@phdthesis{6071,
abstract = {Transcription factors, by binding to specific sequences on the DNA, control the precise spatio-temporal expression of genes inside a cell. However, this specificity is limited, leading to frequent incorrect binding of transcription factors that might have deleterious consequences on the cell. By constructing a biophysical model of TF-DNA binding in the context of gene regulation, I will first explore how regulatory constraints can strongly shape the distribution of a population in sequence space. Then, by directly linking this to a picture of multiple types of transcription factors performing their functions simultaneously inside the cell, I will explore the extent of regulatory crosstalk -- incorrect binding interactions between transcription factors and binding sites that lead to erroneous regulatory states -- and understand the constraints this places on the design of regulatory systems. I will then develop a generic theoretical framework to investigate the coevolution of multiple transcription factors and multiple binding sites, in the context of a gene regulatory network that performs a certain function. As a particular tractable version of this problem, I will consider the evolution of two transcription factors when they transmit upstream signals to downstream target genes. Specifically, I will describe the evolutionary steady states and the evolutionary pathways involved, along with their timescales, of a system that initially undergoes a transcription factor duplication event. To connect this important theoretical model to the prominent biological event of transcription factor duplication giving rise to paralogous families, I will then describe a bioinformatics analysis of C2H2 Zn-finger transcription factors, a major family in humans, and focus on the patterns of evolution that paralogs have undergone in their various protein domains in the recent past. },
author = {Prizak, Roshan},
pages = {189},
publisher = {IST Austria},
title = {{Coevolution of transcription factors and their binding sites in sequence space}},
doi = {10.15479/at:ista:th6071},
year = {2019},
}
@phdthesis{201,
abstract = {We describe arrangements of three-dimensional spheres from a geometrical and topological point of view. Real data (fitting this setup) often consist of soft spheres which show certain degree of deformation while strongly packing against each other. In this context, we answer the following questions: If we model a soft packing of spheres by hard spheres that are allowed to overlap, can we measure the volume in the overlapped areas? Can we be more specific about the overlap volume, i.e. quantify how much volume is there covered exactly twice, three times, or k times? What would be a good optimization criteria that rule the arrangement of soft spheres while making a good use of the available space? Fixing a particular criterion, what would be the optimal sphere configuration? The first result of this thesis are short formulas for the computation of volumes covered by at least k of the balls. The formulas exploit information contained in the order-k Voronoi diagrams and its closely related Level-k complex. The used complexes lead to a natural generalization into poset diagrams, a theoretical formalism that contains the order-k and degree-k diagrams as special cases. In parallel, we define different criteria to determine what could be considered an optimal arrangement from a geometrical point of view. Fixing a criterion, we find optimal soft packing configurations in 2D and 3D where the ball centers lie on a lattice. As a last step, we use tools from computational topology on real physical data, to show the potentials of higher-order diagrams in the description of melting crystals. The results of the experiments leaves us with an open window to apply the theories developed in this thesis in real applications.},
author = {Iglesias Ham, Mabel},
pages = {171},
publisher = {IST Austria},
title = {{Multiple covers with balls}},
doi = {10.15479/AT:ISTA:th_1026},
year = {2018},
}
@phdthesis{9,
abstract = {Immune cells migrating to the sites of infection navigate through diverse tissue architectures and switch their migratory mechanisms upon demand. However, little is known about systemic regulators that could allow the acquisition of these mechanisms. We performed a genetic screen in Drosophila melanogaster to identify regulators of germband invasion by embryonic macrophages into the confined space between the ectoderm and mesoderm. We have found that bZIP circadian transcription factors (TFs) Kayak (dFos) and Vrille (dNFIL3) have opposite effects on macrophage germband infiltration: Kayak facilitated and Vrille inhibited it. These TFs are enriched in the macrophages during migration and genetically interact to control it. Kayak sets a less coordinated mode of migration of the macrophage group and increases the probability and length of Levy walks. Intriguingly, the motility of kayak mutant macrophages was also strongly affected during initial germband invasion but not along another less confined route. Inhibiting Rho1 signaling within the tail ectoderm partially rescued the Kayak mutant phenotype, strongly suggesting that migrating macrophages have to overcome a barrier imposed by the stiffness of the ectoderm. Also, Kayak appeared to be important for the maintenance of the round cell shape and the rear edge translocation of the macrophages invading the germband. Complementary to this, the cortical actin cytoskeleton of Kayak- deficient macrophages was strongly affected. RNA sequencing revealed the filamin Cheerio and tetraspanin TM4SF to be downstream of Kayak. Chromatin immunoprecipitation and immunostaining revealed that the formin Diaphanous is another downstream target of Kayak. Immunostaining revealed that the formin Diaphanous is another downstream target of Kayak. Indeed, Cheerio, TM4SF and Diaphanous are required within macrophages for germband invasion, and expression of constitutively active Diaphanous in macrophages was able to rescue the kayak mutant phenotype. Moreover, Cher and Diaphanous are also reduced in the macrophages overexpressing Vrille. We hypothesize that Kayak, through its targets, increases actin polymerization and cortical tension in macrophages and thus allows extra force generation necessary for macrophage dissemination and migration through confined stiff tissues, while Vrille counterbalances it.},
author = {Belyaeva, Vera},
pages = {96},
publisher = {IST Austria},
title = {{Transcriptional regulation of macrophage migration in the Drosophila melanogaster embryo }},
doi = {10.15479/AT:ISTA:th1064},
year = {2018},
}
@phdthesis{395,
abstract = {Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. Despite the remarkable number of scientific breakthroughs of the last 100 years, the treatment of neurodevelopmental disorders (e.g. autism spectrum disorder, intellectual disability, epilepsy) remains a great challenge. Recent advancements in geno mics, like whole-exome or whole-genome sequencing, have enabled scientists to identify numerous mutations underlying neurodevelopmental disorders. Given the few hundred risk genes that were discovered, the etiological variability and the heterogeneous phenotypic outcomes, the need for genotype -along with phenotype- based diagnosis of individual patients becomes a requisite. Driven by this rationale, in a previous study our group described mutations, identified via whole - exome sequencing, in the gene BCKDK – encoding for a key regulator of branched chain amin o acid (BCAA) catabolism - as a cause of ASD. Following up on the role of BCAAs, in the study described here we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized mainly at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation and severe neurolo gical abnormalities. Additionally, deletion of Slc7a5 from the neural progenitor cell population leads to microcephaly. Interestingly, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Furthermore, whole - exome sequencing of patients diagnosed with neurological dis o r ders helped us identify several patients with autistic traits, microcephaly and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. In conclusion, our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for t he BCAA s in human bra in function. Together with r ecent studies (described in chapter two) that have successfully made the transition into clinical practice, our findings on the role of B CAAs might have a crucial impact on the development of novel individualized therapeutic strategies for ASD. },
author = {Tarlungeanu, Dora-Clara},
pages = {88},
publisher = {IST Austria},
title = {{The branched chain amino acids in autism spectrum disorders }},
doi = {10.15479/AT:ISTA:th_992},
year = {2018},
}
@phdthesis{48,
abstract = {The hippocampus is a key brain region for spatial memory and navigation and is needed at all stages of memory, including encoding, consolidation, and recall. Hippocampal place cells selectively discharge at specific locations of the environment to form a cognitive map of the space. During the rest period and sleep following spatial navigation and/or learning, the waking activity of the place cells is reactivated within high synchrony events. This reactivation is thought to be important for memory consolidation and stabilization of the spatial representations. The aim of my thesis was to directly test whether the reactivation content encoded in firing patterns of place cells is important for consolidation of spatial memories. In particular, I aimed to test whether, in cases when multiple spatial memory traces are acquired during learning, the specific disruption of the reactivation of a subset of these memories leads to the selective disruption of the corresponding memory traces or through memory interference the other learned memories are disrupted as well. In this thesis, using a modified cheeseboard paradigm and a closed-loop recording setup with feedback optogenetic stimulation, I examined how the disruption of the reactivation of specific spiking patterns affects consolidation of the corresponding memory traces. To obtain multiple distinctive memories, animals had to perform a spatial task in two distinct cheeseboard environments and the reactivation of spiking patterns associated with one of the environments (target) was disrupted after learning during four hours rest period using a real-time decoding method. This real-time decoding method was capable of selectively affecting the firing rates and cofiring correlations of the target environment-encoding cells. The selective disruption led to behavioural impairment in the memory tests after the rest periods in the target environment but not in the other undisrupted control environment. In addition, the map of the target environment was less stable in the impaired memory tests compared to the learning session before than the map of the control environment. However, when the animal relearned the task, the same map recurred in the target environment that was present during learning before the disruption. Altogether my work demonstrated that the reactivation content is important: assembly-related disruption of reactivation can lead to a selective memory impairment and deficiency in map stability. These findings indeed suggest that reactivated assembly patterns reflect processes associated with the consolidation of memory traces. },
author = {Gridchyn, Igor},
pages = {104},
publisher = {IST Austria},
title = {{Reactivation content is important for consolidation of spatial memory}},
doi = {10.15479/AT:ISTA:th_1042},
year = {2018},
}
@phdthesis{6263,
abstract = {Antibiotic resistance can emerge spontaneously through genomic mutation and render treatment ineffective. To counteract this process, in addition to the discovery and description of resistance mechanisms,a deeper understanding of resistanceevolvabilityand its determinantsis needed. To address this challenge, this thesisuncoversnew genetic determinants of resistance evolvability using a customized robotic setup, exploressystematic ways in which resistance evolution is perturbed due to dose-responsecharacteristics of drugs and mutation rate differences,and mathematically investigates the evolutionary fate of one specific type of evolvability modifier -a stress-induced mutagenesis allele.We find severalgenes which strongly inhibit or potentiate resistance evolution. In order to identify them, we first developedan automated high-throughput feedback-controlled protocol whichkeeps the population size and selection pressure approximately constant for hundreds of cultures by dynamically re-diluting the cultures and adjusting the antibiotic concentration. We implementedthis protocol on a customized liquid handling robot and propagated 100 different gene deletion strains of Escherichia coliin triplicate for over 100 generations in tetracycline and in chloramphenicol, and comparedtheir adaptation rates.We find a diminishing returns pattern, where initially sensitive strains adapted more compared to less sensitive ones. Our data uncover that deletions of certain genes which do not affect mutation rate,including efflux pump components, a chaperone and severalstructural and regulatory genes can strongly and reproducibly alterresistance evolution. Sequencing analysis of evolved populations indicates that epistasis with resistance mutations is the most likelyexplanation. This work could inspire treatment strategies in which targeted inhibitors of evolvability mechanisms will be given alongside antibiotics to slow down resistance evolution and extend theefficacy of antibiotics.We implemented astochasticpopulation genetics model, toverifyways in which general properties, namely, dose-response characteristics of drugs and mutation rates, influence evolutionary dynamics. In particular, under the exposure to antibiotics with shallow dose-response curves,bacteria have narrower distributions of fitness effects of new mutations. We show that in silicothis also leads to slower resistance evolution. We see and confirm with experiments that increased mutation rates, apart from speeding up evolution, also leadto high reproducibility of phenotypic adaptation in a context of continually strong selection pressure.Knowledge of these patterns can aid in predicting the dynamics of antibiotic resistance evolutionand adapting treatment schemes accordingly.Focusing on a previously described type of evolvability modifier –a stress-induced mutagenesis allele –we find conditions under which it can persist in a population under periodic selectionakin to clinical treatment. We set up a deterministic infinite populationcontinuous time model tracking the frequencies of a mutator and resistance allele and evaluate various treatment schemes in how well they maintain a stress-induced mutator allele. In particular,a high diversity of stresses is crucial for the persistence of the mutator allele. This leads to a general trade-off where exactly those diversifying treatment schemes which are likely to decrease levels of resistance could lead to stronger selection of highly evolvable genotypes.In the long run, this work will lead to a deeper understanding of the genetic and cellular mechanisms involved in antibiotic resistance evolution and could inspire new strategies for slowing down its rate. },
author = {Lukacisinova, Marta},
pages = {91},
publisher = {IST Austria},
title = {{Genetic determinants of antibiotic resistance evolution}},
doi = {10.15479/AT:ISTA:th1072},
year = {2018},
}
@phdthesis{50,
abstract = {The Wnt/planar cell polarity (Wnt/PCP) pathway determines planar polarity of epithelial cells in both vertebrates and invertebrates. The role that Wnt/PCP signaling plays in mesenchymal contexts, however, is only poorly understood. While previous studies have demonstrated the capacity of Wnt/PCP signaling to polarize and guide directed migration of mesenchymal cells, it remains unclear whether endogenous Wnt/PCP signaling performs these functions instructively, as it does in epithelial cells. Here we developed a light-switchable version of the Wnt/PCP receptor Frizzled 7 (Fz7) to unambiguously distinguish between an instructive and a permissive role of Wnt/PCP signaling for the directional collective migration of mesendoderm progenitor cells during zebrafish gastrulation. We show that prechordal plate (ppl) cell migration is defective in maternal-zygotic fz7a and fz7b (MZ fz7a,b) double mutant embryos, and that Fz7 functions cell-autonomously in this process by promoting ppl cell protrusion formation and directed migration. We further show that local activation of Fz7 can direct ppl cell migration both in vitro and in vivo. Surprisingly, however, uniform Fz7 activation is sufficient to fully rescue the ppl cell migration defect in MZ fz7a,b mutant embryos, indicating that Wnt/PCP signaling functions permissively rather than instructively in directed mesendoderm cell migration during zebrafish gastrulation.},
author = {Capek, Daniel},
pages = {95},
publisher = {IST Austria},
title = {{Optogenetic Frizzled 7 reveals a permissive function of Wnt/PCP signaling in directed mesenchymal cell migration}},
doi = {10.15479/AT:ISTA:TH_1031},
year = {2018},
}
@phdthesis{149,
abstract = {The eigenvalue density of many large random matrices is well approximated by a deterministic measure, the self-consistent density of states. In the present work, we show this behaviour for several classes of random matrices. In fact, we establish that, in each of these classes, the self-consistent density of states approximates the eigenvalue density of the random matrix on all scales slightly above the typical eigenvalue spacing. For large classes of random matrices, the self-consistent density of states exhibits several universal features. We prove that, under suitable assumptions, random Gram matrices and Hermitian random matrices with decaying correlations have a 1/3-Hölder continuous self-consistent density of states ρ on R, which is analytic, where it is positive, and has either a square root edge or a cubic root cusp, where it vanishes. We, thus, extend the validity of the corresponding result for Wigner-type matrices from [4, 5, 7]. We show that ρ is determined as the inverse Stieltjes transform of the normalized trace of the unique solution m(z) to the Dyson equation −m(z) −1 = z − a + S[m(z)] on C N×N with the constraint Im m(z) ≥ 0. Here, z lies in the complex upper half-plane, a is a self-adjoint element of C N×N and S is a positivity-preserving operator on C N×N encoding the first two moments of the random matrix. In order to analyze a possible limit of ρ for N → ∞ and address some applications in free probability theory, we also consider the Dyson equation on infinite dimensional von Neumann algebras. We present two applications to random matrices. We first establish that, under certain assumptions, large random matrices with independent entries have a rotationally symmetric self-consistent density of states which is supported on a centered disk in C. Moreover, it is infinitely often differentiable apart from a jump on the boundary of this disk. Second, we show edge universality at all regular (not necessarily extreme) spectral edges for Hermitian random matrices with decaying correlations.},
author = {Alt, Johannes},
pages = {456},
publisher = {IST Austria},
title = {{Dyson equation and eigenvalue statistics of random matrices}},
doi = {10.15479/AT:ISTA:TH_1040},
year = {2018},
}
@phdthesis{49,
abstract = {Nowadays, quantum computation is receiving more and more attention as an alternative to the classical way of computing. For realizing a quantum computer, different devices are investigated as potential quantum bits. In this thesis, the focus is on Ge hut wires, which turned out to be promising candidates for implementing hole spin quantum bits. The advantages of Ge as a material system are the low hyperfine interaction for holes and the strong spin orbit coupling, as well as the compatibility with the highly developed CMOS processes in industry. In addition, Ge can also be isotopically purified which is expected to boost the spin coherence times. The strong spin orbit interaction for holes in Ge on the one hand enables the full electrical control of the quantum bit and on the other hand should allow short spin manipulation times. Starting with a bare Si wafer, this work covers the entire process reaching from growth over the fabrication and characterization of hut wire devices up to the demonstration of hole spin resonance. From experiments with single quantum dots, a large g-factor anisotropy between the in-plane and the out-of-plane direction was found. A comparison to a theoretical model unveiled the heavy-hole character of the lowest energy states. The second part of the thesis addresses double quantum dot devices, which were realized by adding two gate electrodes to a hut wire. In such devices, Pauli spin blockade was observed, which can serve as a read-out mechanism for spin quantum bits. Applying oscillating electric fields in spin blockade allowed the demonstration of continuous spin rotations and the extraction of a lower bound for the spin dephasing time. Despite the strong spin orbit coupling in Ge, the obtained value for the dephasing time is comparable to what has been recently reported for holes in Si. All in all, the presented results point out the high potential of Ge hut wires as a platform for long-lived, fast and fully electrically tunable hole spin quantum bits.},
author = {Watzinger, Hannes},
pages = {77},
publisher = {IST Austria},
title = {{Ge hut wires - from growth to hole spin resonance}},
doi = {10.15479/AT:ISTA:th_1033},
year = {2018},
}
@phdthesis{68,
abstract = {The most common assumption made in statistical learning theory is the assumption of the independent and identically distributed (i.i.d.) data. While being very convenient mathematically, it is often very clearly violated in practice. This disparity between the machine learning theory and applications underlies a growing demand in the development of algorithms that learn from dependent data and theory that can provide generalization guarantees similar to the independent situations. This thesis is dedicated to two variants of dependencies that can arise in practice. One is a dependence on the level of samples in a single learning task. Another dependency type arises in the multi-task setting when the tasks are dependent on each other even though the data for them can be i.i.d. In both cases we model the data (samples or tasks) as stochastic processes and introduce new algorithms for both settings that take into account and exploit the resulting dependencies. We prove the theoretical guarantees on the performance of the introduced algorithms under different evaluation criteria and, in addition, we compliment the theoretical study by the empirical one, where we evaluate some of the algorithms on two real world datasets to highlight their practical applicability.},
author = {Zimin, Alexander},
pages = {92},
publisher = {IST Austria},
title = {{Learning from dependent data}},
doi = {10.15479/AT:ISTA:TH1048},
year = {2018},
}