FPGA-based Query Acceleration for Non-relational Databases

Database management systems are an integral part of today’s everyday life. Trends like smart applications, the internet of things, and business and social networks require applications to deal efficiently with data in various data models close to the underlying domain. Therefore, non-relational database systems provide a wide variety of database models, like graphs and documents. However, current non-relational database systems face performance challenges due to the end of Dennard scaling and therefore performance scaling of CPUs. In the meanwhile, FPGAs have gained traction as accelerators for data management. Our goal is to tackle the performance challenges of non-relational database systems with FPGA acceleration and, at the same time, address design challenges of FPGA acceleration itself. Therefore, we split this thesis up into two main lines of work: graph processing and flexible data processing. Because of the lacking benchmark practices for graph processing accelerators, we propose GraphSim. GraphSim is able to reproduce runtimes of these accelerators based on a memory access model of the approach. Through this simulation environment, we extract three performance-critical accelerator properties: asynchronous graph processing, compressed graph data structure, and multi-channel memory. Since these accelerator properties have not been combined in one system, we propose GraphScale. GraphScale is the first scalable, asynchronous graph processing accelerator working on a compressed graph and outperforms all state-of-the-art graph processing accelerators. Focusing on accelerator flexibility, we propose PipeJSON as the first FPGA-based JSON parser for arbitrary JSON documents. PipeJSON is able to achieve parsing at line-speed, outperforming the fastest, vectorized parsers for CPUs. Lastly, we propose the subgraph query processing accelerator GraphMatch which outperforms state-of-the-art CPU systems for subgraph query processing and is able to flexibly switch queries during runtime in a matter of clock cycles

Interferon modulates adult neurogenesis by regulating mRNA translation and cell cycle in neural stem cells

Stem cells display intrinsic interferon signaling, which protects them from viral infections. In the aging brain, the increased presence of interferons drives a decline in function in neural stem cells, yet the role of interferon in the young brain is poorly studied. Regardless of whether in the young or old brain, how interferon regulates neural stem cells and whether the intrinsic signaling contributes to the modulation of neurogenesis also remains unknown. Here, I apply single-cell transcriptomics to mice lacking type-I and -II interferon receptors, to assess the presence of interferon regulation in the young and old brains. I find that interferons act selectively on neural stem cells, and not neural progenitors, both in the young and the old brain. This selective role of interferons contributes to shaping the intrinsic interferon signaling in neural stem cells. To unveil the molecular underpinnings of the interferon response, I profile the cell cycle progression, transcriptome, translatome, and phospho-proteome of neural stem cells exposed to interferon β. Briefly, interferon β transiently activates mTORC1 while simultaneously arresting neural stem cells in G0, quiescence state. Importantly, the observed uncoupling of mTORC1 and cell cycle by interferon β represses the translation of the key stem cell activity factor Sox2. In addition, interferon β induces a late shutdown of protein synthesis in neural stem cells, mediated by the inhibition of mTORC1 and the upregulation of p-eIF2αS51. This biphasic regulation of mTORC1 activity and inhibition of cell cycle promotes the exit of the activation state of neural stem cells. Last, I identify IFIT1 as a key effector of the interferon-mediated modulation of neurogenesis in neural stem cells. Unpublished results from my group indicate a novel role of IFIT1 in binding eukaryotic mRNAs in neural stem cells, which suggests a potential role of IFIT1 in neurogenesis. My results show that the absence of IFIT1 impairs the dynamics of the neurogenic niches at all ages in the adult brain, as well as their social traits, learning capacity, and memory acquisition. Overall, I profile the molecular underpinnings of the interferon response in neural stem cells and unveil the regulatory role of interferons in regulating neural stem cells in the young homeostatic brain. This regulatory role of interferons on stemness at all ages reveals novel therapeutic implications of interferons not only in neurogenesis but also in cancer and viral infections in the brain as well as neurodegenerative disorders

Context-specificity of spatially selective neurons in the medial entorhinal cortex

This work has investigated the activity of spatially selective neurons in the medial entorhinal cortex following manipulations of non-metric properties of the environment. The types of neurons investigated were head-direction cells, border cells, speed cells, and especially, grid cells. The latter type of cells is thought to encode a universal Euclidian metric of space and be the main neurobiological substrata for path integration. The main findings are: 1) The removal of visual landmarks caused the grid cell and head-direction cell signals to break down, the speed code to change, and the border cell activity to be less confined to the borders of the arena, and 2) the manipulation of non-metric, visual features of the environment affected the firing rate code of grid cells, head-direction cells, border cells and speed cells, thus revealing the context specificity of their activity. Because of such a context specificity, these fundings argue against the notion that grid cells act as the neurobiological substratum of a cognitive representation of a universal Euclidian metric of space. A similar conclusion holds for other cell types. In turn, these results raise doubt about the possibility of ascribing intuitive spatial categories (maps, compasses, speedometers…) to specific cell types in a way that the brain and our intuitions display similar conceptual structures. However, this does not undermine the possibility that certain cell types may play prominent roles in behaviors like path integration; instead, it suggests a much more complicated functional role than what our heuristic spatial intuitions may capture

First-order thermodynamics of modified gravity

Einstein’s General Relativity is the most successful theory of gravity ever formulated and it has been tested to outstanding precision on a wide range of scales. However, the standard cosmological model based on it requires an unknown dark energy, modelled as a fine-tuned cosmological constant, to explain the universe’s current accelerated expansion. Since gravity is not as well-tested on large cosmological scales as within our Solar System, modified gravity theories are a valid alternative. Even beyond cosmology, the true nature of gravity remains elusive. For example, the field equations of gravity theories can be derived as equations of state from purely thermodynamical considerations. This leads to identifying General Relativity with an equilibrium state of gravity and modified gravity with a non-equilibrium one. In this thesis, we present a novel approach to the thermodynamics of modified gravity which provides a concrete realisation of this idea. Applying a non-equilibrium thermodynamical description to the effective fluid describing scalar-tensor gravity, a “thermodynamics of gravitational theories” naturally emerges. Applications of this framework to cosmology, extensions to different classes of modified theories, and the formulation of two complementary descriptions based on temperature and chemical potential sketch a unifying picture of the landscape of gravity theories

Cellular mechanisms underlying tissue pattern emergence in the developing embryo

Mammalian embryo development is highly regulative in nature, with cell fate being reversible to compensate for changes in the nascent environment during early stages. In such regulative paradigms, the complex interactions between cellular processes to accomplish precision in patterning of tissues present exciting open questions in biology. In this thesis, I explore the patterning mechanisms underlying blastocyst maturation during pre-implantation development of the mouse embryo. Development of the mammalian blastocyst involves the progressive segregation of the inner cell mass comprising the embryonic epiblast and the extra-embryonic primitive endoderm, and the expansion of a fluid-filled cavity. A gene regulatory network between fibroblast growth factor signalling and cell fate-specific transcription factors establishes the characteristic salt-and-pepper distribution of epiblast and primitive endoderm cells in the early blastocyst. Following the establishment of the two precursor populations, cells spatially segregate into distinct domains within the embryo. The primitive endoderm forms an epithelial layer at the surface of the fluid cavity, with the pluripotent epiblast enclosed between the trophectoderm and the primitive endoderm. Symmetry-breaking in the blastocyst has been the focus of much research in the past decades. However, a coherent mechanism of blastocyst pattern emergence coordinating cell fate specification, sorting and morphogenesis is lacking. Using reduced systems and advanced live-image analysis, I established a method to characterise cell sorting during fate segregation. Further, combined with biophysical measurements and perturbations, I investigate the interplay between cytoskeletal dynamics, cell migration, and polarity in driving fate segregation. I demonstrate that cell sorting in the inner cell mass is characterised by active migration of primitive endoderm cells towards the cavity surface. The primitive endoderm cells in the early blastocyst display autonomous acquisition of apical polarity, a defining feature essential for their proper segregation into a single epithelial layer enveloping the epiblast. Moreover, in contrast to epiblast cells, apical polarity in primitive endoderm cells facilitates the lowering of surface tension upon encountering the cavity surface, thus being sufficient for cell positioning. Lastly, I provide evidence that cell fate plasticity is lost in late blastocysts due to which the fixed lineage composition of the inner cell mass is optimal exclusively for a particular embryo size. Altogether, the findings presented in this work provide mechanistic insights into segregation of cell fates in the mammalian blastocyst and put forth a novel understanding of robust patterning during embryonic development

Supply and Use of Evidence-Based Learning Activities to Improve Teaching and Learning at the University Level

The aim of this dissertation was to contribute to the understanding of university students’ self-regulated learning and the effectiveness of specific learning activities in a real-world learning setting. In university settings in particular, learning is not only simply delivered by a teacher and absorbed by students but learning success largely depends on students’ behavior. Hence, it is necessary to analyze what students do in a real-world learning setting and how these activities are related to successful learning. To do so, I assessed students’ learning behavior and motivation while attending a lecture class and their association with learning outcomes. In this dissertation, several evidence-based learning activities were implemented in a large university course and their use as well as learning outcomes were evaluated empirically across five cohorts of students between spring 2018 and spring 2022. The dissertation builds on a supply-use model of learning in higher education. In addressing all parts of the model, I describe learning in a university setting and models of self-regulated learning that fit into this context while also discussing different desirable learning outcomes. I present findings on the role of evidence-based learning activities as well as students’ individual prerequisites for academic success. Finally, I present my own empirical findings and, in the last section, I discuss how they can be placed in the context of the state of research. In all three peer-reviewed and internationally published Papers, the use of specific evidence-based learning activities was assessed in large university lecture classes. I continuously aimed to improve the understanding of learning activity use by assessing students’ learning intentions (Paper 1), adapting the assessment of activity use (Papers 2 and 3), and identifying different activity use patterns (Paper 3). Students who used many learning activities gained more knowledge beyond motivation and prior achievement (Papers 1 and 3), they further experienced less motivational decline over the course of one semester (Paper 2), and acquired a more accurate self-assessment of their own knowledge (Paper 3)

Korrelation der Lungenperfusion bei Kindern im Alter von zwei Jahren nach operativ versorgter kongenitaler Zwerchfellhernie mit der Entwicklung einer chronischen Lungenerkrankung

Bei PatientInnen mit kongenitaler Zwerchfellhernie kommt es aufgrund der Verlagerung von Abdomeinalorganen in den Thorax zu einer Lungenhypoplasie. In der Nachsorge nach operativer Versorgung einer CDH erhielt das hier beobachte PatientInnenkollektiv im Alter von 2 Jahren eine MRT-Untersuchung der Lunge. Hier wurde die Perfusion des Lungengewebes quantitativ erfasst und mit dem Vorliegen einer chronischen Lungenerkrankung korreliert. Dabei zeigten Kinder mit chronischer Lungenerkrankung eine signifikant geringere Perfusion des Lungenwegebes, ebenso war die Perfusion der ipsilateralen Lunge signifikant geringer als die der kontralateralen Seit

Development of radiofrequency coils for magnetic resonance-guided particle therapy

The aim of this work was to develop radiofrequency coils suitable for magnetic resonance (MR)-guided particle therapy. For two different MR systems (1.5 T, 0.25 T), a transmit/receive body coil and a receive-only calf coil were designed, constructed, optimized and built. The two coils are characterized by a very thin conductor (thickness: 35 μm) and high radiation transparency to enable precise particle therapy with simultaneous MR imaging. A negligible water equivalent thickness (WET) of the conductor (WET: 0.18−0.19 mm) was measured based on the dose distribution in a water column. In addition, both MR coils can be rotated, allowing flexible particle therapy with multi-angle irradiation. A high homogeneity of the transmit (body coil) and receive (both coils) fields was confirmed in homogeneous phantoms for different rotation angles of the MR coils. The body coil also achieved sufficient transmit power efficiency (0.18−0.27 μT/√W) in the central slice for a complete rotation of the phantom. In terms of image quality, the signal-to-noise ratio (SNR) was measured in a homogeneous phantom, where the body coil (SNR: 109−156) and the calf coil (SNR: 74−90) outperformed commercial coils. Furthermore, the functionality of the two coils was demonstrated in an anthropomorphic phantom (body coil) and in vivo (calf coil)

Exploring the Interplay of Oncolytic Measles Vaccines with the Cancer-Immunity Cycle

Oncolytic vaccine strains of measles virus (MeVac) are studied as novel cancer therapeutics. By preferentially lysing tumor cells, these attenuated viruses induce systemic antitumor immunity. However, MeVac virotherapy alone is insufficient to achieve high rates of complete tumor remissions. Thus, in this study I aimed at identifying immunological mechanisms that limit or restrict the therapeutic potential of oncolytic MeVac. Following the cancer-immunity cycle, I first focused on antigen presentation and T cell priming. I hypothesized that the immune response elicited by MeVac virotherapy is limited by impaired antigen processing, common in tumor cells, and reasoned that delivering pre-processed antigens to the tumor via MeVac vectors could circumvent this limitation. Using a murine system and chicken ovalbumin as model antigen, I showed that dendritic cells and tumor cells exposed to MeVac vectors encoding antigen-derived epitope variants present the encoded epitopes, especially when exposed to MeVac encoding six epitope copies targeted to the proteasome. Increased epitope presentation enhanced priming of naïve OT-I T cells and activation of cognate cytotoxic T lymphocytes. Thus, I proved the concept of using MeVac encoding antigen-derived epitope variants for T cell priming and activation. This project is now continued in the human context. Subsequently, I focused on T cell migration and effector function. Based on efficacy and tumor gene expression data from previous studies, I hypothesized that the efficacy of MeVac virotherapy is limited by insufficient intratumoral expression of specific chemokines and cytotoxic molecules. To assess whether intratumoral overexpression of these molecules improves therapeutic efficacy, I conducted gain of function (GOF) efficacy studies in immunocompetent models of murine melanoma and colon adenocarcinoma. GOF studies with MeVac vectors encoding murine CXCL9, CXCL10, CCL19, or CCL21a, which I generated and characterized, showed that these chemokines do not limit the therapeutic efficacy of oncolytic MeVac. Loss of function studies will reveal whether these molecules are essential for MeVac virotherapy despite not being limiting. The identified cytotoxic molecules will be investigated following the same experimental approach. MeVac virotherapy often results in PD-L1 upregulation on tumor cells. To address whether the PD-1/PD-L1 pathway restricts the efficacy of MeVac virotherapy, I investigated the combination of MeVac with PD-1/PD-L1 blockade in two systems. In an immunocompetent model of murine colon adenocarcinoma, I found that MeVac vectors encoding antibody-like molecules against PD-1 or PD-L1 induce stronger antitumor immune memory compared to MeVac alone. However, this effect was insufficient to improve therapeutic efficacy. In an immunocompetent model of murine pancreatic ductal adenocarcinoma (PDAC), local MeVac plus systemic anti-PD-1 antibody treatment was more effective than either monotherapy. In this model, I showed that MeVac was the main driver of systemic antitumor immunity, but required combination with anti-PD-1 to transiently induce an immune activation gene signature in the tumor. This study provides the basis for a Phase I clinical trial of MeVac plus Pembrolizumab in PDAC patients, currently in preparation. While this work was conducted in wild-type mice, I also established CD46tg mice as a novel animal model to study oncolytic MeVac therapy. My investigations are the first to show that these mice develop systemic tumor-specific and measles virus-specific immunity upon intratumoral MeVac treatment. In gene expression studies, I identified a MeVac-induced tumor immune gene signature that warrants further investigation. Finally, I worked towards the establishment of patient-derived ex vivo tumor slice cultures as a platform to study early effects of oncolytic MeVac in a setting that preserves the patient-specific tumor heterogeneity and microenvironment. Overall, identifying limiting factors of MeVac virotherapy will lead to the rational development of combination approaches that tackle treatment resistance. Furthermore, the refined models that I have established will increase the robustness of preclinical findings, thus improving translation into clinical research. The addendum describes a preclinical study that I conducted to test the cellular immune response of MeVac-susceptible mice to a MeVac-based vaccine candidate against COVID-19

On the geometry of magnetic flows

We investigate the geometry of the dynamics of a charged particle over a Riemannian Manifold with a magnetic force