| 1. |
- Farias, Fabiana H. G., et al.
(författare)
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A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts
- 2019
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 27, s. 432-441
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical presentation and complex etiology involving the interplay between genetic, epigenetic, environmental and hormonal factors. Many common SNPs identified by genome wide-association studies (GWAS) explain only a small part of the disease heritability suggesting the contribution from rare genetic variants, undetectable in GWAS, and complex epistatic interactions. Using targeted re-sequencing of coding and conserved regulatory regions within and around 215 candidate genes selected on the basis of their known role in autoimmunity and genes associated with canine immune-mediated diseases, we identified a rare regulatory variant rs200395694:G > T located in intron 4 of the MEF2D gene encoding the myocyte-specific enhancer factor 2D transcription factor and associated with SLE in Swedish cohorts (504 SLE patients and 839 healthy controls, p = 0.014, CI = 1.1-10). Fisher's exact test revealed an association between the genetic variant and a triad of disease manifestations including Raynaud, anti-U1-ribonucleoprotein (anti-RNP), and anti-Smith (anti-Sm) antibodies (p = 0.00037) among the patients. The DNA-binding activity of the allele was further studied by EMSA, reporter assays, and minigenes. The region has properties of an active cell-specific enhancer, differentially affected by the alleles of rs200395694:G > T. In addition, the risk allele exerts an inhibitory effect on the splicing of the alternative tissue-specific isoform, and thus may modify the target gene set regulated by this isoform. These findings emphasize the potential of dissecting traits of complex diseases and correlating them with rare risk alleles with strong biological effects.
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| 2. |
- Gravina, Giacomo, et al.
(författare)
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Survivin in autoimmune diseases.
- 2017
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Ingår i: Autoimmunity reviews. - : Elsevier BV. - 1873-0183 .- 1568-9972. ; 16:8, s. 845-855
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Forskningsöversikt (refereegranskat)abstract
- Survivin is a protein functionally important for cell division, apoptosis, and possibly, for micro-RNA biogenesis. It is an established marker of malignant cell transformation. In non-malignant conditions, the unique properties of survivin make it indispensable for homeostasis of the immune system. Indeed, it is required for the innate and adaptive immune responses, controlling differentiation and maintenance of CD4(+) and CD8(+) memory T-cells, and in B cell maturation. Recently, survivin has emerged as an important player in the pathogenesis of autoimmune diseases. Under the conditions of unreserved inflammation, survivin enhances antigen presentation, maintains persistence of autoreactive cells, and supports production of autoantibodies. In this context, survivin takes its place as a diagnostic and prognostic marker in rheumatoid arthritis, psoriasis, systemic sclerosis and pulmonary arterial hypertension, neuropathology and multiple sclerosis, inflammatory bowel diseases and oral lichen planus. In this review, we summarise the knowledge about non-malignant properties of survivin and focus on its engagement in cellular and molecular pathology of autoimmune diseases. The review highlights utility of survivin measures for clinical applications. It provides rational for the survivin inhibiting strategies and presents results of recent reports on survivin inhibition in modern therapies of cancers and autoimmune diseases.
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| 3. |
- Lindén, Malin, et al.
(författare)
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FET family fusion oncoproteins target the SWI/SNF chromatin remodeling complex
- 2019
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Ingår i: EMBO Reports. - : EMBO. - 1469-221X .- 1469-3178. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- Members of the human FET family of RNA-binding proteins, comprising FUS, EWSR1, and TAF15, are ubiquitously expressed and engage at several levels of gene regulation. Many sarcomas and leukemias are characterized by the expression of fusion oncogenes with FET genes as 5′ partners and alternative transcription factor-coding genes as 3′ partners. Here, we report that the N terminus of normal FET proteins and their oncogenic fusion counterparts interact with the SWI/SNF chromatin remodeling complex. In contrast to normal FET proteins, increased fractions of FET oncoproteins bind SWI/SNF, indicating a deregulated and enhanced interaction in cancer. Forced expression of FET oncogenes caused changes of global H3K27 trimethylation levels, accompanied by altered gene expression patterns suggesting a shift in the antagonistic balance between SWI/SNF and repressive polycomb group complexes. Thus, deregulation of SWI/SNF activity could provide a unifying pathogenic mechanism for the large group of tumors caused by FET fusion oncoproteins. These results may help to develop common strategies for therapy. © 2019 The Authors. Published under the terms of the CC BY 4.0 license
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| 4. |
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| 5. |
- Andersson, Anna-Maria, 1990-
(författare)
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Mycobacterium tuberculosis and HIV coinfection : Effects on innate immunity and strategies to boost the immune response
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tuberculosis (TB) still remains a big threat today, being the leading cause of death by a single infectious agent. The TB epidemic is fueled by HIV along with the increasing drug-resistance which prolongs the already long treatment duration and decreases the success rate for curing TB. In most cases an infection results in latency but HIV patients have a 20-30 times higher risk of developing active TB. There are around 36.9 million people living with HIV globally, with the highest burden in Africa. Although there are effective treatments against the disease, there is no cure for AIDS and the availability of the lifelong treatment is limited in low-income countries were the burden is highest. HIV infection causes an immunodeficiency characterized by the progressive loss of CD4 T cells which increases the risk of opportunistic infections, and infection by Mycobacterium tuberculosis (Mtb), the causative agent of TB. Mtb spreads through aerosols from one person with active tuberculosis to a healthy person. Upon inhalation the bacteria are phagocytosed by alveolar macrophages that secrete cytokines and chemokines to recruit more cells, such as dendritic cells, macrophages and lymphocytes, leading to the formation of a granuloma. During a single TB infection the bacteria are usually contained within the granuloma, but HIV can disrupt the stable granuloma, causing a rupture and dissemination of Mtb. This inflammatory site is also beneficial to HIV since it promotes replication of the virus within infected cells. HIV and Mtb are two successful intracellular pathogens able to avoid immune defense mechanisms both of the innate and adaptive immunity in order to persist and replicate. Their virulence factors can manipulate or inhibit cell signaling, phagosome maturation, autophagy, ROS production, apoptosis and antigen presentation, to promote survival. Boosting of immune defenses with host-directed therapies (HDT) has been proposed as a treatment strategy against TB, either alone or adjunctive to the current regimen.In this thesis, ways to boost the innate immune responses in Mtb and HIV coinfected macrophages were investigated, along with studies of the effect of HIV on Mtb antigen presentation in coinfected dendritic cells. The initial hypothesis was that autophagy induction through inhibition of mammalian target of rapamycin (mTOR) could suppress Mtb growth in HIV coinfected macrophages. However, during a low grade infection, autophagy induction increased Mtb replication due to a decreased autophagic flux and acidification of Mtb phagosomes. A general autophagic flux was induced, although not localized to the Mtb phagosomes, thus not inducing a xenophagy (autophagy of intracellular pathogens). Other ways of inducing autophagy or boosting the response in coinfected macrophages might be more beneficial and therefore the effect of efferocytosis was investigated. Uptake of apoptotic neutrophils by coinfected macrophages did not induce autophagy but enhanced the control of Mtb by other means. Upon efferocytosis, the macrophages acquired active myeloperoxidase (MPO) from the neutrophils that suppressed Mtb growth. The coinfected macrophages also produced more ROS after efferocytosis. The inhibition of Mtb growth could thus be mediated by MPO and the increased ROS production either directly or indirectly.The possibility to boost the innate immunity could prove to be important during an HIV coinfection, when the adaptive immunity is deficient. In addition to the well-known decline in CD4 T cells during the course of HIV progression, we found that HIV infection of dendritic cells inhibited antigen presentation by suppressing the expression of HLA-DR and co-stimulatory molecules on coinfected dendritic cells. Furthermore, HIV reduced secretion of pro-inflammatory cytokines and suppressed antigen processing through inhibition of autophagy. This impaired antigen presentation in coinfected dendritic cells resulted in a decreased activation and response of Mtb-specific CD4 T cells.In conclusion, this thesis shows how HIV can manipulate antigen presentation in Mtb coinfected dendritic cells and subsequently inhibit the adaptive immune response. It also contributes to insights on how efferocytosis of apoptotic neutrophils can boost the innate immune responses during coinfection. Lastly, autophagy induction through mTOR inhibition does not enhance protection against TB. Induction of autophagy should therefore be handled with care, particularly during HIV coinfection.
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| 6. |
- Andersson, Karin, 1972, et al.
(författare)
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Survivin co-ordinates formation of follicular T-cells acting in synergy with Bcl-6
- 2015
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:24, s. 20043-20057
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Tidskriftsartikel (refereegranskat)abstract
- Follicular T helper (Tfh) cells are recognized by the expression of CXCR5 and the transcriptional regulator Bcl-6. Tfh cells control B cell maturation and antibody production, and if deregulated, may lead to autoimmunity. Here, we study the role of the proto-oncogene survivin in the formation of Tfh cells. We show that blood Tfh cells of patients with the autoimmune condition rheumatoid arthritis, have intracellular expression of survivin. Survivin was co-localized with Bcl-6 in the nuclei of CXCR5(+)CD4 lymphocytes and was immunoprecipitated with the Bcl-6 responsive element of the target genes. Inhibition of survivin in arthritic mice led to the reduction of CXCR5(+) Tfh cells and to low production of autoantibodies. Exposure to survivin activated STAT3 and induced enrichment of PD-1(+)Bcl-6(+) subset within Tfh cells. Collectively, our study demonstrates that survivin belongs to the Tfh cell phenotype and ensures their optimal function by regulating transcriptional activity of Bcl-6.
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| 7. |
- Andersson, Klas, 1975, et al.
(författare)
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Tillit och misstro i icke framgångsrika skolor
- 2018
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Ingår i: Skolan som politisk organisation 3:e uppl, Maria Jarl, Jon Pierre (red.). - : Gleerups Utbildning AB. - 9789140696984
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 8. |
- Andersson, Martin O., et al.
(författare)
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Co-infection with Babesia divergens and Anaplasma phagocytophilum in cattle (Bos taurus), Sweden
- 2017
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Ingår i: Ticks and Tick-borne Diseases. - : Elsevier. - 1877-959X .- 1877-9603. ; 8:6, s. 933-935
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Tidskriftsartikel (refereegranskat)abstract
- Babesiosis is a severe disease in cattle worldwide. In Europe, the main causative agent of bovine babesiosis is Babesia divergens. In some areas, this species is reported to have declined or even disappeared, and its etiological role overtaken by other piroplasmid species. Moreover, co-infection with other tick-transmitted pathogens can be expected to complicate diagnosis in cattle. Hence, molecular identification of the causative agent of babesiosis should be a priority. Therefore, samples from 71 domestic cattle, 39 with clinical signs of babesiosis and 32 without, from southern Sweden were screened for Babesia spp. and Anaplasma spp. using molecular methods Babesia divergens was detected in 38 of the samples, and Anaplasma phagocytophilum in 17. Co-infections with both pathogens were frequent, occurring in 18% of the animals with a B. divergens infection. The possibility of co-infection should be considered in diagnosis and treatment of bovine babesiosis.
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| 9. |
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| 10. |
- Eriksson, Maria, 1969-, et al.
(författare)
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Utvärdering av Mentorer i våldsprevention : Slutrapport
- 2018
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Rapporten presenterar resultaten från en utvärdering av det våldsförebyggande programmet Mentorer i våldsprevention (MVP). Programmet Mentors in Violence Prevention kommer från USA och är ett utbildningsprogram som syftar till att förebygga killars och mäns våld. Organisationen Män för Jämställdhet har översatt programmet från engelska, anpassat det till svenska förhållanden och under perioden 2015-2017 spridit MVP i ett antal skolor i Sverige inom ramen för projektet ”En kommun fri från våld”. Det är den version av MVP som Män för Jämställdhet utvecklat och sprider som den här utvärderingen berör. Utvärderingen har genomförts på uppdrag av Skolverket.
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| 11. |
- Fridén-Saxin, Maria, 1979, et al.
(författare)
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Chroman-4-one and chromone based somatostatin beta-turn mimetics
- 2016
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234. ; 114, s. 59-64
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Tidskriftsartikel (refereegranskat)abstract
- A scaffold approach has been used to develop somatostatin beta-turn mimetics based on chroman-4-one and chromone ring systems. Such derivatives could adopt conformations resembling type II or type II' beta-turns. Side chain equivalents of the crucial Trp8 and Lys9 in somatostatin were introduced in the 2- and 8-positions of the scaffolds using efficient reactions. Interestingly, this proof-of-concept study shows that 4 and 9 have K-i-values in the low mu M range when evaluated for their affinity for the sst2 and sst4 receptors. (C) 2016 Elsevier Masson SAS. All rights reserved.
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| 12. |
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| 13. |
- Jarl, Maria, 1973, et al.
(författare)
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Därför lyckas vissa skolor bättre
- 2017
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Ingår i: Lärorik. Tidskrift för pedagogisk utveckling inom förskola och skola. Linköpings kommun. - 2001-1253. ; :2, s. 3-5
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Annan publikation (övrigt vetenskapligt/konstnärligt)
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| 14. |
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| 15. |
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| 16. |
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| 17. |
- Jarl, Maria, 1973, et al.
(författare)
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Success or failure? Presenting a case selection strategy for studies of school improvement
- 2017
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Ingår i: Education Inquiry. - : Informa UK Limited. - 2000-4508. ; 8:1, s. 17-32
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Tidskriftsartikel (refereegranskat)abstract
- In this article we propose a case selection strategy for comparative studies of school improvement. The strategy is based on two assumptions. First, we emphasize the importance of a strategic selection of cases (schools), which allows systematic comparisons between successful and failing schools. We claim that cases should be selected on the dependent variable, and, more specifically, on the variation in the dependent variable (i.e. school success or no school success). Second, we recognize the importance of a longitudinal perspective in the case selection process. We argue that quantitative longitudinal data should be used to identify consistently succeeding and consistently failing schools. Furthermore, we demonstrate the fruitfulness of the strategy by using it in a case selection process of successful and failing schools in Sweden. In sum, the strategy addresses the demand for research designs, which allow causal inference, in school improvement and school effectiveness studies. Systematic comparisons between successful and failing schools are essential to elaborate our insights of the mechanisms behind school success.
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| 18. |
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| 19. |
- Koffert, J. P., et al.
(författare)
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Metformin treatment significantly enhances intestinal glucose uptake in patients with type 2 diabetes: Results from a randomized clinical trial
- 2017
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Ingår i: Diabetes Research and Clinical Practice. - : Elsevier BV. - 0168-8227 .- 1872-8227. ; 131, s. 208-216
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Tidskriftsartikel (refereegranskat)abstract
- Aims Metformin therapy is associated with diffuse intestinal 18F-fluoro-deoxyglucose (FDG) accumulation in clinical diagnostics using routine FDG-PET imaging. We aimed to study whether metformin induced glucose uptake in intestine is associated with the improved glycaemic control in patients with type 2 diabetes. Therefore, we compared the effects of metformin and rosiglitazone on intestinal glucose metabolism in patients with type 2 diabetes in a randomized placebo controlled clinical trial, and further, to understand the underlying mechanism, evaluated the effect of metformin in rats. Methods Forty-one patients with newly diagnosed type 2 diabetes were randomized to metformin (1g, b.i.d), rosiglitazone (4mg, b.i.d), or placebo in a 26-week double-blind trial. Tissue specific intestinal glucose uptake was measured before and after the treatment period using FDG-PET during euglycemic hyperinsulinemia. In addition, rats were treated with metformin or vehicle for 12weeks, and intestinal FDG uptake was measured in vivo and with autoradiography. Results Glucose uptake increased 2-fold in the small intestine and 3-fold in the colon for the metformin group and associated with improved glycemic control. Rosiglitazone increased only slightly intestinal glucose uptake. In rodents, metformin treatment enhanced intestinal FDG retention (P=0.002), which was localized in the mucosal enterocytes of the small intestine. Conclusions Metformin treatment significantly enhances intestinal glucose uptake from the circulation of patients with type 2 diabetes. This intestine-specific effect is associated with improved glycemic control and localized to mucosal layer. These human findings demonstrate directs effect of metformin on intestinal metabolism and elucidate the actions of metformin. Clinical trial number NCT02526615 © 2017 The Authors
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| 20. |
- Lam, Monika M., 1987-
(författare)
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Characterization of PAC-contaminated soil with the focus on availability, leachability and biological activities
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Current risk assessments of polycyclic aromatic compounds (PACs)-contaminated soil are often based on the 16 priority PAHs and do not consider availability of PACs in soil sufficiently. This may lead to uncertainties of the assessment, since important contaminants can be overlooked and only a small fraction of contaminants is available for the uptake for organisms. The overall aim of this thesis was to develop a refined and enhanced analytical approach based on both chemical and bioassay analysis coupled to passive sampling with polyoxymethylene (POM) and leaching tests that can provide a more comprehensive picture of chemical pollution at PAC-contaminated sites. To achieve this, bioassay-specific relative potency factors (REPs) of PACs were determined for the H4IIE-luc bioassay, detecting AhR-mediated activity, and for the VM7luc4E2 transactivation assay, detecting ER-mediated activity for the use in potency-balance analysis. Results of uptake-experiments of PACs in earthworms and POM suggested that POM is a suitable tool to study availability of AhR and ER agonists in soil. Availability and mobility of PACs in soil were investigated by the use of POM and leaching tests. The results of potency-balance analysis showed that in soil samples, in POM-fractions or in leachates, a large fraction of AhR- or ER-agonists remained unexplained, despite the use of a large number of REPs. In addition, coupling of chemical and biological analysis to passive sampling or leaching tests revealed that only a small fraction of the total mass of PACs in the soil is available or leachable in soil. The results suggests that the use of only the total concentration in soil while ignoring unknown toxicants will lead to great uncertainties in the risk assessment. Therefore, effect-based screening using bioassays, taking availability and mobility of compounds into account, as well as a widened chemical analysis should be included in modern hazard- and risk assessment of PAH contaminated soils.
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| 21. |
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| 22. |
- Yan, Ping, et al.
(författare)
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3D magnetotelluric modelling of the Alnö alkaline and carbonatite ring complex, central Sweden
- 2016
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Ingår i: Tectonophysics. - : Elsevier BV. - 0040-1951 .- 1879-3266. ; 679, s. 218-234
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Tidskriftsartikel (refereegranskat)abstract
- Thirty-four broadband magnetotelluric stations were deployed across the Alno alkaline and carbonatite ring intrusion in central Sweden. The measurements were designed such that both 2D models along existing seismic profiles and a 3D model can be constructed. Alno Island and surrounding areas are densely populated and industrialized and in order to reduce the effect of noise, the remote reference technique was utilized in time series processing. Strike and dimensionality analyses together with the induction arrows show that there is no homogeneous regional strike direction in this area. Therefore, only the determinant of the impedance tensor was used for 2D inversion whereas all elements of the impedance tensor were used for 3D inversion. Representative rock samples were collected from existing outcrops and their resistivities were measured in the laboratory to facilitate interpretation of the inversion models. The results from these measurements show that coarse grained (sovite, white color) and fine-grained (dark color) carbonatites are the most conductive and resistive rock types, respectively. In accordance with the interpretation of the reflection seismic images, the 2D and 3D resistivity models depict the caldera-related ring-type fault system and updoming faulted and fractured systems as major 10-500 Omega m conductors, extending down to about 3 km depth. A central similar to 4000 Omega m resistive unit at about 3 km depth appears to correspond to a solidified fossil magma chamber as speculated from the reflection seismic data and earlier field geological studies.
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