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| 2. |
- Andersson, Martin O., et al.
(author)
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Molecular detection of Babesia capreoli and Babesia venatorum in wild Swedish roe deer, Capreolus capreolus
- 2016
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In: Parasites & Vectors. - : Springer Science and Business Media LLC. - 1756-3305. ; 9:1
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Journal article (peer-reviewed)abstract
- Background: The epidemiology of the zoonotic tick-transmitted parasite Babesia spp. and its occurrence in wild reservoir hosts in Sweden is unclear. In European deer, several parasite species, including Babesia capreoli and the zoonotic B. venatorum and B. divergens has been reported previously. The European roe deer, Capreolus capreolus, is an important and common part of the indigenous fauna in Europe, as well as an important host for Ixodes ricinus ticks, the vector of several Babesia spp. in Europe. Here, we aimed to investigate the occurrence of Babesia spp. in roe deer in Sweden. Findings: Roe deer (n = 77) were caught and sampled for blood. Babesia spp. was detected with a PCR assay targeting the 18S rRNA gene. The prevalence of Babesia spp. was 52 %, and two species were detected; B. capreoli and B. venatorum in 44 and 7.8 % of the individuals, respectively. Infection occurred both in summer and winter. Conclusions: We showed that roe deer in Sweden, close to the edge of their northern inland distributional range, are infected with Babesia spp. The occurrence of B. venatorum in roe deer imply that it is established in Sweden and the zoonotic implication of this finding should be regarded to a greater extent in future.
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| 3. |
- Forsgren, Elin, 1987-
(author)
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Using patient-derived cell models to investigate the role of misfolded SOD1 in ALS
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Protein misfolding and aggregation underlie several neurodegenerative proteinopathies including amyotrophic lateral sclerosis (ALS). Superoxide dismutase 1 (SOD1) was the first gene found to be associated with familial ALS. Overexpression of human mutant or wild type SOD1 in transgenic mouse models induces motor neuron (MN) degeneration and an ALS-like phenotype. SOD1 mutations, leading to the destabilization of the SOD1 protein is associated with ALS pathogenesis. However, how misfolded SOD1 toxicity specifically affects human MNs is not clear. The aim of this thesis was to develop patient-derived, cellular models of ALS to help understand the pathogenic mechanisms underlying SOD1.To understand which cellular pathways impact on the level of misfolded SOD1 in human cells, we established a model using patient-derived fibroblasts and quantified misfolded SOD1 in relation to disturbances in several ALS-related cellular pathways. Misfolded SOD1 levels did not change following reduction in autophagy, inhibition of the mitochondrial respiratory chain, or induction of endoplasmic reticulum (ER)-stress. However, inhibition of the ubiquitin-proteasome system (UPS) lead to a dramatic increase in misfolded SOD1 levels. Hence, an age-related decline in proteasome activity might underlie the late-life onset that is typically seen in SOD1 ALS.To address whether or not SOD1 misfolding is enhanced in human MNs, we used mixed MN/astrocyte cultures (MNCs) generated in vitro from patient-specific induced pluripotent stem cells (iPSCs). Levels of soluble misfolded SOD1 were increased in MNCs as well as in pure iPSC-derived astrocytes compared to other cell types, including sensory neuron cultures. Interestingly, this was the case for both mutant and wild type human SOD1, although the increase was enhanced in SOD1 FALS MNCs. Misfolded SOD1 was also found to exist in the same form as in mouse SOD1 overexpression models and was identified as a substrate for 20S proteasome degradation. Hence, the vulnerability of motor areas to ALS could be explained by increased SOD1 misfolding, specifically in MNs and astrocytes.To investigate factors that might promote SOD1 misfolding, we focussed on the stability of SOD1 mediated by a crucial, stabilizing C57-C146 disulphide bond and its redox status. Formation of disulphide bond is dependent on oxidation by O2 and catalysed by CCS. To investigate whether low O2 tension affects the stability of SOD1 in vitro we cultured fibroblasts and iPSC-derived MNCs under different oxygen tensions. Low oxygen tension promoted disulphide-reduction, SOD1 misfolding and aggregation. This response was much greater in MNCs compared to fibroblasts, suggesting that MNs may be especially sensitive to low oxygen tension and areas with low oxygen supply could serve as foci for ALS initiation.SOD1 truncation mutations often lack C146, and cannot adopt a native fold and are rapidly degraded. We characterized soluble misfolded and aggregated SOD1 in patient-derived cells carrying a novel SOD1 D96Mfs*8 mutation as well as in cells fom an unaffected mutation carrier. The truncated protein has a C-terminal fusion of seven non-native amino acids and was found to be extremely prone to aggregation in vitro. Since not all mutation carriers develop ALS, our results suggested this novel mutation is associated with reduced penetrance.In summary, patient derived cells are useful models to study factors affecting SOD1 misfolded and aggregation. We show for the first time that misfolding of a disordered and disease associated protein is enhanced in disease-related cell types. Showing that misfolded SOD1 exists in human cells in the same form as in transgenic mouse models strengthens the translatability of results obtained in the two species. Our results demonstrate disulphide-reduction and misfolding/aggregation of SOD1 and suggest that 20S proteasome could be an important therapeutic target for early stages of disease. This model provides a great opportunity to study pathogenic mechanisms of both familial and sporadic ALS in patient-derived models of ALS.
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| 4. |
- Freischmidt, Axel, et al.
(author)
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Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia
- 2015
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In: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1097-6256 .- 1546-1726. ; 18:5, s. 631-
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Journal article (peer-reviewed)abstract
- Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.
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| 5. |
- Fälth, Linda, 1973-, et al.
(author)
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An intervention study to prevent ‘summer reading loss’ in a socioeconomically disadvantaged area with second language learners
- 2019
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In: Nordic Journal of Literacy Research. - : NOASP. - 2464-1596. ; 5:3, s. 10-23
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Journal article (peer-reviewed)abstract
- Summer reading loss is a documented reality for many students. Research has established differences in the contribution of summer reading activity between children from families with different economic status. In this study, 120 students in Grade 2 and 115 students in Grade 3 from a socioeconomically vulnerable area participated in a summer reading intervention. In addition, a control group from the same schools comprised of 106 students from Grade 2 and 94 students from Grade 3. Almost 90% of the participating students did not have Swedish as their native language. The participants were tested on reading skills, including word decoding, nonsense-word reading, word comprehension and reading comprehension, before and after the summer vacation. The intervention was planned together with teachers from three participant schools and leisure centers. Before the summer holiday the schools arranged reading weeks and library visits. The students were encouraged to read at home during the vacation and record the number of books read on a digital platform. The results showed that the largest effect sizes between groups (intervention and control) were observed for word decoding in Grade 2 and word comprehension in Grade 3 where the intervention group improved more than the control group. If summer learning loss can be avoided or limited, the treatment can be considered worth implementing
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| 6. |
- Fälth, Linda, 1973-, et al.
(author)
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Assessment Support as Part of Teacher Duties in the Subject of Swedish at the Elementary Level
- 2019
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In: International Journal of Learning, Teaching and Educational Research. - Flacq : Society for Research and Knowledge Management. - 1694-2493 .- 1694-2116. ; 18:4, s. 85-109
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Journal article (peer-reviewed)abstract
- The aim of this study was to examine and describe the use of a formative assessment support regarding reading instruction in grades 1-3, viewed from a teacher perspective. Sixty-five teachers from all parts of Sweden responded to a questionnaire, who had used the support for at least one year. Of the participant teachers, nine were interviewed for the purpose of performing an in-depth analysis of the questions. The teachers stated that the primary use of the assessment results was to identify students in need of extra support, as a basis for performance appraisals, as well as for further lesson planning. Formative assessment was, on the one hand, described as a concrete practical method and, on the other hand, as an attitude. The results also indicate a feeling of frustration that, notwithstanding the current deeper insight into what every student needs, the teaching still proceeds on some middle-ground path or level.
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| 7. |
- Gerdtsson, Anna Sandström, et al.
(author)
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Plasma protein profiling in a stage defined pancreatic cancer cohort – Implications for early diagnosis
- 2016
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In: Molecular Oncology. - : Wiley. - 1574-7891. ; 10:8, s. 1305-1316
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Journal article (peer-reviewed)abstract
- Pancreatic ductal adenocarcinoma (PDAC) is a disease where detection preceding clinical symptoms significantly increases the life expectancy of patients. In this study, a recombinant antibody microarray platform was used to analyze 213 Chinese plasma samples from PDAC patients and normal control (NC) individuals. The cohort was stratified according to disease stage, i.e. resectable disease (stage I/II), locally advanced (stage III) and metastatic disease (stage IV). Support vector machine analysis showed that all PDAC stages could be discriminated from controls and that the accuracy increased with disease progression, from stage I to IV. Patients with stage I/II PDAC could be discriminated from NC with high accuracy based on a plasma protein signature, indicating a possibility for early diagnosis and increased detection rate of surgically resectable tumors.
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| 8. |
- Gustafson, Stefan, 1968-, et al.
(author)
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Effects of a formative assessment system on early reading development
- 2019
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In: Education. - Mobile, AL, United States : Project Innovation. - 0013-1172. ; 140:1, s. 17-27
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Journal article (peer-reviewed)abstract
- We present quantitative results from the pilot-year of a large scale Swedish educational project in reading development called LegiLexi, inspired by research within the Response to intervention and Formative assessment traditions. The vision of the project is that every pupil should reach adequate reading skills at the end of grade 3 in primary school. LegiLexi contains a formative assessment tool and a teacher course, which are linked together. We describe LegiLexi and analyze quantitative effects of the pilot year regarding reading development for pupils in grade 1. The design included three conditions; full access to LegiLexi, access only to the formative assessment tool, and control. Results showed that the group with full access to LegiLexi improved their word decoding and reading comprehension the most. For language comprehension, the Formative assessment only group showed the highest improvements. Thus, the features of LegiLexi seem to help enhance critical reading skills. Some changes will be made in the project to strengthen methodological aspects and further facilitate pupils’ reading development.
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| 9. |
- Keskin, Isil, 1987-, et al.
(author)
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The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension
- 2019
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In: Acta Neuropathologica. - New York : Springer. - 0001-6322 .- 1432-0533. ; 138:1, s. 85-101
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Journal article (peer-reviewed)abstract
- Mutations in superoxide dismutase 1 (SOD1) cause amyotrophic lateral sclerosis (ALS). Disease pathogenesis is linked to destabilization, disorder and aggregation of the SOD1 protein. However, the non-genetic factors that promote disorder and the subsequent aggregation of SOD1 have not been studied. Mainly located to the reducing cytosol, mature SOD1 contains an oxidized disulfide bond that is important for its stability. Since O2 is required for formation of the bond, we reasoned that low O2 tension might be a risk factor for the pathological changes associated with ALS development. By combining biochemical approaches in an extensive range of genetically distinct patient-derived cell lines, we show that the disulfide bond is an Achilles heel of the SOD1 protein. Culture of patient-derived fibroblasts, astrocytes, and induced pluripotent stem cell-derived mixed motor neuron and astrocyte cultures (MNACs) under low oxygen tensions caused reductive bond cleavage and increases in disordered SOD1. The effects were greatest in cells derived from patients carrying ALS-linked mutations in SOD1. However, significant increases also occurred in wild-type SOD1 in cultures derived from non-disease controls, and patients carrying mutations in other common ALS-linked genes. Compared to fibroblasts, MNACs showed far greater increases in SOD1 disorder and even aggregation of mutant SOD1s, in line with the vulnerability of the motor system to SOD1-mediated neurotoxicity. Our results show for the first time that O2 tension is a principal determinant of SOD1 stability in human patient-derived cells. Furthermore, we provide a mechanism by which non-genetic risk factors for ALS, such as aging and other conditions causing reduced vascular perfusion, could promote disease initiation and progression.
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| 10. |
- Kurowska, Zuzanna, et al.
(author)
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Identification of Multiple QTLs Linked to Neuropathology in the Engrailed-1 Heterozygous Mouse Model of Parkinson's Disease
- 2016
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Journal article (peer-reviewed)abstract
- Motor symptoms in Parkinson's disease are attributed to degeneration of midbrain dopaminergic neurons (DNs). Heterozygosity for Engrailed-1 (En1), one of the key factors for programming and maintenance of DNs, results in a parkinsonian phenotype featuring progressive degeneration of DNs in substantia nigra pars compacta (SNpc), decreased striatal dopamine levels and swellings of nigro-striatal axons in the SwissOF1-En1+/- mouse strain. In contrast, C57Bl/6-En1+/- mice do not display this neurodegenerative phenotype, suggesting that susceptibility to En1 heterozygosity is genetically regulated. Our goal was to identify quantitative trait loci (QTLs) that regulate the susceptibility to PD-like neurodegenerative changes in response to loss of one En1 allele. We intercrossed SwissOF1-En1+/- and C57Bl/6 mice to obtain F2 mice with mixed genomes and analyzed number of DNs in SNpc and striatal axonal swellings in 120 F2-En1+/- 17 week-old male mice. Linkage analyses revealed 8 QTLs linked to number of DNs (p = 2.4e-09, variance explained = 74%), 7 QTLs linked to load of axonal swellings (p = 1.7e-12, variance explained = 80%) and 8 QTLs linked to size of axonal swellings (p = 7.0e-11, variance explained = 74%). These loci should be of prime interest for studies of susceptibility to Parkinson's disease-like damage in rodent disease models and considered in clinical association studies in PD.
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