Application and Development of Computational Methods for Ligand-Based Virtual Screening

The detection of novel active compounds that are able to modulate the biological function of a target is the primary goal of drug discovery. Different screening methods are available to identify hit compounds having the desired bioactivity in a large collection of molecules. As a computational method, virtual screening (VS) is used to search compound libraries in silico and identify those compounds that are likely to exhibit a specific activity. Ligand-based virtual screening (LBVS) is a subdiscipline that uses the information of one or more known active compounds in order to identify new hit compounds. Different LBVS methods exist, e.g. similarity searching and support vector machines (SVMs). In order to enable the application of these computational approaches, compounds have to be described numerically. Fingerprints derived from the two-dimensional compound structure, called 2D fingerprints, are among the most popular molecular descriptors available. This thesis covers the usage of 2D fingerprints in the context of LBVS. The first part focuses on a detailed analysis of 2D fingerprints. Their performance range against a wide range of pharmaceutical targets is globally estimated through fingerprint-based similarity searching. Additionally, mechanisms by which fingerprints are capable of detecting structurally diverse active compounds are identified. For this purpose, two different feature selection methods are applied to find those fingerprint features that are most relevant for the active compounds and distinguish them from other compounds. Then, 2D fingerprints are used in SVM calculations. The SVM methodology provides several opportunities to include additional information about the compounds in order to direct LBVS search calculations. In a first step, a variant of the SVM approach is applied to the multi-class prediction problem involving compounds that are active against several related targets. SVM linear combination is used to recover compounds with desired activity profiles and deprioritize compounds with other activities. Then, the SVM methodology is adopted for potency-directed VS. Compound potency is incorporated into the SVM approach through potencyoriented SVM linear combination and kernel function design to direct search calculations to the preferential detection of potent hit compounds. Next, SVM calculations are applied to address an intrinsic limitation of similarity-based methods, i.e., the presence of similar compounds having large differences in their potency. An especially designed SVM approach is introduced to predict compound pairs forming such activity cliffs. Finally, the impact of different training sets on the recall performance of SVM-based VS is analyzed and caveats are identified

Linking maternal warmth and responsiveness to children's self-regulation

The present study demonstrated that a more differentiated view of positive parenting practices is necessary in the study of children's acquisition of self-regulation. Here, the unique contributions of maternal warmth and responsiveness to distress to children's self-regulation were tested in a sample of 102 German mothers and their kindergarten children (51 girls and 51 boys). Behavior regulation and internalization of rules of conduct were examined as specific components of children's self-regulation. As expected, maternal warmth was positively related to the child's behavior regulation. Responsiveness to distress was positively linked to the child's internalization of rules of conduct. No significant interactions between maternal parenting and either the child's gender or effortful control were found. The results are discussed with regard to the unique functions that different parenting practices have for children's self-regulation

Developmental Aspects of Self-Regulation in Germany and Chile: Links among Maternal Warmth, Children’s Self-Regulation, and Social Competence

The present study investigated relations among maternal warmth, children’s self-regulation (i.e., behavior and emotion regulation), and prosocial behavior. The assumed relations were studied in Germany and Chile, two socialization contexts differing in socio-economic and cultural factors. The sample consisted of 76 German and 167 Chilean fourth graders, their mothers, and teachers. Maternal warmth was rated by mothers with the Parenting Practice Questionnaire (PPQ). Children reported the use of emotion regulation strategies on the Questionnaire for the Measurement of Stress and Coping in Children and Adolescents (SSKJ 3-8). Mothers’ and teachers’ ratings on the Strengths and Difficulties Questionnaire (SDQ) were used to measure children’s behavior regulation and prosocial behavior. Regression analyses revealed positive relations of maternal warmth to children’s problem-oriented emotion regulation and of behavior regulation to prosocial behavior in Germany and in Chile. Moreover, mediation analyses revealed indirect positive effects of self-regulation on the relations between maternal warmth and prosocial behavior. These indirect effects occurred for different aspects of self-regulation in Germany (i.e., behavior regulation) and in Chile (i.e., problem-oriented emotion regulation). Results are discussed from a cultural informed developmental perspective

Untersuchung der weichgeweblichen Integration von verschiedenen Abutmentmaterialien und Abutmentoberflächenstrukturen in die periimplantäre Mukosa

In der dentalen Implantologie werden hoch frequentiert neue Implantatsysteme und Werkstoffe auf den Markt gebracht. Dabei spielen sowohl funktionelle, technische aber auch ästhetische Gesichtspunkte eine Rolle. Bestimmte Komponenten, wie Abutments und Suprakonstruktionen bedürfen daher einer wissenschaftlichen Überprüfung. Das Ziel der vorliegenden Studie war es, eine klinische Methode für die histologische Untersuchung der Anlagerung periimplantärer Strukturen an Abutmentmaterialien zu erforschen. Die Reaktion des Weichgewebes auf verschiedene Abutmentwerkstoffe sollte näher charakterisiert werden. Hierzu wurden bei 15 zahnlosen Patienten jeweils 2 SICace Implantate im interforaminalen Unterkieferbereich implantiert und über einen Untersuchungszeitraum von 6 Monaten beobachtet. Die Hohlzylinderversuchsabutments aus Titan (Referenz), Zirkoniumdioxid, Zirkoniumdioxid mit Feldspatkeramik verblendet und Polyetheretherketon (PEEK), wurden nach einer Einheilzeit der Implantate von 3 Monaten inseriert und für weitere 3 Monate belassen. Klinische und radiologische Parameter wurden erhoben. Vor der endgültigen Versorgung der Patienten, 6 Monate nach der Implantatinsertion, wurden die Versuchsabutments entfernt und einer histologischen Aufbereitung zugeführt. Die erhaltenen Dünnschliffpräparate zeigten Abutmentscheiben mit anhaftendem Weichgewebe. Eine histologische Einteilung der Präparate nach verschiedenen Gewebeparametern, sowie die Auszählungen von Leukozyten, sollten Aufschlüsse über die Beschaffenheit der Gewebe bei den unterschiedlichen Materialgruppen geben. Es konnte gezeigt werden, dass innerhalb der Gradeinteilung keine statistisch signifikanten Unterschiede zwischen den 4 Materialtypen bestanden. Ein chronisches leukozytäres Zellinfiltrat konnte bei allen Abutmenttypen festgestellt werden. Die Methode kann zur klinischen und histologischen Untersuchung von Implantatabutmentwerkstoffen empfohlen werden, auch wenn Modifikationen im Bereich des Abutmentdesigns und der Dünnschliffherstellung nötig sind. Eine Verwendung aller untersuchten Materialien ist ebenfalls möglich, kein Werkstoff wies relevante Nachteile gegenüber der Referenz Titan auf. In Zukunft werden Dentalkeramiken und moderne Composite auch den implantatprothetischen Bereich prägen

Generation of realistic nonwoven and foam filter geometry and mesh for filtration simulation using open-source tools

Recovery of liquid aerosols (mists) from industrial processes is typically accomplished through coalescence filtration, employing highly porous nonwoven (fibrous), knitted or foam media which are regarded to potentially provide high collection efficiencies. Highly resolved pore-scale computational fluid dynamics (CFD) analysis of mist filtration processes is increasingly becoming an important tool for design and optimization of such filter media. A key to efficient application-specific optimization of filter media is the ability to generate CFD-suitable virtual filter geometries with controllable geometric parameters including solidity, fibre diameters, morphology, etc. - yet, a review of the literature suggests that the current designs are heavily reliant on computed tomography (CT) scans of available filter media for accurate representation of the pore-scale structures in a computational simulation. In the present study, a novel methodology is presented for generating realistic virtual nonwoven (fibrous) and foam filter geometries with parametric customizability, using open-source tools including Python, OpenFOAM libraries, Gmsh and Blender. Further, a methodology for the generation of a computational mesh suitable for multiphase CFD at the pore-scale is delineated for the two types of filter media generated using the present technique, viz: nonwoven and foam, using open-source tools available within the OpenFOAM framework. The proposed methodology for the generation of virtual filter media and computational mesh is validated by qualitative comparison against with images from electron-microscopy (SEM) scans of real filters as well as comparison of the single-phase pressure drops predicted from CFD simulations using the generated fibrous and foam media with different solidities, fibre (or strand of foam) diameters, filter thicknesses, against the literature. The excellent agreement between the predicted pressure drops and the literature and its consistency over the several different geometric conditions considered for comparison reaffirms the validity of the proposed methodology for efficient virtual filter media development, which can eventually lead to enhanced parametric optimization capabilities and reduced design costs and lead times