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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.
In order to characterise the C*-algebra generated by the singular Bochner-Martinelli integral over a smooth closed hypersurfaces in Cn, we compute its principal symbol. We show then that the Szegö projection belongs to the strong closure of the algebra generated by the singular Bochner-Martinelli integral.
We consider a general class of finite dimensional deterministic dynamical systems with finitely many local attractors each of which supports a unique ergodic probability measure, which includes in particular the class of Morse–Smale systems in any finite dimension. The dynamical system is perturbed by a multiplicative non-Gaussian heavytailed Lévy type noise of small intensity ε > 0. Specifically we consider perturbations leading to a Itô, Stratonovich and canonical (Marcus) stochastic differential equation. The respective asymptotic first exit time and location problem from each of the domains of attractions in case of inward pointing vector fields in the limit of ε-> 0 has been investigated by the authors. We extend these results to domains with characteristic boundaries and show that the perturbed system exhibits a metastable behavior in the sense that there exits a unique ε-dependent time scale on which the random system converges to a continuous time Markov chain switching between the invariant measures. As examples we consider α-stable perturbations of the Duffing equation and a chemical system exhibiting a birhythmic behavior.
We construct a class of elliptic operators in the edge algebra on a manifold M with an embedded submanifold Y interpreted as an edge. The ellipticity refers to a principal symbolic structure consisting of the standard interior symbol and an operator-valued edge symbol. Given a differential operator A on M for every (sufficiently large) s we construct an associated operator As in the edge calculus. We show that ellipticity of A in the usual sense entails ellipticity of As as an edge operator (up to a discrete set of reals s). Parametrices P of A then correspond to parametrices Ps of As, interpreted as Mellin-edge representations of P.
We study maximal subsemigroups of the monoid T(X) of all full transformations on the set X = N of natural numbers containing a given subsemigroup W of T(X), where each element of a given set U is a generator of T(X) modulo W. This note continues the study of maximal subsemigroups of the monoid of all full transformations on an infinite set.
This paper examines and develops matrix methods to approximate the eigenvalues of a fourth order Sturm-Liouville problem subjected to a kind of fixed boundary conditions, furthermore, it extends the matrix methods for a kind of general boundary conditions. The idea of the methods comes from finite difference and Numerov's method as well as boundary value methods for second order regular Sturm-Liouville problems. Moreover, the determination of the correction term formulas of the matrix methods are investigated in order to obtain better approximations of the problem with fixed boundary conditions since the exact eigenvalues for q = 0 are known in this case. Finally, some numerical examples are illustrated.
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.
Amongst the many complex processes taking place in living cells, transport of cargoes across the cytosceleton is fundamental to cell viability and activity. To move cargoes between the different cell parts, cells employ Molecular Motors. The motors operate by transporting cargoes along the so-called cellular micro-tubules, namely rope-like structures that connect, for instance, the cell-nucleus and outer membrane. We introduce a new Markov Chain, the killed Quasi-Random-Walk, for such transport molecules and derive properties like the maximal run length and time. Furthermore we introduce permuted balance, which is a more flexible extension of the ordinary reversibility and introduce the notion of Time Duality, which compares certain passage times pathwise. We give a number of sufficient conditions for Time Duality based on the geometry of the transition graph. Both notions are closely related to properties of the killed Quasi-Random-Walk.
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.
Aus dem Inhalt: Einleitung Kapitel 1. Starke Gesetze der Grossen Zahlen 1. SGGZ unter Wachstumsbedingungen an die p-ten Momente 2. SGGZ für identisch verteilte Zufallsvariablen 3. SGGZ für Prozesse mit *-mixing-Eigenschaft Kapitel 2. Einführung zu diskreten (Sub-,Super-)Martingalen 1. Vorhersagbarkeit 2. gestoppte (Sub-,Super-)Martingale 3. Upcrossings 4. Konvergenzsätze 5. Doob-Zerlegung 6. Eine äquivalente Definition eines (Sub-)Martingals Kapitel 3. Martingale und gleichgradige Integrierbarkeit 1. Gleichmäßige(-f¨ormige,-gradige) Integrierbarkeit 2. gleichgradig integrierbare Martingale Kapitel 4. Martingale und das SGGZ Kapitel 5.”reversed“ (Sub-,Super-)Martingale 1. Konvergenzsätze Kapitel 6. (Sub-,Super-)Martingale mit gerichteter Indexmenge 1. Äquivalente Formulierung eines (Sub-)Martingals 2. Konvergenzsätze Kapitel 7. Quasimartingale,Amarts und Semiamarts 1. Konvergenzsätze 2. Riesz-Zerlegung 3. Doob-Zerlegung Kapitel 8. Amarts und das SGGZ Kapitel 9.”reversed“ Amarts und Semiamarts 1. Konvergenzsätze 2.”Aufwärts“- gegen ”Abwärts“-Adaptiertheit 3. Riesz-Zerlegung 4. Stabilitätsanalyse Kapitel 10. Amarts mit gerichteter Indexmenge 1. Konvergenzsätze 2. Riesz-Zerlegung Anhang A. zur Existenz einer Folge unabhängiger Zufallsvariablen B. Konvergenz
The Ginibre gas is a Poisson point process defined on a space of loops related to the Feynman-Kac representation of the ideal Bose gas. Here we study thermodynamic limits of different ensembles via Martin-Dynkin boundary technique and show, in which way infinitely long loops occur. This effect is the so-called Bose-Einstein condensation.
Let {Tsub(p) : q1 ≤ p ≤ q2} be a family of consistent Csub(0) semigroups on Lφ(Ω) with q1, q2 ∈ [1, ∞)and Ω ⊆ IRn open. We show that certain commutator conditions on Tφ and on the resolvent of its generator Aφ ensure the φ independence of the spectrum of Aφ for φ ∈ [q1, q2]. Applications include the case of Petrovskij correct systems with Hölder continuous coeffcients, Schrödinger operators, and certain elliptic operators in divergence form with real, but not necessarily symmetric, or complex coeffcients.
Content: Introduction 1 Anisotropic operators in a cylinder with a conical base 1.1 Manifolds with conical singularities and opertors of Fuchs type 1.2 Typical operators and symbol structures 2 Weighted wedge Sobolev spaces and edge asymptotics 2.1 Discrete edge asymptotics 2.2 Continuos edge asymptotics with discrete limit at infinity 2.3 Calculus with operator valued symbols 3 Corner asymptotics at infinity 3.1 The structure of singular functions 3.2 Operators with trace and potential conditions 3.3 Asymptotics and (anisotropic) elliptic regularity
This is a survey of recent results concerning the general index locality principle, associated surgery, and their applications to elliptic operators on smooth manifolds and manifolds with singularities as well as boundary value problems. The full version of the paper is submitted for publication in Russian Mathematical Surveys.
We prove the existence of a class of local in time solutions, including static solutions, of the Einstein-Euler system. This result is the relativistic generalisation of a similar result for the Euler-Poisson system obtained by Gamblin [8]. As in his case the initial data of the density do not have compact support but fall off at infinity in an appropriate manner. An essential tool in our approach is the construction and use of weighted Sobolev spaces of fractional order. Moreover, these new spaces allow us to improve the regularity conditions for the solutions of evolution equations. The details of this construction, the properties of these spaces and results on elliptic and hyperbolic equations will be presented in a forthcoming article.
Local asymptotic types
(2002)
A multitype Dawson-Watanabe process is conditioned, in subcritical and critical cases, on non-extinction in the remote future. On every finite time interval, its distribution is absolutely continuous with respect to the law of the unconditioned process. A martingale problem characterization is also given. Several results on the long time behavior of the conditioned mass process - the conditioned multitype Feller branching diffusion - are then proved. The general case is first considered, where the mutation matrix which models the interaction between the types, is irreducible. Several two-type models with decomposable mutation matrices are analyzed too .
A multitype Dawson-Watanabe process is conditioned, in subcritical and critical cases, on non-extinction in the remote future. On every nite time interval, its distribution law is absolutely continuous with respect to the law of the unconditioned process. A martingale problem characterization is also given. The explicit form of the Laplace functional of the conditioned process is used to obtain several results on the long time behaviour of the mass of the conditioned and unconditioned processes. The general case is considered first, where the mutation matrix which modelizes the interaction between the types, is irreducible. Several two-type models with decomposable mutation matrices are also analysed.
Spiele und spieltypische Elemente wie das Sammeln von Treuepunkten sind aus dem Alltag kaum wegzudenken. Zudem werden sie zunehmend in Unternehmen oder in Lernumgebungen eingesetzt. Allerdings ist die Methode Gamification bisher für den pädagogischen Kontext wenig klassifiziert und für Lehrende kaum zugänglich gemacht worden.
Daher zielt diese Bachelorarbeit darauf ab, eine systematische Strukturierung und Aufarbeitung von Gamification sowie innovative Ansätze für die Verwendung spieltypischer Elemente im Unterricht, konkret dem Mathematikunterricht, zu präsentieren. Dies kann eine Grundlage für andere Fachgebiete, aber auch andere Lehrformen bieten und so die Umsetzbarkeit von Gamification in eigenen Lehrveranstaltungen aufzeigen.
In der Arbeit wird begründet, weshalb und mithilfe welcher Elemente Gamification die Motivation und Leistungsbereitschaft der Lernenden langfristig erhöhen, die Sozial- und Personalkompetenzen fördern sowie die Lernenden zu mehr Aktivität anregen kann. Zudem wird Gamification explizit mit grundlegenden mathematikdidaktischen Prinzipien in Verbindung gesetzt und somit die Relevanz für den Mathematikunterricht hervorgehoben.
Anschließend werden die einzelnen Elemente von Gamification wie Punkte, Level, Abzeichen, Charaktere und Rahmengeschichte entlang einer eigens für den pädagogischen Kontext entwickelten Klassifikation „FUN“ (Feedback – User specific elements – Neutral elements) schematisch beschrieben, ihre Funktionen und Wirkung dargestellt sowie Einsatzmöglichkeiten im Unterricht aufgezeigt. Dies beinhaltet Ideen zu lernförderlichem Feedback, Differenzierungsmöglichkeiten und Unterrichtsrahmengestaltung, die in Lehrveranstaltungen aller Art umsetzbar sein können. Die Bachelorarbeit umfasst zudem ein spezifisches Beispiel, einen Unterrichtsentwurf einer gamifizierten Mathematikstunde inklusive des zugehörigen Arbeitsmaterials, anhand dessen die Verwendung von Gamification deutlich wird.
Gamification offeriert oftmals Vorteile gegenüber dem traditionellen Unterricht, muss jedoch wie jede Methode an den Inhalt und die Zielgruppe angepasst werden. Weiterführende Forschung könnte sich mit konkreten motivationalen Strukturen, personenspezifischen Unterschieden sowie mit mathematischen Inhalten wie dem Problemlösen oder dem Wechsel zwischen verschiedenen Darstellungen hinsichtlich gamifizierter Lehrformen beschäftigen.
The aim of this book is to develop the Lefschetz fixed point theory for elliptic complexes of pseudodifferential operators on manifolds with edges. The general Lefschetz theory contains the index theory as a special case, while the case to be studied is much more easier than the index problem. The main topics are: - The calculus of pseudodifferential operators on manifolds with edges, especially symbol structures (inner as well as edge symbols). - The concept of ellipticity, parametrix constructions, elliptic regularity in Sobolev spaces. - Hodge theory for elliptic complexes of pseudodifferential operators on manifolds with edges. - Development of the algebraic constructions for these complexes, such as homotopy, tensor products, duality. - A generalization of the fixed point formula of Atiyah and Bott for the case of simple fixed points. - Development of the fixed point formula also in the case of non-simple fixed points, provided that the complex consists of diferential operarators only. - Investigation of geometric complexes (such as, for instance, the de Rham complex and the Dolbeault complex). Results in this direction are desirable because of both purely mathe matical reasons and applications in natural sciences.
Large emissions
(2020)
In der dualen IT-Ausbildung als Verbindung von beruflicher und akademischer Qualifikation werden die berufstypischen Werkzeuge, wie z. B. Laptops, ebenso in den Lehr-Lern-Prozessen der akademischen Unterrichtseinheiten eingesetzt. Im Prüfungswesen wird oft auf klassische Papierklausuren zurückgegriffen. Unterrichtseinheiten mit hohem Blended-Learning-Anteil ohne E-Prüfung werden dabei als „nicht konsistent“ wahrgenommen. In diesem Artikel wird eine empirische Studie dargelegt, die untersucht, welche Einflüsse aus der persönlichen Lernbiografie bei den Lehrenden in einer dualen IT-Ausbildung dazu führen können, die Möglichkeiten eines E-Assessments als summative Modulprüfung anzunehmen oder abzulehnen. Beispielhaft wurden in der dargelegten Studie Interviews mit Dozenten geführt und diese hinsichtlich der Verbindung zwischen Lernbiografie, Gestaltung der Didaktik der Lehr-Lern-Prozesse, Zufriedenheit und Veränderungsbereitschaft untersucht.
Function spaces with asymptotics is a usual tool in the analysis on manifolds with singularities. The asymptotics are singular ingredients of the kernels of pseudodifferential operators in the calculus. They correspond to potentials supported by the singularities of the manifold, and in this form asymptotics can be treated already on smooth configurations. This paper is aimed at describing refined asymptotics in the Dirichlet problem in a ball. The beauty of explicit formulas highlights the structure of asymptotic expansions in the calculi on singular varieties.
Let Hsub(0), Hsub(1) be Hilbert spaces and L : Hsub(0) -> Hsub(1) be a linear bounded operator with ||L|| ≤ 1. Then L*L is a bounded linear self-adjoint non-negative operator in the Hilbert space Hsub(0) and one can use the Neumann series ∑∞sub(v=0)(I - L*L)v L*f in order to study solvability of the operator equation Lu = f. In particular, applying this method to the ill-posed Cauchy problem for solutions to an elliptic system Pu = 0 of linear PDE's of order p with smooth coefficients we obtain solvability conditions and representation formulae for solutions of the problem in Hardy spaces whenever these solutions exist. For the Cauchy-Riemann system in C the summands of the Neumann series are iterations of the Cauchy type integral. We also obtain similar results 1) for the equation Pu = f in Sobolev spaces, 2) for the Dirichlet problem and 3) for the Neumann problem related to operator P*P if P is a homogeneous first order operator and its coefficients are constant. In these cases the representations involve sums of series whose terms are iterations of integro-differential operators, while the solvability conditions consist of convergence of the series together with trivial necessary conditions.
In this paper, we develop the mathematical tools needed to explore isotopy classes of tilings on hyperbolic surfaces of finite genus, possibly nonorientable, with boundary, and punctured. More specifically, we generalize results on Delaney-Dress combinatorial tiling theory using an extension of mapping class groups to orbifolds, in turn using this to study tilings of covering spaces of orbifolds. Moreover, we study finite subgroups of these mapping class groups. Our results can be used to extend the Delaney-Dress combinatorial encoding of a tiling to yield a finite symbol encoding the complexity of an isotopy class of tilings. The results of this paper provide the basis for a complete and unambiguous enumeration of isotopically distinct tilings of hyperbolic surfaces.
It is shown that the Hankel transformation Hsub(v) acts in a class of weighted Sobolev spaces. Especially, the isometric mapping property of Hsub(v) which holds on L²(IRsub(+),rdr) is extended to spaces of arbitrary Sobolev order. The novelty in the approach consists in using techniques developed by B.-W. Schulze and others to treat the half-line Rsub(+) as a manifold with a conical singularity at r = 0. This is achieved by pointing out a connection between the Hankel transformation and the Mellin transformation.The procedure proposed leads at the same time to a short proof of the Hankel inversion formula. An application to the existence and higher regularity of solutions, including their asymptotics, to the 1-1-dimensional edge-degenerated wave equation is given.
This thesis aims at presenting in an organized fashion the required basics to understand the Glauber dynamics as a way of simulating configurations according to the Gibbs distribution of the Curie-Weiss Potts model. Therefore, essential aspects of discrete-time Markov chains on a finite state space are examined, especially their convergence behavior and related mixing times. Furthermore, special emphasis is placed on a consistent and comprehensive presentation of the Curie-Weiss Potts model and its analysis. Finally, the Glauber dynamics is studied in general and applied afterwards in an exemplary way to the Curie-Weiss model as well as the Curie-Weiss Potts model. The associated considerations are supplemented with two computer simulations aiming to show the cutoff phenomenon and the temperature dependence of the convergence behavior.
The present lecture notes aim for an introduction to the ergodic behaviour of Markov Processes and addresses graduate students, post-graduate students and interested readers.
Different tools and methods for the study of upper bounds on uniform and weak ergodic rates of Markov Processes are introduced. These techniques are then applied to study limit theorems for functionals of Markov processes.
This lecture course originates in two mini courses held at University of Potsdam, Technical University of Berlin and Humboldt University in spring 2013 and Ritsumameikan University in summer 2013.
Alexei Kulik, Doctor of Sciences, is a Leading researcher at the Institute of Mathematics of Ukrainian National Academy of Sciences.
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.
Integral Fourier operators
(2017)
This volume of contributions based on lectures delivered at a school on Fourier Integral Operators
held in Ouagadougou, Burkina Faso, 14–26 September 2015, provides an introduction to Fourier Integral Operators (FIO) for a readership of Master and PhD students as well as any interested layperson. Considering the wide
spectrum of their applications and the richness of the mathematical tools they involve, FIOs lie the cross-road of many a field. This volume offers
the necessary background, whether analytic or geometric, to get acquainted with FIOs, complemented by more advanced material presenting various aspects of active research in that area.
We consider an infinite system of non overlaping globules undergoing Brownian motions in R3. The term globules means that the objects we are dealing with are spherical, but with a radius which is random and time-dependent. The dynamics is modelized by an infinitedimensional Stochastic Differential Equation with local time. Existence and uniqueness of a strong solution is proven for such an equation with fixed deterministic initial condition. We also find a class of reversible measures.
We consider a system of infinitely many hard balls in Rd undergoing Brownian motions and submitted to a smooth pair potential. It is modelized by an infinite-dimensional Stochastic Differential Equation with a local time term. We prove that the set of all equilibrium measures, solution of a Detailed Balance Equation, coincides with the set of canonical Gibbs measures associated to the hard core potential added to the smooth interaction potential.
We consider a system of infinitely many hard balls in R<sup>d undergoing Brownian motions and submitted to a smooth pair potential. It is modelized by an infinite-dimensional stochastic differential equation with a local time term. We prove that the set of all equilibrium measures, solution of a detailed balance equation, coincides with the set of canonical Gibbs measures associated to the hard core potential added to the smooth interaction potential.
The paper deals with elliptic theory on manifolds with boundary represented as a covering space. We compute the index for a class of nonlocal boundary value problems. For a nontrivial covering, the index defect of the Atiyah-Patodi-Singer boundary value problem is computed. We obtain the Poincaré duality in the K-theory of the corresponding manifolds with singularities.
We give a necessary and sufficient condition for the existence of an increasing coupling of N (N >= 2) synchronous dynamics on S-Zd (PCA). Increasing means the coupling preserves stochastic ordering. We first present our main construction theorem in the case where S is totally ordered; applications to attractive PCAs are given. When S is only partially ordered, we show on two examples that a coupling of more than two synchronous dynamics may not exist. We also prove an extension of our main result for a particular class of partially ordered spaces.
We give a necessary and sufficient condition for the existence of an increasing coupling of N (N >= 2) synchronous dynamics on S-Zd (PCA). Increasing means the coupling preserves stochastic ordering. We first present our main construction theorem in the case where S is totally ordered; applications to attractive PCAs are given. When S is only partially ordered, we show on two examples that a coupling of more than two synchronous dynamics may not exist. We also prove an extension of our main result for a particular class of partially ordered spaces.
We study the approach to the theory of hypergeometric functions in several variables via a generalization of the Horn system of differential equations. A formula for the dimension of its solution space is given. Using this formula we construct an explicit basis in the space of holomorphic solutions to the generalized Horn system under some assumptions on its parameters. These results are applied to the problem of describing the complement of the amoeba of a rational function, which was posed in [12].
Our work goes in two directions. At first we want to transfer definitions, concepts and results of the theory of hyperidentities and solid varieties from the total to the partial case. (1) We prove that the operators chi^A_RNF and chi^E_RNF are only monotone and additive and we show that the sets of all fixed points of these operators are characterized only by three instead of four equivalent conditions for the case of closure operators. (2) We prove that V is n − SF-solid iff clone^SF V is free with respect to itself, freely generated by the independent set {[fi(x_1, . . . , x_n)]Id^SF_n V | i \in I}. (3) We prove that if V is n-fluid and ~V |P(V ) =~V −iso |P(V ) then V is kunsolid for k >= n (where P(V ) is the set of all V -proper hypersubstitutions of type \tau ). (4) We prove that a strong M-hyperquasi-equational theory is characterized by four equivalent conditions. The second direction of our work is to follow ideas which are typical for the partial case. (1) We characterize all minimal partial clones which are strongly solidifyable. (2)We define the operator Chi^A_Ph where Ph is a monoid of regular partial hypersubstitutions.Using this concept, we define the concept of a Phyp_R(\tau )-solid strong regular variety of partial algebras and we prove that a PHyp_R(\tau )-solid strong regular variety satisfies four equivalent conditions.
This thesis is concerned with Data Assimilation, the process of combining model predictions with observations. So called filters are of special interest. One is inter- ested in computing the probability distribution of the state of a physical process in the future, given (possibly) imperfect measurements. This is done using Bayes’ rule. The first part focuses on hybrid filters, that bridge between the two main groups of filters: ensemble Kalman filters (EnKF) and particle filters. The first are a group of very stable and computationally cheap algorithms, but they request certain strong assumptions. Particle filters on the other hand are more generally applicable, but computationally expensive and as such not always suitable for high dimensional systems. Therefore it exists a need to combine both groups to benefit from the advantages of each. This can be achieved by splitting the likelihood function, when assimilating a new observation and treating one part of it with an EnKF and the other part with a particle filter.
The second part of this thesis deals with the application of Data Assimilation to multi-scale models and the problems that arise from that. One of the main areas of application for Data Assimilation techniques is predicting the development of oceans and the atmosphere. These processes involve several scales and often balance rela- tions between the state variables. The use of Data Assimilation procedures most often violates relations of that kind, which leads to unrealistic and non-physical pre- dictions of the future development of the process eventually. This work discusses the inclusion of a post-processing step after each assimilation step, in which a minimi- sation problem is solved, which penalises the imbalance. This method is tested on four different models, two Hamiltonian systems and two spatially extended models, which adds even more difficulties.
The classical Lefschetz fixed point formula expresses the number of fixed points of a continuous map f : M -> M in terms of the transformation induced by f on the cohomology of M. In 1966 Atiyah and Bott extended this formula to elliptic complexes over a compact closed manifold. In particular, they presented a holomorphic Lefschtz formula for compact complex manifolds without boundary, a result, in the framework of algebraic geometry due to Eichler (1957) for holomorphic curves. On compact complex manifolds with boundary the Dolbeault complex is not elliptic, hence the Atiyah-Bott theory is no longer applicable. To get rid of the difficulties related to the boundary behaviour of the Dolbeault cohomology, Donelli and Fefferman (1986) derived a fixed point formula for the Bergman metric. The purpose of this paper is to present a holomorphic Lefschtz formula on a compact complex manifold with boundary
The first main goal of this thesis is to develop a concept of approximate differentiability of higher order for subsets of the Euclidean space that allows to characterize higher order rectifiable sets, extending somehow well known facts for functions. We emphasize that for every subset A of the Euclidean space and for every integer k ≥ 2 we introduce the approximate differential of order k of A and we prove it is a Borel map whose domain is a (possibly empty) Borel set. This concept could be helpful to deal with higher order rectifiable sets in applications.
The other goal is to extend to general closed sets a well known theorem of Alberti on the second order rectifiability properties of the boundary of convex bodies. The Alberti theorem provides a stratification of second order rectifiable subsets of the boundary of a convex body based on the dimension of the (convex) normal cone. Considering a suitable generalization of this normal cone for general closed subsets of the Euclidean space and employing some results from the first part we can prove that the same stratification exists for every closed set.
Harness-Prozesse
(2010)
Harness-Prozesse finden in der Forschung immer mehr Anwendung. Vor allem gewinnen Harness-Prozesse in stetiger Zeit an Bedeutung. Grundlegende Literatur zu diesem Thema ist allerdings wenig vorhanden. In der vorliegenden Arbeit wird die vorhandene Grundlagenliteratur zu Harness-Prozessen in diskreter und stetiger Zeit aufgearbeitet und Beweise ausgeführt, die bisher nur skizziert waren. Ziel dessen ist die Existenz einer Zerlegung von Harness-Prozessen über Z beziehungsweise R+ nachzuweisen.
We study the Neumann problem for the de Rham complex in a bounded domain of Rn with singularities on the boundary. The singularities may be general enough, varying from Lipschitz domains to domains with cuspidal edges on the boundary. Following Lopatinskii we reduce the Neumann problem to a singular integral equation of the boundary. The Fredholm solvability of this equation is then equivalent to the Fredholm property of the Neumann problem in suitable function spaces. The boundary integral equation is explicitly written and may be treated in diverse methods. This way we obtain, in particular, asymptotic expansions of harmonic forms near singularities of the boundary.