Computational analysis of transcriptional responses to the Activin signal

Die Signalwege des transformierenden Wachstumsfaktors β (TGF-β) spielen eine entscheidende Rolle bei der Zellproliferation, -migration und -apoptose durch die Aktivierung von Smad-Proteinen. Untersuchungen haben gezeigt, dass die biologischen Wirkungen des TGF-β-Signalwegs stark vom Zellkontext abhängen. In dieser Arbeit ging es darum zu verstehen, wie TGF-β-Signale Zielgene unterschiedlich regulieren können, wie unterschiedliche Dynamiken der Genexpression durch TGF-β-Signale induziert werden und auf welche Weise Smad-Proteine zu unterschiedlichen Expressionsmustern von TGF- β-Zielgenen beitragen. Der Fokus dieser Studie liegt auf den transkriptionsregulatorischen Effekten des Nodal / Activin-Liganden, der zur TGF-β-Superfamilie gehört und ein wichtiger Faktor in der frühen embryonalen Entwicklung ist. Um diese Effekte zu analysieren, habe ich kinetische Modelle entwickelt und mit den Zeitverlaufsdaten von RNA-Polymerase II (Pol II) und Smad2-Chromatin-Bindungsprofilen für die Zielgene kalibriert. Unter Verwendung des Akaike-Informationskriteriums (AIC) zur Bewertung verschiedener kinetischer Modelle stellten wir fest, dass der Nodal / Activin-Signalweg Zielgene über verschiedene Mechanismen reguliert. Im Nodal / Activin-Smad2-Signalweg spielt Smad2 für verschiedene Zielgene unterschiedliche regulatorische Rollen. Wir zeigen, wie Smad2 daran beteiligt ist, die Transkriptions- oder Abbaurate jedes Zielgens separat zu regulieren. Darüber hinaus werden eine Reihe von Merkmalen, die die Transkriptionsdynamik von Zielgenen vorhersagen können, durch logistische Regression ausgewählt. Der hier vorgestellte Ansatz liefert quantitative Beziehungen zwischen der Dynamik des Transkriptionsfaktors und den Transkriptionsantworten. Diese Arbeit bietet auch einen allgemeinen mathematischen Rahmen für die Untersuchung der Transkriptionsregulation anderer Signalwege.Transforming growth factor-β (TGF-β) signaling pathways play a crucial role in cell proliferation, migration, and apoptosis through the activation of Smad proteins. Research has shown that the biological effects of TGF-β signaling pathway are highly cellular-context-dependent. In this thesis work, I aimed at understanding how TGF-β signaling can regulate target genes differently, how different dynamics of gene expressions are induced by TGF-β signal, and what is the role of Smad proteins in differing the profiles of target gene expression. In this study, I focused on the transcriptional responses to the Nodal/Activin ligand, which is a member of the TGF-β superfamily and a key regulator of early embryonic development. Kinetic models were developed and calibrated with the time course data of RNA polymerase II (Pol II) and Smad2 chromatin binding profiles for the target genes. Using the Akaike information criterion (AIC) to evaluate different kinetic models, we discovered that Nodal/Activin signaling regulates target genes via different mechanisms. In the Nodal/Activin-Smad2 signaling pathway, Smad2 plays different regulatory roles on different target genes. We show how Smad2 participates in regulating the transcription or degradation rate of each target gene separately. Moreover, a series of features that can predict the transcription dynamics of target genes are selected by logistic regression. The approach we present here provides quantitative relationships between transcription factor dynamics and transcriptional responses. This work also provides a general computational framework for studying the transcription regulations of other signaling pathways

Generalized Hofstadter model on a cubic optical lattice: From nodal bands to the three-dimensional quantum Hall effect

We propose that a tunable generalized three-dimensional Hofstadter Hamiltonian can be realized by engineering the Raman-assisted hopping of ultracold atoms in a cubic optical lattice. The Hamiltonian describes a periodic lattice system under artificial magnetic fluxes in three dimensions. For certain hopping configurations, the bulk bands can have Weyl points and nodal loops, respectively, allowing the study of both the two nodal semimetal states within this system. Furthermore, we illustrate that with proper rational fluxes and hopping parameters, the system can exhibit the three-dimensional quantum Hall effect when the Fermi level lies in the band gaps, which is topologically characterized by one or two nonzero Chern numbers. Our proposed optical-lattice system provides a promising platform for exploring various exotic topological phases in three dimensions.Comment: 10 pages, 5 figure

Faster Mutation Analysis via Equivalence Modulo States

Mutation analysis has many applications, such as asserting the quality of test suites and localizing faults. One important bottleneck of mutation analysis is scalability. The latest work explores the possibility of reducing the redundant execution via split-stream execution. However, split-stream execution is only able to remove redundant execution before the first mutated statement. In this paper we try to also reduce some of the redundant execution after the execution of the first mutated statement. We observe that, although many mutated statements are not equivalent, the execution result of those mutated statements may still be equivalent to the result of the original statement. In other words, the statements are equivalent modulo the current state. In this paper we propose a fast mutation analysis approach, AccMut. AccMut automatically detects the equivalence modulo states among a statement and its mutations, then groups the statements into equivalence classes modulo states, and uses only one process to represent each class. In this way, we can significantly reduce the number of split processes. Our experiments show that our approach can further accelerate mutation analysis on top of split-stream execution with a speedup of 2.56x on average.Comment: Submitted to conferenc