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Virtualization allows the creation of virtual instances of physical devices, such as network and processing units. In a virtualized system, governed by a hypervisor, resources are shared among virtual machines (VMs). Virtualization has been receiving increasing interest as away to reduce costs through server consolidation and to enhance the flexibility of physical infrastructures. Although virtualization provides many benefits, it introduces new security challenges; that is, the introduction of a hypervisor introduces threats since hypervisors expose new attack surfaces.
Intrusion detection is a common cyber security mechanism whose task is to detect malicious activities in host and/or network environments. This enables timely reaction in order to stop an on-going attack, or to mitigate the impact of a security breach. The wide adoption of virtualization has resulted in the increasingly common practice of deploying conventional intrusion detection systems (IDSs), for example, hardware IDS appliances or common software-based IDSs, in designated VMs as virtual network functions (VNFs). In addition, the research and industrial communities have developed IDSs specifically designed to operate in virtualized environments (i.e., hypervisorbased IDSs), with components both inside the hypervisor and in a designated VM. The latter are becoming increasingly common with the growing proliferation of virtualized data centers and the adoption of the cloud computing paradigm, for which virtualization is as a key enabling technology.
To minimize the risk of security breaches, methods and techniques for evaluating IDSs in an accurate manner are essential. For instance, one may compare different IDSs in terms of their attack detection accuracy in order to identify and deploy the IDS that operates optimally in a given environment, thereby reducing the risks of a security breach. However, methods and techniques for realistic and accurate evaluation of the attack detection accuracy of IDSs in virtualized environments (i.e., IDSs deployed as VNFs or hypervisor-based IDSs) are lacking. That is, workloads that exercise the sensors of an evaluated IDS and contain attacks targeting hypervisors are needed. Attacks targeting hypervisors are of high severity since they may result in, for example, altering the hypervisors’s memory and thus enabling the execution of malicious code with hypervisor privileges. In addition, there are no metrics and measurement methodologies
for accurately quantifying the attack detection accuracy of IDSs in virtualized environments with elastic resource provisioning (i.e., on-demand allocation or deallocation of virtualized hardware resources to VMs). Modern hypervisors allow for hotplugging virtual CPUs and memory on the designated VM where the intrusion detection engine of hypervisor-based IDSs, as well as of IDSs deployed as VNFs, typically operates. Resource hotplugging may have a significant impact on the attack detection accuracy of an evaluated IDS, which is not taken into account by existing metrics for quantifying IDS attack detection accuracy. This may lead to inaccurate measurements, which, in turn, may result in the deployment of misconfigured or ill-performing IDSs, increasing
the risk of security breaches.
This thesis presents contributions that span the standard components of any system
evaluation scenario: workloads, metrics, and measurement methodologies. The scientific contributions of this thesis are:
A comprehensive systematization of the common practices and the state-of-theart on IDS evaluation. This includes: (i) a definition of an IDS evaluation design space allowing to put existing practical and theoretical work into a common context in a systematic manner; (ii) an overview of common practices in IDS evaluation reviewing evaluation approaches and methods related to each part of the design space; (iii) and a set of case studies demonstrating how different IDS evaluation approaches are applied in practice. Given the significant amount of existing practical and theoretical work related to IDS evaluation, the presented systematization is beneficial for improving the general understanding of the topic by providing an overview of the current state of the field. In addition, it is beneficial for identifying and contrasting advantages and disadvantages of different IDS evaluation methods and practices, while also helping to identify specific requirements and best practices for evaluating current and future IDSs.
An in-depth analysis of common vulnerabilities of modern hypervisors as well as a set of attack models capturing the activities of attackers triggering these vulnerabilities. The analysis includes 35 representative vulnerabilities of hypercall handlers (i.e., hypercall vulnerabilities). Hypercalls are software traps from a kernel of a VM to the hypervisor. The hypercall interface of hypervisors, among device drivers and VM exit events, is one of the attack surfaces that hypervisors expose. Triggering a hypercall vulnerability may lead to a crash of the hypervisor or to altering the hypervisor’s memory. We analyze the origins
of the considered hypercall vulnerabilities, demonstrate and analyze possible attacks that trigger them (i.e., hypercall attacks), develop hypercall attack models(i.e., systematized activities of attackers targeting the hypercall interface), and discuss future research directions focusing on approaches for securing hypercall interfaces.
A novel approach for evaluating IDSs enabling the generation of workloads that contain attacks targeting hypervisors, that is, hypercall attacks. We propose an approach for evaluating IDSs using attack injection (i.e., controlled execution of attacks during regular operation of the environment where an IDS under test is deployed). The injection of attacks is performed based on attack models that capture realistic attack scenarios. We use the hypercall attack models developed as part of this thesis for injecting hypercall attacks.
A novel metric and measurement methodology for quantifying the attack detection accuracy of IDSs in virtualized environments that feature elastic resource provisioning. We demonstrate how the elasticity of resource allocations in such environments may impact the IDS attack detection accuracy and show that using existing metrics in such environments may lead to practically challenging and inaccurate measurements. We also demonstrate the practical use of the metric we propose through a set of case studies, where we evaluate common conventional IDSs deployed as VNFs.
In summary, this thesis presents the first systematization of the state-of-the-art on IDS evaluation, considering workloads, metrics and measurement methodologies as integral parts of every IDS evaluation approach. In addition, we are the first to examine the hypercall attack surface of hypervisors in detail and to propose an approach using attack injection for evaluating IDSs in virtualized environments. Finally, this thesis presents the first metric and measurement methodology for quantifying the attack detection accuracy of IDSs in virtualized environments that feature elastic resource provisioning.
From a technical perspective, as part of the proposed approach for evaluating IDSsthis thesis presents hInjector, a tool for injecting hypercall attacks. We designed hInjector to enable the rigorous, representative, and practically feasible evaluation of IDSs using attack injection. We demonstrate the application and practical usefulness of hInjector, as well as of the proposed approach, by evaluating a representative hypervisor-based IDS designed to detect hypercall attacks. While we focus on evaluating the capabilities of IDSs to detect hypercall attacks, the proposed IDS evaluation approach can be generalized and applied in a broader context. For example, it may be directly used to also evaluate security mechanisms of hypervisors, such as hypercall access control (AC) mechanisms. It may also be applied to evaluate the capabilities
of IDSs to detect attacks involving operations that are functionally similar to hypercalls,
for example, the input/output control (ioctl) calls that the Kernel-based Virtual Machine (KVM) hypervisor supports. For IDSs in virtualized environments featuring elastic resource provisioning, our approach for injecting hypercall attacks can be applied in combination with the attack detection accuracy metric and measurement methodology we propose. Our approach for injecting hypercall attacks, and our metric and measurement methodology, can also be applied independently beyond the scenarios considered in this thesis. The wide spectrum of security mechanisms in virtualized environments whose evaluation can directly benefit from the contributions of this thesis (e.g., hypervisor-based IDSs, IDSs deployed as VNFs, and AC mechanisms) reflects the practical implication of the thesis.
The present work addressed the influence of spins on fundamental processes in organic
semiconductors. In most cases, the role of spins in the conversion of sun light
into electricity was of particular interest. However, also the reversed process, an electric
current creating luminescence, was investigated by means of spin sensitive measurements.
In this work, many material systems were probed with a variety of innovative
detection techniques based on electron paramagnetic resonance spectroscopy.
More precisely, the observable could be customized which resulted in the experimental
techniques photoluminescence detected magnetic resonance (PLDMR), electrically
detected magnetic resonance (EDMR), and electroluminescence detected magnetic
resonance (ELDMR). Besides the commonly used continuous wave EPR spectroscopy,
this selection of measurement methods yielded an access to almost all intermediate
steps occurring in organic semiconductors during the conversion of light into electricity
and vice versa. Special attention was paid to the fact that all results were applicable
to realistic working conditions of the investigated devices, i.e. room temperature application and realistic illumination conditions.
Motoneuron diseases form a heterogeneous group of pathologies characterized by the progressive degeneration of motoneurons. More and more genetic factors associated with motoneuron diseases encode proteins that have a function in RNA metabolism, suggesting that disturbed RNA metabolism could be a common underlying problem in several, perhaps all, forms of motoneuron diseases. Recent results suggest that SMN interacts with hnRNP R and TDP-43 in neuronal processes, which are not part of the classical SMN complex. This point to an additional function of SMN, which could contribute to the high vulnerability of spinal motoneurons in spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). The current study elucidates functional links between SMN, the causative factor of SMA (spinal muscular atrophy), hnRNP R, and TDP-43, a genetic factor in ALS (amyotrophic lateral sclerosis). In order to characterize the functional interaction of SMN with hnRNP R and TDP-43, we produced recombinant proteins and investigated their interaction by co-immunoprecipitation. These proteins bind directly to each other, indicating that no other co-factors are needed for this interaction. SMN potentiates the ability of hnRNP R and TDP-43 to bind to ß-actin mRNA. Depletion of SMN alters the subcellular distribution of hnRNP R in motoneurons both in SMN-knockdown motoneurons and SMA mutant mouse (delta7 SMA). These data point to functions of SMN beyond snRNP assembly which could be crucial for recruitment and transport of RNA particles into axons and axon terminals, a mechanism which may contribute to SMA pathogenesis and ALS.
ALS and FTLD (frontotemporal lobar degeneration) are linked by several lines of evidence with respect to clinical and pathological characteristics. Both sporadic and familial forms are a feature of the ALS-FTLD spectrum, with numerous genes having been associated with these pathological conditions. Both diseases are characterized by the pathological cellular aggregation of proteins. Interestingly, some of these proteins such as TDP-43 and FUS have also common relations not only with ALS-FTLD but also with SMA. Intronic hexanucleotide expansions in C9ORF72 are common in ALS and FTLD but it is unknown whether loss of function, toxicity by the expanded RNA or dipeptides from non ATG-initiated translation is responsible for the pathophysiology. This study tries to characterize the cellular function of C9ORF72 protein. To address this, lentiviral based knockdown and overexpression of C9ORF72 was used in isolated mouse motoneurons. The results clearly show that survival of these motoneurons was not affected by altered C9ORF72 levels, whereas adverse effects on axon growth and growth cone size became apparent after C9ORF72 suppression. Determining the protein interactome revealed several proteins in complexes with C9ORF72. Interestingly, C9ORF72 is present in a complex with cofilin and other actin binding proteins that modulate actin dynamics. These interactions were confirmed both by co-precipitation analyses and in particular by functional studies showing altered actin dynamics in motoneurons with reduced levels of C9ORF72. Importantly, the phosphorylation of cofilin is enhanced in C9ORF72 depleted motoneurons and patient derived lymphoblastoid cells with reduced C9ORF72 levels. These findings indicate that C9ORF72 regulates axonal actin dynamics and the loss of this function could contribute to disease pathomechanisms in ALS and FTLD.
Unsaturated bridges that link the two cyclopentadienyl ligands together in strained ansa metallocenes are rare and limited to carbon-carbon double bonds. The synthesis and isolation of a strained ferrocenophane containing an unsaturated two-boron bridge, isoelectronic with a C=C double bond, was achieved by reduction of a carbene-stabilized 1,1’-bis(dihaloboryl)ferrocene. A combination of spectroscopic and electrochemical measurements as well as density functional theory (DFT) calculations was used to assess the influence of the unprecedented strained cis configuration on the optical and electrochemical properties of the carbene-stabilized diborene unit. Initial reactivity studies show that the dibora[2]ferrocenophane is prone to boron-boron double bond cleavage reactions.
Neuropathic pain, caused by neuronal damage, is a severely impairing mostly chronic condition. Its underlying molecular mechanisms have not yet been thoroughly understood in their variety. In this doctoral thesis, I investigated the role of microRNAs (miRNAs) in a murine model of peripheral neuropathic pain. MiRNAs are small, non-coding RNAs known to play a crucial role in post-transcriptional gene regulation, mainly in cell proliferation and differentiation. Initially, expression patterns in affected dorsal root ganglia (DRG) at different time points after setting a peripheral nerve lesion were studied. DRG showed an increasingly differential expression pattern over the course of one week. Interestingly, a similar effect, albeit to a smaller extent, was observed in corresponding contralateral ganglia. Five miRNA (miR-124, miR-137, miR-183, miR-27b, and miR-505) were further analysed. qPCR, in situ hybridization, and bioinformatical analysis point towards a role for miR-137 and -183 in neuropathic pain as both were downregulated. Furthermore, miR-137 is shown to be specific for non-peptidergic non-myelinated nociceptors (C fibres) in DRG. As the ganglia consist of highly heterocellular tissue, I also developed a neuron-specific approach. Primarily damaged neurons were separated from intact adjacent neurons using fluorescence-activated cell-sorting and their gene expression pattern was analysed using a microarray. Thereby, not only were information obtained about mRNA expression in both groups but, by bioinformatical tools, also inferences on miRNA involvement. The general expression pattern was consistent with previous findings. Still, several genes were found differentially expressed that had not been described in this context before. Among these are corticoliberin or cation-regulating proteins like Otopetrin1. Bioinformatical data conformed, in part, to results from whole DRG, e.g. they implied a down-regulation of miR-124, -137, and -183. However, these results were not significant.
In summary, I found that a) miRNA expression in DRG is influenced by nerve lesions typical of neuropathic pain and that b) these changes develop simultaneously to over-expression of galanin, a marker for neuronal damage. Furthermore, several miRNAs (miR-183, -137) exhibit distinct expression patterns in whole-DRG as well as in neuron-specific approaches. Therefore, further investigation of their possible role in initiation and maintenance of neuropathic pain seems promising.
Finally, the differential expression of genes like Corticoliberin or Otopetrin 1, previously not described in neuropathic pain, has already resulted in follow-up projects.
Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by symptoms of inattentiveness and hyperactivity/impulsivity. Besides, increasing evidence points to ADHD patients showing emotional dysfunctions and concomitant problems in social life. However, systematic research on emotional dysfunctions in ADHD is still rare, and to date most studies lack conceptual differentiation between emotion processing and emotion regulation. The aim of this thesis was to systematically investigate emotion processing and emotion regulation in adult ADHD in a virtual reality paradigm implementing social interaction. Emotional reactions were assessed on experiential, physiological, and behavioral levels.
Experiment 1 was conducted to develop a virtual penalty kicking paradigm implying social feedback and to test it in a healthy sample. This paradigm should then be applied in ADHD patients later on. Pleasant and unpleasant trials in this paradigm consisted of hits respectively misses and subsequent feedback from a virtual coach. In neutral trials, participants were teleported to different spots of the virtual stadium. Results indicated increased positive affectivity (higher valence and arousal ratings, higher zygomaticus activations, and higher expression rates of positive emotional behavior) in response to pleasant compared to neutral trials. Reactions to unpleasant trials were contradictory, indicating increased levels of both positive and negative affectivity, compared to neutral trials. Unpleasant vs. neutral trials revealed lower valence ratings, higher arousal ratings, higher zygomaticus activations, slightly lower corrugator activations, and higher expression rates of both positive and negative emotional behavior. The intensity of emotional reactions correlated with experienced presence in the virtual reality.
To better understand the impact of hits or misses per se vs. hits or misses with coach feedback healthy participants’ emotional reactions, only 50% of all shots were followed by coach feedback in experiment 2. Neutral trials consisted of shots over the free soccer field which were followed by coach feedback in 50 % of all trials. Shots and feedback evoked more extreme valence and arousal ratings, higher zygomaticus activations, lower corrugator activations, and higher skin conductance responses than shots alone across emotional conditions. Again, results speak for the induction of positive emotions in pleasant trials whereas the induction of negative emotions in unpleasant trials seems ambiguous. Technical improvements of the virtual reality were reflected in higher presence ratings than in experiment 1.
Experiment 3 investigated emotional reactions of adult ADHD patients and healthy controls after emotion processing and response-focused emotion regulation. Participants successively
went through an ostensible online ball-tossing game (cyber ball) inducing negative emotions, and an adapted version of the virtual penalty kicking game. Throughout cyber ball, participants were included or ostracized by two other players in different experimental blocks. Participants were instructed to explicitly show, not regulate, or hide their emotions in different experimental blocks. Results provided some evidence for deficient processing of positive emotions in ADHD. Patients reported slightly lower positive affect than controls during cyber ball, gave lower valence ratings than controls in response to pleasant penalty kicking trials, and showed lower zygomaticus activations than controls especially during penalty kicking. Patients in comparison with controls showed slightly increased processing of unpleasant events during cyber ball (higher ratings of negative affect, especially in response to ostracism), but not during penalty kicking. Patients showed lower baseline skin conductance levels than controls, and impaired skin conductance modulations. Compared to controls, patients showed slight over-expression of positive as well as negative emotional behavior. Emotion regulation analyses revealed no major difficulties of ADHD vs. controls in altering their emotional reactions through deliberate response modulation. Moreover, patients reported to habitually apply adaptive emotion regulation strategies even more frequently than controls. The analyses of genetic high-risk vs. low-risk groups for ADHD across the whole sample revealed similar results as analyses for patients vs. controls for zygomaticus modulations during emotion processing, and for modulations of emotional reactions due to emotion regulation.
To sum up, the virtual penalty kicking paradigm proved to be successful for the induction of positive, but not negative emotions. The importance of presence in virtual reality for the intensity of induced emotions could be replicated. ADHD patients showed impaired processing of primarily positive emotions. Aberrations in negative emotional responding were less clear and need further investigation. Results point to adult ADHD in comparison to healthy controls suffering from baseline deficits in autonomic arousal and deficits in arousal modulation. Deficits of ADHD in the deliberate application of response-focused emotion regulation could not be found.
Human Vγ9Vδ2 T cells are the main γδ T cell subset in the circulation, accounting for up to 5% of the total peripheral blood lymphocyte population. They have been suggested to be important in response to tumors and infections. Their immune mechanisms encompass cell killing via cytotoxicity and secretion of pro-inflammatory cytokines such as IFNγ and tumor necrosis factor (TNF). The main stimulators of Vγ9Vδ2 T cells are isopentenyl pyrophosphate (IPP) and (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), denominated phosphoantigens (PAg).
A major advance in the understanding of PAg detection and Vγ9Vδ2 T cell activation has been the identification of the butyrophlin 3A (BTN3A) proteins as key mediators in these processes. In humans, three isoforms constitute the BTN3A family: BTN3A1, BTN3A2, and BTN3A3; and their genes are localized on the short arm of chromosome 6. The role of BTN3A1 has been highlighted by BTN3A-specific monoclonal antibody 20.1 (mAb 20.1), which has an agonist effect and causes proliferation, expansion, and activation of primary human Vγ9Vδ2 T cells. On the other hand, BTN3A-specific monoclonal antibody 103.2 (mAb 103.2) is antagonistic, inhibiting the Vγ9Vδ2 T cell response. The actual mechanism underlying both PAg- and mAb 20.1-mediated activation is not completely elucidated, but the importance of BTN3A1 is clear.
The main objective of this dissertation was to characterize the role of BTN3A1 in the PAg-dependent and PAg-independent Vγ9Vδ2 T cell activation and to evaluate its contribution in the response to influeza A virus infected cells. This research work demonstrated, by using Vγ9Vδ2 TCR MOP-transduced murine cells (reporter cells), that human chromosome 6 (Chr6) is mandatory for PAg-induced stimulation, but not for stimulation with mAb 20.1. The reporter cells responded to mAb 20.1 in cultures with BTN3A1-transduced Chinese hamster ovary cells (CHO BTN3A1) as antigen presenting cells. Nevertheless, for PAg-dependent activation the presence of Chr6 in CHO BTN3A1 was mandatory.
Although reporter cells expressing clonotypically different Vγ9Vδ2 TCRs showed similar PAg response, they clearly differed in the mAb 20.1 response. The reporter cell line transduced with Vγ9Vδ2 TCR D1C55 demonstrated essentially no response to mAb 20.1 compared to Vγ9Vδ2 TCR MOP cells. These findings were further supported by experiments performed with human PBMCs-derived Vγ9Vδ2 T cell clones. The results indicate heterogeneity in the PAg- and 20.1-dependent responses, in terms of CD25 and CD69 expression, among three different Vγ9Vδ2 T cells clones.
Co-cultures of reporter cells with Raji RT1BI and PAg plus mAb 20.1 or single chain antibody 20.1 (sc 20.1) revealed no additive or synergistic activating effects. In contrast, mAb 20.1 or sc 20.1 inhibited the PAg-mediated activation of the reporter cells.
The comparison of the relative contribution of the isoforms BTN3A2 and BTN3A3, in the activation of Vγ9Vδ2 T cells, was undertaken by overexpression of these isoforms in CHO cells. The results showed that BTN3A2 contributes to both PAg- and mAb-induced Vγ9Vδ2 T cell activation. On the contrary, BTN3A3 does not support PAg-mediated γδ T cell response.
Additionally, mutations in the proposed PAg- and mAb 20.1-binding sites of the extracellular BTN3A1 domain were generated by means of site-directed mutagenesis. These mutations revoked the mAb 20.1-induced Vγ9Vδ2 T cell activation, but not that induced by PAg.
Finally, co-cultures of Vγ9Vδ2 TCR MOP-transduced murine reporter cells with influenza A/PR/8/34-infected cells, or infection of PBMCs with this virus strain indicated that BTN3A1 might be dispensable for the Vγ9Vδ2 T cell response against influenza A.
The data of this research work points out that: i) in addition to BTN3A1, other Chr6-encoded genes are necessary for Vγ9Vδ2 T cell activation with PAg; ii) clonotypical (CDR3) differences influence the PAg- and mAb 20.1-mediated Vγ9Vδ2 T cell activation; iii) the PAg- and mAb 20.1-induced responses are not synergistic and interfere with each other; iv) BTN3A2 and BTN3A3 isoforms differ in the ability to support PAg- or mAb 20.1-dependent Vγ9Vδ2 T cell activation; v) the importance of the intracellular B30.2 domain of BTN3A1, in the Vγ9Vδ2 T cell activation, might be higher than that of the extracellular domain; and vi) in spite of the importance of BTN3A1 in the activation of Vγ9Vδ2 T cells, it is possible that many molecules with redundant functions are involved in the elimination of influenza virus infection by these cells.
In summary, it is possible to hypothesize a model in which BTN3A1 detects prenyl pyrophosphates in the cytoplasm via its B30.2 domain and in association with another protein(s). The binding of PAg to this domain induces a multimerization of BTN3A1 or a conformational change of its extracellular domain (mimicked by mAb 20.1). These modifications might be recognized by the Vγ9Vδ2 TCR or by an associated T cell protein. In the case that the TCR directly recognizes BTN3A1, the intensity of the response will depend on the Vγ9Vδ2 TCR clonotype. Future research will allow to gain a better understanding of BTN3A1, its interaction with other proteins, its actual role in the activation of Vγ9Vδ2 T cells, and its importance in specific models of cancer or infection. This knowledge will be necessary to transform these cells into effective tools in the clinic.
Molecular Beam Epitaxy and Characterization of Bi-Based V\(_2\)VI\(_3\) Topological Insulators
(2016)
The present thesis is addressed to the growth and characterization of Bi-based V2VI3 topological insulators (TIs). The TIs were grown by molecular beam epitaxy (MBE) on differently passivated Si(111) substrates, as well as InP(111) substrates. This allows the study of the influence of the substrate on the structural and electrical properties of the TIs.
The Bi2Se3 layers show a change of mosaicity-tilt and -twist for growth on the differently prepared Si(111) substrates, as well as a significant increase of crystalline quality for growth on the lateral nearly lattice matched InP(111). The rocking curve FWHMs observed for thick layers grown on InP are comparable to these of common zincblende layers, which are close to the resolution limit of standard high resolution X-ray diffraction (HRXRD) setups. The unexpected high structural crystalline quality achieved in this material system is remarkable due to the presence of weak van der Waals bonds between every block of five atomic layers, i.e. a quintuple layer (QL), in growth direction.
In addition to the mosaicity also twin domains, present in films of the V2VI3 material system, are studied. The twin defects are observed in Bi2Se3 layers grown on Si(111) and lattice matched InP(111) suggesting that the two dimensional surface lattice of the substrates can not determine the stacking order ABCABC... or ACBACB... in locally separated growth seeds. Therefore the growth on misoriented and rough InP(111) is analyzed.
The rough InP(111) with its facets within a hollow exceeding the height of a QL is able to provide its stacking information to the five atomic layers within a QL. By varying the roughness of the InP substrate surface, due to thermal annealing, the influence on the twinning within the layer is confirmed resulting in a complete suppression of twin domains on rough InP(111).
Focusing on the electrical properties of the Bi2Se3 films, the increased structural quality for films grown on lattice matched flat InP(111)B results in a marginal reduction of carrier density by about 10% compared to the layers grown on H-passivated Si(111), whereas the suppression of twin domains for growth on rough InP(111)B resulted in a reduction of carrier density by an order of magnitude. This implies, that the twin domains are a main crystal defect responsible for the high carrier density in the presented Bi2Se3 thin films.
Besides the binary Bi2Se3 also alloys with Sb and Te are fabricated to examine the influence of the compound specific point defects on the carrier density. Therefore growth series of the ternary materials Bi2Te(3-y)Se(y), Bi(2-x)Sb(x)Se3, and Bi(2-x)Sb(x)Te3, as well as the quaternary Bi(2-x)Sb(x)Te(3-y)Se(y) are studied.
To further reduce the carrier density of twin free Bi2Se3 layers grown on InP(111)B:Fe a series of Bi(2-x)Sb(x)Se3 alloys were grown under comparable growth conditions. This results in a reduction of the carrier density with a minimum in the composition range of about x=0.9-1.0.
The Bi(2-x)Sb(x)Te3 alloys exhibit a pn-transition, due to the dominating n-type and p-type point defects in its binary compounds, which is determined to reduce the bulk carrier density enabling the study the TI surface states. This pn-transition plays a significant role in realizing predicted applications and exotic effects, such as the quantum anomalous Hall effect.
The magnetic doping of topological insulators with transition metals is studied by incorporating Cr and V in the alloy Bi(2-x)Sb(x)Te3 by codeposition. The preferential incorporation of Cr on group-V sites is confirmed by EDX and XRD, whereas the incorporation of Cr reduces the crystalline quality of the layer. Magnetotransport measurements of the Cr-doped TIs display an anomalous Hall effect confirming the realization of a magnetic TI thin film. The quantum anomalous Hall effect is observed in V-doped Bi(2-x)Sb(x)Te3, where the V-doping results in higher Curie temperatures, as well as higher coercive fields compared to the Cr-doping of the TIs.
Moreover the present thesis contributes to the understanding of the role of the substrate concerning the crystalline quality of van der Waals bonded layers, such as the V2VI3 TIs, MoS2 and WoTe2. Furthermore, the fabrication of the thin film TIs Bi(2-x)Sb(x)Te(3-y)Se(y) in high crystalline quality serves as basis to explore the physics of topological insulators.
First-order proximal methods that solve linear and bilinear elliptic optimal control problems with a sparsity cost functional are discussed. In particular, fast convergence of these methods is proved. For benchmarking purposes, inexact proximal schemes are compared to an inexact semismooth Newton method. Results of numerical experiments are presented to demonstrate the computational effectiveness of proximal schemes applied to infinite-dimensional elliptic optimal control problems and to validate the theoretical estimates.
Background
Medulloblastoma is the most common malignant brain tumor in children and can be divided in different molecular subgroups. Patients whose tumor is classified as a Group 3 tumor have a dismal prognosis. However only very few tumor models are available for this subgroup.
Methods
We established a robust orthotopic xenograft model with a cell line derived from the malignant pleural effusions of a child suffering from a Group 3 medulloblastoma.
Results
Besides classical characteristics of this tumor subgroup, the cells display cancer stem cell characteristics including neurosphere formation, multilineage differentiation, CD133/CD15 expression, high ALDH-activity and high tumorigenicity in immunocompromised mice with xenografts exactly recapitulating the original tumor architecture.
Conclusions
This model using unmanipulated, human medulloblastoma cells will enable translational research, specifically focused on Group 3 medulloblastoma.
Background
Enhanced macromolecule biosynthesis is integral to growth and proliferation of cancer cells. Lipid biosynthesis has been predicted to be an essential process in cancer cells. However, it is unclear which enzymes within this pathway offer the best selectivity for cancer cells and could be suitable therapeutic targets.
Results
Using functional genomics, we identified stearoyl-CoA desaturase (SCD), an enzyme that controls synthesis of unsaturated fatty acids, as essential in breast and prostate cancer cells. SCD inhibition altered cellular lipid composition and impeded cell viability in the absence of exogenous lipids. SCD inhibition also altered cardiolipin composition, leading to the release of cytochrome C and induction of apoptosis. Furthermore, SCD was required for the generation of poly-unsaturated lipids in cancer cells grown in spheroid cultures, which resemble those found in tumour tissue. We also found that SCD mRNA and protein expression is elevated in human breast cancers and predicts poor survival in high-grade tumours. Finally, silencing of SCD in prostate orthografts efficiently blocked tumour growth and significantly increased animal survival.
Conclusions
Our data implicate lipid desaturation as an essential process for cancer cell survival and suggest that targeting SCD could efficiently limit tumour expansion, especially under the metabolically compromised conditions of the tumour microenvironment.
A novel growth method has been developed, allowing for the growth of strained HgTe shells on CdTe nanowires (NWs). The growth of CdTe-HgTe core-shell NWs required high attention in controlling basic parameters like substrate temperature and the intensity of supplied material fluxes. The difficulties in finding optimized growth conditions have been successfully overcome in this work.
We found the lateral redistribution of liquid growth seeds with a ZnTe growth start to be crucial to trigger vertical CdTe NW growth. Single crystalline zinc blende CdTe NWs grew, oriented along [111]B. The substrate temperature was the most critical parameter to achieve straight and long wires. In order to adjust it, the growth was monitored by reflection high-energy electron diffraction, which was used for fine tuning of the temperature over time in each growth run individually. For optimized growth conditions, a periodic diffraction pattern allowed for the detailed analysis of atomic arrangement on the surfaces and in the bulk. The ability to do so reflected the high crystal quality and ensemble uniformity of our CdTe NWs. The NW sides were formed by twelve stable, low-index crystalline facets. We observed two types stepped and polar sides, separated by in total six flat and non-polar facets.
The high crystalline quality of the cores allowed to grow epitaxial HgTe shells around. We reported on two different heterostructure geometries. In the first one, the CdTe NWs exhibit a closed HgTe shell, while for the second one, the CdTe NWs are overgrown mainly on one side. Scanning electron microscopy and scanning transmission electron microscopy confirmed, that many of the core-shell NWs are single crystalline zinc blende and have a high uniformity. The symmetry of the zinc blende unit cell was reduced by residual lattice strain. We used high-resolution X-ray diffraction to reveal the strain level caused by the small lattice mismatch in the heterostructures. Shear strain has been induced by the stepped hetero-interface, thereby stretching the lattice of the HgTe shell by 0.06 % along a direction oriented with an angle of 35 ° to the interface.
The different heterostructures obtained, were the base for further investigation of quasi-one-dimensional crystallites of HgTe. We therefore developed methods to reliably manipulate, align, localize and contact individual NWs, in order to characterize the charge transport in our samples. Bare CdTe cores were insulating, while the HgTe shells were conducting. At low temperature we found the mean free path of charge carriers to be smaller, but the phase coherence length to be larger than the sample size of several hundred nanometers. We observed universal conductance fluctuations and therefore drew the conclusion, that the trajectories of charge carriers are defined by elastic backscattering at randomly distributed scattering sites. When contacted with superconducting leads, we saw induced superconductivity, multiple Andreev reflections and the associated excess current. Thus, we achieved HgTe/superconductor interfaces with high interfacial transparency.
In addition, we reported on the appearance of peaks in differential resistance at Delta/e for HgTe-NW/superconductor and 2*Delta/e for superconductor/HgTe-NW/superconductor junctions, which is possibly related to unconventional pairing at the HgTe/superconductor interface. We noticed that the great advantage of our self-organized growth is the possibility to employ the metallic droplet, formerly seeding the NW growth, as a superconducting contact. The insulating wire cores with a metallic droplet at the tip have been overgrown with HgTe in a fully in-situ process. A very high interface quality was achieved in this case.
Wilms tumor protein 1 (WT1) is a suitable target to develop an immunotherapeutic approach against high risk acute myeloid leukemia (AML), particularly their relapse after allogeneic hematopoietic stem cell transplantation (HSCT). As an intracellular protein traversing between nucleus and cytoplasm, recombinant expression of WT1 is difficult. Therefore, an induction of WT1-specific T-cell responses is mostly based on peptide vaccination as well as dendritic cell (DC) electroporation with mRNA encoding full-length protein to mount WT1-derived peptide variations presented to T cells. Alternatively, the WT1 peptide presentation could be broadened by forcing receptor-mediated endocytosis of DCs.
In this study, antibody fusion proteins consisting of an antibody specific to the human DEC205 endocytic receptor and various fragments of WT1 (anti-hDEC205-WT1) were generated for a potential DC-targeted recombinant WT1 vaccine. Anti-hDEC205-WT1 antibody fusion proteins containing full-length or major parts of WT1 were not efficiently expressed and secreted due to their poor solubility and secretory capacity. However, small fragment-containing variants: anti-hDEC205-WT110-35, anti-hDEC205-WT191-138, anti-hDEC205-WT1223-273, and anti-hDEC205-WT1324-371 were obtained in good yields.
Since three of these fusion proteins contain the most of the known immunogenic epitopes in their sequences, the anti-hDEC205-WT191-138, anti-hDEC205-WT1223-273, and anti-hDEC205-WT1324-371 were tested for their T-cell stimulatory capacities. Mature monocyte-derived DCs loaded with anti-hDEC205-WT191-138 could induce ex vivo T-cell responses in 12 of 16 blood samples collected from either healthy or HSC transplanted individuals compared to included controls (P < 0.01). Furthermore, these T cells could kill WT1-overexpressing THP-1 leukemia cells in vitro after expansion.
In conclusion, alongside proving the difficulty in expression and purification of intracellular WT1 as a vaccine protein, our results from this work introduce an alternative therapeutic vaccine approach to improve an anti-leukemia immune response in the context of allogeneic HSCT and potentially beyond.
This article introduces a new consistent variance-based estimator called ordinal consistent partial least squares (OrdPLSc). OrdPLSc completes the family of variance-based estimators consisting of PLS, PLSc, and OrdPLS and permits to estimate structural equation models of composites and common factors if some or all indicators are measured on an ordinal categorical scale. A Monte Carlo simulation (N =500) with different population models shows that OrdPLSc provides almost unbiased estimates. If all constructs are modeled as common factors, OrdPLSc yields estimates close to those of its covariance-based counterpart, WLSMV, but is less efficient. If some constructs are modeled as composites, OrdPLSc is virtually without competition.
Traditional species identification based on morphological characters is laborious
and requires expert knowledge. It is further complicated in the case of
species assemblages or degraded and processed material. DNA-barcoding,
species identification based on genetic data, has become a suitable alternative,
yet species assemblages are still difficult to study. In the past decade
meta-barcoding has widely been adopted for the study of species communities,
due to technological advances in modern sequencing platforms and
because manual separation of individual specimen is not required. Here,
meta-barcoding is put into context and applied to the study of bee-collected
pollen as well as bacterial communities. These studies provide the basis
for a critical evaluation of the powers and limitations of meta-barcoding. Advantages
identified include species identification without the need for expert
knowledge as well as the high throughput of samples and sequences. In
microbiology, meta-barcoding can facilitate directed cultivation of taxa of interest
identified with meta-barcoding data. Disadvantages include insufficient
species resolution due to short read lengths and incomplete reference
databases, as well as limitations in abundance estimation of taxa and functional
profiling. Despite these, meta-barcoding is a powerful method for the
analysis of species communities and holds high potential especially for automated
biomonitoring.
Although the physiological roles of BChE are not yet determined to date, the importance of this enzyme is continuously increasing as it was found to be associated with several disorders like diabetes mellitus type 2, cardiovascular diseases, obesity and especially with Alzheimer’s disease (AD). In consequence, for investigations of BChE’s pathological role in these diseases and to find new medication strategies, the development of selective and potent inhibitors is necessary.
For this purpose, the current work progresses in five chapters on the exploration of the chemical, physical and biochemical properties of tetrahydroquinazoline based carbamates which were previously reported to be selective BChE inhibitors with potency in the low nanomolar range.
1) A Novel Way to Radiolabel Human Butyrylcholinesterase for PET through Irreversible Transfer of the Radiolabeled Moiety:
PET-radiotracers represent an innovative tool to determine the distribution and the expression of a biological target in vivo. BChE lacks to a large degree of such tracers with a few exceptions. In this work, methods were developed to incorporate the radioisotopes 11C and 18F into the carbamate moiety of an tetrahydroquinazoline based inhibitor. In contrast to reversibly acting PET-probes, the described radiotracers were proven by kinetic studies to transfer the radioisotope covalently onto the active site of BChE, thus labeling the enzyme directly and permanently.
2) Discovery of Highly Selective and Nanomolar Carbamate-Based Butyrylcholinesterase Inhibitors by Rational Investigation into Their Inhibition Mode:
To investigate the role of the tetrahydroquinazoline carrier scaffold on BChE inhibition, carbamate based inhibitors were synthesized. These compounds were successively used to perform kinetic investigations to determine their inhibition mode. Based on these data, a plausible binding model was postulated explaining the influence of the tetrahydroquinazoline carrier scaffold for binding at BChE’s active site just before carbamate transfer takes place. Additionally, these compounds feature neuroprotective properties and prevent oxidative stress induced cell death in their carbamate form as well as after the release of the tetrahydroquinazoline carrier scaffold.
3) Dual Addressing of Butyrylcholinesterase by Targeting the Catalytic Active Site (CAS) and the Peripheral Anionic Site (PAS):
Compounds which are dual-targeting the CAS and the PAS of BChE are the most potent and selective BChE inhibitors to date with inhibition values in the picomolar range. In this work, a strategy is described how to turn tetrahydroquinazoline based carbamates into dual binding BChE inhibitors. These inhibitors feature a carbamate moiety which is covalently transferred onto the CAS of BChE, and in addition provide a second pharmacophore connected via a linker to the carbamate moiety which is proposed to target the PAS. Preliminary results reveal a high tolerance of BChE towards different linker lengths without decrease in affinity.
4) Investigation into Selective Debenzylation and Ring Cleavage of Quinazoline based Heterocycles:
The tetrahydroquinazoline system is well investigated in terms of its synthesis and its selective oxidation. To explore the reactivity of this system, a tetracyclic tetrahydroquinazoline was exposed to common reduction agents. These experiments revealed a high sensitivity of the tetrahydroquinazoline core towards several reduction conditions
5) Experimental and Theoretical Investigation into the Stability of Cyclic Aminals:
Tetrahydroquinazolines are known to degrade in acidic media through hydrolysis of their aminal system; but literature is lacking of a systematic investigation into this behavior. Therefore, different tetrahydroquinazolines were synthesized and exposed to phosphate buffered systems with defined pH-values. A clear increase of the hydrolysis rate of the aminal system was determined in dependency of an increasing acidic media. Computational studies predicted and experimental studies proved that hydrolysis takes place in an acidic environment while the condensation of this system is preferred in neutral or basic aqueous media.
To simplify a judgment, people often base it on easily accessible information. One cue that is usually readily available is processing fluency – a metacognitive feeling of ease of cognitive processing. Consequently, processing fluency is used as a cue for many different types of judgment, such as judgment of truth, confidence, and novelty. The present work describes results of three studies investigating various aspects of processing fluency effects on judgment.
Processing fluency has been sometimes equated with speed of a cognitive process. Therefore, response times have been used for evaluation of processing fluency. However, response times in experimental tasks often do not encompass only the time needed for a given process, but also the time needed for a decision based on the resulting information. The study described in Chapter II uses a novel experimental method that enables separation of reading and decision times. The results show that people make a decision about liking of pseudowords faster when the pseudowords are hard-to-pronounce (i.e., disfluent) than when they are moderate in pronounceability. This suggests that response times cannot be used as a proxy for processing fluency when they include the time needed to make a decision.
One of the studies of judgmental effects of processing fluency showed that food additives with easier pronounceable names are judged to be less harmful than those with hard-to-pronounce names. While people encounter food additives that are safe more often, this environmental association may be in the opposite direction for some categories of objects. For example, people are more likely to see names of especially dangerous criminals in the news. Chapter III describes a study which initially tested whether the fluency-safety association may be in the opposite direction for some categories of objects as a consequence of this selective exposure to especially dangerous exemplars. The results did not show support for this hypothesis. Furthermore, subsequent studies suggest that the previously found association between fluency and safety is replicable with the original stimuli used in the previous research, but not with newly constructed stimuli.
Chapter IV describes a study which applied a finding from the processing fluency literature to a positive psychology exercise in order to increase its effectiveness. Namely, the experiment manipulated the number of good things that participants listed daily for two weeks as part of the exercise. While listing more things was considered harder, the number of things listed each day had no effect on effectiveness of the exercise.
This dissertation focuses on the drivers of international capital flows to emerging markets, as well as the determinants of crises in emerging markets. Particular emphasis is devoted to the role of U.S. monetary policy. The dissertation consists of three independent chapters.
Chapter 1 is a survey of the voluminous empirical literature on the drivers of capital flows to emerging markets. The contribution of the survey is to provide a comprehensive assessment of what we can say with relative confidence about the empirical drivers of EM capital flows. The evidence is structured based on the recognition that the drivers of capital flows vary over time and across different types of capital flows. The drivers are classified using the traditional framework for external and domestic factors (often referred to as “push versus pull” drivers), which is augmented by a distinction between cyclical and structural factors. Push factors are found to matter most for portfolio flows, somewhat less for banking flows, and least for foreign direct investment (FDI). Pull factors matter for all three components, but most for banking flows. A historical perspective suggests that the recent literature may have overemphasized the importance of cyclical factors at the expense of longer-term structural trends.
Chapter 2 undertakes an empirical analysis of the drivers of portfolio flows to emerging markets, focusing on the role of Fed policy. A time series model is estimated to analyze two different concepts of high frequency portfolio flows, including monthly data on flows into investment funds and a novel dataset on monthly portfolio flows obtained from individual national sources. The evidence presented in this chapter suggests a more nuanced interpretation of the role of U.S. monetary policy. In the existing literature, it is traditionally argued that Fed policy tightening is unambiguously negative for capital flows to emerging markets. By contrast, the findings presented in this dissertation suggest that it is the surprise element of monetary policy that affects EM portfolio inflows. A shift in market expectations towards easier future U.S. monetary policy leads to greater foreign portfolio inflows and vice versa. Given current market expectations of sustained increases in the federal funds rate in coming years, EM portfolio flows could be boosted by a slower pace of Fed tightening than currently expected or could be reduced by a faster pace of Fed tightening.
Chapter 3 examines the role of U.S. monetary policy in determining the incidence of emerging market crises. A negative binomial count model and a panel logit model are estimated to analyze the determinants of currency crises, banking crises, and sovereign defaults in a group of 27 emerging economies. The estimation results suggest that the probability of crises is substantially higher (1) when the federal funds rate is above its natural level, (2) during Fed policy tightening cycles, and (3) when market participants are surprised by signals that the Fed will tighten policy faster than previously expected. These findings contrast with the existing literature, which generally views domestic factors as the dominant determinants of emerging market crises. The findings also point to a heightened risk of emerging market crises in the coming years if the Fed continues to tighten monetary policy.
Polymorphonuclear neutrophils (PMNs) are phagocytic cells of the innate immune system that efficiently kill bacteria. However, they also have regulatory effects on other immune cells and contribute to immunosuppression in cancer, which worsens the outcome. In particular, this has been demonstrated for a subset of granulocytic cells called myeloid- derived suppressor cells (MDSCs), but its distinction from PMNs is controversial. Most authors have explored the suppressive effects of MDSCs on T cells, but recent data suggest that NK cells are also affected. NK cells are crucial for the combat of tumor cells, in particular leukemic cells. There is hardly data available on the interaction between NK cells and suppressive granulocytic cells. Therefore, the aim of this thesis was to explore the effects of MDSCs and PMNs on the NK cell function against the leukemia cell line K562.
In co-culture experiments, I demonstrate that granulocytic MDSCs and PMNs had similar effects on NK cell function and homeostasis. On the one hand, they positively influenced the survival and maturation of NK cells. On the other, they inhibited the activation, cytotoxicity and cytokine production of NK cells, both IFNγ and TNFα, in response to K562 target cells. Furthermore, I show a down-regulation of the activating receptor NKp30 on NK cells in the presence of MDSCs or PMNs, which may form part of the underlying suppressive mechanisms.
However, there is also evidence for the involvement of other molecules. Further investigations are needed to confirm a relevant suppression of NK cells by granulocytic cells in cancer patients, and to identify therapeutic targets. The recognition that regular PMNs have similar effects on NK cells as MDSCs could simplify future experiments, since MDSCs are heterogeneous and laborious to isolate and identify.
NKcells and granulocytes are among the first immune cells to reconstitute after hematopoietic stem cell transplantation, and NK cells may be particularly exposed to suppressive effects of granulocytes this scenario. Modulating these suppressive effects of granulocytes on NK cells therapeutically may yield a better NK cell function and an improved cancer prognosis.