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  • 1
    Publication Date: 2022-03-11
    Description: This thesis presents a method for interpolating data using a neural network. The data is sparse and perturbed and is used as training data for a small neural network. For severely perturbed data, the network does not manage to find a smooth interpolation. But as the data resembles the solution to the one-dimensional and time-independent heat equation, the weak form of this PDE and subsequently its functional can be written down. If the functional is minimized, a solution to the weak form of the heat equation is found. The functional is now added to the traditional loss function of a neural network, the mean squared error between the network prediction and the given data, in order to smooth out fluctuations and interpolate between distanced grid points. This way, the network minimizes both the mean squared error and the functional, resulting in a smoother curve that can be used to predict u(x) for any grid point x.
    Language: English
    Type: masterthesis , doc-type:masterThesis
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  • 2
    Publication Date: 2023-07-17
    Language: English
    Type: article , doc-type:article
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  • 3
    Publication Date: 2024-02-09
    Description: We previously reported the successful design, synthesis and testing of the prototype opioid painkiller NFEPP that does not elicit adverse side effects. The design process of NFEPP was based on mathematical modelling of extracellular interactions between G-protein coupled receptors (GPCRs) and ligands, recognizing that GPCRs function differently under pathological versus healthy conditions. We now present an additional and novel stochastic model of GPCR function that includes intracellular dissociation of G-protein subunits and modulation of plasma membrane calcium channels and their dependence on parameters of inflamed and healthy tissue (pH, radicals). The model is validated against in vitro experimental data for the ligands NFEPP and fentanyl at different pH values and radical concentrations. We observe markedly reduced binding affinity and calcium channel inhibition for NFEPP at normal pH compared to lower pH, in contrast to the effect of fentanyl. For increasing radical concentrations, we find enhanced constitutive G-protein activation but reduced ligand binding affinity. Assessing the different effects, the results suggest that, compared to radicals, low pH is a more important determinant of overall GPCR function in an inflamed environment. Future drug design efforts should take this into account.
    Language: English
    Type: article , doc-type:article
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  • 4
    Publication Date: 2024-02-09
    Description: Initiated by mathematical modelling of extracellular interactions between G-protein coupled receptors (GPCRs) and ligands in normal versus diseased (inflamed) environments, we previously reported the successful design, synthesis and testing of the prototype opioid painkiller NFEPP that does not elicit adverse side effects. Uniquely, this design recognised that GPCRs function differently under pathological versus healthy conditions. We now present a novel stochastic model of GPCR function that includes intracellular dissociation of G-protein subunits and modulation of plasma membrane calcium channels associated with parameters of inflamed tissue (pH, radicals). By means of molecular dynamics simulations, we also assessed qualitative changes of the reaction rates due to additional disulfide bridges inside the GPCR binding pocket and used these rates for stochastic simulations of the corresponding reaction jump process. The modelling results were validated with in vitro experiments measuring calcium currents and G-protein activation. We found markedly reduced G-protein dissociation and calcium channel inhibition induced by NFEPP at normal pH, and enhanced constitutive G-protein activation but lower probability of ligand binding with increasing radical concentrations. These results suggest that, compared to radicals, low pH is a more important determinant of overall GPCR function in an inflamed environment. Future drug design efforts should take this into account.
    Language: English
    Type: reportzib , doc-type:preprint
    Format: application/pdf
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