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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.