Chimera States on a Ring of Strongly Coupled Relaxation Oscillators

Weakly coupled oscillators can exhibit seemingly incongruous synchronization patterns comprised of coherent and incoherent spatial domains known as chimera states. However, the weak coupling approximation is invalid when the characteristic phase response curve of an oscillator does not scale linearly with the coupling strength and instead changes its shape. In chemical experiments with photo-coupled relaxation oscillators, we find that beyond weak coupling chimera patterns consist of different coexisting cluster states. Numerical modeling reveals that the observed cluster states result from a phase-dependent excitability that is also commonly observed in neural tissue and cardiac pacemaker cells.DFG, 414044773, Open Access Publizieren 2019 - 2020 / Technische Universität BerlinDFG, GRK 1558, Kollektive Dynamik im Nichtgleichgewicht: in kondensierter Materie und biologischen SystemenDFG, SFB 910, Kontrolle selbstorganisierender nichtlinearer Systeme: Theoretische Methoden und Anwendungskonzept

A systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-TFPI recycling antibodies

Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies