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Alzheimer’s Disease (AD) is the most common neurodegenerative disorder marked by progressive loss of memory and cognitive ability. The pathology of AD is characterised by the presence of amyloid plaques, intracellular neurofibrillary tangles and pronounced cell death. The aim of this thesis was to investigate pathways involved in the Aß cascade of neurodegeneration. Since novel findings indicate that already this Aß species exerts neurotoxic effects long before hyperphosphorylated tau, neurofibrillary tangles and extracellular Aß plaques appear, the investigations were accomplished with specific regard to the effects of intracellular Aß. The Swedish double mutation in the APP gene results in six- to eightfold increased Aß production of both Aß1-40 and Aß1-42 compared to human wildtype APP cells (APPwt). Data obtained from PC12 cells indicate that it is possible to specifically increase the Aß load without enhancing APP expression levels. On the basis of these findings, it seemed possible to investigate dose-dependent effects of Aß in multiple experimental designs. These assay designs were created in order to mimick different in-vivo situations that are discussed to occur in AD patients: APPsw PC12 cells exhibit low physiological concentrations of Aß within picomolar range in contrast to APPsw HEK cells, expressing Aß levels within the nanomolar range. Of note, the APPsw HEK cells showed a specific and highly significant increase in the intracellular accumulation of insoluble Aß1-42. Moreover, an intracellular accumulation of Aß and APP was found in the mitochondria of the HEK APPsw cells suggesting a direct impact on mitochondrial function on these cells. This effect might finally lead to disturbances in the energy metabolism of the cell or to increased cell death. Furthermore, baseline g- and ß-secretase activity was assessed since these enzymes represent promising therapeutic targets to slow or halt the disease process. As expected, ß-secretase activity was significantly elevated in all APPsw cell lines. This might be due to the proximity of the Swedish double mutation next to the N-terminus of the Aß sequence. Interestingly, g-secretase activity was similarly increased in PC12 APPsw cells. In addition, the toxicity of different Aß species was investigated in SY5Y and PC12 cells with regard to their effect on cellular viability mirrored by mitochondrial activity using MTT assay. Here, it turned out that not monomers, but already dimers are neurotoxic correlates. Fibrillar Aß species showed the highest toxicity. In the next step, SY5Y cells forming endogenous, dimeric APP and Aß were investigated. In accordance with previous findings, these cells showed a decreased MTT reduction potential in comparison to APPwt and control SY5Y cells reflecting a decrease of cellular viability. The impaired energy metabolism of the cells was even more drastically mirrored by reduced baseline ATP levels. In the second part of this thesis, the expression and intracellular distribution of Bcl-2 family proteins and pro-apoptotic mitochondrial factors under baseline conditions and during oxidative stress were analyzed in the APPwt and APPsw bearing cells. The most prominent finding was the reduction of expression levels of the anti-apoptotic factor Bcl-xL in the cytosolic fractions of APPwt and APPsw PC12 cells. This might indicate that a lack of anti-apoptotic factors or their altered intracellular distribution, rather than an increase in caspase-dependent pro-apoptotic factors, could be responsible for the increased vulnerability of APPwt- and APPsw-transfected PC12 cells against oxidative stress. Since total Bcl-xL expression was unaffected in PC12 cells, in contrast to APPwt and APPsw-expressing SY5Y and HEK cells revealing significantly decreased Bcl-xL expression levels. Thus, alterations in Bcl-xL distribution seem to be an early event in the disease process. Increasing Bcl-xL expression might potentially be one promising strategy for AD modification. PC12 and HEK cells bearing APPsw or APPwt were treated with the potent g-secretase inhibitor DAPT. Of note, DAPT did not only efficiently block Aß production, but additionally led to an elevation of the MTT reduction potential, reflecting an increase in cellular viability. As another disease-modifying strategy, several efforts are undertaken to ameliorate AD-relevant symptoms by the treatment with nerve growth factor (NGF). Generally, it is known that substituted pyrimidines have modest growth-promoting effects. Here, KP544, a novel substituted pyrimidine, was characterised. This drug increased MTT reduction potential in terminally differentiated and undifferentiated PC12 cells. Furthermore, treatment with KP544 led to a reduction in Aß1-40 secretion. Thus, one may conclude that the target of KP544, GSK-3ß, represents a connecting link between the two main pathological hallmarks of AD and might thus be a very promising therapeutic target for AD.
We propose a compositional analysis for sentences of the kind "You only have to go to the North End to get good cheese", referred to as the Sufficiency Modal Construction in the recent literature. We argue that the SMC is ambiguous depending on the kind of ordering induced by only. So is the exceptive construction – its cross-linguistic counterpart. Only is treated as inducing either a 'comparative possibility' scale or an 'implication-based' partial order on propositions. The properties of the 'comparative possibility' scale explain the absence of the prejacent presupposition that is usually associated with only. By integrating the scalarity into the semantics of the SMC, we explain the polarity facts observed in both variants of the construction. The sufficiency meaning component is argued to be due to a pragmatic inference.
The German causal preposition durch ('by', 'through') poses a challenge to formal-semantic analyses applying strict compositionality. To deal with this challenge, a formalism which builds on recent important developments in Discourse Representation Theory is developed, including a more elaborate analysis of presuppositional phenomena as well as the integration into the theory of unification as a mode of composition. It is argued that that the observed unificational phenomena belong in the realm of pragmatics, providing an argument for presuppositional phenomena at a sentence- and word-internal level.
In recent years, research in parsing has extended in several new directions. One of these directions is concerned with parsing languages other than English. Treebanks have become available for many European languages, but also for Arabic, Chinese, or Japanese. However, it was shown that parsing results on these treebanks depend on the types of treebank annotations used. Another direction in parsing research is the development of dependency parsers. Dependency parsing profits from the non-hierarchical nature of dependency relations, thus lexical information can be included in the parsing process in a much more natural way. Especially machine learning based approaches are very successful (cf. e.g.). The results achieved by these dependency parsers are very competitive although comparisons are difficult because of the differences in annotation. For English, the Penn Treebank has been converted to dependencies. For this version, Nivre et al. report an accuracy rate of 86.3%, as compared to an F-score of 92.1 for Charniaks parser. The Penn Chinese Treebank is also available in a constituent and a dependency representations. The best results reported for parsing experiments with this treebank give an F-score of 81.8 for the constituent version and 79.8% accuracy for the dependency version. The general trend in comparisons between constituent and dependency parsers is that the dependency parser performs slightly worse than the constituent parser. The only exception occurs for German, where F-scores for constituent plus grammatical function parses range between 51.4 and 75.3, depending on the treebank, NEGRA or TüBa-D/Z. The dependency parser based on a converted version of Tüba-D/Z, in contrast, reached an accuracy of 83.4%, i.e. 12 percent points better than the best constituent analysis including grammatical functions.
We model the impact of bank mergers on loan competition, reserve holdings and aggregate liquidity. A merger changes the distribution of liquidity shocks and creates an internal money market, leading to financial cost efficiencies and more precise estimates of liquidity needs. The merged banks may increase their reserve holdings through an internalization effect or decrease them because of a diversification effect. The merger also affects loan market competition, which in turn modifies the distribution of bank sizes and aggregate liquidity needs. Mergers among large banks tend to increase aggregate liquidity needs and thus the public provision of liquidity through monetary operations of the central bank. JEL Classification: G24, G32, G34
The expressions few and a few are typically considered to be separate quantifiers. I challenge this assumption, showing that with the appropriate definition of few, a few can be derived compositionally as a + few. The core of the analysis is a proposal that few has a denotation as a one-place predicate which incorporates a negation operator. From this, argument interpretations can be derived for expressions such as few students and a few students, differing only in the scope of negation. I show that this approach adequately captures the interpretive differences between few and a few. I further show that other such pairs are blocked by a constraint against the vacuous application of a.
This paper demonstrates that there are no empirical and theoretical motivations for regarding verbal predicate focus constructions as (diachronically) derived from cleft constructions. Instead, it is argued that predicate fronting for the purpose of focus or topic is comparable to verb (phrase) fronting structures in other languages (e.g., Germanic). The proposed analysis further indicates that related doubling strategies observed in certain languages are the consequences of parallel chains that license the fronted verb (phrase) in the left periphery, and the Agree-tense-aspect features inside the proposition.