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- Gawel, Danuta, et al.
(författare)
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A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases
- 2019
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Ingår i: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genomic medicine has paved the way for identifying biomarkers and therapeutically actionable targets for complex diseases, but is complicated by the involvement of thousands of variably expressed genes across multiple cell types. Single-cell RNA-sequencing study (scRNA-seq) allows the characterization of such complex changes in whole organs. Methods: The study is based on applying network tools to organize and analyze scRNA-seq data from a mouse model of arthritis and human rheumatoid arthritis, in order to find diagnostic biomarkers and therapeutic targets. Diagnostic validation studies were performed using expression profiling data and potential protein biomarkers from prospective clinical studies of 13 diseases. A candidate drug was examined by a treatment study of a mouse model of arthritis, using phenotypic, immunohistochemical, and cellular analyses as read-outs. Results: We performed the first systematic analysis of pathways, potential biomarkers, and drug targets in scRNA-seq data from a complex disease, starting with inflamed joints and lymph nodes from a mouse model of arthritis. We found the involvement of hundreds of pathways, biomarkers, and drug targets that differed greatly between cell types. Analyses of scRNA-seq and GWAS data from human rheumatoid arthritis (RA) supported a similar dispersion of pathogenic mechanisms in different cell types. Thus, systems-level approaches to prioritize biomarkers and drugs are needed. Here, we present a prioritization strategy that is based on constructing network models of disease-associated cell types and interactions using scRNA-seq data from our mouse model of arthritis, as well as human RA, which we term multicellular disease models (MCDMs). We find that the network centrality of MCDM cell types correlates with the enrichment of genes harboring genetic variants associated with RA and thus could potentially be used to prioritize cell types and genes for diagnostics and therapeutics. We validated this hypothesis in a large-scale study of patients with 13 different autoimmune, allergic, infectious, malignant, endocrine, metabolic, and cardiovascular diseases, as well as a therapeutic study of the mouse arthritis model. Conclusions: Overall, our results support that our strategy has the potential to help prioritize diagnostic and therapeutic targets in human disease.
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| 4. |
- Andersson, Per, Professor, 1964-, et al.
(författare)
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Factors influencing the value of CPD activities among VET teachers
- 2018
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Ingår i: International Journal for Research in Vocational Education and Training. - 2197-8638 .- 2197-8646. ; 5:2, s. 140-164
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Tidskriftsartikel (refereegranskat)abstract
- Context: Teachers in vocational education and training (VET teachers) have specific conditions for their continuing professional development (CPD). They have a background in an initial occupation, in which they now teach and train the next generation. Thus, as VET teachers, they are expected to master the knowledge and skills of that occupa- tion, even if they have now crossed the boundary from the community of their initial occupation to the community of the school. This study explores the perceived values among VET teachers of different activities that may contribute to their CPD in teaching subjects/initial occupations. The study examines VET at the upper secondary level in Sweden. Here, the VET teachers have the main responsibility for students’ vocational learning in the vocational subjects, including the work-based parts. In the latter parts, the teachers are supplemented by supervisors at the workplace.Approach: We argue for the duality of a VET teacher identity with a professional competence that comprises two intertwined parts – teaching skills, and knowledge of the teaching subjects based in the teachers’ initial occupations. Our study is based on a situated learning perspective, and the empirical findings particularly concern values created from learning through participation and boundary crossing. CPD activities typi- cally include some form of participation in and/or boundary crossing between school and work-life practices. In the analysis we also include the possible influence of institutional, situational, and dispositional drivers and barriers for participation in different activities. The research question was: what factors can explain the variation in perceived values created by participation in different CPD activities among VET teachers? The study was conducted as a survey of 886 Swedish VET teachers. Focus was put on the values created through different types of activity, values for the teachers’ vocational knowledge, for networks in working life, and for teaching. The data were primarily analysed using logistic regression modelling.Findings: Dispositional drivers, the teacher’s sex, and regular performance of the ac- tivity are important for the perceived value. The dispositional factor is the one most commonly retained, and it has a consistently positive effect. Factors such as educa- tional background and vocational training have weaker influence, which suggests that individual driving factors are important when VET teachers assess the value of CPD activities.Conclusions: The study covers a general challenge for VET teachers, but is of particular relevance in systems with a high degree of school-based VET, full-time employed VET teachers, and VET teachers who are responsible for students’ vocational learning. Here, the values for vocational knowledge, for networks, and for teaching that are created through different activities are important for the VET teacher identity. They are also interrelated, and together they provide professional development in relation to the initial occupation, and for the occupation as a vocational teacher.
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| 5. |
- Andersson, Per, Professor, 1964-, et al.
(författare)
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Lärares tolkning och tillämpning av styrdokument i kommunal vuxenutbildning
- 2023
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- I denna forskningsrapport presenteras en omfattande studie av hur lärare verksamma inom komvux olika skolformsdelar tolkar och tillämpar de läroplansanknutna styrdokumenten i sin undervisning. Med hjälp av läroplansteoretiska begrepp diskuteras resultat från en enkät som har besvarats av 1321 lärare och intervjuer som har genomförts med 63 lärare. Studien visar att de läroplansanknutna styrdokumenten utgör en ram som tolkas och tillämpas av lärare i relation till en rad andra ramar som exempelvis tid, elevsammansättning, läromedel, marknadsorganisering och fragmentisering. Sammantaget pekar resultaten på ett behov av en översyn av komvux styrdokument likväl som villkoren för lärarnas undervisning med syfte att få dem mer samstämmiga.
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| 7. |
- Hellberg, Sandra, et al.
(författare)
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Dynamic Response Genes in CD4+ T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis
- 2016
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Ingår i: Cell Reports. - : Cell Press. - 2211-1247. ; 16:11, s. 2928-2939
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS and has a varying disease course as well as variable response to treatment. Biomarkers may therefore aid personalized treatment. We tested whether in vitro activation of MS patient-derived CD4+ T cells could reveal potential biomarkers. The dynamic gene expression response to activation was dysregulated in patient-derived CD4+ T cells. By integrating our findings with genome-wide association studies, we constructed a highly connected MS gene module, disclosing cell activation and chemotaxis as central components. Changes in several module genes were associated with differences in protein levels, which were measurable in cerebrospinal fluid and were used to classify patients from control individuals. In addition, these measurements could predict disease activity after 2 years and distinguish low and high responders to treatment in two additional, independent cohorts. While further validation is needed in larger cohorts prior to clinical implementation, we have uncovered a set of potentially promising biomarkers.
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| 8. |
- Magnusson, Rasmus, 1992-, et al.
(författare)
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LASSIM-A network inference toolbox for genome-wide mechanistic modeling
- 2017
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Ingår i: PLoS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 13:6, s. Article no. e1005608 -
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Tidskriftsartikel (refereegranskat)abstract
- Recent technological advancements have made time-resolved, quantitative, multi-omics data available for many model systems, which could be integrated for systems pharmacokinetic use. Here, we present large-scale simulation modeling (LASSIM), which is a novel mathematical tool for performing large-scale inference using mechanistically defined ordinary differential equations (ODE) for gene regulatory networks (GRNs). LASSIM integrates structural knowledge about regulatory interactions and non-linear equations with multiple steady state and dynamic response expression datasets. The rationale behind LASSIM is that biological GRNs can be simplified using a limited subset of core genes that are assumed to regulate all other gene transcription events in the network. The LASSIM method is implemented as a general-purpose toolbox using the PyGMO Python package to make the most of multicore computers and high performance clusters, and is available at https://gitlab.com/Gustafsson-lab/lassim. As a method, LASSIM works in two steps, where it first infers a non-linear ODE system of the pre-specified core gene expression. Second, LASSIM in parallel optimizes the parameters that model the regulation of peripheral genes by core system genes. We showed the usefulness of this method by applying LASSIM to infer a large-scale non-linear model of naive Th2 cell differentiation, made possible by integrating Th2 specific bindings, time-series together with six public and six novel siRNA-mediated knock-down experiments. ChIP-seq showed significant overlap for all tested transcription factors. Next, we performed novel time-series measurements of total T-cells during differentiation towards Th2 and verified that our LASSIM model could monitor those data significantly better than comparable models that used the same Th2 bindings. In summary, the LASSIM toolbox opens the door to a new type of model-based data analysis that combines the strengths of reliable mechanistic models with truly systems-level data. We demonstrate the power of this approach by inferring a mechanistically motivated, genome-wide model of the Th2 transcription regulatory system, which plays an important role in several immune related diseases.
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