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Ulcerative colitis (UC) is part of the inflammatory bowels diseases, and moderate to severe UC patients can be treated with anti-tumour necrosis alpha monoclonal antibodies, including infliximab (IFX). Even though treatment of UC patients by IFX has been in place for over a decade, many gaps in modelling of IFX PK in this population remain. This is even more true for acute severe UC (ASUC) patients for which early prediction of IFX pharmacokinetic (PK) could highly improve treatment outcome. Thus, this review aims to compile and analyse published population PK models of IFX in UC and ASUC patients, and to assess the current knowledge on disease activity impact on IFX PK. For this, a semi-systematic literature search was conducted, from which 26 publications including a population PK model analysis of UC patients receiving IFX therapy were selected. Amongst those, only four developed a model specifically for UC patients, and only three populations included severe UC patients. Investigations of disease activity impact on PK were reported in only 4 of the 14 models selected. In addition, the lack of reported model codes and assessment of predictive performance make the use of published models in a clinical setting challenging. Thus, more comprehensive investigation of PK in UC and ASUC is needed as well as more adequate reports on developed models and their evaluation in order to apply them in a clinical setting.
Background
Cytochrome P450 (CYP) 3A contributes to the metabolism of many approved drugs. CYP3A perpetrator drugs can profoundly alter the exposure of CYP3A substrates. However, effects of such drug-drug interactions are usually reported as maximum effects rather than studied as time-dependent processes. Identification of the time course of CYP3A modulation can provide insight into when significant changes to CYP3A activity occurs, help better design drug-drug interaction studies, and manage drug-drug interactions in clinical practice.
Objective
We aimed to quantify the time course and extent of the in vivo modulation of different CYP3A perpetrator drugs on hepatic CYP3A activity and distinguish different modulatory mechanisms by their time of onset, using pharmacologically inactive intravenous microgram doses of the CYP3A-specific substrate midazolam, as a marker of CYP3A activity.
Methods
Twenty-four healthy individuals received an intravenous midazolam bolus followed by a continuous infusion for 10 or 36 h. Individuals were randomized into four arms: within each arm, two individuals served as a placebo control and, 2 h after start of the midazolam infusion, four individuals received the CYP3A perpetrator drug: voriconazole (inhibitor, orally or intravenously), rifampicin (inducer, orally), or efavirenz (activator, orally). After midazolam bolus administration, blood samples were taken every hour (rifampicin arm) or every 15 min (remaining study arms) until the end of midazolam infusion. A total of 1858 concentrations were equally divided between midazolam and its metabolite, 1'-hydroxymidazolam. A nonlinear mixed-effects population pharmacokinetic model of both compounds was developed using NONMEM (R). CYP3A activity modulation was quantified over time, as the relative change of midazolam clearance encountered by the perpetrator drug, compared to the corresponding clearance value in the placebo arm.
Results
Time course of CYP3A modulation and magnitude of maximum effect were identified for each perpetrator drug. While efavirenz CYP3A activation was relatively fast and short, reaching a maximum after approximately 2-3 h, the induction effect of rifampicin could only be observed after 22 h, with a maximum after approximately 28-30 h followed by a steep drop to almost baseline within 1-2 h. In contrast, the inhibitory impact of both oral and intravenous voriconazole was prolonged with a steady inhibition of CYP3A activity followed by a gradual increase in the inhibitory effect until the end of sampling at 8 h. Relative maximum clearance changes were +59.1%, +46.7%, -70.6%, and -61.1% for efavirenz, rifampicin, oral voriconazole, and intravenous voriconazole, respectively.
Conclusions
We could distinguish between different mechanisms of CYP3A modulation by the time of onset. Identification of the time at which clearance significantly changes, per perpetrator drug, can guide the design of an optimal sampling schedule for future drug-drug interaction studies. The impact of a short-term combination of different perpetrator drugs on the paradigm CYP3A substrate midazolam was characterized and can define combination intervals in which no relevant interaction is to be expected.
Alpine ecosystems on the Tibetan Plateau are being threatened by ongoing climate warming and intensified human activities. Ecological time-series obtained from sedimentary ancient DNA (sedaDNA) are essential for understanding past ecosystem and biodiversity dynamics on the Tibetan Plateau and their responses to climate change at a high taxonomic resolution. Hitherto only few but promising studies have been published on this topic. The potential and limitations of using sedaDNA on the Tibetan Plateau are not fully understood. Here, we (i) provide updated knowledge of and a brief introduction to the suitable archives, region-specific taphonomy, state-of-the-art methodologies, and research questions of sedaDNA on the Tibetan Plateau; (ii) review published and ongoing sedaDNA studies from the Tibetan Plateau; and (iii) give some recommendations for future sedaDNA study designs. Based on the current knowledge of taphonomy, we infer that deep glacial lakes with freshwater and high clay sediment input, such as those from the southern and southeastern Tibetan Plateau, may have a high potential for sedaDNA studies. Metabarcoding (for microorganisms and plants), metagenomics (for ecosystems), and hybridization capture (for prehistoric humans) are three primary sedaDNA approaches which have been successfully applied on the Tibetan Plateau, but their power is still limited by several technical issues, such as PCR bias and incompleteness of taxonomic reference databases. Setting up high-quality and open-access regional taxonomic reference databases for the Tibetan Plateau should be given priority in the future. To conclude, the archival, taphonomic, and methodological conditions of the Tibetan Plateau are favorable for performing sedaDNA studies. More research should be encouraged to address questions about long-term ecological dynamics at ecosystem scale and to bring the paleoecology of the Tibetan Plateau into a new era.
The objectives of this study were the identification in (morbidly) obese and nonobese patients of (i) the most appropriate body size descriptor for fosfomycin dose adjustments and (ii) adequacy of the currently employed dosing regimens. Plasma and target site (interstitial fluid of subcutaneous adipose tissue) concentrations after fosfomycin administration (8 g) to 30 surgery patients (15 obese/15 nonobese) were obtained from a prospective clinical trial. After characterization of plasma and microdialysis-derived target site pharmacokinetics via population analysis, short-term infusions of fosfomycin 3 to 4 times daily were simulated. The adequacy of therapy was assessed by probability of pharmacokinetic/pharmacodynamic target attainment (PTA) analysis based on the unbound drug-related targets of an %fT(>= MIC) (the fraction of time that unbound fosfomycin concentrations exceed the MIC during 24 h) of 70 and an fAUC(0-24h)/MIC (the area under the concentration-time curve from 0 to 24 h for the unbound fraction of fosfomycin relative to the MIC) of 40.8 to 83.3. Lean body weight, fat mass, and creatinine clearance calculated via adjusted body weight (ABW) (CLCRCG_ABW) of all patients (body mass index [BMI] = 20.1 to 52.0 kg/m(2)) explained a considerable proportion of between-patient pharmacokinetic variability (up to 31.0% relative reduction). The steady-state unbound target site/plasma concentration ratio was 26.3% lower in (morbidly) obese than nonobese patients. For infections with fosfomycin-susceptible pathogens (MIC <= 16 mg/L), intermittent "high-dosage" intravenous (i.v.) fosfomycin (8 g, three times daily) was sufficient to treat patients with a CLCRCG_ABW of,130 mL/min, irrespective of the pharmacokinetic/pharmacodynamic indices considered. For infections by Pseudomonas aeruginosa with a MIC of 32 mg/L, when the index fAUC0-24h/MIC is applied, fosfomycin might represent a promising treatment option in obese and nonobese patients, especially in combination therapy to complement beta-lactams, in which carbapenem-resistant P. aeruginosa is critical. In conclusion, fosfomycin showed excellent target site penetration in obese and nonobese patients. Dosing should be guided by renal function rather than obesity status.
The drug concentrations targeted in meropenem and piperacillin/tazobactam therapy also depend on the susceptibility of the pathogen. Yet, the pathogen is often unknown, and antibiotic therapy is guided by empirical targets. To reliably achieve the targeted concentrations, dosing needs to be adjusted for renal function. We aimed to evaluate a meropenem and piperacillin/tazobactam monitoring program in intensive care unit (ICU) patients by assessing (i) the adequacy of locally selected empirical targets, (ii) if dosing is adequately adjusted for renal function and individual target, and (iii) if dosing is adjusted in target attainment (TA) failure. In a prospective, observational clinical trial of drug concentrations, relevant patient characteristics and microbiological data (pathogen, minimum inhibitory concentration (MIC)) for patients receiving meropenem or piperacillin/tazobactam treatment were collected. If the MIC value was available, a target range of 1-5 x MIC was selected for minimum drug concentrations of both drugs. If the MIC value was not available, 8-40 mg/L and 16-80 mg/L were selected as empirical target ranges for meropenem and piperacillin, respectively. A total of 356 meropenem and 216 piperacillin samples were collected from 108 and 96 ICU patients, respectively. The vast majority of observed MIC values was lower than the empirical target (meropenem: 90.0%, piperacillin: 93.9%), suggesting empirical target value reductions. TA was found to be low (meropenem: 35.7%, piperacillin 50.5%) with the lowest TA for severely impaired renal function (meropenem: 13.9%, piperacillin: 29.2%), and observed drug concentrations did not significantly differ between patients with different targets, indicating dosing was not adequately adjusted for renal function or target. Dosing adjustments were rare for both drugs (meropenem: 6.13%, piperacillin: 4.78%) and for meropenem irrespective of TA, revealing that concentration monitoring alone was insufficient to guide dosing adjustment. Empirical targets should regularly be assessed and adjusted based on local susceptibility data. To improve TA, scientific knowledge should be translated into easy-to-use dosing strategies guiding antibiotic dosing.
Congenital adrenal hyperplasia (CAH) is the most common form of adrenal insufficiency in childhood; it requires cortisol replacement therapy with hydrocortisone (HC, synthetic cortisol) from birth and therapy monitoring for successful treatment. In children, the less invasive dried blood spot (DBS) sampling with whole blood including red blood cells (RBCs) provides an advantageous alternative to plasma sampling.
Potential differences in binding/association processes between plasma and DBS however need to be considered to correctly interpret DBS measurements for therapy monitoring. While capillary DBS samples would be used in clinical practice, venous cortisol DBS samples from children with adrenal insufficiency were analyzed due to data availability and to directly compare and thus understand potential differences between venous DBS and plasma. A previously published HC plasma pharmacokinetic (PK) model was extended by leveraging these DBS concentrations.
In addition to previously characterized binding of cortisol to albumin (linear process) and corticosteroid-binding globulin (CBG; saturable process), DBS data enabled the characterization of a linear cortisol association with RBCs, and thereby providing a quantitative link between DBS and plasma cortisol concentrations. The ratio between the observed cortisol plasma and DBS concentrations varies highly from 2 to 8. Deterministic simulations of the different cortisol binding/association fractions demonstrated that with higher blood cortisol concentrations, saturation of cortisol binding to CBG was observed, leading to an increase in all other cortisol binding fractions.
In conclusion, a mathematical PK model was developed which links DBS measurements to plasma exposure and thus allows for quantitative interpretation of measurements of DBS samples.
The spatio-temporal epidemic type aftershock sequence (ETAS) model is widely used to describe the self-exciting nature of earthquake occurrences. While traditional inference methods provide only point estimates of the model parameters, we aim at a fully Bayesian treatment of model inference, allowing naturally to incorporate prior knowledge and uncertainty quantification of the resulting estimates. Therefore, we introduce a highly flexible, non-parametric representation for the spatially varying ETAS background intensity through a Gaussian process (GP) prior. Combined with classical triggering functions this results in a new model formulation, namely the GP-ETAS model. We enable tractable and efficient Gibbs sampling by deriving an augmented form of the GP-ETAS inference problem. This novel sampling approach allows us to assess the posterior model variables conditioned on observed earthquake catalogues, i.e., the spatial background intensity and the parameters of the triggering function. Empirical results on two synthetic data sets indicate that GP-ETAS outperforms standard models and thus demonstrate the predictive power for observed earthquake catalogues including uncertainty quantification for the estimated parameters. Finally, a case study for the l'Aquila region, Italy, with the devastating event on 6 April 2009, is presented.
Let X be an infinite linearly ordered set and let Y be a nonempty subset of X. We calculate the relative rank of the semigroup OP(X,Y) of all orientation-preserving transformations on X with restricted range Y modulo the semigroup O(X,Y) of all order-preserving transformations on X with restricted range Y. For Y = X, we characterize the relative generating sets of minimal size.
We construct and examine the prototype of a deep learning-based ground-motion model (GMM) that is both fully data driven and nonergodic. We formulate ground-motion modeling as an image processing task, in which a specific type of neural network, the U-Net, relates continuous, horizontal maps of earthquake predictive parameters to sparse observations of a ground-motion intensity measure (IM). The processing of map-shaped data allows the natural incorporation of absolute earthquake source and observation site coordinates, and is, therefore, well suited to include site-, source-, and path-specific amplification effects in a nonergodic GMM. Data-driven interpolation of the IM between observation points is an inherent feature of the U-Net and requires no a priori assumptions. We evaluate our model using both a synthetic dataset and a subset of observations from the KiK-net strong motion network in the Kanto basin in Japan. We find that the U-Net model is capable of learning the magnitude???distance scaling, as well as site-, source-, and path-specific amplification effects from a strong motion dataset. The interpolation scheme is evaluated using a fivefold cross validation and is found to provide on average unbiased predictions. The magnitude???distance scaling as well as the site amplification of response spectral acceleration at a period of 1 s obtained for the Kanto basin are comparable to previous regional studies.
We present the extension of the Kalmag model, proposed as a candidate for IGRF-13, to the twentieth century.
The dataset serving its derivation has been complemented by new measurements coming from satellites, ground-based observatories and land, marine and airborne surveys.
As its predecessor, this version is derived from a combination of a Kalman filter and a smoothing algorithm, providing mean models and associated uncertainties. These quantities permit a precise estimation of locations where mean solutions can be considered as reliable or not.
The temporal resolution of the core field and the secular variation was set to 0.1 year over the 122 years the model is spanning.
Nevertheless, it can be shown through ensembles a posteriori sampled, that this resolution can be effectively achieved only by a limited amount of spatial scales and during certain time periods.
Unsurprisingly, highest accuracy in both space and time of the core field and the secular variation is achieved during the CHAMP and Swarm era. In this version of Kalmag, a particular effort was made for resolving the small-scale lithospheric field.
Under specific statistical assumptions, the latter was modeled up to spherical harmonic degree and order 1000, and signal from both satellite and survey measurements contributed to its development.
External and induced fields were jointly estimated with the rest of the model. We show that their large scales could be accurately extracted from direct measurements whenever the latter exhibit a sufficiently high temporal coverage.
Temporally resolving these fields down to 3 hours during the CHAMP and Swarm missions, gave us access to the link between induced and magnetospheric fields. In particular, the period dependence of the driving signal on the induced one could be directly observed.
The model is available through various physical and statistical quantities on a dedicated website at https://ionocovar.agnld.uni-potsdam.de/Kalmag/.
We consider the case of scattering by several obstacles in Rd for d ≥ 2.
In this setting, the absolutely continuous part of the Laplace operator Δ with Dirichlet boundary conditions and the free Laplace operator Δ0 are unitarily equivalent.
For suitable functions that decay sufficiently fast, we have that the difference g(Δ) - g(Δ0) is a trace-class operator and its trace is described by the Krein spectral shift function.
In this article, we study the contribution to the trace (and hence the Krein spectral shift function) that arises from assembling several obstacles relative to a setting where the obstacles are completely separated. In the case of two obstacles, we consider the Laplace operators Δ1 and Δ2 obtained by imposing Dirichlet boundary conditions only on one of the objects.
Our main result in this case states that then g(Δ) - g(Δ1) - g(Δ2) C g(Δ0) is a trace-class operator for a much larger class of functions (including functions of polynomial growth) and that this trace may still be computed by a modification of the Birman–Krein formula. In case g(x) D x 2 , 1 the relative trace has a physical meaning as the vacuum energy of the massless scalar field and is expressible as an integral involving boundary layer operators.
Such integrals have been derived in the physics literature using nonrigorous path integral derivations and our formula provides both a rigorous justification as well as a generalization.
Devising optimal interventions for constraining stochastic systems is a challenging endeavor that has to confront the interplay between randomness and dynamical nonlinearity.
Existing intervention methods that employ stochastic path sampling scale poorly with increasing system dimension and are slow to converge.
Here we propose a generally applicable and practically feasible methodology that computes the optimal interventions in a noniterative scheme.
We formulate the optimal dynamical adjustments in terms of deterministically sampled probability flows approximated by an interacting particle system.
Applied to several biologically inspired models, we demonstrate that our method provides the necessary optimal controls in settings with terminal, transient, or generalized collective state constraints and arbitrary system dynamics.
Das Eigene und das Fremde
(2023)
Die vorliegende Arbeit stellt eine Untersuchung des Fremdverstehens von Lehrkräften im Mathematikunterricht dar. Mit ‚Fremdverstehen‘ soll dabei – in Anlehnung an den Soziologen Alfred Schütz – der Prozess bezeichnet werden, in welchem eine Lehrkraft versucht, das Verhalten einer Schülerin oder eines Schülers zu verstehen, indem sie dieses Verhalten auf ein Erleben zurückführt, das ihm zugrunde gelegen haben könnte. Als ein wesentliches Merkmal des Prozesses stellt Schütz in seiner Theorie des Fremdverstehens heraus, dass das Fremdverstehen eines Menschen immer auch auf seinen eigenen Erlebnissen basiert. Aus diesem Grund wird in der Arbeit ein methodischer Zweischritt vorgenommen: Es werden zunächst die mathematikbezogenen Erlebnisse zweier Lehrkräfte nachgezeichnet, bevor dann ihr Fremdverstehen in konkreten Situationen im Mathematikunterricht rekonstruiert wird. In der ersten Teiluntersuchung (= der Rekonstruktion eigener Erlebnisse der untersuchten Lehrkräfte) erfolgt die Datenerhebung mit Hilfe biographisch-narrativer Interviews, in denen die untersuchten Lehrkräfte angeregt werden, ihre mathematikbezogene Lebensgeschichte zu erzählen. Die Analyse dieser Interviews wird im Sinne der rekonstruktiven Fallanalyse vorgenommen. Insgesamt führt die erste Teiluntersuchung zu textlichen Darstellungen der rekonstruierten mathematikbezogenen Lebensgeschichte der untersuchten Mathematiklehrkräfte. In der zweiten Teiluntersuchung (= der Rekonstruktion des Fremdverstehens der untersuchten Lehrkräfte) werden dann narrative Interviews geführt, in denen die untersuchten Lehrkräfte von ihrem Fremdverstehen in konkreten Situationen im Mathematikunterricht erzählen. Die Analyse dieser Interviews erfolgt mit Hilfe eines dreischrittigen Analyseverfahrens, welches die Autorin eigens zum Zweck der Rekonstruktion von Fremdverstehen entwickelte. Am Ende dieser zweiten Teiluntersuchung werden sowohl das rekonstruierte Fremdverstehen der Lehrkräfte in verschiedenen Unterrichtssituationen dargestellt als auch Strukturen, die sich in ihrem Fremdverstehen abzeichnen. Mit Hilfe einer theoretischen Verallgemeinerung werden schließlich – auf Basis der Ergebnisse der zweiten Teiluntersuchung – Aussagen über fünf Merkmale des Fremdverstehens von Lehrkräften im Mathematikunterricht im Allgemeinen gewonnen. Mit diesen Aussagen vermag die Arbeit eine erste Beschreibung davon hervorzubringen, wie sich das Phänomen des Fremdverstehens von Lehrkräften im Mathematikunterricht ausgestalten kann.
Zahlen in den Fingern
(2023)
Die Debatte über den Einsatz von digitalen Werkzeugen in der mathematischen Frühförderung ist hoch aktuell. Lernspiele werden konstruiert, mit dem Ziel, mathematisches, informelles Wissen aufzubauen und so einen besseren Schulstart zu ermöglichen. Doch allein die digitale und spielerische Aufarbeitung führt nicht zwingend zu einem Lernerfolg. Daher ist es umso wichtiger, die konkrete Implementation der theoretischen Konstrukte und Interaktionsmöglichkeiten mit den Werkzeugen zu analysieren und passend aufzubereiten.
In dieser Masterarbeit wird dazu exemplarisch ein mathematisches Lernspiel namens „Fingu“ für den Einsatz im vorschulischen Bereich theoretisch und empirisch im Rahmen der Artifact-Centric Activity Theory (ACAT) untersucht. Dazu werden zunächst die theoretischen Hintergründe zum Zahlensinn, Zahlbegriffserwerb, Teil-Ganze-Verständnis, der Anzahlwahrnehmung und -bestimmung, den Anzahlvergleichen und der Anzahldarstellung mithilfe von Fingern gemäß der Embodied Cognition sowie der Verwendung von digitalen Werkzeugen und Multi-Touch-Geräten umfassend beschrieben. Anschließend wird die App Fingu erklärt und dann theoretisch entlang des ACAT-Review-Guides analysiert. Zuletzt wird die selbstständig durchgeführte Studie mit zehn Vorschulkindern erläutert und darauf aufbauend Verbesserungs- und Entwicklungsmöglichkeiten der App auf wissenschaftlicher Grundlage beigetragen. Für Fingu lässt sich abschließend festhalten, dass viele Prozesse wie die (Quasi-)Simultanerfassung oder das Zählen gefördert werden können, für andere wie das Teil-Ganze-Verständnis aber noch Anpassungen und/oder die Begleitung durch Erwachsene nötig ist.
Non-local boundary conditions for the spin Dirac operator on spacetimes with timelike boundary
(2023)
Non-local boundary conditions – for example the Atiyah–Patodi–Singer (APS) conditions – for Dirac operators on Riemannian manifolds are rather well-understood, while not much is known for such operators on Lorentzian manifolds. Recently, Bär and Strohmaier [15] and Drago, Große, and Murro [27] introduced APS-like conditions for the spin Dirac operator on Lorentzian manifolds with spacelike and timelike boundary, respectively. While Bär and Strohmaier [15] showed the Fredholmness of the Dirac operator with these boundary conditions, Drago, Große, and Murro [27] proved the well-posedness of the corresponding initial boundary value problem under certain geometric assumptions.
In this thesis, we will follow the footsteps of the latter authors and discuss whether the APS-like conditions for Dirac operators on Lorentzian manifolds with timelike boundary can be replaced by more general conditions such that the associated initial boundary value problems are still wellposed.
We consider boundary conditions that are local in time and non-local in the spatial directions. More precisely, we use the spacetime foliation arising from the Cauchy temporal function and split the Dirac operator along this foliation. This gives rise to a family of elliptic operators each acting on spinors of the spin bundle over the corresponding timeslice. The theory of elliptic operators then ensures that we can find families of non-local boundary conditions with respect to this family of operators. Proceeding, we use such a family of boundary conditions to define a Lorentzian boundary condition on the whole timelike boundary. By analyzing the properties of the Lorentzian boundary conditions, we then find sufficient conditions on the family of non-local boundary conditions that lead to the well-posedness of the corresponding Cauchy problems. The well-posedness itself will then be proven by using classical tools including energy estimates and approximation by solutions of the regularized problems.
Moreover, we use this theory to construct explicit boundary conditions for the Lorentzian Dirac operator. More precisely, we will discuss two examples of boundary conditions – the analogue of the Atiyah–Patodi–Singer and the chirality conditions, respectively, in our setting. For doing this, we will have a closer look at the theory of non-local boundary conditions for elliptic operators and analyze the requirements on the family of non-local boundary conditions for these specific examples.
This thesis bridges two areas of mathematics, algebra on the one hand with the Milnor-Moore theorem (also called Cartier-Quillen-Milnor-Moore theorem) as well as the Poincaré-Birkhoff-Witt theorem, and analysis on the other hand with Shintani zeta functions which generalise multiple zeta functions.
The first part is devoted to an algebraic formulation of the locality principle in physics and generalisations of classification theorems such as Milnor-Moore and Poincaré-Birkhoff-Witt theorems to the locality framework. The locality principle roughly says that events that take place far apart in spacetime do not infuence each other. The algebraic formulation of this principle discussed here is useful when analysing singularities which arise from events located far apart in space, in order to renormalise them while keeping a memory of the fact that they do not influence each other. We start by endowing a vector space with a symmetric relation, named the locality relation, which keeps track of elements that are "locally independent". The pair of a vector space together with such relation is called a pre-locality vector space. This concept is extended to tensor products allowing only tensors made of locally independent elements. We extend this concept to the locality tensor algebra, and locality symmetric algebra of a pre-locality vector space and prove the universal properties of each of such structures. We also introduce the pre-locality Lie algebras, together with their associated locality universal enveloping algebras and prove their universal property. We later upgrade all such structures and results from the pre-locality to the locality context, requiring the locality relation to be compatible with the linear structure of the vector space. This allows us to define locality coalgebras, locality bialgebras, and locality Hopf algebras. Finally, all the previous results are used to prove the locality version of the Milnor-Moore and the Poincaré-Birkhoff-Witt theorems. It is worth noticing that the proofs presented, not only generalise the results in the usual (non-locality) setup, but also often use less tools than their counterparts in their non-locality counterparts.
The second part is devoted to study the polar structure of the Shintani zeta functions. Such functions, which generalise the Riemman zeta function, multiple zeta functions, Mordell-Tornheim zeta functions, among others, are parametrised by matrices with real non-negative arguments. It is known that Shintani zeta functions extend to meromorphic functions with poles on afine hyperplanes. We refine this result in showing that the poles lie on hyperplanes parallel to the facets of certain convex polyhedra associated to the defining matrix for the Shintani zeta function. Explicitly, the latter are the Newton polytopes of the polynomials induced by the columns of the underlying matrix. We then prove that the coeficients of the equation which describes the hyperplanes in the canonical basis are either zero or one, similar to the poles arising when renormalising generic Feynman amplitudes. For that purpose, we introduce an algorithm to distribute weight over a graph such that the weight at each vertex satisfies a given lower bound.
Point processes are a common methodology to model sets of events. From earthquakes to social media posts, from the arrival times of neuronal spikes to the timing of crimes, from stock prices to disease spreading -- these phenomena can be reduced to the occurrences of events concentrated in points. Often, these events happen one after the other defining a time--series.
Models of point processes can be used to deepen our understanding of such events and for classification and prediction. Such models include an underlying random process that generates the events. This work uses Bayesian methodology to infer the underlying generative process from observed data. Our contribution is twofold -- we develop new models and new inference methods for these processes.
We propose a model that extends the family of point processes where the occurrence of an event depends on the previous events. This family is known as Hawkes processes. Whereas in most existing models of such processes, past events are assumed to have only an excitatory effect on future events, we focus on the newly developed nonlinear Hawkes process, where past events could have excitatory and inhibitory effects. After defining the model, we present its inference method and apply it to data from different fields, among others, to neuronal activity.
The second model described in the thesis concerns a specific instance of point processes --- the decision process underlying human gaze control. This process results in a series of fixated locations in an image. We developed a new model to describe this process, motivated by the known Exploration--Exploitation dilemma. Alongside the model, we present a Bayesian inference algorithm to infer the model parameters.
Remaining in the realm of human scene viewing, we identify the lack of best practices for Bayesian inference in this field. We survey four popular algorithms and compare their performances for parameter inference in two scan path models.
The novel models and inference algorithms presented in this dissertation enrich the understanding of point process data and allow us to uncover meaningful insights.
Übungsbuch zur Stochastik
(2023)
Dieses Buch stellt Übungen zu den Grundbegriffen und Grundsätzen der Stochastik und ihre Lösungen zur Verfügung. So wie man Tonleitern in der Musik trainiert, so berechnet man Übungsaufgaben in der Mathematik. In diesem Sinne soll dieses Übungsbuch vor allem als Vorlage dienen für das eigenständige, eigenverantwortliche Lernen und Üben.
Die Schönheit und Einzigartigkeit der Wahrscheinlichkeitstheorie besteht darin, dass sie eine Vielzahl von realen Phänomenen modellieren kann. Daher findet man hier Aufgaben mit Verbindungen zur Geometrie, zu Glücksspielen, zur Versicherungsmathematik, zur Demographie und vielen anderen Themen.
Das Mathematik-Teilprojekt SPIES-M zielt auf eine stärkere Professionsorientierung und die Verknüpfung von Fachwissenschaft und Fachdidaktik in der universitären Lehrkräftebildung. Zu allen großen Inhaltsgebieten der Mathematik wurden neue Lehrveranstaltungen konzipiert und in den Studienordnungen sämtlicher Lehrämter Mathematik an der Universität Potsdam implementiert. Für die Konzeption wurden theoriebasiert Gestaltungsprinzipien herausgearbeitet, die sowohl für das Design als auch für die Evaluation und Weiterentwicklung der Lehrveranstaltungen nach dem Design-Research-Ansatz genutzt werden können. Die Umsetzung der Gestaltungsprinzipien wird am Beispiel der Fundamentalen Idee der Proportionalität verdeutlicht und dabei aufgezeigt, wie Studierende dazu befähigt werden können, fachdidaktisches Wissen aus fachmathematischen Inhalten zu generieren. Die Entwicklung des Professionswissens der Studierenden wird mithilfe unterschiedlicher Instrumente untersucht, um Rückschlüsse auf die Wirksamkeit der neu konzipierten Lehrveranstaltungen zu ziehen. Für die Untersuchungen im Mixed-Methods-Design werden neben Beobachtungen in Lehrveranstaltungen eigens konzipierte Wissenstests, Gruppeninterviews, Unterrichtsentwürfe aus Praxisphasen und Lerntagebücher genutzt. Die Studierendenperspektive wird durch Befragungen zur wahrgenommenen (Berufs-)Relevanz der Lehrveranstaltungen erhoben. Weiteres wesentliches Element der Begleitforschung ist die kollegiale Supervision durch sogenannte „Spies“ (Spione), die die Veranstaltungen kriteriengeleitet beobachten und anschließend gemeinsam mit den Dozierenden reflektieren. Die bisherigen Ergebnisse werden hier präsentiert und hinsichtlich ihrer Implikationen diskutiert. Die im Projekt entwickelten Gestaltungsprinzipien als Werkzeug für Design und Evaluation sowie das Spies-Konzept der kollegialen Supervision werden für die Qualitätsentwicklung von Lehrveranstaltungen zum Transfer vorgeschlagen.
In this paper we consider surfaces which are critical points of the Willmore functional subject to constrained area.
In the case of small area we calculate the corrections to the intrinsic geometry induced by the ambient curvature.
These estimates together with the choice of an adapted geometric center of mass lead to refined position estimates in relation to the scalar curvature of the ambient manifold.
Deriving mechanism-based pharmacodynamic models by reducing quantitative systems pharmacology models
(2023)
Quantitative systems pharmacology (QSP) models integrate comprehensive qualitative and quantitative knowledge about pharmacologically relevant processes. We previously proposed a first approach to leverage the knowledge in QSP models to derive simpler, mechanism-based pharmacodynamic (PD) models. Their complexity, however, is typically still too large to be used in the population analysis of clinical data. Here, we extend the approach beyond state reduction to also include the simplification of reaction rates, elimination of reactions, and analytic solutions. We additionally ensure that the reduced model maintains a prespecified approximation quality not only for a reference individual but also for a diverse virtual population. We illustrate the extended approach for the warfarin effect on blood coagulation. Using the model-reduction approach, we derive a novel small-scale warfarin/international normalized ratio model and demonstrate its suitability for biomarker identification. Due to the systematic nature of the approach in comparison with empirical model building, the proposed model-reduction algorithm provides an improved rationale to build PD models also from QSP models in other applications.
Cell-level systems biology model to study inflammatory bowel diseases and their treatment options
(2023)
To help understand the complex and therapeutically challenging inflammatory bowel diseases (IBDs), we developed a systems biology model of the intestinal immune system that is able to describe main aspects of IBD and different treatment modalities thereof. The model, including key cell types and processes of the mucosal immune response, compiles a large amount of isolated experimental findings from literature into a larger context and allows for simulations of different inflammation scenarios based on the underlying data and assumptions. In the context of a large and diverse virtual IBD population, we characterized the patients based on their phenotype (in contrast to healthy individuals, they developed persistent inflammation after a trigger event) rather than on a priori assumptions on parameter differences to a healthy individual. This allowed to reproduce the enormous diversity of predispositions known to lead to IBD. Analyzing different treatment effects, the model provides insight into characteristics of individual drug therapy. We illustrate for anti-TNF-alpha therapy, how the model can be used (i) to decide for alternative treatments with best prospects in the case of nonresponse, and (ii) to identify promising combination therapies with other available treatment options.
Amoeboid cell motility takes place in a variety of biomedical processes such as cancer metastasis, embryonic morphogenesis, and wound healing. In contrast to other forms of cell motility, it is mainly driven by substantial cell shape changes. Based on the interplay of explorative membrane protrusions at the front and a slower-acting membrane retraction at the rear, the cell moves in a crawling kind of way. Underlying these protrusions and retractions are multiple physiological processes resulting in changes of the cytoskeleton, a meshwork of different multi-functional proteins. The complexity and versatility of amoeboid cell motility raise the need for novel computational models based on a profound theoretical framework to analyze and simulate the dynamics of the cell shape.
The objective of this thesis is the development of (i) a mathematical framework to describe contour dynamics in time and space, (ii) a computational model to infer expansion and retraction characteristics of individual cell tracks and to produce realistic contour dynamics, (iii) and a complementing Open Science approach to make the above methods fully accessible and easy to use.
In this work, we mainly used single-cell recordings of the model organism Dictyostelium discoideum. Based on stacks of segmented microscopy images, we apply a Bayesian approach to obtain smooth representations of the cell membrane, so-called cell contours. We introduce a one-parameter family of regularized contour flows to track reference points on the contour (virtual markers) in time and space. This way, we define a coordinate system to visualize local geometric and dynamic quantities of individual contour dynamics in so-called kymograph plots. In particular, we introduce the local marker dispersion as a measure to identify membrane protrusions and retractions in a fully automated way.
This mathematical framework is the basis of a novel contour dynamics model, which consists of three biophysiologically motivated components: one stochastic term, accounting for membrane protrusions, and two deterministic terms to control the shape and area of the contour, which account for membrane retractions. Our model provides a fully automated approach to infer protrusion and retraction characteristics from experimental cell tracks while being also capable of simulating realistic and qualitatively different contour dynamics. Furthermore, the model is used to classify two different locomotion types: the amoeboid and a so-called fan-shaped type.
With the complementing Open Science approach, we ensure a high standard regarding the usability of our methods and the reproducibility of our research. In this context, we introduce our software publication named AmoePy, an open-source Python package to segment, analyze, and simulate amoeboid cell motility. Furthermore, we describe measures to improve its usability and extensibility, e.g., by detailed run instructions and an automatically generated source code documentation, and to ensure its functionality and stability, e.g., by automatic software tests, data validation, and a hierarchical package structure.
The mathematical approaches of this work provide substantial improvements regarding the modeling and analysis of amoeboid cell motility. We deem the above methods, due to their generalized nature, to be of greater value for other scientific applications, e.g., varying organisms and experimental setups or the transition from unicellular to multicellular movement. Furthermore, we enable other researchers from different fields, i.e., mathematics, biophysics, and medicine, to apply our mathematical methods. By following Open Science standards, this work is of greater value for the cell migration community and a potential role model for other Open Science contributions.
We present a Reduced Order Model (ROM) which exploits recent developments in Physics Informed Neural Networks (PINNs) for solving inverse problems for the Navier-Stokes equations (NSE). In the proposed approach, the presence of simulated data for the fluid dynamics fields is assumed. A POD-Galerkin ROM is then constructed by applying POD on the snapshots matrices of the fluid fields and performing a Galerkin projection of the NSE (or the modified equations in case of turbulence modeling) onto the POD reduced basis. A POD-Galerkin PINN ROM is then derived by introducing deep neural networks which approximate the reduced outputs with the input being time and/or parameters of the model. The neural networks incorporate the physical equations (the POD-Galerkin reduced equations) into their structure as part of the loss function. Using this approach, the reduced model is able to approximate unknown parameters such as physical constants or the boundary conditions. A demonstration of the applicability of the proposed ROM is illustrated by three cases which are the steady flow around a backward step, the flow around a circular cylinder and the unsteady turbulent flow around a surface mounted cubic obstacle.
Introduction:
Hydrocortisone is the standard of care in cortisol replacement therapy for congenital adrenal hyperplasia patients. Challenges in mimicking cortisol circadian rhythm and dosing individualization can be overcome by the support of mathematical modelling. Previously, a non-linear mixed-effects (NLME) model was developed based on clinical hydrocortisone pharmacokinetic (PK) pediatric and adult data. Additionally, a physiologically-based pharmacokinetic (PBPK) model was developed for adults and a pediatric model was obtained using maturation functions for relevant processes. In this work, a middle-out approach was applied. The aim was to investigate whether PBPK-derived maturation functions could provide a better description of hydrocortisone PK inter-individual variability when implemented in the NLME framework, with the goal of providing better individual predictions towards precision dosing at the patient level.
Methods:
Hydrocortisone PK data from 24 adrenal insufficiency pediatric patients and 30 adult healthy volunteers were used for NLME model development, while the PBPK model and maturation functions of clearance and cortisol binding globulin (CBG) were developed based on previous studies published in the literature.
Results:
Clearance (CL) estimates from both approaches were similar for children older than 1 year (CL/F increasing from around 150 L/h to 500 L/h), while CBG concentrations differed across the whole age range (CBG(NLME) stable around 0.5 mu M vs. steady increase from 0.35 to 0.8 mu M for CBG (PBPK)). PBPK-derived maturation functions were subsequently included in the NLME model. After inclusion of the maturation functions, none, a part of, or all parameters were re-estimated. However, the inclusion of CL and/or CBG maturation functions in the NLME model did not result in improved model performance for the CL maturation function (& UDelta;OFV > -15.36) and the re-estimation of parameters using the CBG maturation function most often led to unstable models or individual CL prediction bias.
Discussion:
Three explanations for the observed discrepancies could be postulated, i) non-considered maturation of processes such as absorption or first-pass effect, ii) lack of patients between 1 and 12 months, iii) lack of correction of PBPK CL maturation functions derived from urinary concentration ratio data for the renal function relative to adults. These should be investigated in the future to determine how NLME and PBPK methods can work towards deriving insights into pediatric hydrocortisone PK.
This paper deals with the long-term behavior of positive operator semigroups on spaces of bounded functions and of signed measures, which have applications to parabolic equations with unbounded coefficients and to stochas-tic analysis. The main results are a Tauberian type theorem characterizing the convergence to equilibrium of strongly Feller semigroups and a generalization of a classical convergence theorem of Doob. None of these results requires any kind of time regularity of the semigroup.
The Gutenberg-Richter (GR) and the Omori-Utsu (OU) law describe the earthquakes' energy release and temporal clustering and are thus of great importance for seismic hazard assessment. Motivated by experimental results, which indicate stress-dependent parameters, we consider a combined global data set of 127 main shock-aftershock sequences and perform a systematic study of the relationship between main shock-induced stress changes and associated seismicity patterns. For this purpose, we calculate space-dependent Coulomb Stress (& UDelta;CFS) and alternative receiver-independent stress metrics in the surrounding of the main shocks. Our results indicate a clear positive correlation between the GR b-value and the induced stress, contrasting expectations from laboratory experiments and suggesting a crucial role of structural heterogeneity and strength variations. Furthermore, we demonstrate that the aftershock productivity increases nonlinearly with stress, while the OU parameters c and p systematically decrease for increasing stress changes. Our partly unexpected findings can have an important impact on future estimations of the aftershock hazard.
Hardy inequalities on graphs
(2024)
The dissertation deals with a central inequality of non-linear potential theory, the Hardy inequality. It states that the non-linear energy functional can be estimated from below by a pth power of a weighted p-norm, p>1. The energy functional consists of a divergence part and an arbitrary potential part. Locally summable infinite graphs were chosen as the underlying space. Previous publications on Hardy inequalities on graphs have mainly considered the special case p=2, or locally finite graphs without a potential part.
Two fundamental questions now arise quite naturally: For which graphs is there a Hardy inequality at all? And, if it exists, is there a way to obtain an optimal weight? Answers to these questions are given in Theorem 10.1 and Theorem 12.1. Theorem 10.1 gives a number of characterizations; among others, there is a Hardy inequality on a graph if and only if there is a Green's function. Theorem 12.1 gives an explicit formula to compute optimal Hardy weights for locally finite graphs under some additional technical assumptions. Examples show that Green's functions are good candidates to be used in the formula.
Emphasis is also placed on illustrating the theory with examples. The focus is on natural numbers, Euclidean lattices, trees and star graphs. Finally, a non-linear version of the Heisenberg uncertainty principle and a Rellich inequality are derived from the Hardy inequality.
State space models enjoy wide popularity in mathematical and statistical modelling across disciplines and research fields. Frequent solutions to problems of estimation and forecasting of a latent signal such as the celebrated Kalman filter hereby rely on a set of strong assumptions such as linearity of system dynamics and Gaussianity of noise terms.
We investigate fallacy in mis-specification of the noise terms, that is signal noise
and observation noise, regarding heavy tailedness in that the true dynamic frequently produces observation outliers or abrupt jumps of the signal state due to realizations of these heavy tails not considered by the model. We propose a formalisation of observation noise mis-specification in terms of Huber’s ε-contamination as well as a computationally cheap solution via generalised Bayesian posteriors with a diffusion Stein divergence loss resulting in the diffusion score matching Kalman filter - a modified algorithm akin in complexity to the regular Kalman filter. For this new filter interpretations of novel terms, stability and an ensemble variant are discussed. Regarding signal noise mis-specification, we propose a formalisation in the frame work of change point detection and join ideas from the popular CUSUM algo-
rithm with ideas from Bayesian online change point detection to combine frequent reliability constraints and online inference resulting in a Gaussian mixture model variant of multiple Kalman filters. We hereby exploit open-end sequential probability ratio tests on the evidence of Kalman filters on observation sub-sequences for aggregated inference under notions of plausibility.
Both proposed methods are combined to investigate the double mis-specification problem and discussed regarding their capabilities in reliable and well-tuned uncertainty quantification. Each section provides an introduction to required terminology and tools as well as simulation experiments on the popular target tracking task and the non-linear, chaotic Lorenz-63 system to showcase practical performance of theoretical considerations.