| 1. |
- Carreras-Puigvert, Jordi, et al.
(författare)
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A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family
- 2017
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- The NUDIX enzymes are involved in cellular metabolism and homeostasis, as well as mRNA processing. Although highly conserved throughout all organisms, their biological roles and biochemical redundancies remain largely unclear. To address this, we globally resolve their individual properties and inter-relationships. We purify 18 of the human NUDIX proteins and screen 52 substrates, providing a substrate redundancy map. Using crystal structures, we generate sequence alignment analyses revealing four major structural classes. To a certain extent, their substrate preference redundancies correlate with structural classes, thus linking structure and activity relationships. To elucidate interdependence among the NUDIX hydrolases, we pairwise deplete them generating an epistatic interaction map, evaluate cell cycle perturbations upon knockdown in normal and cancer cells, and analyse their protein and mRNA expression in normal and cancer tissues. Using a novel FUSION algorithm, we integrate all data creating a comprehensive NUDIX enzyme profile map, which will prove fundamental to understanding their biological functionality.
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| 2. |
- Morgan, Daniel, et al.
(författare)
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Perturbation-based gene regulatory network inference to unravel oncogenic mechanisms
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- The gene regulatory network (GRN) of human cells encodes mechanisms to ensure proper functioning. However, if this GRN is dysregulated, the cell may enter into a disease state such as cancer. Understanding the GRN as a system can therefore help identify novel mechanisms underlying disease, which can lead to new therapies. To deduce regulatory interactions relevant to cancer, we applied a recent computational inference framework to data from perturbation experiments in squamous carcinoma cell line A431. GRNs were inferred using several methods, and the false discovery rate was controlled by the NestBoot framework. We developed a novel approach to assess the predictiveness of inferred GRNs against validation data, despite the lack of a gold standard. The best GRN was significantly more predictive than the null model, both in cross-validated benchmarks and for an independent dataset of the same genes under a different perturbation design. The inferred GRN captures many known regulatory interactions central to cancer-relevant processes in addition to predicting many novel interactions, some of which were experimentally validated, thus providing mechanistic insights that are useful for future cancer research.
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| 3. |
- Tjärnberg, Andreas, et al.
(författare)
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Avoiding pitfalls in L-1-regularised inference of gene networks
- 2015
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Ingår i: Molecular Biosystems. - : Royal Society of Chemistry (RSC). - 1742-206X .- 1742-2051. ; 11:1, s. 287-296
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Tidskriftsartikel (refereegranskat)abstract
- Statistical regularisation methods such as LASSO and related L-1 regularised regression methods are commonly used to construct models of gene regulatory networks. Although they can theoretically infer the correct network structure, they have been shown in practice to make errors, i.e. leave out existing links and include non-existing links. We show that L-1 regularisation methods typically produce a poor network model when the analysed data are ill-conditioned, i.e. the gene expression data matrix has a high condition number, even if it contains enough information for correct network inference. However, the correct structure of network models can be obtained for informative data, data with such a signal to noise ratio that existing links can be proven to exist, when these methods fail, by using least-squares regression and setting small parameters to zero, or by using robust network inference, a recent method taking the intersection of all non-rejectable models. Since available experimental data sets are generally ill-conditioned, we recommend to check the condition number of the data matrix to avoid this pitfall of L-1 regularised inference, and to also consider alternative methods.
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| 4. |
- Tjärnberg, Andreas, et al.
(författare)
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GeneSPIDER - gene regulatory network inference benchmarking with controlled network and data properties
- 2017
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Ingår i: Molecular Biosystems. - : Royal Society of Chemistry (RSC). - 1742-206X .- 1742-2051. ; 13:7, s. 1304-1312
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Tidskriftsartikel (refereegranskat)abstract
- A key question in network inference, that has not been properly answered, is what accuracy can be expected for a given biological dataset and inference method. We present GeneSPIDER - a Matlab package for tuning, running, and evaluating inference algorithms that allows independent control of network and data properties to enable data-driven benchmarking. GeneSPIDER is uniquely suited to address this question by first extracting salient properties from the experimental data and then generating simulated networks and data that closely match these properties. It enables data-driven algorithm selection, estimation of inference accuracy from biological data, and a more multifaceted benchmarking. Included are generic pipelines for the design of perturbation experiments, bootstrapping, analysis of linear dependence, sample selection, scaling of SNR, and performance evaluation. With GeneSPIDER we aim to move the goal of network inference benchmarks from simple performance measurement to a deeper understanding of how the accuracy of an algorithm is determined by different combinations of network and data properties.
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| 5. |
- Tjärnberg, Andreas, et al.
(författare)
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GeneSPIDER - Generation and Simulation Package for Informative Data ExploRation
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- A range of tools are available to model, simulate and analyze gene regulatory networks (GRNs). However, these tools provide limited ability to control network topology, system dynamics, design of experiments, data properties, or noise characteristics. Independent control of these properties is the key to drawing conclusions on which inference method to use and what result to expect from it, as well as obtaining desired approximations of real biological systems. To draw conclusions on the relation between a network or data property and the performance of an inference method in simulations, system approximations with varying properties are needed. We present a Matlab package \gs for generation and analysis of networks and data in a dynamical systems framework with focus on the ability to vary properties. It supplies not only essential components that have been missing, but also wrappers to existing tools in common use. In particular, it contains tools for controlling and analyzing network topology (random, small-world, scale-free), stability of linear time-invariant systems, signal to noise ratio (SNR), and Interampatteness. It also contains methods for design of perturbation experiments, bootstrapping, analysis of linear dependence, sample selection, scaling of the SNR, and performance evaluation. GeneSPIDER offers control of network and data properties in simulations, together with tools to analyze these properties and draw conclusions on the quality of inferred GRNs. It can be fetched freely from the online =git= repository https://bitbucket.org/sonnhammergrni/genespider.
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| 6. |
- Tjärnberg, Andreas, et al.
(författare)
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Optimal Sparsity Criteria for Network Inference
- 2013
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Ingår i: Journal of Computational Biology. - : Mary Ann Liebert Inc. - 1066-5277 .- 1557-8666. ; 20:5, s. 398-408
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Tidskriftsartikel (refereegranskat)abstract
- Gene regulatory network inference (that is, determination of the regulatory interactions between a set of genes) provides mechanistic insights of central importance to research in systems biology. Most contemporary network inference methods rely on a sparsity/regularization coefficient, which we call zeta (zeta), to determine the degree of sparsity of the network estimates, that is, the total number of links between the nodes. However, they offer little or no advice on how to select this sparsity coefficient, in particular, for biological data with few samples. We show that an empty network is more accurate than estimates obtained for a poor choice of zeta. In order to avoid such poor choices, we propose a method for optimization of zeta, which maximizes the accuracy of the inferred network for any sparsity-dependent inference method and data set. Our procedure is based on leave-one-out cross-optimization and selection of the zeta value that minimizes the prediction error. We also illustrate the adverse effects of noise, few samples, and uninformative experiments on network inference as well as our method for optimization of zeta. We demonstrate that our zeta optimization method for two widely used inference algorithms-Glmnet and NIR-gives accurate and informative estimates of the network structure, given that the data is informative enough.
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