## 510 Mathematik

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The classical Navier-Stokes equations of hydrodynamics are usually written in terms of vector analysis. More promising is the formulation of these equations in the language of differential forms of degree one. In this way the study of Navier-Stokes equations includes the analysis of the de Rham complex. In particular, the Hodge theory for the de Rham complex enables one to eliminate the pressure from the equations. The Navier-Stokes equations constitute a parabolic system with a nonlinear term which makes sense only for one-forms. A simpler model of dynamics of incompressible viscous fluid is given by Burgers' equation. This work is aimed at the study of invariant structure of the Navier-Stokes equations which is closely related to the algebraic structure of the de Rham complex at step 1. To this end we introduce Navier-Stokes equations related to any elliptic quasicomplex of first order differential operators. These equations are quite similar to the classical Navier-Stokes equations including generalised velocity and pressure vectors. Elimination of the pressure from the generalised Navier-Stokes equations gives a good motivation for the study of the Neumann problem after Spencer for elliptic quasicomplexes. Such a study is also included in the work.We start this work by discussion of Lamé equations within the context of elliptic quasicomplexes on compact manifolds with boundary. The non-stationary Lamé equations form a hyperbolic system. However, the study of the first mixed problem for them gives a good experience to attack the linearised Navier-Stokes equations. On this base we describe a class of non-linear perturbations of the Navier-Stokes equations, for which the solvability results still hold.

During the drug discovery & development process, several phases encompassing a number of preclinical and clinical studies have to be successfully passed to demonstrate safety and efficacy of a new drug candidate. As part of these studies, the characterization of the drug's pharmacokinetics (PK) is an important aspect, since the PK is assumed to strongly impact safety and efficacy. To this end, drug concentrations are measured repeatedly over time in a study population. The objectives of such studies are to describe the typical PK time-course and the associated variability between subjects. Furthermore, underlying sources significantly contributing to this variability, e.g. the use of comedication, should be identified. The most commonly used statistical framework to analyse repeated measurement data is the nonlinear mixed effect (NLME) approach. At the same time, ample knowledge about the drug's properties already exists and has been accumulating during the discovery & development process: Before any drug is tested in humans, detailed knowledge about the PK in different animal species has to be collected. This drug-specific knowledge and general knowledge about the species' physiology is exploited in mechanistic physiological based PK (PBPK) modeling approaches -it is, however, ignored in the classical NLME modeling approach.
Mechanistic physiological based models aim to incorporate relevant and known physiological processes which contribute to the overlying process of interest. In comparison to data--driven models they are usually more complex from a mathematical perspective. For example, in many situations, the number of model parameters outrange the number of measurements and thus reliable parameter estimation becomes more complex and partly impossible. As a consequence, the integration of powerful mathematical estimation approaches like the NLME modeling approach -which is widely used in data-driven modeling -and the mechanistic modeling approach is not well established; the observed data is rather used as a confirming instead of a model informing and building input.
Another aggravating circumstance of an integrated approach is the inaccessibility to the details of the NLME methodology so that these approaches can be adapted to the specifics and needs of mechanistic modeling. Despite the fact that the NLME modeling approach exists for several decades, details of the mathematical methodology is scattered around a wide range of literature and a comprehensive, rigorous derivation is lacking. Available literature usually only covers selected parts of the mathematical methodology. Sometimes, important steps are not described or are only heuristically motivated, e.g. the iterative algorithm to finally determine the parameter estimates.
Thus, in the present thesis the mathematical methodology of NLME modeling is systemically described and complemented to a comprehensive description,
comprising the common theme from ideas and motivation to the final parameter estimation. Therein, new insights for the interpretation of different approximation methods used in the context of the NLME modeling approach are given and illustrated; furthermore, similarities and differences between them are outlined. Based on these findings, an expectation-maximization (EM) algorithm to determine estimates of a NLME model is described.
Using the EM algorithm and the lumping methodology by Pilari2010, a new approach on how PBPK and NLME modeling can be combined is presented and exemplified for the antibiotic levofloxacin. Therein, the lumping identifies which processes are informed by the available data and the respective model reduction improves the robustness in parameter estimation. Furthermore, it is shown how apriori known factors influencing the variability and apriori known unexplained variability is incorporated to further mechanistically drive the model development. Concludingly, correlation between parameters and between covariates is automatically accounted for due to the mechanistic derivation of the lumping and the covariate relationships.
A useful feature of PBPK models compared to classical data-driven PK models is in the possibility to predict drug concentration within all organs and tissue in the body. Thus, the resulting PBPK model for levofloxacin is used to predict drug concentrations and their variability within soft tissues which are the site of action for levofloxacin. These predictions are compared with data of muscle and adipose tissue obtained by microdialysis, which is an invasive technique to measure a proportion of drug in the tissue, allowing to approximate the concentrations in the interstitial fluid of tissues. Because, so far, comparing human in vivo tissue PK and PBPK predictions are not established, a new conceptual framework is derived. The comparison of PBPK model predictions and microdialysis measurements shows an adequate agreement and reveals further strengths of the presented new approach.
We demonstrated how mechanistic PBPK models, which are usually developed in the early stage of drug development, can be used as basis for model building in the analysis of later stages, i.e. in clinical studies. As a consequence, the extensively collected and accumulated knowledge about species and drug are utilized and updated with specific volunteer or patient data. The NLME approach combined with mechanistic modeling reveals new insights for the mechanistic model, for example identification and quantification of variability in mechanistic processes. This represents a further contribution to the learn & confirm paradigm across different stages of drug development.
Finally, the applicability of mechanism--driven model development is demonstrated on an example from the field of Quantitative Psycholinguistics to analyse repeated eye movement data. Our approach gives new insight into the interpretation of these experiments and the processes behind.

In a bounded domain with smooth boundary in R^3 we consider the stationary Maxwell equations
for a function u with values in R^3 subject to a nonhomogeneous condition
(u,v)_x = u_0 on
the boundary, where v is a given vector field and u_0 a function on the boundary. We specify this problem within the framework of the Riemann-Hilbert boundary value problems for the Moisil-Teodorescu system. This latter is proved to satisfy the Shapiro-Lopaniskij condition if an only if the vector v is at no point tangent to the boundary. The Riemann-Hilbert problem for the Moisil-Teodorescu system fails to possess an adjoint boundary value problem with respect to the Green formula, which satisfies the Shapiro-Lopatinskij condition. We develop the construction of Green formula to get a proper concept of adjoint boundary value problem.

Numerous reports of relatively rapid climate changes over the past century make a clear case of the impact of aerosols and clouds, identified as sources of largest uncertainty in climate projections. Earth’s radiation balance is altered by aerosols depending on their size, morphology and chemical composition. Competing effects in the atmosphere can be further studied by investigating the evolution of aerosol microphysical properties, which are the focus of the present work.
The aerosol size distribution, the refractive index, and the single scattering albedo are commonly used such properties linked to aerosol type, and radiative forcing. Highly advanced lidars (light detection and ranging) have reduced aerosol monitoring and optical profiling into a routine process. Lidar data have been widely used to retrieve the size distribution through the inversion of the so-called Lorenz-Mie model (LMM). This model offers a reasonable treatment for spherically approximated particles, it no longer provides, though, a viable description for other naturally occurring arbitrarily shaped particles, such as dust particles. On the other hand, non-spherical geometries as simple as spheroids reproduce certain optical properties with enhanced accuracy. Motivated by this, we adapt the LMM to accommodate the spheroid-particle approximation introducing the notion of a two-dimensional (2D) shape-size distribution.
Inverting only a few optical data points to retrieve the shape-size distribution is classified as a non-linear ill-posed problem. A brief mathematical analysis is presented which reveals the inherent tendency towards highly oscillatory solutions, explores the available options for a generalized solution through regularization methods and quantifies the ill-posedness. The latter will improve our understanding on the main cause fomenting instability in the produced solution spaces. The new approach facilitates the exploitation of additional lidar data points from depolarization measurements, associated with particle non-sphericity. However, the generalization of LMM vastly increases the complexity of the problem. The underlying theory for the calculation of the involved optical cross sections (T-matrix theory) is computationally so costly, that would limit a retrieval analysis to an unpractical point. Moreover the discretization of the model equation by a 2D collocation method, proposed in this work, involves double integrations which are further time consuming. We overcome these difficulties by using precalculated databases and a sophisticated retrieval software (SphInX: Spheroidal Inversion eXperiments) especially developed for our purposes, capable of performing multiple-dataset inversions and producing a wide range of microphysical retrieval outputs.
Hybrid regularization in conjunction with minimization processes is used as a basis for our algorithms. Synthetic data retrievals are performed simulating various atmospheric scenarios in order to test the efficiency of different regularization methods. The gap in contemporary literature in providing full sets of uncertainties in a wide variety of numerical instances is of major concern here. For this, the most appropriate methods are identified through a thorough analysis on an overall-behavior basis regarding accuracy and stability. The general trend of the initial size distributions is captured in our numerical experiments and the reconstruction quality depends on data error level. Moreover, the need for more or less depolarization points is explored for the first time from the point of view of the microphysical retrieval. Finally, our approach is tested in various measurement cases giving further insight for future algorithm improvements.

We study the interplay between analysis on manifolds with singularities and complex analysis and develop new structures of operators based on the Mellin transform and tools for iterating the calculus for higher singularities. We refer to the idea of interpreting boundary value problems (BVPs) in terms of pseudo-differential operators with a principal symbolic hierarchy, taking into account that BVPs are a source of cone and edge operator algebras. The respective cone and edge pseudo-differential algebras in turn are the starting point of higher corner theories. In addition there are deep relationships between corner operators and complex analysis. This will be illustrated by the Mellin symbolic calculus.

This thesis is focused on the study and the exact simulation of two classes of real-valued Brownian diffusions: multi-skew Brownian motions with constant drift and Brownian diffusions whose drift admits a finite number of jumps.
The skew Brownian motion was introduced in the sixties by Itô and McKean, who constructed it from the reflected Brownian motion, flipping its excursions from the origin with a given probability. Such a process behaves as the original one except at the point 0, which plays the role of a semipermeable barrier. More generally, a skew diffusion with several semipermeable barriers, called multi-skew diffusion, is a diffusion everywhere except when it reaches one of the barriers, where it is partially reflected with a probability depending on that particular barrier. Clearly, a multi-skew diffusion can be characterized either as solution of a stochastic differential equation involving weighted local times (these terms providing the semi-permeability) or by its infinitesimal generator as Markov process.
In this thesis we first obtain a contour integral representation for the transition semigroup of the multiskew Brownian motion with constant drift, based on a fine analysis of its complex properties. Thanks to this representation we write explicitly the transition densities of the two-skew Brownian motion with constant drift as an infinite series involving, in particular, Gaussian functions and their tails.
Then we propose a new useful application of a generalization of the known rejection sampling method. Recall that this basic algorithm allows to sample from a density as soon as one finds an - easy to sample - instrumental density verifying that the ratio between the goal and the instrumental densities is a bounded function. The generalized rejection sampling method allows to sample exactly from densities for which indeed only an approximation is known. The originality of the algorithm lies in the fact that one finally samples directly from the law without any approximation, except the machine's.
As an application, we sample from the transition density of the two-skew Brownian motion with or without constant drift. The instrumental density is the transition density of the Brownian motion with constant drift, and we provide an useful uniform bound for the ratio of the densities. We also present numerical simulations to study the efficiency of the algorithm.
The second aim of this thesis is to develop an exact simulation algorithm for a Brownian diffusion whose drift admits several jumps. In the literature, so far only the case of a continuous drift (resp. of a drift with one finite jump) was treated. The theoretical method we give allows to deal with any finite number of discontinuities. Then we focus on the case of two jumps, using the transition densities of the two-skew Brownian motion obtained before. Various examples are presented and the efficiency of our approach is discussed.

This is a brief survey of a constructive technique of analytic continuation related to an explicit integral formula of Golusin and Krylov (1933). It goes far beyond complex analysis and applies to the Cauchy problem for elliptic partial differential equations as well. As started in the classical papers, the technique is elaborated in generalised Hardy spaces also called Hardy-Smirnov spaces.