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Correctness of program transformations and translations in concurrent programming is the focus of our research. In this case study the relation of the synchronous pi-calculus and a core language of Concurrent Haskell (CH) with asynchronous communication is investigated. We show that CH embraces the synchronous pi-calculus. The formal foundations are contextual semantics in both languages, where may- as well as should-convergence are observed. We succeed in defining and proving smart properties of a particular translation mapping the synchronous pi-calculus into CH. This implies that pi-processes are error-free if and only if their translation is an error-free CH-program Our result shows that the chosen semantics is not only powerful, but can also be applied in concrete and technically complex situations. The developed translation uses private names. We also automatically check potentially correct translations that use global names instead of private names. As a complexity parameter we use the number of MVars introduced by the transformation, where MVars are synchronized 1-place buffers. The automated refutation of incorrect translations leads to a classification of potentially correct translations, and to the conjecture that one global MVar is insufficient.
Correctness of program transformations and translations in concurrent programming is the focus of our research. In this case study the relation of the synchronous pi-calculus and a core language of Concurrent Haskell (CH) with asynchronous communication is investigated. We show that CH embraces the synchronous pi-calculus. The formal foundations are contextual semantics in both languages, where may- as well as should-convergence are observed. We succeed in defining and proving smart properties of a particular translation mapping the synchronous pi-calculus into CH. This implies that pi-processes are error-free if and only if their translation is an error-free CH-program Our result shows that the chosen semantics is not only powerful, but can also be applied in concrete and technically complex situations. The developed translation uses private names. We also automatically check potentially correct translations that use global names instead of private names. As a complexity parameter we use the number of MVars introduced by the transformation, where MVars are synchronized 1-place buffers. The automated refutation of incorrect translations leads to a classification of potentially correct translations, and to the conjecture that one global MVar is insufficient.
Correctness of program transformations and translations in concurrent programming is the focus of our research. In this case study the relation of the synchronous pi-calculus and a core language of Concurrent Haskell (CH) with asynchronous communication is investigated. We show that CH embraces the synchronous pi-calculus. The formal foundations are contextual semantics in both languages, where may- as well as should-convergence are observed. We succeed in defining and proving smart properties of a particular translation mapping the synchronous pi-calculus into CH. This implies that pi-processes are error-free if and only if their translation is an error-free CH-program Our result shows that the chosen semantics is not only powerful, but can also be applied in concrete and technically complex situations. The developed translation uses private names. We also automatically check potentially correct translations that use global names instead of private names. As a complexity parameter we use the number of MVars introduced by the transformation, where MVars are synchronized 1-place buffers. The automated refutation of incorrect translations leads to a classification of potentially correct translations, and to the conjecture that one global MVar is insufficient.
We investigate translations from the synchronous pi-calculus
into a core language of Concurrent Haskell (CH). Synchronous messagepassing of the pi-calculus is encoded as sending messages and adding synchronization using Concurrent Haskell’s mutable shared-memory locations (MVars). Our correctness criterion for translations is invariance of may- and should-convergence. This embraces that all executions of a process are error-free if and only if this also holds for the translated program. We exhibit a particular correct translation that uses a fresh, private MVar per communication interaction and that is in addition adequate, and which is also fully abstract on closed expressions. A metaresult is that CH has the expressive power and the concurrency capabilities of the synchronous pi-calculus.
We also automatically check variants of translations of synchronous communication into an asynchronous calculus where only an a priori fixed number of MVars per channel (and not per communication interaction!) is available. We obtain non-correctness results for classes of small translations, and exemplary argue for the correctness (and adequacy) for two translations with a higher number of MVars. We introduce a classification of the potentially correct translations.
We consider matching, rewriting, critical pairs and the Knuth-Bendix confluence test on rewrite rules in a nominal setting extended by atom-variables. Computing critical pairs is done using nominal unification, and rewriting using nominal matching. We utilise atom-variables to formulate rewrite rules, which is an improvement over previous approaches, using usual nominal unification, nominal matching and nominal equivalence of expressions coupled with a freshness constraint. We determine the complexity of several problems in a quantified freshness logic. In particular we show that nominal matching is Πp2-complete. We prove that the adapted Knuth-Bendix confluence test is applicable to a nominal rewrite system with atom-variabes and thus, that there is a decidable test whether confluence of the ground instance of the abstract rewrite system holds. We apply the nominal Knuth Bendix confluence criterion to the theory of monads, and compute a convergent nominal rewrite system modulo alpha-equivalence.
A sound and complete algorithm for nominal unification of higher-order expressions with a recursive let is described, and shown to run in non-deterministic polynomial time. We also explore specializations like nominal letrec-matching for expressions, for DAGs, and for garbage-free expressions and determine their complexity. As extension a nominal unification algorithm for higher-order expressions with recursive let and atom-variables is constructed, where we show that it also runs in non-deterministic polynomial time.
In the last two decades, our understanding of human gene regulation has improved tremendously. There are plentiful computational methods which focus on integrative data analysis of humans, and model organisms, like mouse and drosophila. However, these tools are not directly employable by researchers working on non-model organisms to answer fundamental biological, and evolutionary questions. We aimed to develop new tools, and adapt existing software for the analysis of transcriptomic and epigenomic data of one such non-model organism, Paramecium tetraurelia, an unicellular eukaryote. Paramecium contains two diploid (2n) germline micronuclei (MIC) and a polyploid (800n) somatic macronuclei (MAC). The transcriptomic and epigenomic regulatory landscape of the MAC genome, which has 80% protein-coding genes and short intergenic regions, is poorly understood.
We developed a generic automated eukaryotic short interfering RNA (siRNA) analysis tool, called RAPID. Our tool captures diverse siRNA characteristics from small RNA sequencing data and provides easily navigable visualisations. We also introduced a normalisation technique to facilitate comparison of multiple siRNA-based gene knockdown studies. Further, we developed a pipeline to characterise novel genome-wide endogenous short interfering RNAs (endo-siRNAs). In contrary to many organisms, we found that the endo-siRNAs are not acting in cis, to silence their parent mRNA. We also predicted phasing of siRNAs, which are regulated by the RNA interference (RNAi) pathway.
Further, using RAPID, we investigated the aberrations of endo-siRNAs, and their respective transcriptomic alterations caused by an RNAi pathway triggered by feeding small RNAs against a target gene. We find that the small RNA transcriptome is altered, even if a gene unrelated to RNAi pathway is targeted. This is important in the context of investigations of genetically modified organisms (GMOs). We suggest that future studies need to distinguish transcriptomic changes caused by RNAi inducing techniques and actual regulatory changes.
Subsequently, we adapted existing epigenomics analysis tools to conduct the first comprehensive epigenomic characterisation of nucleosome positioning and histone modifications of the Paramecium MAC. We identified well positioned nucleosomes shifted downstream of the transcription start site. GC content seems to dictate, in cis, the positioning of nucleosomes, histone marks (H3K4me3, H3K9ac, and H3K27me3), and Pol II in the AT-rich Paramecium genome. We employed a chromatin state segmentation approach, on nucleosomes and histone marks, which revealed genes with active, repressive, and bivalent chromatin states. Further, we constructed a regulatory association network of all the aforementioned data, using the sparse partial correlation network technique. Our analysis revealed subsets of genes, whose expression is positively associated with H3K27me3, different to the otherwise reported negative association with gene expression in many other organisms.
Further, we developed a Random Forests classifier to predict gene expression using genic (gene length, intron frequency, etc.) and epigenetic features. Our model has a test performance (PR-AUC) of 0.83. Upon evaluating different feature sets, we found that genic features are as predictive, of gene expression, as the epigenetic features. We used Shapley local feature explanation values, to suggest that high H3K4me3, high intron frequency, low gene length, high sRNA, and high GC content are the most important elements for determining gene expression status.
In this thesis, we developed novel tools, and employed several bioinformatics and machine learning methods to characterise the regulatory landscape of the Paramecium’s (epi)genome.
We empirically investigate algorithms for solving Connected Components in the external memory model. In particular, we study whether the randomized O(Sort(E)) algorithm by Karger, Klein, and Tarjan can be implemented to compete with practically promising and simpler algorithms having only slightly worse theoretical cost, namely Borůvka’s algorithm and the algorithm by Sibeyn and collaborators. For all algorithms, we develop and test a number of tuning options. Our experiments are executed on a large set of different graph classes including random graphs, grids, geometric graphs, and hyperbolic graphs. Among our findings are: The Sibeyn algorithm is a very strong contender due to its simplicity and due to an added degree of freedom in its internal workings when used in the Connected Components setting. With the right tunings, the Karger-Klein-Tarjan algorithm can be implemented to be competitive in many cases. Higher graph density seems to benefit Karger-Klein-Tarjan relative to Sibeyn. Borůvka’s algorithm is not competitive with the two others.
Dieser Arbeit war zum Ziel gesetzt, Methoden zur Simulation von neuronalen Prozessen zu entwickeln, zu implementieren, einzusetzen und zu vergleichen. Ein besonderes Augenmerk lag dabei auf der Frage, wo eine volle räumliche Auflösung der Modelle benötigt wird und wo darauf zugunsten von vereinfachenden niederdimensionalen Modellen, die wesentlich weniger Ressourcen und mathematischen Sachverstand erfordern, verzichtet werden kann. Außerdem wurde speziell bei der Beschreibung der verschiedenen Modelle für die Elektrik der Nervenzellen das Anliegen verfolgt, deren Zusammenhänge und die Natur vereinfachender Annahmen herauszuarbeiten, um deutlich zu machen, an welchen Stellen Probleme bei der Benutzung der weniger komplexen Modelle auftreten können.
In etlichen Beispielen wurde daraufhin untersucht, inwieweit die Vereinfachung auf ein eindimensionales Kabelmodell sowie der Verzicht auf die Betrachtung einzelner Ionensorten die realistische Darstellung der zellulären Elektrik beeinträchtigen können. Dabei stellte sich heraus, dass alle betrachteten Modelle für das rein elektrische Verhalten der Neuronen im Wesentlichen dieselben Ergebnisse liefern, weshalb zu dessen Simulation in den allermeisten Fällen ein 1D-Kabelmodell völlig ausreichend und angezeigt sein dürfte.
Nur wenn Größen von Interesse sind, die in diesem Modell nicht erfasst werden, etwa das Außenraumpotential oder die Ionenkonzentrationen, muss auf genauere Modelle zurückgegriffen werden. Außerdem ist in einer Konvergenzstudie exemplarisch vorgeführt worden, dass bereits eine recht grobe Darstellung der zugrundeliegenden Rechengitter genügt, um korrekte Ergebnisse bei der Simulation der rein elektrischen Signale sicherzustellen.
In scharfem Kontrast steht hierzu die Simulation von einzelnen Ionen-Dynamiken. Bereits in der Untersuchung des Poisson-Nernst-Planck-Modells für das Membranpotential erwies sich, dass für eine korrekte Simulation der diffusiven Anteile der Ionenbewegung wesentlich feinere Gitter benötigt werden.
Noch viel deutlicher wurde dies in Simulationen von Calcium-Wellen in Dendriten, wo -- neben anderen Einsichten -- aufgezeigt werden konnte, dass nicht nur eine feine axiale
(und Zeit-) Auflösung der Dendritengeometrie zur Sicherstellung exakter Ergebnisse notwendig ist, sondern auch die räumliche Auflösung in die übrigen Dimensionen wichtig ist, weswegen eine eindimensionale Kabeldarstellung der Calcium-Dynamik erheblich fehlerbehaftet und
(jedenfalls im Zusammenhang mit Ryanodin-Rezeptorkanälen) von deren Nutzung dringend abzuraten ist. Auch die Darstellung von Kanälen als eine kontinuierliche Dichte in der Membran kann, wie darüber hinaus vorgeführt wurde, problematisch sein.
Ihre exaktere Modellierung, etwa durch Einbettung auch probabilistischer Einzelkanaldarstellungen in das räumliche Modell sollte in zukünftigen Arbeiten noch mehr thematisiert werden.
Mit Blick auf die Wiederverwendbarkeit bereits implementierter Funktionalität innerhalb dieser Arbeiten wurden spezielle Teile dieser Funktionalität hier in einem gesonderten
Kapitel genauer beschrieben. Als komplexes Beispiel für das, was simulationstechnisch bereits im Bereich des Machbaren
liegt, und gleichsam für eine Anwendung, die zeigt, wie möglichst viele der im Rahmen dieser Arbeit entwickelten Methoden miteinander kombiniert werden können, wurde die
Calcium-Dynamik eines kompletten Dendriten innerhalb eines großen aktiven neuronalen Netzwerks simuliert.