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Cold target recoil ion momentum spectroscopy (COLTRIM) has been employed to image the momentum distributions of continuum electrons liberated in the impact of slow He2+ on He and H2. The distributions were measured for fully determined motion of the nuclei that is as a function of the impact parameter and in a well de ned scattering plane The single ionization (SI) of H2 leading to H2+ recoil ions in nondissociative states (He2+ + H+ -> He2+ + H+ + e-) and the transfer ionization (TI) of H2 leading to H2 dissociation into two free protons (He2+ H2 -> He+ + H+ + H+ + e-) were investigated. Similar measurements have been carried out for He target, the corresponding atomic two electron system, i.e. the single ionization (SI) (He2+ + He -> He+ + He2+ e- and the transfer ionization (TI) (He2+ + He -> He+ + He2+ + e-). These measurements have been exploited to understand the results obtained for H target. In comparing the continuum electron momentum distributions for H2 with that for He, a high degree of similarity is observed. In the case of transfer ionization of H2, the electron momentum distributions generated for parallel and perpendicular molecular orientations revealed no orientation dependence. The in scattering plane electron momentum distributions for the transfer ionization of H2 by He2+ and for the transfer ionization of He by He2e showed that the salient feature of these distributions for both collisions systems consists in the appearance of two groups of electrons with difeerent structures. In addition to the group of the saddle electrons forming two jets separated by a valley along the projectile axis we nd a new group of electrons moving with a velocity higher than the projectile velocity These new fast forward electrons result from a narrow range of impact parameters and appear as image saddle in the projectile frame. In contrast to the transfer ionization of He, the fast forward electrons group disappears in the in scattering plane electron momentum distribution generated for the single ionization of He. Instead of this group another new group of electrons appear These electrons exhibit an amount of backscattering These backward elec trons appear as image saddle in the target frame The structures that the saddle electrons show are owing to the quasi molecular nature of the collision process For the TI of H2, the TI of He and the SI of He, a pi-orbital shape of the electron momentum distribution is observed This indicates the importance of the rotational coupling 2-p-theta -> 2p-pi in the initial promotion of the ground state followed by further promotions to the continuum The backward electrons as well as the fast forward electrons are not discussed in the theoretical literature at all. However, a number of obvious indications of the existence of the backward and fast forward electrons could be seen in the experimental works of Abdallah et al. as well as in the theoretical calculations of Sidky et al One might speculate that electrons which are promoted on the saddle for some time during the collision could finally swing around the He+ ion in the way out of the collision, i.e. either around the projectile in the forward direction as in the TI case forming the fast forward electrons or around the recoil ion in the backward direction as in the SI case forming the backward electrons. This might be a result of the strong gradient, and hence the large acceleration of the screened He+ potential.
Alzheimer’s disease (AD) is the most common neurodegenerative disorder world wide, causing presenile dementia and death of millions of people. During AD damage and massive loss of brain cells occur. Alzheimer’s disease is genetically heterogeneous and may therefore represent a common phenotype that results from various genetic and environmental influences and risk factors. In approximately 10% of patients, changes of the genetic information were detected (gene mutations). In these cases, Alzheimer’s disease is inherited as an autosomal dominant trait (familial Alzheimer’s disease, FAD). In rare cases of familial Alzheimer’s disease (about 1-3%), mutations have been detected in genes on chromosomes 14 and 1 (encoding for Presenilin 1 and 2, respectively), and on chromosome 21 encoding for the amyloid precursor protein (APP), which is responsible for the release of the cell-damaging protein amyloid-beta (ß-amyloid, Aß). Familial forms of early-onset Alzheimer’s disease are rare; however, their importance extends far beyond their frequency, because they allow to identify some of the critical pathogenetic pathways of the disease. All familial Alzheimer mutations share a common feature: they lead to an enhanced production of the Aß, which is the major constituent of senile plaques in brains of AD patients. New data indicates that Aß promotes neuronal degeneration. Therefore, one aim of these thesis was to elucidate the neurotoxic biochemical pathways induced by Aß, investigating the effect of the FAD Swedish APP double mutation (APPsw) on oxidative stress-induced cell death mechanisms. This mutation results in a three- to sixfold increased Aß production compared to wild-type APP (APPwt). As cell models, the neuronal PC12 (rat pheochromocytoma) and the HEK (human embryonic kidney 293) cell lines were used, which have been transfected with human wiltyp APP or human APP containing the Swedish double mutation. The used cell models offer two important advantages. First, compared to experiments using high concentrations of Aß at micromolar levels applied extracellularly to cells, PC12 APPsw cells secret low Aß levels similar to the situation in FAD brains. Thus, this cell model represents a very suitable approach to elucidate the AD-specific cell death pathways mimicking physiological conditions. Second, these two cell lines (PC12 and HEK APPwt and APPsw) with different production levels of Aß may additionally allow to study dose-dependent effects of Aß. The here obtained results provide evidence for the enhanced cell vulnerability caused by the Swedish APP mutation and elucidate the cell death mechanism probably initiated by intracellulary produced Aß. Here it seems likely that increased production of Aß at physiological levels primes APPsw PC12 cells to undergo cell death only after additional stress, while chronic high levels in HEK cells already lead to enhanced basal apoptotic levels. Crucial effects of the Swedish APP mutation include the impairments of cellular energy metabolism affecting mitochondrial membrane potential and ATP levels as well as the additional activation of caspase 2, caspase 8 and JNK in response to oxidative stress. Thereby ,the following model can be proposed: PC12 cells harboring the Swedish APP mutation have a reduced energy metabolism compared to APPwt or control cells. However, this effect does not leads to enhanced basal apoptotic levels of cultured cells. An exposure of PC12 cells to oxidative stress leads to mitochondrial dysfunction, e.g., decrease in mitochondrial membrane potential and depletion in ATP. The consequence is the activation of the intrinsic apoptotic pathway releasing cytochrome c and Smac resulting in the activation of caspase 9. This effect is amplified by the overexpression of APP, since both APPsw and APPwt PC12 cells show enhanced cytochrome c and Smac release as well as enhanced caspase 9 activity as vector transfected control. In APPsw PC12 cells a parallel pathway is additionally emphased. Due to reduced ATP levels or enhanced Aß production JNK is activated. Furthermore, the extrinsic apoptotic pathway is enhanced, since caspase 8 and caspase 2 activation was clearly enhanced by the Swedish APP mutation. Both pathways may then converge by activating the effector enzyme, caspase 3, and the execution of cell death. In addition, caspase independent effects also needs to be considered. One possibility could be the implication of AIF since AIF expression was found to be induced by the Swedish APP mutation. In APPsw HEK cells high chronic Aß levels leads to enhanced apoptotic levels, reduce mitochondrial membrane potential and ATP levels even under basal conditions. Summarizing, a hypothetical sequence of events is proposed linking FAD, Aß production, JNK-activation, mitochondrial dysfunction with caspase pathway and neuronal loss for our cell model. The brain has a high metabolic rate and is exposured to gradually rising levels of oxidative stress during life. In Swedish FAD patients the levels of oxidative stress are increased in the temporal inferior cortex. This study using a cell model mimicking the in vivo situation in AD brains indicates that probably both, increased Aß production and the gradual rise of oxidative stress throughout life converge at a final common pathway of an increased vulnerability of neurons to apoptotic cell death from FAD patients. Presenilin (PS) 1 is an aspartyl protease, involved in the gamma-secretase mediated proteolysis of Amyloid-ß-protein (Aß), the major constituent of senile plaques in brains of Alzheimer’s disease (AD) patients. Recent studies have suggested an additional role for presenilin proteins in apoptotic cell death observed in AD. Since PS 1 is proteolytic cleaved by caspase 3, it has been prosposed that the resulting C-terminal fragment of PS1 (PSCas) could play a role in signal transduction during apoptosis. Moreover, it was shown that mutant presenilins causing early-onset of familial Alzheimer's disease (FAD) may render cells vulnerable to apoptosis. The mechanism by which PS1 regulates apoptotic cell death is yet not understood. Therefore one aim of our present study was to clarify the involvement of PS1 in the proteolytic cascade of apoptosis and if the cleavage of PS1 by caspase 3 has an regulatory function. Here it is demonstrated that both, PS1 and PS1Cas lead to a reduced vulnerability of PC12 and Jurkat cells to different apoptotic stimuli. However a mutation at the caspase 3 recognition site (D345A/ PSmut), which inhibits cleavage of PS1 by caspase 3, show no differences in the effect of PS1 or PSCas towards apoptotic stimuli. This suggest that proteolysis of PS1 by caspase 3 is not a determinant, but only a secondary effect during apoptosis. Since several FAD mutation distributed through the whole PS1 gene lead to enhanced apoptosis, an abolishment of the antiapoptotic effect of PS1 might contribute to the massive neurodegeneration in early age of FAD patients. Here, the regulate properties of PS1 in apoptosis may not be through an caspase 3 dependent cleavage and generation of PSCas, but rather through interaction of PS1 with other proteins involved in apoptosis.
The German financial market is often characterized as a bank-based system with strong bank-customer relationships. The corresponding notion of a housebank is closely related to the theoretical idea of relationship lending. It is the objective of this paper to provide a direct comparison between housebanks and "normal" banks as to their credit policy. Therefore, we analyze a new data set, representing a random sample of borrowers drawn from the credit portfolios of five leading German banks over a period of five years. We use credit-file data rather than industry survey data and, thus, focus the analysis on information that is directly related to actual credit decisions. In particular, we use bank-internal borrower rating data to evaluate borrower quality, and the bank's own assessment of its housebank status to control for information-intensive relationships.
This paper reviews the factors that will determine the shape of financial markets under EMU. It argues that financial markets will not be unified by the introduction of the euro. National central banks have a vested interest in preserving local idiosyncracies (e.g. the Wechsels in Germany) and they might be allowed to do so by promoting the use of so-called tier two assets under the common monetary policy. Moreover, a host of national regulations (prudential and fiscal) will make assets expressed in euro imperfect substitutes across borders. Prudential control will also continue to be handled differently from country to country. In the long run these national idiosyncracies cannot survive competitive pressures in the euro area. The year 1999 will thus see the beginning of a process of unification of financial markets that will be irresistible in the long run, but might still take some time to complete.
In this paper we analyze the relation between fund performance and market share. Using three performance measures we first establish that significant differences in the risk-adjusted returns of the funds in the sample exist. Thus, investors may react to past fund performance when making their investment decisions. We estimated a model relating past performance to changes in market share and found that past performance has a significant positive effect on market share. The results of a specification test indicate that investors react to risk-adjusted returns rather than to raw returns. This suggests that investors may be more sophisticated than is often assumed.
From the mid-seventies on, the central banks of most major industrial countries switched to monetary targeting. The Bundesbank was the first central bank to take this step, making the switch at the end of 1974. This changeover to monetary targeting was due to the difficulties which the Bundesbank - like other central banks - was facing in pursuing its original strategy, and whichcame to a head in the early seventies, when inflation escalated. A second factor was the collapse of the Bretton Woods system of fixed exchange rates, which created the necessary scope for national monetary targeting. Finally, the advance of monetarist ideas fostered the explicit turn towards monetary targets, although the Bundesbank did not implement these in a mechanistic way. Whereas the Bundesbank has adhered to its policy of monetary targeting up to the present, nowadays monetary targeting plays only a minor role worldwide. Many central banks have switched to the strategy of direct inflation targeting. Others favour a more discretionary approach or a policy which is geared to the exchange rate. In the academic debate, monetary targeting is often presented as an outdated approach which has long since lost its basis of stable money demand. These findings give riseto a number of questions: Has monetary targeting actually become outdated? Which role is played by the concrete design of this strategy, and, against this background, how easily can it be transferred to European monetary union? This paper aims to answer these questions, drawing on the particular experience which the Bundesbank has gained of monetary targeting. It seems appropriate to discuss monetary targeting by using a specific example, since this notion is not very precise. This applies, for example, to the money definition used, the way the target is derived, the stringency applied in pursuing the target and the monetary management procedure.
In this speech (given at the CFSresearch conference on the Implementation of Price Stability held at the Bundesbank Frankfurt am Main, 10. - 12. Sept 1998), John Vickers discusses theoretical and practical issues relating to inflation targeting as used in the United Kingdom doing the past six years. After outlining the role of the Bank s Monetary Policy Committee, he considers the Committee s task from a theoretical perspective, beforediscussing the concept and measurement of domestically generated inflation.
Credit Unions are cooperative financial institutions specializing in the basic financial needs of certain groups of consumers. A distinguishing feature of credit unions is the legal requirement that members share a common bond. This organizing principle recently became the focus of national attention as the Supreme Court and the U.S. Congress took opposite sides in a controversy regarding the number of common bonds that could co-exist within the membership of a single credit union. Despite its importance, little research has been done into how common bonds affect how credit unions actually operate. We frame the issues with a simple theoretical model of credit-union formation and consolidation. To provide intuition into the flexibility of multiple-group credit unions in serving members, we simulate the model and present some comparative-static results. We then apply a semi-parametric empirical model to a large dataset drawn from federally chartered occupational credit unions in 1996 to investigate the effects of common bonds. Our results suggest that credit unions with multiple common bonds have higher participation rates than credit unions that are otherwise similar but whose membership shares a single common bond.
"In this paper, I analyse the conduct of business rules included in the Directive on Markets in Financial Instruments (MiFID) which has replaced the Investment Services Directive (ISD). These rules, in addition to being part of the regulation of investment intermediaries, operate as contractual standards in the relationships between intermediaries and their clients. While the need to harmonise similar rules is generally acknowledged, in the present paper I ask whether the Lamfalussy regulatory architecture, which governs securities lawmaking in the EU, has in some way improved regulation in this area. In section II, I examine the general aspects of the Lamfalussy process. In section III, I critically analyse the MiFID s provisions on conduct of business obligations, best execution of transactions and client order handling, taking into account the new regime of trade internalisation by investment intermediaries and the ensuing competition between these intermediaries and market operators. In sectionIV, I draw some general conclusions on the re-regulation made under the Lamfalussy regulatory structure and its limits. In this section, I make a few preliminary comments on the relevance of conduct of business rules to contract law, the ISD rules of conduct and the role of harmonisation."
In contrast to the class A heat stress transcription factors (Hsfs) of plants, a considerable number of Hsfs assigned to classes B and C have no evident function as transcription activators on their own. In the course of my PhD work I showed that tomato HsfB1, a heat stress induced member of class B Hsf family, is a novel type of transcriptional coactivator in plants. Together with class A Hsfs, e.g. tomato HsfA1, it plays an important role in efficient transcrition initiation during heat stress by forming a type of enhanceosome on fragments of Hsp promoter. Characterization of promoter architecture of hsp promoters led to the identification of novel, complex heat stress element (HSE) clusters, which are required for optimal synergistic interactions of HsfA1 and HsfB1. In addition, HsfB1 showed synergistic activation of the expression of a subset of viral and house keeping promoters. CaMV35S promoter, the most widely expressed constitutive promoter turned out to be the the most interesting candidate to study this effect in detail. Because, for most house-keeping promoters tested during this study, the activators responsible for constitutive expression are not known, but in case of CaMV35S promoter they are quite well known (the bZip proteins, TGA1/2). These proteins belong to the acidic activators, similar to class A Hsfs. Actually, on heat stress inducible promoters HsfA1 or other class A Hsfs are the synergistic partners of HsfB1, whereas on house-keeping or viral promoters, HsfB1 shows synergistic transcriptional activation in cooperation with the promoter specific acidic activators, e.g. with TGA proteins on 35S promoter. In agreement with this the binding sites for HsfB1 were identified in both house-keeping and 35S promoter. It has been suggested during this study that HsfB1 acts in the maintenance of transcription of a sub-set of house-keeping and viral genes during heat stress. The coactivator function of HsfB1 depends on a single lysine residue in the GRGK motif in its CTD. Since, this motif is highly conserved among histones as the acetylation motif, especially in histones H2A and H4,. It was suggested that the GRGK motif acts as a recruitment motif, and together with the other acidic activator is responsible for corecruitment of a histone acetyl transferase (HAT). So, the effect of mammalian CBP (a well known HAT) and its plant orthologs (HAC1) was tested on the stimulation of synergistic reporter gene activation obtained with HsfA1 and HsfB1. Both in plant and mammalian cells, CBP/HAC1 further stimulated the HsfA1/B1 synergistic effect. Corecruitment of HAC1 was proven by in vitro pull down assays, where the NTD of HAC1 interacted specifically both with HsfA1 and HsfB1. Formation of a ternary complex between HsfA1, HsfB1 and CBP/HAC1 was shown via coimmunoprecipitation and electrophoretic mobility shift assays (EMSA). In conclusion, the work presented in my thesis presents a new model for transcriptional regulation during an ongoing heat stress.
In an attempt to search for potential candidate molecules involved in the pathogenesis of endometriosis, a novel 2910 bp cDNA encoding a putative 411 amino acid protein, shrew-1 was discovered. By computational analysis it was predicted to be an integral membrane protein with an outside-in transmembrane domain but no homology with any known protein or domain could be identified. Antibodies raised against the putative open-reading frame peptide of shrew-1 labelled a protein of ca. 48 kDa in extracts of shrew-1 mRNA positive tissues and also detected ectopically expressed shrew-1. In the course of my PhD work, I confirmed the prediction that shrew-1 is indeed a transmembrane protein, by expressing epitope-tagged shrew-1 in epithelial cells and analysing the transfected cells by surface biotinylation and immunoblots. Additionally, I could show that shrew-1 is able to target to E-cadherin-mediated adherens junctions and interacts with the E-cadherin-catenin complex in polarised MCF7 and MDCK cells, but not with the N-cadherin-catenin complex in non-polarised epithelial cells. A direct interaction of shrew-1 with beta-catenin could be shown in an in vitro pull-down assay. From this data, it could be assumed that shrew-1 might play a role in the function and/or regulation of the dynamics of E-cadherin-mediated junctional complexes. In the next part of my thesis, I showed that stable overexpression of shrew-1 in normal MDCK cells. causes changes in morphology of the cells and turns them invasive. Furthermore, transcription by ²-catenin was activated in these MDCK cells stably overexpressing shrew-1. It was probably the imbalance of shrew-1 protein at the adherens junctions that led to the misregulation of adherens junctions associated proteins, i.e. E-cadherin and beta-catenin. Caveolin-1 is another integral membrane protein that forms complexes with Ecadherin- beta-catenin complexes and also plays a role in the endocytosis of E-cadherin during junctional disruption. By immunofluorescence and biochemical studies, caveolin-1 was identified as another interacting partner of shrew-1. However, the functional relevance of this interaction is still not clear. In conclusion, it can be said that shrew-1 interacts with the key players of invasion and metastasis, E-cadherin and caveolin-1, suggesting its possible role in these processes and making it an interesting candidate to unravel other unknown mechanisms involved in the complex process of invasion.
This paper proves correctness of Nocker s method of strictness analysis, implemented for Clean, which is an e ective way for strictness analysis in lazy functional languages based on their operational semantics. We improve upon the work of Clark, Hankin and Hunt, which addresses correctness of the abstract reduction rules. Our method also addresses the cycle detection rules, which are the main strength of Nocker s strictness analysis. We reformulate Nocker s strictness analysis algorithm in a higherorder lambda-calculus with case, constructors, letrec, and a nondeterministic choice operator used as a union operator. Furthermore, the calculus is expressive enough to represent abstract constants like Top or Inf. The operational semantics is a small-step semantics and equality of expressions is defined by a contextual semantics that observes termination of expressions. The correctness of several reductions is proved using a context lemma and complete sets of forking and commuting diagrams. The proof is based mainly on an exact analysis of the lengths of normal order reductions. However, there remains a small gap: Currently, the proof for correctness of strictness analysis requires the conjecture that our behavioral preorder is contained in the contextual preorder. The proof is valid without referring to the conjecture, if no abstract constants are used in the analysis.
Work on proving congruence of bisimulation in functional programming languages often refers to [How89,How96], where Howe gave a highly general account on this topic in terms of so-called lazy computation systems . Particularly in implementations of lazy functional languages, sharing plays an eminent role. In this paper we will show how the original work of Howe can be extended to cope with sharing. Moreover, we will demonstrate the application of our approach to the call-by-need lambda-calculus lambda-ND which provides an erratic non-deterministic operator pick and a non-recursive let. A definition of a bisimulation is given, which has to be based on a further calculus named lambda-~, since the na1ve bisimulation definition is useless. The main result is that this bisimulation is a congruence and contained in the contextual equivalence. This might be a step towards defining useful bisimulation relations and proving them to be congruences in calculi that extend the lambda-ND-calculus.
In this paper we demonstrate how to relate the semantics given by the nondeterministic call-by-need calculus FUNDIO [SS03] to Haskell. After introducing new correct program transformations for FUNDIO, we translate the core language used in the Glasgow Haskell Compiler into the FUNDIO language, where the IO construct of FUNDIO corresponds to direct-call IO-actions in Haskell. We sketch the investigations of [Sab03b] where a lot of program transformations performed by the compiler have been shown to be correct w.r.t. the FUNDIO semantics. This enabled us to achieve a FUNDIO-compatible Haskell-compiler, by turning o not yet investigated transformations and the small set of incompatible transformations. With this compiler, Haskell programs which use the extension unsafePerformIO in arbitrary contexts, can be compiled in a "safe" manner.
This paper proposes a non-standard way to combine lazy functional languages with I/O. In order to demonstrate the usefulness of the approach, a tiny lazy functional core language FUNDIO , which is also a call-by-need lambda calculus, is investigated. The syntax of FUNDIO has case, letrec, constructors and an IO-interface: its operational semantics is described by small-step reductions. A contextual approximation and equivalence depending on the input-output behavior of normal order reduction sequences is defined and a context lemma is proved. This enables to study a semantics of FUNDIO and its semantic properties. The paper demonstrates that the technique of complete reduction diagrams enables to show a considerable set of program transformations to be correct. Several optimizations of evaluation are given, including strictness optimizations and an abstract machine, and shown to be correct w.r.t. contextual equivalence. Correctness of strictness optimizations also justifies correctness of parallel evaluation. Thus this calculus has a potential to integrate non-strict functional programming with a non-deterministic approach to input-output and also to provide a useful semantics for this combination. It is argued that monadic IO and unsafePerformIO can be combined in Haskell, and that the result is reliable, if all reductions and transformations are correct w.r.t. to the FUNDIO-semantics. Of course, we do not address the typing problems the are involved in the usage of Haskell s unsafePerformIO. The semantics can also be used as a novel semantics for strict functional languages with IO, where the sequence of IOs is not fixed.
Context unification is a variant of second order unification. It can also be seen as a generalization of string unification to tree unification. Currently it is not known whether context unification is decidable. A specialization of context unification is stratified context unification, which is decidable. However, the previous algorithm has a very bad worst case complexity. Recently it turned out that stratified context unification is equivalent to satisfiability of one-step rewrite constraints. This paper contains an optimized algorithm for strati ed context unification exploiting sharing and power expressions. We prove that the complexity is determined mainly by the maximal depth of SO-cycles. Two observations are used: i. For every ambiguous SO-cycle, there is a context variable that can be instantiated with a ground context of main depth O(c*d), where c is the number of context variables and d is the depth of the SO-cycle. ii. the exponent of periodicity is O(2 pi ), which means it has an O(n)sized representation. From a practical point of view, these observations allow us to conclude that the unification algorithm is well-behaved, if the maximal depth of SO-cycles does not grow too large.
Context unification is a variant of second-order unification and also a generalization of string unification. Currently it is not known whether context uni cation is decidable. An expressive fragment of context unification is stratified context unification. Recently, it turned out that stratified context unification and one-step rewrite constraints are equivalent. This paper contains a description of a decision algorithm SCU for stratified context unification together with a proof of its correctness, which shows decidability of stratified context unification as well as of satisfiability of one-step rewrite constraints.
It is well known that first order uni cation is decidable, whereas second order and higher order unification is undecidable. Bounded second order unification (BSOU) is second order unification under the restriction that only a bounded number of holes in the instantiating terms for second order variables is permitted, however, the size of the instantiation is not restricted. In this paper, a decision algorithm for bounded second order unification is described. This is the fist non-trivial decidability result for second order unification, where the (finite) signature is not restricted and there are no restrictions on the occurrences of variables. We show that the monadic second order unification (MSOU), a specialization of BSOU is in sum p s. Since MSOU is related to word unification, this is compares favourably to the best known upper bound NEXPTIME (and also to the announced upper bound PSPACE) for word unification. This supports the claim that bounded second order unification is easier than context unification, whose decidability is currently an open question.