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The widespread usage of products containing volatile organic compounds (VOC) has lead to a general human exposure to these chemicals in work places or homes being suspected to contribute to the growing incidence of environmental diseases. Since the causal molecular mechanisms for the development of these disorders are not completely understood, the overall objective of this thesis was to investigate VOC-mediated molecular effects on human lung cells in vitro at VOC concentrations comparable to exposure scenarios below current occupational limits. Although differential expression of single proteins in response to VOCs has been reported, effects on complex protein networks (proteome) have not been investigated. However, this information is indispensable when trying to ascertain a mechanism for VOC action on the cellular level and establishing preventive strategies. For this study, the alveolar epithelial cell line A549 has been used. This cell line, cultured in a two-phase (air/liquid) model allows the most direct exposure and had been successfully applied for the analysis of inflammatory effects in response to VOCs. Mass spectrometric identification of 266 protein spots provided the first proteomic map of A549 cell line to this extent that may foster future work with this frequently used cellular model. The distribution of three typical air contaminants, monochlorobenzene (CB), styrene and 1,2 dichlorobenzene (1,2-DCB), between gas and liquid phase of the exposure model has been analyzed by gas chromatography. The obtained VOC partitioning was in agreement with available literature data. Subsequently the adapted in vitro system has been successfully employed to characterize the effects of the aromatic compound styrene on the proteome of A549 cells (Chapter 4). Initially, the cell toxicity has been assessed in order to ensure that most of the concentrations used in the following proteomic approach were not cytotoxic. Significant changes in abundance and phosphorylation in the total soluble protein fraction of A549 cells have been detected following styrene exposure. All proteins have been identified using mass spectrometry and the main cellular functions have been assigned. Validation experiments on protein and transcript level confirmed the results of the 2-DE experiments. From the results, two main cellular pathways have been identified that were induced by styrene: the cellular oxidative stress response combined with moderate pro-apoptotic signaling. Measurement of cellular reactive oxygen species (ROS) as well as the styrene-mediated induction of oxidative stress marker proteins confirmed the hypothesis of oxidative stress as the main molecular response mechanism. Finally, adducts of cellular proteins with the reactive styrene metabolite styrene 7,8 oxide (SO) have been identified. Especially the SO-adducts observed at both the reactive centers of thioredoxin reductase 1, which is a key element in the control of the cellular redox state, may be involved in styrene-induced ROS formation and apoptosis. A similar proteomic approach has been carried out with the halobenzenes CB and 1,2-DCB (Chapter 5). In accordance with previous findings, cell toxicity assessment showed enhanced toxicity compared to the one caused by styrene. Significant changes in abundance and phosphorylation of total soluble proteins of A549 cells have been detected following exposure to subtoxic concentrations of CB and 1,2-DCB. All proteins have been identified using mass spectrometry and the main cellular functions have been assigned. As for the styrene experiment, the results indicated two main pathways to be affected in the presence of chlorinated benzenes, cell death signaling and oxidative stress response. The strong induction of pro-apoptotic signaling has been confirmed for both treatments by detection of the cleavage of caspase 3. Likewise, the induction of redox-sensitive protein species could be correlated to an increased cellular level of ROS observed following CB treatment. Finally, common mechanisms in the cellular response to aromatic VOCs have been investigated (Chapter 6). A similar number (4.6-6.9%) of all quantified protein spots showed differential expression (p<0.05) following cell exposure to styrene, CB or 1,2-DCB. However, not more than three protein spots showed significant regulation in the same direction for all three volatile compounds: voltage-dependent anion-selective channel protein 2, peroxiredoxin 1 and elongation factor 2. However, all of these proteins are important molecular targets in stress- and cell death-related signaling pathways.
Large-scale volcanic deformation recently detected by radar interferometry (InSAR) provides new information and thus new scientific challenges for understanding volcano-tectonic activity and magmatic systems. The destabilization of such a system at depth noticeably affects the surrounding environment through magma injection, ground displacement and volcanic eruptions. To determine the spatiotemporal evolution of the Lazufre volcanic area located in the central Andes, we combined short-term ground displacement acquired by InSAR with long-term geological observations. Ground displacement was first detected using InSAR in 1997. By 2008, this displacement affected 1800 km2 of the surface, an area comparable in size to the deformation observed at caldera systems. The original displacement was followed in 2000 by a second, small-scale, neighbouring deformation located on the Lastarria volcano. We performed a detailed analysis of the volcanic structures at Lazufre and found relationships with the volcano deformations observed with InSAR. We infer that these observations are both likely to be the surface expression of a long-lived magmatic system evolving at depth. It is not yet clear whether Lazufre may trigger larger unrest or volcanic eruptions; however, the second deformation detected at Lastarria and the clear increase of the large-scale deformation rate make this an area of particular interest for closer continuous monitoring.
Business process management aims at capturing, understanding, and improving work in organizations. The central artifacts are process models, which serve different purposes. Detailed process models are used to analyze concrete working procedures, while high-level models show, for instance, handovers between departments. To provide different views on process models, business process model abstraction has emerged. While several approaches have been proposed, a number of abstraction use case that are both relevant for industry and scientifically challenging are yet to be addressed. In this paper we systematically develop, classify, and consolidate different use cases for business process model abstraction. The reported work is based on a study with BPM users in the health insurance sector and validated with a BPM consultancy company and a large BPM vendor. The identified fifteen abstraction use cases reflect the industry demand. The related work on business process model abstraction is evaluated against the use cases, which leads to a research agenda.
Data obtained from foreign data sources often come with only superficial structural information, such as relation names and attribute names. Other types of metadata that are important for effective integration and meaningful querying of such data sets are missing. In particular, relationships among attributes, such as foreign keys, are crucial metadata for understanding the structure of an unknown database. The discovery of such relationships is difficult, because in principle for each pair of attributes in the database each pair of data values must be compared. A precondition for a foreign key is an inclusion dependency (IND) between the key and the foreign key attributes. We present with Spider an algorithm that efficiently finds all INDs in a given relational database. It leverages the sorting facilities of DBMS but performs the actual comparisons outside of the database to save computation. Spider analyzes very large databases up to an order of magnitude faster than previous approaches. We also evaluate in detail the effectiveness of several heuristics to reduce the number of necessary comparisons. Furthermore, we generalize Spider to find composite INDs covering multiple attributes, and partial INDs, which are true INDs for all but a certain number of values. This last type is particularly relevant when integrating dirty data as is often the case in the life sciences domain - our driving motivation.
A deterministic cycle scheduling of partitions at the operating system level is supposed for a multiprocessor system. In this paper, we propose a tool for generating such schedules. We use constraint based programming and develop methods and concepts for a combined interactive and automatic partition scheduling system. This paper is also devoted to basic methods and techniques for modeling and solving this partition scheduling problem. Initial application of our partition scheduling tool has proved successful and demonstrated the suitability of the methods used.
In the most abstract definition of its operational semantics, the declarative and concurrent programming language CHR is trivially non-terminating for a significant class of programs. Common refinements of this definition, in closing the gap to real-world implementations, compromise on declarativity and/or concurrency. Building on recent work and the notion of persistent constraints, we introduce an operational semantics avoiding trivial non-termination without compromising on its essential features.
Different properties of programs, implemented in Constraint Handling Rules (CHR), have already been investigated. Proving these properties in CHR is fairly simpler than proving them in any type of imperative programming language, which triggered the proposal of a methodology to map imperative programs into equivalent CHR. The equivalence of both programs implies that if a property is satisfied for one, then it is satisfied for the other. The mapping methodology could be put to other beneficial uses. One such use is the automatic generation of global constraints, at an attempt to demonstrate the benefits of having a rule-based implementation for constraint solvers.
Deductive databases need general formulas in rule bodies, not only conjuctions of literals. This is well known since the work of Lloyd and Topor about extended logic programming. Of course, formulas must be restricted in such a way that they can be effectively evaluated in finite time, and produce only a finite number of new tuples (in each iteration of the TP-operator: the fixpoint can still be infinite). It is also necessary to respect binding restrictions of built-in predicates: many of these predicates can be executed only when certain arguments are ground. Whereas for standard logic programming rules, questions of safety, allowedness, and range-restriction are relatively easy and well understood, the situation for general formulas is a bit more complicated. We give a syntactic analysis of formulas that guarantees the necessary properties.
Abstract interpretation-based model checking provides an approach to verifying properties of infinite-state systems. In practice, most previous work on abstract model checking is either restricted to verifying universal properties, or develops special techniques for temporal logics such as modal transition systems or other dual transition systems. By contrast we apply completely standard techniques for constructing abstract interpretations to the abstraction of a CTL semantic function, without restricting the kind of properties that can be verified. Furthermore we show that this leads directly to implementation of abstract model checking algorithms for abstract domains based on constraints, making use of an SMT solver.
The interest in extensions of the logic programming paradigm beyond the class of normal logic programs is motivated by the need of an adequate representation and processing of knowledge. One of the most difficult problems in this area is to find an adequate declarative semantics for logic programs. In the present paper a general preference criterion is proposed that selects the ‘intended’ partial models of generalized logic programs which is a conservative extension of the stationary semantics for normal logic programs of [Prz91]. The presented preference criterion defines a partial model of a generalized logic program as intended if it is generated by a stationary chain. It turns out that the stationary generated models coincide with the stationary models on the class of normal logic programs. The general wellfounded semantics of such a program is defined as the set-theoretical intersection of its stationary generated models. For normal logic programs the general wellfounded semantics equals the wellfounded semantics.