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Alternative polyadenylation (APA) is a widespread mechanism that contributes to the sophisticated dynamics of gene regulation. Approximately 50% of all protein-coding human genes harbor multiple polyadenylation (PA) sites; their selective and combinatorial use gives rise to transcript variants with differing length of their 3' untranslated region (3'UTR). Shortened variants escape UTR-mediated regulation by microRNAs (miRNAs), especially in cancer, where global 3'UTR shortening accelerates disease progression, dedifferentiation and proliferation. Here we present APADB, a database of vertebrate PA sites determined by 3' end sequencing, using massive analysis of complementary DNA ends. APADB provides (A)PA sites for coding and non-coding transcripts of human, mouse and chicken genes. For human and mouse, several tissue types, including different cancer specimens, are available. APADB records the loss of predicted miRNA binding sites and visualizes next-generation sequencing reads that support each PA site in a genome browser. The database tables can either be browsed according to organism and tissue or alternatively searched for a gene of interest. APADB is the largest database of APA in human, chicken and mouse. The stored information provides experimental evidence for thousands of PA sites and APA events. APADB combines 3' end sequencing data with prediction algorithms of miRNA binding sites, allowing to further improve prediction algorithms. Current databases lack correct information about 3'UTR lengths, especially for chicken, and APADB provides necessary information to close this gap. Database URL: http://tools.genxpro.net/apadb/
Mathematical modeling of Arabidopsis thaliana with focus on network decomposition and reduction
(2014)
Systems biology has become an important research field during the last decade. It focusses on the understanding of the systems which emit the measured data. An important part of this research field is the network analysis, investigating biological networks. An essential point of the inspection of these network models is their validation, i.e., the successful comparison of predicted properties to measured data. Here especially Petri nets have shown their usefulness as modeling technique, coming with sound analysis methods and an intuitive representation of biological network data.
A very important tool for network validation is the analysis of the Transition-invariants (TI), which represent possible steady-state pathways, and the investigation of the liveness property. The computational complexity of the determination of both, TI and liveness property, often hamper their investigation.
To investigate this issue, a metabolic network model is created. It describes the core metabolism of Arabidopsis thaliana, and it is solely based on data from the literature. The model is too complex to determine the TI and the liveness property.
Several strategies are followed to enable an analysis and validation of the network. A network decomposition is utilized in two different ways: manually, motivated by idea to preserve the integrity of biological pathways, and automatically, motivated by the idea to minimize the number of crossing edges. As a decomposition may not be preserving important properties like the coveredness, a network reduction approach is suggested, which is mathematically proven to conserve these important properties. To deal with the large amount of data coming from the TI analysis, new organizational structures are proposed. The liveness property is investigated by reducing the complexity of the calculation method and adapting it to biological networks.
The results obtained by these approaches suggest a valid network model. In conclusion, the proposed approaches and strategies can be used in combination to allow the validation and analysis of highly complex biological networks.
A concurrent implementation of software transactional memory in Concurrent Haskell using a call-by-need functional language with processes and futures is given. The description of the small-step operational semantics is precise and explicit, and employs an early abort of conflicting transactions. A proof of correctness of the implementation is given for a contextual semantics with may- and should-convergence. This implies that our implementation is a correct evaluator for an abstract specification equipped with a big-step semantics.
Towards correctness of program transformations through unification and critical pair computation
(2011)
Correctness of program transformations in extended lambda calculi with a contextual semantics is usually based on reasoning about the operational semantics which is a rewrite semantics. A successful approach to proving correctness is the combination of a context lemma with the computation of overlaps between program transformations and the reduction rules, and then of so-called complete sets of diagrams. The method is similar to the computation of critical pairs for the completion of term rewriting systems.We explore cases where the computation of these overlaps can be done in a first order way by variants of critical pair computation that use unification algorithms. As a case study we apply the method to a lambda calculus with recursive let-expressions and describe an effective unification algorithm to determine all overlaps of a set of transformations with all reduction rules. The unification algorithm employs many-sorted terms, the equational theory of left-commutativity modelling multi-sets, context variables of different kinds and a mechanism for compactly representing binding chains in recursive let-expressions.
The interactive verification system VeriFun is based on a polymorphic call-by-value functional language and on a first-order logic with initial model semantics w.r.t. constructors. It is designed to perform automatic induction proofs and can also deal with partial functions. This paper provides a reconstruction of the corresponding logic and semantics using the standard treatment of undefinedness which adapts and improves the VeriFun-logic by allowing reasoning on nonterminating expressions and functions. Equality of expressions is defined as contextual equivalence based on observing termination in all closing contexts. The reconstruction shows that several restrictions of the VeriFun framework can easily be removed, by natural generalizations: mutual recursive functions, abstractions in the data values, and formulas with arbitrary quantifier prefix can be formulated. The main results of this paper are: an extended set of deduction rules usable in VeriFun under the adapted semantics is proved to be correct, i.e. they respect the observational equivalence in all extensions of a program. We also show that certain classes of theorems are conservative under extensions, like universally quantified equations. Also other special classes of theorems are analyzed for conservativity.
The interactive verification system VeriFun is based on a polymorphic call-by-value functional language and on a first-order logic with initial model semantics w.r.t. constructors. This paper provides a reconstruction of the corresponding logic when partial functions are permitted. Typing is polymorphic for the definition of functions but monomorphic for terms in formulas. Equality of terms is defined as contextual equivalence based on observing termination in all contexts. The reconstruction also allows several generalizations of the functional language like mutual recursive functions and abstractions in the data values. The main results are: Correctness of several program transformations for all extensions of a program, which have a potential usage in a deduction system. We also proved that universally quantified equations are conservative, i.e. if a universally quantified equation is valid w.r.t. a program P, then it remains valid if the program is extended by new functions and/or new data types.
Motivated by the question of correctness of a specific implementation of concurrent buffers in the lambda calculus with futures underlying Alice ML, we prove that concurrent buffers and handled futures can correctly encode each other. Correctness means that our encodings preserve and reflect the observations of may- and must-convergence, and as a consequence also yields soundness of the encodings with respect to a contextually defined notion of program equivalence. While these translations encode blocking into queuing and waiting, we also describe an adequate encoding of buffers in a calculus without handles, which is more low-level and uses busy-waiting instead of blocking. Furthermore we demonstrate that our correctness concept applies to the whole compilation process from high-level to low-level concurrent languages, by translating the calculus with buffers, handled futures and data constructors into a small core language without those constructs.
We investigate methods and tools for analyzing translations between programming languages with respect to observational semantics. The behavior of programs is observed in terms of may- and mustconvergence in arbitrary contexts, and adequacy of translations, i.e., the reflection of program equivalence, is taken to be the fundamental correctness condition. For compositional translations we propose a notion of convergence equivalence as a means for proving adequacy. This technique avoids explicit reasoning about contexts, and is able to deal with the subtle role of typing in implementations of language extensions.
We investigate methods and tools for analyzing translations between programming languages with respect to observational semantics. The behavior of programs is observed in terms of may- and mustconvergence in arbitrary contexts, and adequacy of translations, i.e., the reflection of program equivalence, is taken to be the fundamental correctness condition. For compositional translations we propose a notion of convergence equivalence as a means for proving adequacy. This technique avoids explicit reasoning about contexts, and is able to deal with the subtle role of typing in implementations of language extensions.
We investigate methods and tools for analysing translations between programming languages with respect to observational semantics. The behaviour of programs is observed in terms of may- and mustconvergence in arbitrary contexts, and adequacy of translations, i.e., the reflection of program equivalence, is taken to be the fundamental correctness condition. For compositional translations we propose a notion of convergence equivalence as a means for proving adequacy. This technique avoids explicit reasoning about contexts, and is able to deal with the subtle role of typing in implementations of language extensions.
We investigate methods and tools for analysing translations between programming languages with respect to observational semantics. The behaviour of programs is observed in terms of may- and mustconvergence in arbitrary contexts, and adequacy of translations, i.e., the reflection of program equivalence, is taken to be the fundamental correctness condition. For compositional translations we propose a notion of convergence equivalence as a means for proving adequacy. This technique avoids explicit reasoning about contexts, and is able to deal with the subtle role of typing in implementations of language extensions.
The paper proposes a variation of simulation for checking and proving contextual equivalence in a non-deterministic call-by-need lambda-calculus with constructors, case, seq, and a letrec with cyclic dependencies. It also proposes a novel method to prove its correctness. The calculus’ semantics is based on a small-step rewrite semantics and on may-convergence. The cyclic nature of letrec bindings, as well as nondeterminism, makes known approaches to prove that simulation implies contextual equivalence, such as Howe’s proof technique, inapplicable in this setting. The basic technique for the simulation as well as the correctness proof is called pre-evaluation, which computes a set of answers for every closed expression. If simulation succeeds in finite computation depth, then it is guaranteed to show contextual preorder of expressions.
This paper proves several generic variants of context lemmas and thus contributes to improving the tools for observational semantics of deterministic and non-deterministic higher-order calculi that use a small-step reduction semantics. The generic (sharing) context lemmas are provided for may- as well as two variants of must-convergence, which hold in a broad class of extended process- and extended lambda calculi, if the calculi satisfy certain natural conditions. As a guide-line, the proofs of the context lemmas are valid in call-by-need calculi, in callby-value calculi if substitution is restricted to variable-by-variable and in process calculi like variants of the π-calculus. For calculi employing beta-reduction using a call-by-name or call-by-value strategy or similar reduction rules, some iu-variants of ciu-theorems are obtained from our context lemmas. Our results reestablish several context lemmas already proved in the literature, and also provide some new context lemmas as well as some new variants of the ciu-theorem. To make the results widely applicable, we use a higher-order abstract syntax that allows untyped calculi as well as certain simple typing schemes. The approach may lead to a unifying view of higher-order calculi, reduction, and observational equality.
This paper proves several generic variants of context lemmas and thus contributes to improving the tools to develop observational semantics that is based on a reduction semantics for a language. The context lemmas are provided for may- as well as two variants of mustconvergence and a wide class of extended lambda calculi, which satisfy certain abstract conditions. The calculi must have a form of node sharing, e.g. plain beta reduction is not permitted. There are two variants, weakly sharing calculi, where the beta-reduction is only permitted for arguments that are variables, and strongly sharing calculi, which roughly correspond to call-by-need calculi, where beta-reduction is completely replaced by a sharing variant. The calculi must obey three abstract assumptions, which are in general easily recognizable given the syntax and the reduction rules. The generic context lemmas have as instances several context lemmas already proved in the literature for specific lambda calculi with sharing. The scope of the generic context lemmas comprises not only call-by-need calculi, but also call-by-value calculi with a form of built-in sharing. Investigations in other, new variants of extended lambda-calculi with sharing, where the language or the reduction rules and/or strategy varies, will be simplified by our result, since specific context lemmas are immediately derivable from the generic context lemma, provided our abstract conditions are met.
We present a higher-order call-by-need lambda calculus enriched with constructors, case-expressions, recursive letrec-expressions, a seq-operator for sequential evaluation and a non-deterministic operator amb that is locally bottom-avoiding. We use a small-step operational semantics in form of a single-step rewriting system that defines a (nondeterministic) normal order reduction. This strategy can be made fair by adding resources for bookkeeping. As equational theory we use contextual equivalence, i.e. terms are equal if plugged into any program context their termination behaviour is the same, where we use a combination of may- as well as must-convergence, which is appropriate for non-deterministic computations. We show that we can drop the fairness condition for equational reasoning, since the valid equations w.r.t. normal order reduction are the same as for fair normal order reduction. We evolve different proof tools for proving correctness of program transformations, in particular, a context lemma for may- as well as mustconvergence is proved, which restricts the number of contexts that need to be examined for proving contextual equivalence. In combination with so-called complete sets of commuting and forking diagrams we show that all the deterministic reduction rules and also some additional transformations preserve contextual equivalence.We also prove a standardisation theorem for fair normal order reduction. The structure of the ordering <=c a is also analysed: Ω is not a least element, and <=c already implies contextual equivalence w.r.t. may-convergence.
We present a higher-order call-by-need lambda calculus enriched with constructors, case-expressions, recursive letrec-expressions, a seq-operator for sequential evaluation and a non-deterministic operator amb that is locally bottom-avoiding. We use a small-step operational semantics in form of a single-step rewriting system that defines a (nondeterministic) normal order reduction. This strategy can be made fair by adding resources for bookkeeping. As equational theory we use contextual equivalence, i.e. terms are equal if plugged into any program context their termination behaviour is the same, where we use a combination of may- as well as must-convergence, which is appropriate for non-deterministic computations. We show that we can drop the fairness condition for equational reasoning, since the valid equations w.r.t. normal order reduction are the same as for fair normal order reduction. We evolve different proof tools for proving correctness of program transformations, in particular, a context lemma for may- as well as mustconvergence is proved, which restricts the number of contexts that need to be examined for proving contextual equivalence. In combination with so-called complete sets of commuting and forking diagrams we show that all the deterministic reduction rules and also some additional transformations preserve contextual equivalence.We also prove a standardisation theorem for fair normal order reduction. The structure of the ordering <=c a is also analysed: Ω is not a least element, and <=c already implies contextual equivalence w.r.t. may-convergence.
We develop a proof method to show that in a (deterministic) lambda calculus with letrec and equipped with contextual equivalence the call-by-name and the call-by-need evaluation are equivalent, and also that the unrestricted copy-operation is correct. Given a let-binding x = t, the copy-operation replaces an occurrence of the variable x by the expression t, regardless of the form of t. This gives an answer to unresolved problems in several papers, it adds a strong method to the tool set for reasoning about contextual equivalence in higher-order calculi with letrec, and it enables a class of transformations that can be used as optimizations. The method can be used in different kind of lambda calculi with cyclic sharing. Probably it can also be used in non-deterministic lambda calculi if the variable x is “deterministic”, i.e., has no interference with non-deterministic executions. The main technical idea is to use a restricted variant of the infinitary lambda-calculus, whose objects are the expressions that are unrolled w.r.t. let, to define the infinite developments as a reduction calculus on the infinite trees and showing a standardization theorem.
The goal of this report is to prove correctness of a considerable subset of transformations w.r.t. contextual equivalence in an extended lambda-calculus LS with case, constructors, seq, let, and choice, with a simple set of reduction rules; and to argue that an approximation calculus LA is equivalent to LS w.r.t. the contextual preorder, which enables the proof tool of simulation. Unfortunately, a direct proof appears to be impossible.
The correctness proof is by defining another calculus L comprising the complex variants of copy, case-reduction and seq-reductions that use variable-binding chains. This complex calculus has well-behaved diagrams and allows a proof of correctness of transformations, and that the simple calculus LS, the calculus L, and the calculus LA all have an equivalent contextual preorder.