| 31. |
- Huss, Mikael, et al.
(författare)
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Currency and commodity metabolites : their identification and relation to the modularity of metabolic networks
- 2007
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Ingår i: IET Systems Biology. - : Institution of Engineering and Technology (IET). - 1751-8849 .- 1751-8857. ; 1:5, s. 280-285
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Tidskriftsartikel (refereegranskat)abstract
- The large-scale shape and function of metabolic networks are intriguing topics of systems biology. Such networks are on one hand commonly regarded as modular (i.e. built by a number of relatively independent subsystems), but on the other hand they are robust in a way not necessarily expected of a purely modular system. To address this question, we carefully discuss the partition of metabolic networks into subnetworks. The practice of preprocessing such networks by removing the most abundant substances, 'currency metabolites', is formalized into a network-based algorithm. We study partitions for metabolic networks of many organisms and find cores of currency metabolites and modular peripheries of what we call 'commodity metabolites'. The networks are found to be more modular than random networks but far from perfectly divisible into modules. We argue that cross-modular edges are the key for the robustness of metabolism.
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| 32. |
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| 33. |
- Huss, Mikael, et al.
(författare)
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Modelling self-sustained rhythmic activity in lamprey hemisegmental networks
- 2006
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Ingår i: Neurocomputing. - : Elsevier BV. - 0925-2312 .- 1872-8286. ; 69:10-12, s. 1097-1102
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies of the lamprey spinal cord have shown that hemisegmental preparations can display rhythmic activity in response to a constant input drive. This activity is believed to be generated by a network of recurrently connected excitatory interneurons. A recent study found and characterized self-sustaining rhythmic activity-locomotor bouts-after brief electrical stimulation of hemisegmental preparations. The mechanisms behind the bouts are still unclear. We have developed a computational model of the hemisegmental network. The model addresses the possible involvement of NMDA, AMPA, acetylcholine, and metabotropic glutamate receptors as well as axonal delays in locomotor bouts.
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| 34. |
- Huss, Mikael, et al.
(författare)
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Prediction of transcription factor binding to DNA using rule induction methods
- 2006
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Ingår i: Journal of Integrative Bioinformatics - JIB. - 1613-4516. ; 3:2, s. 42-
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we seek to develop a predictive model for finding the strength of bindingbetween a particular transcription factor (TF) variant and a particular DNA target variant.The DNA binding paired domains of the Pax transcription factors, which are our mainfocus, show seemingly fuzzy and degenerate binding to various DNA targets, and paireddomain-DNA binding is not a problem well suited for previously proposed algorithms.Here, we introduce a simple way to use rule induction for predicting the strength of TFDNAbinding. We have created a dataset consisting of 597 example cases for paireddomain-DNA binding by collecting information about all published and quantifiedinteractions between TF and DNA sequence variants. Application of the rule inductionbased method on this dataset yields a high, although far from ideal accuracy of 69.7%(based on cross-validation), but perhaps more importantly, several useful rules forpredicting the binding strength have been found. Although the primary motivation forintroducing the rule induction based methods is the lack of efficient algorithms for paireddomain-DNA binding prediction, we also show that the method can be applied with somesuccess to a more well-studied TF-DNA binding prediction task involving the earlygrowth response (EGR) TF family.
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| 35. |
- Huss, Mikael, et al.
(författare)
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Role of A-current in lamprey locomotor network neurons
- 2003
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Ingår i: Neurocomputing. - : Elsevier BV. - 0925-2312 .- 1872-8286. ; 52-54, s. 295-300
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Tidskriftsartikel (refereegranskat)abstract
- A compartmental model of lamprey central pattern generator neurons was built in order to examine the effects of a fast, transient, high-voltage-activated potassium current (A-current) found experimentally. The model consisted of a soma, a compartment corresponding to the axon initial segment, and a dendritic tree. The simulation showed that the A-current was necessary for repetitive spiking in the single neuron following current injection. The functional role of adding an A-current was also examined in a network model. In this model, the A-current stabilizes the swimming rhythm by making the burst cycle duration and the number of spikes per burst less variable. All these effects are also seen experimentally.
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| 36. |
- Huss, Mikael, et al.
(författare)
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Roles of ionic currents in lamprey CPG neurons : a modeling study
- 2007
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Ingår i: Journal of Neurophysiology. - : American Physiological Society. - 0022-3077 .- 1522-1598. ; 97:4, s. 2696-2711
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Tidskriftsartikel (refereegranskat)abstract
- The spinal network underlying locomotion in the lamprey consists of a core network of glutamatergic and glycinergic interneurons, previously studied experimentally and through mathematical modeling. We present a new and more detailed computational model of lamprey locomotor network neurons, based primarily on detailed electrophysiological measurements and incorporating new experimental findings. The model uses a Hodgkin Huxley-like formalism and consists of 86 membrane compartments containing 12 types of ion currents. One of the goals was to introduce a fast, transient potassium current (K-t) and two sodium-dependent potassium currents, one faster (K-NaF) and one slower (K-NaS), in the model. Not only has the model lent support to the interpretation of experimental results but it has also provided predictions for further experimental analysis of single-network neurons. For example, K-t was shown to be one critical factor for controlling action potential duration. In addition, the model has proved helpful in investigating the possible influence of the slow afterhyperpolarization on repetitive firing during ongoing activation. In particular, the balance between the simulated slow sodium-dependent and calcium-dependent potassium currents has been explored, as well as the possible involvement of dendritic conductances.
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| 37. |
- Huss, Mikael, et al.
(författare)
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Tonically driven and self-sustaining activity in the lamprey hemicord : when can they co-exist?
- 2007
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Ingår i: Neurocomputing. - : Elsevier BV. - 0925-2312 .- 1872-8286. ; 70:10-12, s. 1882-1886
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Tidskriftsartikel (refereegranskat)abstract
- In lamprey hernisegmental preparations, two types of rhythmic activity are found: slower tonically driven activity which varies according to the external drive, and faster, more stereotypic activity that arises after a transient electrical stimulus. We present a simple conceptual model where a bistable excitable system can exhibit the two states. We then show that a neuronal network model can display the desired characteristics, given that synaptic dynamics-facilitation and saturation-are included. The model behaviour and its dependence on key parameters are illustrated. We discuss the relevance of our model to the lamprey locomotor system.
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| 38. |
- Ihle, Michaela Angelika, et al.
(författare)
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Expression of cell cycle regulators and frequency of TP53 mutations in high risk gastrointestinal stromal tumors prior to adjuvant imatinib treatment
- 2018
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:2
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Tidskriftsartikel (refereegranskat)abstract
- Despite of multitude investigations no reliable prognostic immunohistochemical biomark-ers in GIST have been established so far with added value to predict the recurrence risk of high risk GIST besides mitotic count, primary location and size. In this study, we analyzed the prognostic relevance of eight cell cycle and apoptosis modulators and of TP53 mutations for prognosis in GIST with high risk of recurrence prior to adjuvant treatment with imatinib. In total, 400 patients with high risk for GIST recurrence were randomly assigned for adjuvant imatinib either for one or for three years following laparotomy. 320 primary tumor samples with available tumor tissue were immunohistochemically analyzed prior to treatment for the expression of cell cycle regulators and apoptosis modulators cyclin D1, p21, p16, CDK4, E2F1, MDM2, p53 and p-RB1. TP53 mutational analysis was possible in 245 cases. A high expression of CDK4 was observed in 32.8% of all cases and was associated with a favorable recurrence free survival (RFS), whereas high expression of MDM2 (12.2%) or p53 (35.3%) was associated with a shorter RFS. These results were independent from the primary KIT or PDGFRA mutation. In GISTs with higher mitotic counts was a significantly increased expression of cyclin D1, p53 and E2F1. The expression of p16 and E2F1 significantly correlated to a non-gastric localization. Furthermore, we observed a significant higher expression of p21 and E2F1 in KIT mutant GISTs compared to PDGFRA mutant and wt GISTs. The overall frequency of TP53 mutations was low (n = 8; 3.5%) and could not be predicted by the immunohistochemical expression of p53. In summary, mutation analysis in TP53 plays a minor role in the subgroup of high-risk GIST before adjuvant treatment with imatinib. Strong expression of MDM2 and p53 correlated with a shorter recurrence free survival, whereas a strong expression of CDK4 correlated to a better recurrence free survival.
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| 39. |
- James, Tojo, et al.
(författare)
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Impact of genetic risk loci for multiple sclerosis on expression of proximal genes in patients
- 2018
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 27:5, s. 912-928
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Tidskriftsartikel (refereegranskat)abstract
- Despite advancements in genetic studies, it is difficult to understand and characterize the functional relevance of disease-associated genetic variants, especially in the context of a complex multifactorial disease such as multiple sclerosis (MS). As a large proportion of expression quantitative trait loci (eQTLs) are context-specific, we performed RNA-Seq in peripheral blood mononuclear cells from MS patients (n = 145) to identify eQTLs in regions centered on 109 MS risk single nucleotide polymorphisms and 7 associated human leukocyte antigen variants. We identified 77 statistically significant eQTL associations, including pseudogenes and non-coding RNAs. Thirty-eight out of 40 testable eQTL effects were colocalized with the disease association signal. As many eQTLs are tissue specific, we aimed to detail their significance in different cell types. Approximately 70% of the eQTLs were replicated and characterized in at least one major peripheral blood mononuclear cell-derived cell type. Furthermore, 40% of eQTLs were found to be more pronounced in MS patients compared with non-inflammatory neurological diseases patients. In addition, we found two single nucleotide polymorphisms to be significantly associated with the proportions of three different cell types. Mapping to enhancer histone marks and predicted transcription factor binding sites added additional functional evidence for eight eQTL regions. As an example, we found that rs71624119, shared with three other autoimmune diseases and located in a primed enhancer (H3K4me1) with potential binding for STAT transcription factors, significantly associates with ANKRD55 expression. This study provides many novel and validated targets for future functional characterization of MS and other diseases.
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| 40. |
- Johansson, Henrik J., et al.
(författare)
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Breast cancer quantitative proteome and proteogenomic landscape
- 2019
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- In the preceding decades, molecular characterization has revolutionized breast cancer (BC) research and therapeutic approaches. Presented herein, an unbiased analysis of breast tumor proteomes, inclusive of 9995 proteins quantified across all tumors, for the first time recapitulates BC subtypes. Additionally, poor-prognosis basal-like and luminal B tumors are further subdivided by immune component infiltration, suggesting the current classification is incomplete. Proteome-based networks distinguish functional protein modules for breast tumor groups, with co-expression of EGFR and MET marking ductal carcinoma in situ regions of normal-like tumors and lending to a more accurate classification of this poorly defined subtype. Genes included within prognostic mRNA panels have significantly higher than average mRNA-protein correlations, and gene copy number alterations are dampened at the protein-level; underscoring the value of proteome quantification for prognostication and phenotypic classification. Furthermore, protein products mapping to non-coding genomic regions are identified; highlighting a potential new class of tumor-specific immunotherapeutic targets.
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