## 510 Mathematik

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- Operators on singular manifolds (2016)
- 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.

- On the exact simulation of (skew) Brownian diffusions with discontinuous drift (2016)
- 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.

- A Radó Theorem for the Porous Medium Equation (2017)
- We prove that each locally Lipschitz continuous function satisfying the porous medium equation away from the set of its zeroes is actually a weak solution of this equation in the whole domain.

- Golusin-Krylov Formulas in Complex Analysis (2017)
- 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.

- Mathematical modelling of host-disease-drug interactions in HIV disease (2016)
- The human immunodeficiency virus (HIV) has resisted nearly three decades of efforts targeting a cure. Sustained suppression of the virus has remained a challenge, mainly due to the remarkable evolutionary adaptation that the virus exhibits by the accumulation of drug-resistant mutations in its genome. Current therapeutic strategies aim at achieving and maintaining a low viral burden and typically involve multiple drugs. The choice of optimal combinations of these drugs is crucial, particularly in the background of treatment failure having occurred previously with certain other drugs. An understanding of the dynamics of viral mutant genotypes aids in the assessment of treatment failure with a certain drug combination, and exploring potential salvage treatment regimens. Mathematical models of viral dynamics have proved invaluable in understanding the viral life cycle and the impact of antiretroviral drugs. However, such models typically use simplified and coarse-grained mutation schemes, that curbs the extent of their application to drug-specific clinical mutation data, in order to assess potential next-line therapies. Statistical models of mutation accumulation have served well in dissecting mechanisms of resistance evolution by reconstructing mutation pathways under different drug-environments. While these models perform well in predicting treatment outcomes by statistical learning, they do not incorporate drug effect mechanistically. Additionally, due to an inherent lack of temporal features in such models, they are less informative on aspects such as predicting mutational abundance at treatment failure. This limits their application in analyzing the pharmacology of antiretroviral drugs, in particular, time-dependent characteristics of HIV therapy such as pharmacokinetics and pharmacodynamics, and also in understanding the impact of drug efficacy on mutation dynamics. In this thesis, we develop an integrated model of in vivo viral dynamics incorporating drug-specific mutation schemes learned from clinical data. Our combined modelling approach enables us to study the dynamics of different mutant genotypes and assess mutational abundance at virological failure. As an application of our model, we estimate in vivo fitness characteristics of viral mutants under different drug environments. Our approach also extends naturally to multiple-drug therapies. Further, we demonstrate the versatility of our model by showing how it can be modified to incorporate recently elucidated mechanisms of drug action including molecules that target host factors. Additionally, we address another important aspect in the clinical management of HIV disease, namely drug pharmacokinetics. It is clear that time-dependent changes in in vivo drug concentration could have an impact on the antiviral effect, and also influence decisions on dosing intervals. We present a framework that provides an integrated understanding of key characteristics of multiple-dosing regimens including drug accumulation ratios and half-lifes, and then explore the impact of drug pharmacokinetics on viral suppression. Finally, parameter identifiability in such nonlinear models of viral dynamics is always a concern, and we investigate techniques that alleviate this issue in our setting.

- Construction of series of perfect lattices by layer superposition (2016)
- We construct a new series of perfect lattices in n dimensions by the layer superposition method of Delaunay-Barnes.

- Deciphering multiple changes in complex climate time series using Bayesian inference (2016)
- Change points in time series are perceived as heterogeneities in the statistical or dynamical characteristics of the observations. Unraveling such transitions yields essential information for the understanding of the observed system’s intrinsic evolution and potential external influences. A precise detection of multiple changes is therefore of great importance for various research disciplines, such as environmental sciences, bioinformatics and economics. The primary purpose of the detection approach introduced in this thesis is the investigation of transitions underlying direct or indirect climate observations. In order to develop a diagnostic approach capable to capture such a variety of natural processes, the generic statistical features in terms of central tendency and dispersion are employed in the light of Bayesian inversion. In contrast to established Bayesian approaches to multiple changes, the generic approach proposed in this thesis is not formulated in the framework of specialized partition models of high dimensionality requiring prior specification, but as a robust kernel-based approach of low dimensionality employing least informative prior distributions. First of all, a local Bayesian inversion approach is developed to robustly infer on the location and the generic patterns of a single transition. The analysis of synthetic time series comprising changes of different observational evidence, data loss and outliers validates the performance, consistency and sensitivity of the inference algorithm. To systematically investigate time series for multiple changes, the Bayesian inversion is extended to a kernel-based inference approach. By introducing basic kernel measures, the weighted kernel inference results are composed into a proxy probability to a posterior distribution of multiple transitions. The detection approach is applied to environmental time series from the Nile river in Aswan and the weather station Tuscaloosa, Alabama comprising documented changes. The method’s performance confirms the approach as a powerful diagnostic tool to decipher multiple changes underlying direct climate observations. Finally, the kernel-based Bayesian inference approach is used to investigate a set of complex terrigenous dust records interpreted as climate indicators of the African region of the Plio-Pleistocene period. A detailed inference unravels multiple transitions underlying the indirect climate observations, that are interpreted as conjoint changes. The identified conjoint changes coincide with established global climate events. In particular, the two-step transition associated to the establishment of the modern Walker-Circulation contributes to the current discussion about the influence of paleoclimate changes on the environmental conditions in tropical and subtropical Africa at around two million years ago.

- An open mapping theorem for the Navier-Stokes equations (2016)
- We consider the Navier-Stokes equations in the layer R^n x [0,T] over R^n with finite T > 0. Using the standard fundamental solutions of the Laplace operator and the heat operator, we reduce the Navier-Stokes equations to a nonlinear Fredholm equation of the form (I+K) u = f, where K is a compact continuous operator in anisotropic normed Hölder spaces weighted at the point at infinity with respect to the space variables. Actually, the weight function is included to provide a finite energy estimate for solutions to the Navier-Stokes equations for all t in [0,T]. On using the particular properties of the de Rham complex we conclude that the Fréchet derivative (I+K)' is continuously invertible at each point of the Banach space under consideration and the map I+K is open and injective in the space. In this way the Navier-Stokes equations prove to induce an open one-to-one mapping in the scale of Hölder spaces.

- Relating diameter and mean curvature for varifolds (2016)
- The main results of this thesis are formulated in a class of surfaces (varifolds) generalizing closed and connected smooth submanifolds of Euclidean space which allows singularities. Given an indecomposable varifold with dimension at least two in some Euclidean space such that the first variation is locally bounded, the total variation is absolutely continuous with respect to the weight measure, the density of the weight measure is at least one outside a set of weight measure zero and the generalized mean curvature is locally summable to a natural power (dimension of the varifold minus one) with respect to the weight measure. The thesis presents an improved estimate of the set where the lower density is small in terms of the one dimensional Hausdorff measure. Moreover, if the support of the weight measure is compact, then the intrinsic diameter with respect to the support of the weight measure is estimated in terms of the generalized mean curvature. This estimate is in analogy to the diameter control for closed connected manifolds smoothly immersed in some Euclidean space of Peter Topping. Previously, it was not known whether the hypothesis in this thesis implies that two points in the support of the weight measure have finite geodesic distance.