| 1. |
- Groundstroem, Henrik, et al.
(author)
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A systematic mapping of Nordic youth surveys
- 2020
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Conference paper (peer-reviewed)abstract
- Aim: The aim of this study was to map the existing Nordic youth surveys and to answer the following research questions: how many youth surveys are conducted in the Nordic countries?, what major youth surveys are being conducted in all Nordic countries?, and what themes do the existing questionnaires deal with in the various countries?Method: Data was collected from January to April 2018 through a systematic mapping technique and the surveys were analyzed according to quality criteria.Results: The results showed a total of 143 surveys and after exclusion due to poor survey quality, 82 fit the inclusion criteria. In the Nordic countries, six surveys were identified that covered all Nordic countries. The themes that youth surveys usually focus on are criminality, school, physical and mental health, addiction, societal participation and family relationships.Conclusion: Many similar youth surveys exist both nationally and on a Nordic level. During the last forty years, there has also been an exponential increase in surveys aimed at young people. A larger coordination of these surveys would be beneficial and increase their quality as well as limit the number of surveys that young people are exposed to. This study identifies the need for a coordinated Nordic youth survey and the potential benefits on a regional, national and Nordic level.
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| 2. |
- Diaz de Grenu, Borja, et al.
(author)
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Fluorescent Discrimination between Traces of Chemical Warfare Agents and Their Mimics
- 2014
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In: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 136:11, s. 4125-4128
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Journal article (peer-reviewed)abstract
- An array of fluorogenic probes is able to discriminate between nerve agents, sarin, soman, tabun, VX and their mimics, in water or organic solvent, by qualitative fluorescence patterns and quantitative multivariate analysis, thus making the system suitable for the in-the-field detection of traces of chemical warfare agents as well as to differentiate between the real nerve agents and other related compounds.
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| 3. |
- Lövfors, William, 1991-, et al.
(author)
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A comprehensive mechanistic model of adipocyte signaling with layers of confidence
- 2023
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In: npj Systems Biology and Applications. - : Springer Nature. - 2056-7189. ; 9:1
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Journal article (peer-reviewed)abstract
- Adipocyte signaling, normally and in type 2 diabetes, is far from fully understood. We have earlier developed detailed dynamic mathematical models for several well-studied, partially overlapping, signaling pathways in adipocytes. Still, these models only cover a fraction of the total cellular response. For a broader coverage of the response, large-scale phosphoproteomic data and systems level knowledge on protein interactions are key. However, methods to combine detailed dynamic models with large-scale data, using information about the confidence of included interactions, are lacking. We have developed a method to first establish a core model by connecting existing models of adipocyte cellular signaling for: (1) lipolysis and fatty acid release, (2) glucose uptake, and (3) the release of adiponectin. Next, we use publicly available phosphoproteome data for the insulin response in adipocytes together with prior knowledge on protein interactions, to identify phosphosites downstream of the core model. In a parallel pairwise approach with low computation time, we test whether identified phosphosites can be added to the model. We iteratively collect accepted additions into layers and continue the search for phosphosites downstream of these added layers. For the first 30 layers with the highest confidence (311 added phosphosites), the model predicts independent data well (70–90% correct), and the predictive capability gradually decreases when we add layers of decreasing confidence. In total, 57 layers (3059 phosphosites) can be added to the model with predictive ability kept. Finally, our large-scale, layered model enables dynamic simulations of systems-wide alterations in adipocytes in type 2 diabetes.
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| 4. |
- Magnusson, Rasmus, 1992-, et al.
(author)
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Cross-talks via mTORC2 can explain enhanced activation in response to insulin in diabetic patients
- 2017
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In: Bioscience Reports. - : PORTLAND PRESS LTD. - 0144-8463 .- 1573-4935. ; 37
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Journal article (peer-reviewed)abstract
- The molecular mechanisms of insulin resistance in Type 2 diabetes have been extensively studied in primary human adipocytes, and mathematical modelling has clarified the central role of attenuation of mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activity in the diabetic state. Attenuation of mTORC1 in diabetes quells insulin-signalling network-wide, except for the mTOR in complex 2 (mTORC2)-catalysed phosphorylation of protein kinase B (PKB) at Ser(473) (PKB-S473P), which is increased. This unique increase could potentially be explained by feedback and interbranch cross-talk signals. To examine if such mechanisms operate in adipocytes, we herein analysed data from an unbiased phosphoproteomic screen in 3T3-L1 adipocytes. Using a mathematical modelling approach, we showed that a negative signal from mTORC1-p70 S6 kinase (S6K) to rictor-mTORC2 in combination with a positive signal from PKB to SIN1-mTORC2 are compatible with the experimental data. This combined cross-branch signalling predicted an increased PKB-S473P in response to attenuation of mTORC1 - a distinguishing feature of the insulin resistant state in human adipocytes. This aspect of insulin signalling was then verified for our comprehensive model of insulin signalling in human adipocytes. Introduction of the cross-branch signals was compatible with all data for insulin signalling in human adipocytes, and the resulting model can explain all data network-wide, including the increased PKB-S473P in the diabetic state. Our approach was to first identify potential mechanisms in data from a phosphoproteomic screen in a cell line, and then verify such mechanisms in primary human cells, which demonstrates how an unbiased approach can support a direct knowledge-based study.
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| 5. |
- Magnusson, Rasmus, 1992-
(author)
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High Confidence Network Predictions from Big Biological Data
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Biology functions in a most intriguing fashion, with human cells being regulated by multiplex networks of proteins and their dependent systems that control everything from proliferation to cell death. Notably, there are cases when these networks fail to function properly. In some diseases there are multiple small perturbations that push the otherwise healthy cells into a state of malfunction. These maladies are referred to as complex diseases, and include common disorders such as allergy, diabetes type II, and multiple sclerosis, and due to their complexity there is no universally defined approach to fully understand their pathogenesis or pathophysiology. While these perturbations can be measured using high-throughput technologies, the interplay of these perturbations is generally to complex to understand without any structured mathematical analysis. There is today numerous such methods that put the small perturbations of complex diseases into relation of interactions among each other. However, the methods have historically struggled with notable uncertainty in their predictions.This uncertainty can be addressed by at least two different approaches. First, mechanistically realistic mathematical modelling is an approach that has the capacity to accurately describe almost any biological system, but such models can to-date only describe small systems and networks. Secondly, large-scale mathematical modelling approaches exist, but the faithfulness of the models to the underlying biology has been compromised to achieve algorithms that are computationally effective.In this Ph.D. thesis, I suggest how high confidence predictions of network interactions can be extracted from big biological. First, I show how large-scale data can be used when building high-quality ODE models (Paper I). Secondly, by developing the software LASSIM, I show how ODE models can be expanded to the size of entire cell systems (Paper II). However, while LASSIM showed that powerful non-linear ODE-modelling can be applied to understand big biological data, it still remained a machine learning-based approach in contrast to hypothesis-driven model development.Instead, two more studies revolving around large-scale modelling approaches were initiated. The third study suggested that ambiguities in model selection and interaction identification greatly compromise the accuracy of available tools, and that the novel software of Paper III, LiPLike, can be used to remove such predictions. Intriguingly, while LiPLike was able to effectively discard false identifications, the accuracy of predictions remained relatively low. This low accuracy was thought to arise from model simplifications, and therefore the next study aimed at finding methods that come closer to the true biological system (Paper IV). In particular, the study aimed at predicting protein abundance -the true mediators of biological functionality- from the much more easily accessible mRNA levels, and found that such models could be used to get several new insights on protein mechanisms, which was exemplified by the identification of important biomarkers of autoimmune diseases.The analysis of big biological data and the underlying networks is a centrepiece of understanding both diseases and how cell functionality is orchestrated. The work that is presented in this Ph.D. thesis represents a journey between fields with different views on how these networks should be inferred. In particular, it aimed to combine the accuracy of small-scale mechanistic modelling with the system-spanning potential of large-scale linear system modelling, and this thesis thus provides a tool-bench of methods and insights on how knowledge can be extracted from big biological data, and in extension it is a small step towards a generation of new comprehensions of biological systems and complex diseases.
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| 6. |
- Magnusson, Rasmus, 1992-, et al.
(author)
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LASSIM-A network inference toolbox for genome-wide mechanistic modeling
- 2017
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In: PLoS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 13:6, s. Article no. e1005608 -
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Journal article (peer-reviewed)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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