggesting that PTEN is an inflammatory marker in CD. In paper IV, the genetic associations between microscopic colitis (MC) and TJ genes were analyzed in a Swedish population. The strongest association was identified between a SNP marker in PTEN and MC and also the sub-phenotype collagenous colitis (CC). Furthermore, significant associations were observed between genetic variations of MAGI1 and MC and also between a SNP marker in F11R and CC. Moreover, decreased expression levels of PTEN and MAGI1 were primarily associated to CC and the MC subtype lymphocytic colitis (LC), respectively, in comparison with controls. In conclusion, genes encoding proteins involved in the regulation of the intestinal epithelial integrity, including those contributing to TJ structures, may predispose individuals to intestinal inflammation, such as IBD and MC. Furthermore, MORC4 may be a predisposing factor for CD and one-year mortality after SCT for hematological malignancies

Context-dependent demographic and genetic effects of translocation from a captive breeding project

Translocations are a widespread approach to conserve threatened populations. Given the rapid decline and genetic deterioration of many natural populations, translocations are expected to become even more common in the future. The success of translocations is, however, dependent on multiple context-dependent factors, such as demographic and genetic status, habitat quality and animal behaviour. The Scandinavian arctic fox (Vulpes lagopus) exists in a small, fragmented population that is demographically vulnerable and exposed to inbreeding depression. In the early 2000 s, releases of arctic foxes from the Norwegian Captive Breeding Programme were initiated with the purpose of reintroducing populations to formerly inhabited areas and promoting connectivity. Since 2008/2009, 61 foxes have been released in Junkeren, Norway to re-establish an unoccupied area. We used a combination of field observations and microsatellite genotyping from the release site and two neighbouring subpopulations to investigate (i) the probability of establishment and reproduction for released foxes at the release site and in neighbouring subpopulations, and (ii) the impact on litter size and genetic composition in the recipient populations. Results showed that 18% of the released foxes were established at the release site, or in neighbouring subpopulations and 11.5% reproduced successfully. The extent of post-release dispersal into neighbouring subpopulations was also relatively high (11.5%). During the study period, the number of litters more than doubled in the subpopulations with released foxes contributing 29.5% to this increase, but no clear effect of immigration on litter size was found. There was a slight increase in genetic variation in one of the subpopulations, and a significant decline in genetic divergence between subpopulations. We conclude that despite extensive releases, demographic and genetic effects were highly context-dependent. This study highlights the challenges of reinforcement programmes in small populations and reintroductions to unoccupied sites, especially for highly mobile species in a fragmented landscape. conservation; immigration; translocation; genetic variation; demography; arctic fox; Vulpes lagopus; captive breeding; conservation breeding.publishedVersio

Genomic Consequences of Fragmentation in the Endangered Fennoscandian Arctic Fox (Vulpes lagopus)

Accelerating climate change is causing severe habitat fragmentation in the Arctic, threatening the persistence of many cold-adapted species. The Scandinavian arctic fox (V. lagopus) is highly fragmented, with a once continuous, circumpolar distribution, it struggled to recover from a demographic bottleneck in the late 19th century. The future persistence of the entire Scandinavian population is highly dependent on the northernmost Fennoscandian subpopulations (Scandinavia and the Kola Peninsula), to provide a link to the viable Siberian population. By analyzing 43 arctic fox genomes, we quantified genomic variation and inbreeding in these populations. Signatures of genome erosion increased from Siberia to northern Sweden indicating a stepping-stone model of connectivity. In northern Fennoscandia, runs of homozygosity (ROH) were on average ~1.47-fold longer than ROH found in Siberia, stretching almost entire scaffolds. Moreover, consistent with recent inbreeding, northern Fennoscandia harbored more homozygous deleterious mutations, whereas Siberia had more in heterozygous state. This study underlines the value of documenting genome erosion following population fragmentation to identify areas requiring conservation priority. With the increasing fragmentation and isolation of Arctic habitats due to global warming, understanding the genomic and demographic consequences is vital for maintaining evolutionary potential and preventing local extinctions. inbreeding; runs of homozygosity; bottleneck; fragmentation; mutational load; conservatio

Nature diversity act in Regional plan for Hardangervidda and five small hydropower plants in Valldalen, Odda kommune

I denne masteroppgaven undersøker jeg på hvordan naturmangfoldloven er brukt i Regional plan for Hardangervidda og gjennom konsesjonsbehandling av fem småkraftsøknader i Valldalen i Odda kommune, som omfattes av den regionale planen. Jeg ser spesielt på §§ 8-10 om henholdsvis kunnskapsgrunnlaget, føre-var-prinsippet og økosystemtilnærming og samlet belastning. «Regional plan for Hardangervidda – fylkesdelplan 2011-2025» ble utarbeidet på bestilling fra Miljøverndepartementet (2007a), som ønsket fylkesdelplaner med fastsetting av nasjonale villreinområder. Planen ble utarbeidet ved samarbeid mellom Hordaland, Telemark og Buskerud fylkeskommune, og ble vedtatt plan høsten 2011 av de reseptive fylkestingene. Småkraft AS søkte i 2011 konsesjon for fem småkraftverk i Valldalen, og søknadene ligger per mai 2013 til avgjørelse hos Norges vassdrags- energidirektorat (NVE). Naturmangfoldloven trådte i kraft i 2009, hvilket var etter at planarbeidet med den regionale planen for Hardangervidda var påbegynt, men før den ble vedtatt. I dette case-studiet har jeg gjennomført semistrukturerte kvalitative forskningsintervju med sentrale aktører i utarbeidelsen av Regional plan for Hardangervidda, og berørte aktører i konsesjonsprosessen i Valldalen. Den regionale planen, samt høringsuttalelser fra konsesjonsprosessen er analysert. Resultatene viser at naturmangfoldloven trekkes inn i Regional plan for Hardangervidda primært gjennom et tilleggsnotat med vurderinger etter naturmangfoldlovens §§ 8-12. Prinsippene er i tillegg delvis innarbeidet i planen, men det poengteres i plandokumentet at det er naturlig at naturmangfoldloven blir grundigere vurdert i den lokale planleggingen og ved rullering av den regionale planen. At planen med tilleggsnotat ble vedtatt uten innsigelse fra Miljøverndepartementet må sees på som et signal om at planen oppfylte saksbehandlingsreglene i naturmangfoldloven. I høringsuttalelsene til konsesjonssøknadene trekkes prinsippene i §§ 8-10 eksplisitt inn av Fylkesmannen i Hordaland, og i implisitt av en rekke andre høringsparter. Primært er det uttalelser fra motstandere av småkraftutbyggingene som trekker inn elementer fra naturmangfoldloven i sin argumentasjon. Høringsuttalelsene er et produkt av en medvirkningsprosess, og denne prosessen har betydning for hvem som deltar og hvilke opplysninger som blir spilt inn til NVE, som skal fatte vedtak om konsesjon skal gis eller ikke. Manglende kjennskap til naturmangfoldloven kan være en årsak til at loven i liten grad trekkes direkte inn i uttalelsene. Til tross for opplæring i loven med representanter fra både Fylkesmannen i Hordaland, Hordaland fylkeskommune og Odda kommune, er det kun Fylkesmannen som viser direkte til naturmangfoldloven i sin uttalelse. Det er ulik oppfatning om hva som fungerer som avbøtende tiltak, og tiltakene som foreslås kan grovt deles inn i tiltak som er avbøtende for friluftsliv og tiltak som er avbøtende for naturmangfold. Nasjonale mål og forventninger for fornybar energi står ofte i spenning med mål for naturmangfold og landskapsbilde, men naturmangfoldloven kan potensielt redusere slike spenninger. In this paper I examine how the nature diversity act is used in the Regional plan for Hardangervidda and through licensing of five small hydropower plants in Valldalen in Odda municipality. I look specifically at §§ 8-10 considering knowledge, the precautionary principle and ecosystem approach and cumulative environmental effects. "Regional plan for Hardangervidda – county sub plan 2011-2025" was produced on order from the Ministry of the Environment (2007), who wanted county sub-plans determining national wild reindeer areas. The plan was developed through collaboration between Hordaland, Telemark and Buskerud County Council, and was approved during the autumn 2011 of the receptive county councils. In 2011 Småkraft AS applied for concession for five small hydropower plants in Valldalen, and as of May 2013 the decision is still to be made by the Norwegian Water Resources and Energy Directorate (NVE). The nature diversity act came into force in 2009, which was after the planning process with the regional plan for Hardangervidda had begun, but before it was authorized. In this case study, I conducted semi-structured qualitative interviews with key participants from the preparation of the Regional plan for Hardangervidda, and participants in the licensing process in Valldalen. The regional plan, as well as submissions from the licensing process is analyzed. The results show that the nature diversity act is incorporated into the Regional plan for Hardangervidda primarily through an additional note with an assessment of the principals of the nature diversity act §§ 8-12. The principals are also partially incorporated in the plan, but the planning document points out that it is natural that nature diversity act is thoroughly considered in the local planning and the rollover of the regional plan. That the plan with the supplementary note was adopted without objection from the Ministry of the Environment should be seen as a signal that the plan met the procedural provisions of the nature diversity act. In submissions to the license applications, the principles of §§ 8-10 is explicitly expressed by the County Governor of Hordaland, and implicitly by a number of others. It is primarily the statements by opponents of small hydropower plants that include elements from the nature diversity act in its reasoning. These submissions are products of a participatory process, and this process is important for whom that participates and for what information NVE receives. NVE will decide whether to grant a license or not. Lack of knowledge about the nature diversity act may be one reason why the law is seldom drawn directly into the submissions. Despite the fact that representatives from the County Governor of Hordaland, Hordaland County Council and Odda municipality have be educated in the act, only the County Governor refers directly to nature diversity act in his submission. There are differing opinions about what works as mitigation measures, and measures proposed can be divided into measures for mitigating outdoor activities and measures for mitigating biodiversity. National goals and expectations for renewable energy are often in tension with the goal of biodiversity and landscape esthetics

Naturmangfoldloven i Regional plan for Hardangervidda og konsesjonsbehandling av fem småkraftverk i Valldalen, Odda kommune

I denne masteroppgaven undersøker jeg på hvordan naturmangfoldloven er brukt i Regional plan for Hardangervidda og gjennom konsesjonsbehandling av fem småkraftsøknader i Valldalen i Odda kommune, som omfattes av den regionale planen. Jeg ser spesielt på §§ 8-10 om henholdsvis kunnskapsgrunnlaget, føre-var-prinsippet og økosystemtilnærming og samlet belastning. «Regional plan for Hardangervidda – fylkesdelplan 2011-2025» ble utarbeidet på bestilling fra Miljøverndepartementet (2007a), som ønsket fylkesdelplaner med fastsetting av nasjonale villreinområder. Planen ble utarbeidet ved samarbeid mellom Hordaland, Telemark og Buskerud fylkeskommune, og ble vedtatt plan høsten 2011 av de reseptive fylkestingene. Småkraft AS søkte i 2011 konsesjon for fem småkraftverk i Valldalen, og søknadene ligger per mai 2013 til avgjørelse hos Norges vassdrags- energidirektorat (NVE). Naturmangfoldloven trådte i kraft i 2009, hvilket var etter at planarbeidet med den regionale planen for Hardangervidda var påbegynt, men før den ble vedtatt. I dette case-studiet har jeg gjennomført semistrukturerte kvalitative forskningsintervju med sentrale aktører i utarbeidelsen av Regional plan for Hardangervidda, og berørte aktører i konsesjonsprosessen i Valldalen. Den regionale planen, samt høringsuttalelser fra konsesjonsprosessen er analysert. Resultatene viser at naturmangfoldloven trekkes inn i Regional plan for Hardangervidda primært gjennom et tilleggsnotat med vurderinger etter naturmangfoldlovens §§ 8-12. Prinsippene er i tillegg delvis innarbeidet i planen, men det poengteres i plandokumentet at det er naturlig at naturmangfoldloven blir grundigere vurdert i den lokale planleggingen og ved rullering av den regionale planen. At planen med tilleggsnotat ble vedtatt uten innsigelse fra Miljøverndepartementet må sees på som et signal om at planen oppfylte saksbehandlingsreglene i naturmangfoldloven. I høringsuttalelsene til konsesjonssøknadene trekkes prinsippene i §§ 8-10 eksplisitt inn av Fylkesmannen i Hordaland, og i implisitt av en rekke andre høringsparter. Primært er det uttalelser fra motstandere av småkraftutbyggingene som trekker inn elementer fra naturmangfoldloven i sin argumentasjon. Høringsuttalelsene er et produkt av en medvirkningsprosess, og denne prosessen har betydning for hvem som deltar og hvilke opplysninger som blir spilt inn til NVE, som skal fatte vedtak om konsesjon skal gis eller ikke. Manglende kjennskap til naturmangfoldloven kan være en årsak til at loven i liten grad trekkes direkte inn i uttalelsene. Til tross for opplæring i loven med representanter fra både Fylkesmannen i Hordaland, Hordaland fylkeskommune og Odda kommune, er det kun Fylkesmannen som viser direkte til naturmangfoldloven i sin uttalelse. Det er ulik oppfatning om hva som fungerer som avbøtende tiltak, og tiltakene som foreslås kan grovt deles inn i tiltak som er avbøtende for friluftsliv og tiltak som er avbøtende for naturmangfold. Nasjonale mål og forventninger for fornybar energi står ofte i spenning med mål for naturmangfold og landskapsbilde, men naturmangfoldloven kan potensielt redusere slike spenninger. In this paper I examine how the nature diversity act is used in the Regional plan for Hardangervidda and through licensing of five small hydropower plants in Valldalen in Odda municipality. I look specifically at §§ 8-10 considering knowledge, the precautionary principle and ecosystem approach and cumulative environmental effects. "Regional plan for Hardangervidda – county sub plan 2011-2025" was produced on order from the Ministry of the Environment (2007), who wanted county sub-plans determining national wild reindeer areas. The plan was developed through collaboration between Hordaland, Telemark and Buskerud County Council, and was approved during the autumn 2011 of the receptive county councils. In 2011 Småkraft AS applied for concession for five small hydropower plants in Valldalen, and as of May 2013 the decision is still to be made by the Norwegian Water Resources and Energy Directorate (NVE). The nature diversity act came into force in 2009, which was after the planning process with the regional plan for Hardangervidda had begun, but before it was authorized. In this case study, I conducted semi-structured qualitative interviews with key participants from the preparation of the Regional plan for Hardangervidda, and participants in the licensing process in Valldalen. The regional plan, as well as submissions from the licensing process is analyzed. The results show that the nature diversity act is incorporated into the Regional plan for Hardangervidda primarily through an additional note with an assessment of the principals of the nature diversity act §§ 8-12. The principals are also partially incorporated in the plan, but the planning document points out that it is natural that nature diversity act is thoroughly considered in the local planning and the rollover of the regional plan. That the plan with the supplementary note was adopted without objection from the Ministry of the Environment should be seen as a signal that the plan met the procedural provisions of the nature diversity act. In submissions to the license applications, the principles of §§ 8-10 is explicitly expressed by the County Governor of Hordaland, and implicitly by a number of others. It is primarily the statements by opponents of small hydropower plants that include elements from the nature diversity act in its reasoning. These submissions are products of a participatory process, and this process is important for whom that participates and for what information NVE receives. NVE will decide whether to grant a license or not. Lack of knowledge about the nature diversity act may be one reason why the law is seldom drawn directly into the submissions. Despite the fact that representatives from the County Governor of Hordaland, Hordaland County Council and Odda municipality have be educated in the act, only the County Governor refers directly to nature diversity act in his submission. There are differing opinions about what works as mitigation measures, and measures proposed can be divided into measures for mitigating outdoor activities and measures for mitigating biodiversity. National goals and expectations for renewable energy are often in tension with the goal of biodiversity and landscape esthetics

Módulo 1: apresentação - curso ciclo de gestão do investimento público

Este módulo busca descrever o percurso institucional do investimento público, o que se convencionou denominar de ciclo de gestão do investimento público, e explicitar o papel e as implicações das oito etapas básicas para o alcance de um sistema de investimento público eficiente.Número de páginas: 20 p.Contabilidade PúblicaEconomia do Setor PúblicoGestão EstratégicaGestão Públic

Evaluation of Circulating Cardiovascular Biomarker Levels for Early Detection of Congenital Heart Disease in Newborns in Sweden

Importance: Congenital heart disease (CHD) is the most common congenital malformation in humans worldwide. Circulating cardiovascular biomarkers could potentially improve the early detection of CHD, even in asymptomatic newborns. Objectives: To assess the performance of a dried blood spot (DBS) test to measure the cardiovascular biomarker amino terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP) levels in newborns and to compare DBS with standard EDTA analysis in control newborns during the first week of life. Design, Setting, and Participants: This diagnostic study was conducted in a single regional pediatric service in southern Sweden. Healthy, term neonates born between July 1, 2018, and May 31, 2019, were prospectively enrolled and compared against retrospectively identified newborns with CHD born between September 1, 2003, and September 30, 2019. Neonates who required inpatient treatment beyond the standard postnatal care were excluded. Exposure: New DBS test for NT-proBNP quantification in newborns that used 3 μL of blood vs the current screening standard. Main Outcomes and Measures: Performance of the new test and when combined with pulse oximetry screening was measured by receiver operating characteristic curve analysis. Performance of the new test and EDTA screening was compared using Pearson linear correlation analysis. Results: The DBS samples of 115 neonates (81 control newborns and 34 newborns with CHD, of whom 63 were boys [55%] and the mean [SD] gestational age was 39.6 [1.4] weeks) were analyzed. The new NT-proBNP test alone identified 71% (n = 24 of 34) of all CHD cases and 68% (n = 13 of 19) of critical CHD cases as soon as 2 days after birth. Detection of any CHD type improved to 82% (n = 28 of 34 newborns) and detection of critical CHD improved to 89% (n = 17 of 19 newborns) when combined pulse oximetry screening and NT-proBNP test results were used. Performance of the NT-proBNP test was excellent when control newborns were matched to newborns with CHD born between July 1, 2018, and May 31, 2019 (area under the curve, 0.96; SE, 0.027; 95% CI, 0.908-1.0; asymptotic P < .05). Conclusions and Relevance: This study found that NT-proBNP assay using minimal DBS samples appears to be timely and accurate in detecting CHD in newborns and to discriminate well between healthy newborns and newborns with various types of CHD. This finding warrants further studies in larger cohorts and highlights the potential of NT-proBNP to improve neonatal CHD screening

Matematikkundervisning

Denna boken är skriven av en grupp erfarna norska och svenska lärarutbildare i matematik. Boken bygger på utprövad erfarenhet - såväl egen som andras - och på aktuell, relevant forskning i matematikdidaktik. Texten väver samman matematik och matematikdidaktik, det vill säga ämnet som det undervisas i och frågor om hur ämnet kan läras och undervisas. Boken innehåller det som är absolut viktigast att få med sig i den grundläggande lärarutbildningen i matmatik

Fur colour in the Arctic fox: genetic architecture and consequences for fitness

Genome-wide association studies provide good opportunities for studying the genetic basis of adaptive traits in wild populations. Yet, previous studies often failed to identify major effect genes. In this study, we used high-density single nucleotide polymorphism and individual fitness data from a wild non-model species. Using a whole-genome approach, we identified the MC1R gene as the sole causal gene underlying Arctic fox Vulpes lagopus fur colour. Further, we showed the adaptive importance of fur colour genotypes through measures of fitness that link ecological and evolutionary processes. We found a tendency for blue foxes that are heterozygous at the fur colour locus to have higher fitness than homozygous white foxes. The effect of genotype on fitness was independent of winter duration but varied with prey availability, with the strongest effect in years of increasing rodent populations. MC1R is located in a genomic region with high gene density, and we discuss the potential for indirect selection through linkage and pleiotropy. Our study shows that whole-genome analyses can be successfully applied to wild species and identify major effect genes underlying adaptive traits. Furthermore, we show how this approach can be used to identify knowledge gaps in our understanding of interactions between ecology and evolution