TY - JOUR A1 - Schulze, Bert-Wolfgang A1 - Seiler, Jörg T1 - Elliptic complexes on manifolds with boundary JF - The journal of geometric analysis N2 - We show that elliptic complexes of (pseudo) differential operators on smooth compact manifolds with boundary can always be complemented to a Fredholm problem by boundary conditions involving global pseudodifferential projections on the boundary (similarly as the spectral boundary conditions of Atiyah, Patodi, and Singer for a single operator). We prove that boundary conditions without projections can be chosen if, and only if, the topological Atiyah-Bott obstruction vanishes. These results make use of a Fredholm theory for complexes of operators in algebras of generalized pseudodifferential operators of Toeplitz type which we also develop in the present paper. KW - Elliptic complexes KW - Manifolds with boundary KW - Atiyah-Bott obstruction KW - Toeplitz-type pseudodifferential operators Y1 - 2018 U6 - https://doi.org/10.1007/s12220-018-0014-6 SN - 1050-6926 SN - 1559-002X VL - 29 IS - 1 SP - 656 EP - 706 PB - Springer CY - New York ER - TY - JOUR A1 - Biskaborn, Boris A1 - Smith, Sharon L. A1 - Noetzli, Jeannette A1 - Matthes, Heidrun A1 - Vieira, Goncalo A1 - Streletskiy, Dmitry A. A1 - Schoeneich, Philippe A1 - Romanovsky, Vladimir E. A1 - Lewkowicz, Antoni G. A1 - Abramov, Andrey A1 - Allard, Michel A1 - Boike, Julia A1 - Cable, William L. A1 - Christiansen, Hanne H. A1 - Delaloye, Reynald A1 - Diekmann, Bernhard A1 - Drozdov, Dmitry A1 - Etzelmueller, Bernd A1 - Grosse, Guido A1 - Guglielmin, Mauro A1 - Ingeman-Nielsen, Thomas A1 - Isaksen, Ketil A1 - Ishikawa, Mamoru A1 - Johansson, Margareta A1 - Johannsson, Halldor A1 - Joo, Anseok A1 - Kaverin, Dmitry A1 - Kholodov, Alexander A1 - Konstantinov, Pavel A1 - Kroeger, Tim A1 - Lambiel, Christophe A1 - Lanckman, Jean-Pierre A1 - Luo, Dongliang A1 - Malkova, Galina A1 - Meiklejohn, Ian A1 - Moskalenko, Natalia A1 - Oliva, Marc A1 - Phillips, Marcia A1 - Ramos, Miguel A1 - Sannel, A. Britta K. A1 - Sergeev, Dmitrii A1 - Seybold, Cathy A1 - Skryabin, Pavel A1 - Vasiliev, Alexander A1 - Wu, Qingbai A1 - Yoshikawa, Kenji A1 - Zheleznyak, Mikhail A1 - Lantuit, Hugues T1 - Permafrost is warming at a global scale JF - Nature Communications N2 - Permafrost warming has the potential to amplify global climate change, because when frozen sediments thaw it unlocks soil organic carbon. Yet to date, no globally consistent assessment of permafrost temperature change has been compiled. Here we use a global data set of permafrost temperature time series from the Global Terrestrial Network for Permafrost to evaluate temperature change across permafrost regions for the period since the International Polar Year (2007-2009). During the reference decade between 2007 and 2016, ground temperature near the depth of zero annual amplitude in the continuous permafrost zone increased by 0.39 +/- 0.15 degrees C. Over the same period, discontinuous permafrost warmed by 0.20 +/- 0.10 degrees C. Permafrost in mountains warmed by 0.19 +/- 0.05 degrees C and in Antarctica by 0.37 +/- 0.10 degrees C. Globally, permafrost temperature increased by 0.29 +/- 0.12 degrees C. The observed trend follows the Arctic amplification of air temperature increase in the Northern Hemisphere. In the discontinuous zone, however, ground warming occurred due to increased snow thickness while air temperature remained statistically unchanged. Y1 - 2019 U6 - https://doi.org/10.1038/s41467-018-08240-4 SN - 2041-1723 VL - 10 PB - Nature Publ. Group CY - London ER - TY - BOOK ED - Kuzle, Ana ED - Rott, Benjamin ED - Gebel, Inga T1 - Implementation research on problem solving in school settings BT - Proceedings of the 2018 Joint Conference of ProMath and the GDM Working Group on Problem Solving T3 - Ars inveniendi et dejudicandi ; 13 Y1 - 2019 SN - 978-3-95987-116-7 SN - 978-3-95987-115-0 PB - WTM-Verlag CY - Münster ER - TY - GEN A1 - Krause, Andreas A1 - Kloft, Charlotte A1 - Huisinga, Wilhelm A1 - Karlsson, Mats A1 - Pinheiro, José A1 - Bies, Robert A1 - Rogers, James A1 - Mentré, France A1 - Musser, Bret J. T1 - Comment on Jaki et al., A proposal for a new PhD level curriculum on quantitative methods for drug development T2 - Pharmaceutical statistics : the journal of applied statistics in the pharmaceutical industry Y1 - 2019 SN - 1539-1604 SN - 1539-1612 VL - 18 IS - 3 SP - 278 EP - 281 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Edlund, Helena A1 - Grisic, Ana-Marija A1 - Steenholdt, Casper A1 - Ainsworth, Mark Andrew A1 - Brynskov, Torn A1 - Huisinga, Wilhelm A1 - Kloft, Charlotte T1 - Absence of Relationship Between Crohn's Disease Activity Index or C-Reactive Protein and Infliximab Exposure Calls for Objective Crohn's Disease Activity Measures for the Evaluation of Treatment Effects at Treatment Failure JF - Therapeutic drug monitoring : official journal of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology N2 - Background: Circulating infliximab (IFX) concentrations correlate with clinical outcomes, forming the basis of the IFX concentration monitoring in patients with Crohn's disease. This study aims to investigate and refine the exposure-response relationship by linking the disease activity markers "Crohn's disease activity index" (CDAI) and C-reactive protein (CRP) to IFX exposure. In addition, we aim to explore the correlations between different disease markers and exposure metrics. Methods: Data from 47 Crohn's disease patients of a randomized controlled trial were analyzed post hoc. All patients had secondary treatment failure at inclusion and had received intensified IFX of 5 mg/kg every 4 weeks for up to 20 weeks. Graphical analyses were performed to explore exposure-response relationships. Metrics of exposure included area under the concentration-time curve (AUC) and trough concentrations (Cmin). Disease activity was measured by CDAI and CRP values, their change from baseline/last visit, and response/remission outcomes at week 12. Results: Although trends toward lower Cmin and lower AUC in nonresponders were observed, neither CDAI nor CRP showed consistent trends of lower disease activity with higher IFX exposure across the 30 evaluated relationships. As can be expected, Cmin and AUC were strongly correlated with each other. Contrarily, the disease activity markers were only weakly correlated with each other. Conclusions: No significant relationship between disease activity, as evaluated by CDAI or CRP, and IFX exposure was identified. AUC did not add benefit compared with Cmin. These findings support the continued use of Cmin and call for stringent objective disease activity (bio-)markers (eg, endoscopy) to form the basis of personalized IFX therapy for Crohn's disease patients with IFX treatment failure. Y1 - 2019 U6 - https://doi.org/10.1097/FTD.0000000000000590 SN - 0163-4356 SN - 1536-3694 VL - 41 IS - 2 SP - 235 EP - 242 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - THES A1 - Knöchel, Jane T1 - Model reduction of mechanism-based pharmacodynamic models and its link to classical drug effect models T1 - Modellreduktion von mechanistischen pharmacodynamischen Modellen und deren Verbindung zu klassischen Wirkstoff-Effekt-Modellen N2 - Continuous insight into biological processes has led to the development of large-scale, mechanistic systems biology models of pharmacologically relevant networks. While these models are typically designed to study the impact of diverse stimuli or perturbations on multiple system variables, the focus in pharmacological research is often on a specific input, e.g., the dose of a drug, and a specific output related to the drug effect or response in terms of some surrogate marker. To study a chosen input-output pair, the complexity of the interactions as well as the size of the models hinders easy access and understanding of the details of the input-output relationship. The objective of this thesis is the development of a mathematical approach, in specific a model reduction technique, that allows (i) to quantify the importance of the different state variables for a given input-output relationship, and (ii) to reduce the dynamics to its essential features -- allowing for a physiological interpretation of state variables as well as parameter estimation in the statistical analysis of clinical data. We develop a model reduction technique using a control theoretic setting by first defining a novel type of time-limited controllability and observability gramians for nonlinear systems. We then show the superiority of the time-limited generalised gramians for nonlinear systems in the context of balanced truncation for a benchmark system from control theory. The concept of time-limited controllability and observability gramians is subsequently used to introduce a state and time-dependent quantity called the input-response (ir) index that quantifies the importance of state variables for a given input-response relationship at a particular time. We subsequently link our approach to sensitivity analysis, thus, enabling for the first time the use of sensitivity coefficients for state space reduction. The sensitivity based ir-indices are given as a product of two sensitivity coefficients. This allows not only for a computational more efficient calculation but also for a clear distinction of the extent to which the input impacts a state variable and the extent to which a state variable impacts the output. The ir-indices give insight into the coordinated action of specific state variables for a chosen input-response relationship. Our developed model reduction technique results in reduced models that still allow for a mechanistic interpretation in terms of the quantities/state variables of the original system, which is a key requirement in the field of systems pharmacology and systems biology and distinguished the reduced models from so-called empirical drug effect models. The ir-indices are explicitly defined with respect to a reference trajectory and thereby dependent on the initial state (this is an important feature of the measure). This is demonstrated for an example from the field of systems pharmacology, showing that the reduced models are very informative in their ability to detect (genetic) deficiencies in certain physiological entities. Comparing our novel model reduction technique to the already existing techniques shows its superiority. The novel input-response index as a measure of the importance of state variables provides a powerful tool for understanding the complex dynamics of large-scale systems in the context of a specific drug-response relationship. Furthermore, the indices provide a means for a very efficient model order reduction and, thus, an important step towards translating insight from biological processes incorporated in detailed systems pharmacology models into the population analysis of clinical data. N2 - Die kontinuierliche Erforschung von biologischen Prozessen hat zur Entwicklung umfangreicher, mechanistischer systembiologischer Modelle von pharmakologisch relevanten Netzwerken beigetragen. Während diese Modelle in der Regel darauf ausgelegt sind, die Auswirkung von Stimuli oder Störungen auf die Systemdynamik zu untersuchen, liegt der Fokus in der pharmakologis- chen Forschung häufig auf einer bestimmten Kontrolle, z.B. der Dosis eines Wirkstoffes, und einer bestimmten Ausgangsgröße, welche in Bezug steht zu dem Wirkstoff-Effekt oder das Ansprechen auf einen Wirkstoff über einen Surrogatmarker. Die Untersuchung und ein einfaches Verständnis einer spezifischen Eingabe-Ausgabe-Beziehung wird durch die Komplexität der Interaktionen sowie der Größe des Modells erschwert. Das Ziel dieser vorliegenden Arbeit ist die Entwicklung eines mathematischen Ansatzes, insbesondere eines Modellreduktionsverfahrens, der es ermöglicht, (i) die Bedeutung der verschiedenen Zustandsvariablen für eine gegebene Eingabe-Ausgabe-Beziehung zu quantifizieren, und (ii) die Dynamik des Systems auf seine wesentlichen Merkmale zu reduzieren, während gleichzeitig die physiologische Interpretierbarkeit von Zustandsvariablen sowie eine Parameterschätzung im Rahmen von einer statistischen Analyse klinischer Daten ermöglicht wird. Unter Verwendung eines kontrolltheoretischen Settings entwickeln wir eine Modellreduktionstechnik, indem wir vorerst einen neuartigen Typ von zeitlich begrenzten Kontrolllierbarkeits- und Beobachtbarkeitsgramian für nichtlineare Systeme definieren. Anschließend zeigen wir die Überlegenkeit der zeitlich begrenzten verallgemeinerten Gramian für nichtlineare Systeme im Kontext von Balanced Truncation am Beispiel eines Benchmark-Systems aus der Kontrolltheorie. Wir nutzten das Konzept der zeitlich begrenzten Kontrolllierbarkeits- und Beobachtbarkeitsgramian, um eine neue Zustands- und zeitabhängige Größe, die als Input-Response (IR-) Index bezeichnet wird, einzuführen. Dieser Index quantifiziert die Bedeutung von Zustandsvariablen zu einem bestimmten Zeitpunkt für eine bestimmte Eingabe-Ausgabe-Beziehung. Schließlich verknüpfen wir unseren Ansatz mit der Sensitivitätsanalyse und ermöglichen so erstmals die Verwendung von Sensitivitätskoeffizienten im Rahmen der Reduktion des Zustandsraumes. Wir erhalten die sensitivitätsbasierten IR-Indizes als Produkt zweier Sensitivitätskoeffizienten. Dies ermöglicht nicht nur eine effizientere Berechnung, sondern auch eine klare Unterscheidung, inwieweit die Eingabe eine Zustandsvariable beeinflusst und inwieweit eine Zustandsvariable die Ausgabe beeinflusst. Mit Hilfe der IR-Indizes erhalten wir einen Einblick in den koordinierten Ablauf der Aktivierung von spezifischen Zustandsvariablen für eine ausgewählte Eingabe-Ausgabe-Beziehung. Unser entwickeltes Modellreduktionsverfahren resultiert in reduzierten Modelle, welche eine mechanistische Interpretation hinsichtlich der Originalgrößen und Zustandsvariablen des Ursprungssystems zulassen. Dies war eine wichtige Anforderung an das Verfahren von Seiten der Systempharmakologie und -biologie. Die reduzierten Modelle unterscheiden sich damit wesentlich von den so genannten empirischen Wirkstoff-Effekt-Modellen. Die IR-Indizes sind explizit in Bezug auf eine Referenzlösung definiert und damit vom Anfangszustand abhängig (dies ist ein wichtiges Merkmal der Indizes). Wir zeigen anhand eines Beispiels aus dem Bereich der Systempharmakologie, dass die reduzierten Modelle sehr aussagekräftig sind, um (genetische) Mängel in bestimmten physiologischen Einheiten festzustellen. Der Vergleich unseres neuartigen Modellreduktionsverfahrens mit den bereits vorhandenen Verfahren zeigt dessen Überlegenheit. Der neuartige IR-Index als Maß für die Wichtigkeit von Zustandsvariablen bietet ein leistungsfähiges mathematisches Werkzeug zum Verständnis und der Analyse der komplexen Dynamik von großen Systemen im Kontext einer bestimmten Wirkstoff-Effekt-Beziehung. Darüber hinaus sind die Indizes eine wichtige Grundlage für das eingeführte und sehr effiziente Modellreduktionsverfahren. Insgesamt stellt dies einen wichtigen Schritt zur Nutzung von Erkenntnissen über biologische Prozesse in Form von detaillierten systempharmakologischen Modellen in der Populationsanalyse klinischer Daten dar. KW - model order reduction KW - control theory KW - large-scale mechanistic systems KW - systems pharmacology KW - Modellreduktion KW - Kontrolltheorie KW - komplexe mechanistische Systeme KW - Systempharmakologie Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-440598 ER - TY - JOUR A1 - Kucharski, Maciej A1 - Ergintav, Arzu A1 - Ahmad, Wael Abdullah A1 - Krstić, Miloš A1 - Ng, Herman Jalli A1 - Kissinger, Dietmar T1 - A Scalable 79-GHz Radar Platform Based on Single-Channel Transceivers JF - IEEE Transactions on Microwave Theory and Techniques N2 - This paper presents a scalable E-band radar platform based on single-channel fully integrated transceivers (TRX) manufactured using 130-nm silicon-germanium (SiGe) BiCMOS technology. The TRX is suitable for flexible radar systems exploiting massive multiple-input-multipleoutput (MIMO) techniques for multidimensional sensing. A fully integrated fractional-N phase-locked loop (PLL) comprising a 39.5-GHz voltage-controlled oscillator is used to generate wideband frequency-modulated continuous-wave (FMCW) chirp for E-band radar front ends. The TRX is equipped with a vector modulator (VM) for high-speed carrier modulation and beam-forming techniques. A single TRX achieves 19.2-dBm maximum output power and 27.5-dB total conversion gain with input-referred 1-dB compression point of -10 dBm. It consumes 220 mA from 3.3-V supply and occupies 3.96 mm(2) silicon area. A two-channel radar platform based on full-custom TRXs and PLL was fabricated to demonstrate high-precision and high-resolution FMCW sensing. The radar enables up to 10-GHz frequency ramp generation in 74-84-GHz range, which results in 1.5-cm spatial resolution. Due to high output power, thus high signal-to-noise ratio (SNR), a ranging precision of 7.5 mu m for a target at 2 m was achieved. The proposed architecture supports scalable multichannel applications for automotive FMCW using a single local oscillator (LO). KW - Automotive KW - E-band KW - frequency-modulated continuous-wave (FMCW) KW - patch antenna KW - phase-locked loop (PLL) KW - power amplifier (PA) KW - radar KW - scalable KW - transceiver (TRX) Y1 - 2019 U6 - https://doi.org/10.1109/TMTT.2019.2914104 SN - 0018-9480 SN - 1557-9670 VL - 67 IS - 9 SP - 3882 EP - 3896 PB - Inst. of Electr. and Electronics Engineers CY - Piscataway ER - TY - JOUR A1 - Gerlach, Moritz Reinhardt A1 - Glück, Jochen T1 - Convergence of positive operator semigroups JF - Transactions of the American Mathematical Society N2 - We present new conditions for semigroups of positive operators to converge strongly as time tends to infinity. Our proofs are based on a novel approach combining the well-known splitting theorem by Jacobs, de Leeuw, and Glicksberg with a purely algebraic result about positive group representations. Thus, we obtain convergence theorems not only for one-parameter semigroups but also for a much larger class of semigroup representations. Our results allow for a unified treatment of various theorems from the literature that, under technical assumptions, a bounded positive C-0-semigroup containing or dominating a kernel operator converges strongly as t ->infinity. We gain new insights into the structure theoretical background of those theorems and generalize them in several respects; especially we drop any kind of continuity or regularity assumption with respect to the time parameter. KW - Positive semigroups KW - semigroup representations KW - asymptotic behavior KW - kernel operator Y1 - 2019 U6 - https://doi.org/10.1090/tran/7836 SN - 0002-9947 SN - 1088-6850 VL - 372 IS - 9 SP - 6603 EP - 6627 PB - American Mathematical Soc. CY - Providence ER - TY - JOUR A1 - Edeko, Nikolai A1 - Gerlach, Moritz Reinhardt A1 - Kühner, Viktoria T1 - Measure-preserving semiflows and one-parameter Koopman semigroups JF - Semigroup forum N2 - For a finite measure space X, we characterize strongly continuous Markov lattice semigroups on Lp(X) by showing that their generator A acts as a derivation on the dense subspace D(A)L(X). We then use this to characterize Koopman semigroups on Lp(X) if X is a standard probability space. In addition, we show that every measurable and measure-preserving flow on a standard probability space is isomorphic to a continuous flow on a compact Borel probability space. KW - Measure-preserving semiflow KW - Koopman semigroup KW - Derivation KW - Topological model Y1 - 2019 U6 - https://doi.org/10.1007/s00233-018-9960-3 SN - 0037-1912 SN - 1432-2137 VL - 98 IS - 1 SP - 48 EP - 63 PB - Springer CY - New York ER - TY - JOUR A1 - Gerlach, Moritz Reinhardt A1 - Glück, Jochen T1 - Mean ergodicity vs weak almost periodicity JF - Studia mathematica N2 - We provide explicit examples of positive and power-bounded operators on c(0) and l(infinity) which are mean ergodic but not weakly almost periodic. As a consequence we prove that a countably order complete Banach lattice on which every positive and power-bounded mean ergodic operator is weakly almost periodic is necessarily a KB-space. This answers several open questions from the literature. Finally, we prove that if T is a positive mean ergodic operator with zero fixed space on an arbitrary Banach lattice, then so is every power of T . KW - positive operators KW - weakly almost periodic KW - order continuous norm KW - KB-space KW - mean ergodic Y1 - 2019 U6 - https://doi.org/10.4064/sm170918-20-3 SN - 0039-3223 SN - 1730-6337 VL - 248 IS - 1 SP - 45 EP - 56 PB - Polska Akademia Nauk, Instytut Matematyczny CY - Warszawa ER -