We use the results of Quigley and Shah to give a formula for the geometric fixed points of real topological cyclic homology of a bounded below ring spectrum with anti-involution. The anti-involution on a ring spectrum $A$ gives rise to a spectrum with canonical left and right $A$-module structures, whose tensor product over $A$ can be equipped with an action by the cyclic group of order 2. Our formula is then given by the homotopy equalizer of two maps from the homotopy fixed points to the Tate construction. Furthermore, we show that this homotopy equalizer is equivalent to the one given in the computation by Dotto, Moi and Patchkoria, thereby proving their result with different methods.
As an application of our result we calculate the real topological cyclic homology of group ring spectra for abelian groups and certain classes of dihedral groups. We do this for arbitrary ground ring spectra, whose underlying spectra are bounded below. This is accomplished via a decomposition formula for the dihedral bar construction of a group.
Weniger anzeigenEntlang des Strukturwandels von Öffentlichkeit, bei dem digitale vernetzte Öffentlichkeiten die jüngste Ausprägung darstellen, geht nicht nur ein gesellschaftlicher Wandel einher, sondern auch erhebliche Veränderungen im Kommunikationsverhalten von Organisationen als Public Affairs-Akteur*innen sowie deren Praktiker*innen. Die Dissertation untersucht auf Basis des Strukturwandels von Öffentlichkeit, wie die Public Affairs-Praktiker*innen der DAX-40-Unternehmen mit dem Wandel von Öffentlichkeit und digitalen vernetzten Öffentlichkeiten umgehen. Dabei werden die Kommunikationsmittel und -formen analysiert, die zur Erreichung der Public Affairs-Ziele eingesetzt werden.
Bislang existieren nur wenige empirische Erkenntnisse zu diesem Forschungsfeld, weshalb die Arbeit darauf abzielt, diese Lücke zu schließen. In Zeiten des digitalen Wandels stehen Organisationen vor neuen Herausforderungen. Die strukturelle Organisation der Public Affairs-Arbeit muss angepasst, das (digitale) Kommunikationsrepertoire erweitert und die Verknüpfung zu anderen Unternehmensbereichen optimiert werden. Daher beleuchtet die Arbeit, wie Unternehmen mit den vielfältigen Herausforderungen der digitalen Public Affairs-Arbeit umgehen. Zentrale Forschungsfragen umfassen unter anderem den Umgang mit digitalen Kommunikationsformen, das Selbstverständnis der Praktiker*innen und die Nutzung sozialer Medien. Im Fokus der empirischen Untersuchung stehen 21 DAX-40-Unternehmen, deren Praktiker*innen im Rahmen von qualitativen Expert*innen-Interviews Erkenntnisse zum Forschungsinteresse liefern. Unterstützt durch eine Vorab-Systematisierung relevanter Spezifika der DAX-40-Unternehmen, wie deren Online-Auftritte, soll die Forschungsfrage der vorliegenden Arbeit beantwortet werden. Die Ergebnisse zeigen, dass in digitalen vernetzten Öffentlichkeiten dem Individuum, also den Public Affairs-Praktiker*innen eine herausragende und noch wissenschaftlich unzureichend anerkannte Rolle zukommt, da ein Großteil der Kommunikation hin zu politischen Entscheider*innen oder auch Monitoring und Recherche-Arbeiten über die eigenen Praktiker*innen-Profile stattfindet. Ebenfalls skizziert sich die digitale Public Affairs-Arbeit von Unternehmen als sehr vielschichtig, strategisch und individuell gestaltet. Über allem liegt die Skepsis eher in einem nicht-öffentlichen Rahmen der Public Affairs-Arbeit nachzugehen, anstatt diese öffentlich zu betreiben.
Durch die vorliegende Arbeit wird die Forschungsliteratur zu digitaler Public Affairs-Arbeit von Unternehmen und im speziellen von DAX-40-Unternehmen erweitert. Die Betrachtung aus kommunikationswissenschaftlicher Sicht schließt eine Lücke in Wissenschaft und Praxis und zeigt die vielfältigen Herausforderungen, denen Unternehmen im digitalen Wandel gegenüberstehen.
Weniger anzeigenCanine digital squamous cell carcinomas (CDSCC) tend to behave more aggressively than other areas of the skin. Furthermore, CDSCC in dark-haired animals are more biologically aggressive than in light-haired animals. However, up to date there is no standardized histological evaluation and comparison of DSCC morphology between dark and light breeds. In addition, dark-haired dogs have a known predisposition to develop DSCC. Additionally, some studies have suggested that dogs with a copy number > 4 in the KITLG locus, which is associated with melanogenesis, have an increased susceptibility to the development of DSCC. However, if the KITLG copy number had an effect on the morphology and histopathological features of DSCC still remains largely unknown. Study 1 included the histological evaluation of DSCC from 94 dogs, divided into two groups, (1) dark-haired (n = 76) and (2) light-haired breeds (n = 18). Group 1 was further subdivided into three subgroups, (1a) various black-haired breeds (n = 11), (1b) black Schnauzers (n = 34) and (1c) black & tan breeds (n = 31). For an objective evaluation, two known grading schemes for squamous cell carcinomas were used comparatively. As a result, both histological grading systems exhibited significant differences between groups 1 and 2. Digital SCC of the light-haired dogs were consistently better differentiated than those of group 1. There were no significant differences between the different dark-haired breeds in any of the individual characteristics assessed (invasive front, degree of invasion, nuclear pleomorphism, tumor cell buds, smallest tumor nest size and amount of tumor stroma). For study 2, 70 blood samples were collected from dogs with DSCC (partially overlapping with study 1). This study was designed to test whether and to what extent the previously evaluated histologic grades correlated with the number of copies KITLG locus determined by ddPCR. For the second study, the grouping was established as follows; Group 0/unknown haircoat color (n = 11); Group 1.a/black non-Schnauzers (n = 15); group 1.b/black Schnauzers (n = 33); group 1.c/black & tan dogs (n = 7); group 2/light-haired animals (n = 4). The results showed a significant correlation between increased KITLG copy number and more malignant histologic grading. This suggests that KITLG may have a role in the development of DSCC by causing different, more aggressive morphologic features. The compilation of these two studies may help to better characterize and understand canine squamous cell carcinoma of the toe. By taking genetic predispositions into account, a better and individualized assessment of the risk of disease in black dogs and thus earlier treatment is possible.
Weniger anzeigenThis thesis investigates personality functioning and maladaptive traits as indicators and treatment targets in various, mostly clinical and adult populations. While personality functioning derives from object relations and mentalization theories, both theories of etiology and treatment within a psychodynamic paradigm, maladaptive traits derive from a lexical or multivariate paradigm within personality psychology. This thesis sought to answer questions on these concepts' assessment, etiological claims, and clinical utility. To these aims, five empirical studies are included. The first study investigated the psychodynamic theory that early childhood adversities and personality functioning interact in predicting adult psychopathology. Using a large representative sample, the study found that these factors explained up to 91% of the variance in symptoms of depression, anxiety, and somatization. In addition, previous analyses based on this data corroborate that personality functioning may be assessed reliably using a short questionnaire. The second study developed the PID5BF+ questionnaire to assess maladaptive traits as per DSM-5 and ICD-11. This measurement, validated on large clinical and non-clinical samples, successfully distinguishes between various psychopathologies, including differentiating internalizing disorders and borderline personality disorder. A slightly refined version was tested in 13 languages across 16,327 participants, proved reliable, and is now globally used in mental health studies. The third study investigated the lexical approach of maladaptive traits together with the etiologically informed approach of personality functioning, using data from mental health app users. It found that aspects of personality functioning, as outlined in object relations and mentalization theory, are central to psychopathology and explain large proportions of higher order variance in a hierarchical taxonomy of psychopathology. Specifically, interpersonal aspects of personality functioning were linked to externalizing disorders, while self-related aspects were associated with internalizing disorders. The study also demonstrated that personality functioning accounts for a significant portion of longitudinal variance in affective well-being and psychosocial functioning. Additionally, it highlighted that while personality functioning captures broad psychopathology aspects, maladaptive traits are more useful in capturing variance that is specific to particular disorders.
Study 4 explored if maladaptive traits are malleable through clinical psychological interventions, comparing a guided online intervention with face-to-face/blended psychotherapy in small clinical samples. While both treatments effectively reduced mental health symptoms, their impacts on maladaptive traits differed. The online intervention primarily influenced negative affectivity, consistent with its focus on targeting neuroticism. In contrast, the face-to-face therapy resulted in significant changes across all maladaptive trait domains and the overall personality dysfunction score. Notably, in the face-to-face setting, the reduction of personality dysfunction was a more robust predictor of post-treatment symptom reduction than in the online treatment. Study 5, a large randomized controlled trial, investigated the effects of a self-guided internet-based intervention, employing multiple imputation and random forest lee-bound methods to handle missing data. Precision of these methods depends on baseline variables that predict future outcomes and behaviors of the participants. Personality functioning and maladaptive traits were significant predictors for trial dropout, indicating that individuals with greater personality dysfunction tend to disengage more from self-guided digital mental health interventions, suggesting a need for more personalized support for this population in such interventions. Taken together, these studies establish that personality functioning is instrumental in capturing broad aspects of psychopathology, while maladaptive traits are more specific to individual psychopathologies. The findings suggest the potential for expanding the dual assessment approach of severity and style in the diagnostics of personality disorder according to ICD-11 to general psychopathology. Additionally, these studies show that personality dysfunction and maladaptive traits can change through clinical interventions and are useful in handling missing data in clinical trials. This thesis underscores the emerging relevance of these concepts, rooted in early psychological theories, for modern mental health research and practice.
Weniger anzeigenPectins are abundant polysaccharides in plant-derived biomass, with a plethora of possible applications such as usage as food preservative, formulation for cancer treatment and corrosion inhibitors for steels among many others. These acidic polysaccharides of high structural complexity have important biological functions in the plant cell wall. One domain of pectin, rhamnogalacturonan-II (RG-II) is the most complex oligosaccharide known to date. It is constructed from at least 13 different monosaccharides and at least 21 distinct glycosidic linkages. Despite its complexity, it is widely conserved in the plant kingdom. RG-II molecules form borate diesters with each other, an essential structure in the cell wall for plant growth. However, very little is known about the biosynthesis, the structure-function relationships and the three-dimensional structure of RG-II. Synthetic oligosaccharides that are well-defined and of high purity are very valuable tools to study RG-II. Here, a synthetic approach to a highly complex side chain A nonasaccharide equipped with an aminoalkyl linker for later immobilization on surfaces or fuctionalization with fluorescent dyes was developed. The main challenges were to design a retrosynthetic approach for the branched target nonasaccharide with a highly orthogonal protective group strategy, to find suitable glycosylation strategies to construct all nine glycosidic bonds, including four 1,2-cis-glycosidic bonds between monosaccharides, and the 1,2-cis-selective installation of an aminoalkyl linker at the reducing end. Using this strategy, small amounts of a protected version of the full side chain A analogue containing one backbone galacturonic acid were succesfully synthesized in 89 steps. Key transformation was a final [4+5]-glycosylation that requires further optimization. The results demonstrate that even the most complex oligosaccharides become synthetically accessible if modern synthetic glycochemistry methods are applied and further developed. Additionally, three linear side chain A fragments were synthesized. The obtained side chain A fragments are important tools for the investigation of RG-II biosynthesis. Furthermore, they may be useful to investigate structure-function relationships and the three-dimensional structure of the highly complex RG-II structure, which remain currently elusive. With the developed synthetic methods further RG-II fragments can be synthesized, expanding the molecular toolbox for studying RG-II biology.
Weniger anzeigenThe subterranean naked mole-rat (Heterocephalus glaber, NM-R) is a rodent that has attracted growing research interest from a biomedical and zoological perspective. NM-Rs exhibit unique physiological characteristics including eusociality, pain insensitivity, cancer resistance, an unusual immune system, a long lifespan, and the lower basal metabolic rate than expected for its body mass. In addition, NM-Rs are poikilothermic mammals. So far, the precise mechanisms of cold detection processes remain poorly understood. The transient receptor potential melastatin 8 (TRPM8) ion channel is the principal cold receptor in mammals, a better understanding of the role of TRPM8 is needed to improve our current knowledge of the thermosensory system in NM-R. We used RNAScope and immunofluorescence to better understand the expression and localization of TRPM8 in sensory and non-sensory tissues. TRPM8 is expressed in the NM-R DRGs but more TRPM8+ NF200+ neurons are found in NM-R compared to mice. Approximately 33.7% of TRPM8-positive neurons also express NF200, indicating a significant presence in myelinated sensory neurons, while 39.33% and 19.14% of these neurons co-express CGRP and TRPV1, respectively. Interestingly, TRPM8 was also observed in large-diameter neurons and was not limited to smaller neurons typically associated with cold sensing in mice. Furthermore, we identified TRPM8 expression in the near lamina I of the dorsal horn of the NM-R spinal cord, which is similar to mice. Notably, we observed abundant and specific Trpm8 mRNA expression in the neurons of grey matter within the NM-R spinal cord. A notable discovery was the identification of a unique extended N-terminal sequence in NM-R TRPM8 compared with TRPM8 sequences from more than 30 mammals. We confirmed a unique extended N-terminal variant of the TRPM8 ion channel in NM-Rs using RT-PCR and a custom Ex-trpm8 probe designed for the 415–854 bp region from the NM-R Trpm8 mRNA. To explore the functional implications of this extended N-terminal sequence, we performed calcium imaging assays using HEK293T cells expressing NM-R TRPM8. The results demonstrated that the extended sequence significantly diminishes the response of TRPM8 to cold, menthol, and icilin. When this sequence was deleted, TRPM8 function was restored to levels similar to the mouse TRPM8. Additionally, fusing this N-terminal extension to mouse TRPM8 reduced its responsiveness, suggesting that the extended sequence modulates cold sensitivity in NM-Rs. VII Further experiments using calcium imaging of cultured NM-R DRG neurons and skin-nerve preparations demonstrated that NM-Rs retain intact cold sensation, which is largely independent of TRPM8. Cold-sensitive neurons were more abundant in NM-Rs than in mice, particularly among larger neurons. Additionally, cold-sensitive fibers in NM-Rs exhibited faster conduction velocities compared to those in mice, suggesting the involvement of alternative pathways for cold detection and potential evolutionary adaptations for rapid cold sensing in subterranean environments. These findings suggest that NM-Rs may have evolved unique TRPM8 isoforms and alternative mechanisms for cold perception, which may reflect adaptations to their distinct ecological niche. These findings not only advance our understanding of cold detection in NM-Rs but also raise intriguing questions about the evolutionary divergence of TRPM8 function in this species.
Weniger anzeigenSearch trees on graphs (STGs) are a far-reaching generalization of binary search trees (BSTs), where the key space is a graph instead of a totally ordered set. Intuitively, instead of comparing keys, we compare vertices, which tells us their relative position in the graph.
STGs can alternatively be seen as (1) a data structure for vertex searching that can be built on top of certain graphs that support vertex comparisons (e.g., quadtrees) or (2)~as a hierarchical decomposition of the underlying graph. For the latter purpose, search trees have appeared in the literature under different names (e.g., elimination trees and spines), and there are strong connections to the ubiquitous notions of tree-depth and tree-width.
Many computational and combinatorial questions about BSTs naturally generalize to the STG setting. In this thesis, we concentrate on the following three.
Suppose we are given a query distribution and want to compute the search tree that minimizes the expected search time. This is the optimal static search tree problem. Computing optimal static BSTs is possible in quadratic time, but for STGs no polynomial-time algorithm is known, even when the underlying graph is a tree. We discuss multiple approximation algorithms for trees and graphs of bounded tree-width, as well as NP-hardness of the problem in the general case.
In contrast to static search trees, which cannot be modified after construction, dynamic search trees may be restructured after each search using the rotation operation. We generalize the well-known Splay algorithm from BSTs to STGs in the special case where the underlying graph is a tree. We also use that algorithm for a dynamic forest data structure, including an implementation and its experimental evaluation.
Finally, the rotation distance between two STGs is the minimum number of rotations needed to transform one into the other. We are interested in the maximum rotation distance for a given underlying graph, which is exactly the diameter of the so-called graph associahedron of the underlying graph. Somewhat surprisingly, there is a tight connection between this combinatorial problem and the static and dynamic search tree problems. We present several new results, including a simple algorithm to compute the diameter of a graph associahedron when the underlying graph is a tree of bounded path-width.
Weniger anzeigenDie Kognition umfasst alle geistigen Prozesse, die es einem Menschen ermöglicht, Informationen zu verarbeiten, zu speichern, anzuwenden und spielt eine zentrale Rolle bei Wahrnehmung, Denken, Problemlösung und Verhalten. Diese Habilitationsschrift befasst sich mit der Untersuchung von Kognitionsstörungen bei unterschiedlichen neurologischen Erkrankungen. Übergeordnetes Ziel dieser wissenschaftlichen Arbeit war es, Kognitionsstörungen und neuropsychiatrischen Symptomen genauer zu untersuchen und einen Beitrag zum Verständnis der zu Grunde liegenden pathophysiologischen Mechanismen zu leisten. In den ersten beiden Arbeiten wurden motorische und nicht-motorische Symptome und deren Korrelation bei Patienten mit idiopathischem Parkinson-Syndrom (iPS) untersucht. Es zeigte sich, dass die motorische Unterbeweglichkeit, häufig gleichzeitig mit neuropsychiatrischen Symptomen wie Angst, Traurigkeit und Konzentrationsstörungen auftritt, jedoch meist in unterschiedlichem Ausmaß. Veränderungen der motorischen Symptomatik korrelieren jedoch nicht immer gleichzeitig mit einer Veränderung der nicht-motorischen Symptome. In der dritten Arbeit wurden Patienten mit subjektivem kognitivem Abbau (SCD) untersucht. Erstmalig konnte gezeigt werden, dass SCD-Patienten im Vergleich zur gesunden Kontrollgruppe in der neuropsychologischen Testung doch geringfügige Defizite in den Bereichen Gedächtnis, Aufmerksamkeit und Sprache haben. Hervorzuheben ist zudem eine Assoziation der kognitiven Defizite mit bestimmten Neurodegenerationsmarkern - β-Amyloid und Tau – im Liquor. Die beiden letzten Arbeiten untersuchen residuelle Symptome nach durchgemachter COVID-19 Erkrankung, im Sinne eines post-COVID-19-Syndroms (PCS). Der Großteil der Patienten, die sich in unserer neurologischen PCS-Sprechstunde vorstellten, waren Frauen im mittleren Alter, die überwiegend von kognitiven Einschränkungen und Fatigue berichteten. Bei Patienten mit führend bestehenden Gedächtnisstörungen konnten wir bei über der Hälfte anti-neuronale Autoantikörper nachweisen, die dann auch noch hochsignifikant mit pathologischen MoCA Testergebnissen assoziiert waren, was auf die mögliche Rolle von Autoimmunprozessen bei der Entstehung kognitiver Störungen hinweist. Insgesamt leistet die Habilitationsschrift einen wichtigen Beitrag zum Verständnis der vielfältigen Ursachen und Mechanismen von Kognitionsstörungen bei neurologischen Erkrankungen. Die gewonnenen Erkenntnisse sind von großer Bedeutung für die klinische Praxis und bieten Ansätze für die frühzeitige Erkennung und Therapie von kognitiven Beeinträchtigungen, die das Leben der Patienten erheblich beeinflussen können. Die Arbeit stellt somit einen wichtigen Schritt in der Forschung zu Kognitionsstörungen, insbesondere im Hinblick auf autoimmunologische Mechanismen, dar.
Weniger anzeigenPeste des petits ruminants (PPR) is a viral disease that affects domestic small ruminants (goats and sheep) and some wild small ruminants. By 2015, more than 70 countries in Africa and Asia were confirmed as affected although the threat to Europe through Turkey and Bulgaria was quickly neutralised. In Uganda, PPR was first reported in 2007 the Karamoja subregion of northeastern Uganda in 2007, a region comprised of 9 different districts. PPR persisted in this region. Upon eradication of Rinderpest in 2011, PPR was identified as the next target for eradication because of how closely related their aetiologies and epidemiological situations were. Indeed, in 2016, the Food and Agriculture Organisation of the United Nations (FAO) and the World Organisation for Animal Health (WOAH) launched a four-stage global PPR control and eradication (PPR-GCEP) by 2030. The control plan was set up to leverage on the momentum gained from PPR control activities to tackle other small ruminant diseases identified by small ruminant keepers through joint activities such as concurrent vaccination against multiple diseases. The PPR-GCEP demands that every PPR affected country complies with the program and implements respective activities to warrant progression from one stage to another until PPR is eradicated following a self-administered PPR Monitoring and Assessment Tool (PMAT). After all steps are achieved, countries will apply for declaration of freedom from disease and continue with activities aimed at maintenance of disease-free status. This thesis was designed to update the PPR epidemiological situation in Uganda, by generating data to fit into PPR-GCEP stage 1 (assessment stage) as well as identify areas for targeting of interventions – which is the cornerstone for the PPR-GCEP stage III (control stage), activities that directly contribute the PPR-GCEP. To achieve the set objectives, this study employed a range of advanced epidemiology, and social network analysis techniques to analyse archived PPR outbreak data and small ruminants movement data respectively. Additionally, the study employed molecular biology and molecular epidemiology techniques to identify the circulating PPR virus and other relevant coinfections in all cases of PPR-like disease reported in Uganda during the study period (202-2022).
Despite the disease persistence in this region for over a decade before it spread to other districts of Uganda, this study identified that the Karamoja subregion was now a diminishing hotspot whereas two new foci of transmission had come up in the central and southwestern regions of Uganda. Concentration of control interventions by government of Uganda and development partners in the Karamoja subregion coupled with rampant shipment of animals between districts from the northern, central, and western regions could have resulted in this shift in the disease focus. However, the districts in the pastoral production system (where the Karamoja subregion falls), had the highest levels of exposure to PPRV as compared to agropastoral and mixed cop-livestock production systems because of the stark difference in the small ruminant management practices amongst these systems. Small ruminants in the pastoral production system are allowed to roam freely on a large expanse of land whereas the those in the other systems are somewhat restricted in movement by fenced farms and or tethering by ropes which greatly protects limits their chances of contact with other flocks with potentially infected animals.
This study confirmed PPRV, CCPP, ORFV and GTPV coinfection among animals from 15 different reports of PPR-like disease that were investigated in this study. This observation further complicates field clinical diagnosis of PPR especially in countries without extensive laboratory diagnostics capacity such as Uganda. In conclusion, there is need to incorporate the detected coinfections in the panel of molecular diagnostics in Uganda to be able to achieve the target of effective PPR control of PPR and other small ruminant diseases. Furthermore, this study reports for the first-time coinfection of other important small ruminant diseases together with PPRV, an observation we believe will improve preparedness for proper disease management options such as chemotherapeutic treatment and vaccination to simultaneously target different disease pathogens. Animal movement control especially at international borders needs to be strengthened to reduce the likelihood of importing or exporting PPR infected small ruminants.
Findings of this study provide a basis for more robust timing and prioritization of control interventions such as vaccination to contribute to the global goal of control and eradication by 2030. For instance, these findings can be used to test a risk based PPR vaccination program by prioritising vaccination of small ruminants in PPR Up Trend districts. The districts that were identified as influential in the small ruminant networks can be good starting points to correctly institute animal disease control measures especially quarantine, vaccination and enhanced biosecurity. Such influential districts have previously been linked with the likelihood of driving the spread of infectious diseases in a very short time because of how quickly animals from them can potentially reach many districts in the country. The districts such as Kaberamaido, Lira, Nabilatuk that demonstrated high levels of connectivity especially by the different centrality measures should be prioritized for surveillance and control activities to increase the impact and effectiveness of such activities.
Districts such as Kampala, Mukono, Wakiso and Lira with high degree centrality and betweenness would increase the accuracy and sensitivity of active surveillance efforts other than blindly implementing such activities. This would in turn improve timely detection ofdisease outbreaks and reduce the spatial extent and impact thus improving the profitability of small ruminant production venture. Prioritization of interventions in terms of both space and time and for example districts with uptrend, drought-prone and those with high density of small ruminants and the time of the year when the amount of rainfall is low. Targeting PPR control interventions (vaccination and livestock movement control) to and from pastoral and agro-pastoral small ruminant production systems that are prone to PPR incursions is recommended to prevent PPRV spread to low-risk smallholder small ruminant production systems.
Weniger anzeigenThis dissertation explores the mechanisms underpinning the joint effects of multi- ple global change factors (GCFs) on soil properties and functions incorporating the rapid development of machine learning methods and AI tools. In chapter 2, we addresses the complex interactions between multiple GCFs and their joint effects on soil properties and functions. By developing a factor pool of 12 GCFs and calculating dissimilarity indices for factor combinations, the study shows that higher factor number and more dissimilar factors result in more pronounced deviations in soil properties and functions from null model predictions. These devi- ations often manifest as synergistic interactions, particularly in critical soil functions such as decomposition rates and enzyme activities. It highlights that not only the number of GCFs but also their dissimilarity plays a key role in driving soil responses, offering a new perspective for future research on the interactions of multiple global change factors. In chapter 3, in addition to the mechanistic insights, the dissertation introduces a practical null model analysis workflow for evaluating interactions among multi- ple stressors in soil ecology. The workflow not only facilitates the identification of interactions among factors but also efficiently generates null model predictions for a large number of randomly selected factor combinations. By incorporating it with other modeling frameworks, this flexible model workflow can be adapted to various hypothesis testing in GCF studies. Two case studies demonstrate the utility of this approach, offering a robust framework for future research on impacts of multiple GCFs on soil ecosystems. In chapter 4, the dissertation delves into the rapid development and increasing integration of artificial intelligence (AI), specifically generative models, into environ- mental science and ecology. This chapter explores the dual-edged nature of these technologies. On the one hand, LLMs and generative AI offer significant advan- tages, such as streamlining research workflows, enhancing environmental commu- nication, and broadening public engagement with ecological issues. On the other hand, we also emphasizes the potential risks associated with the unregulated use of AI in environmental sciences, such as the spread of misinformation and biased outputs. Moreover, the potential for AI-generated scientific data to be fabricated or manipulated raises concerns about the integrity of research findings in the field of ecology. Overall, this dissertation contributes insights into two critical areas of environ- mental research: the conbined effects of multiple GCFs on soil ecosystems, and the transformative potential of AI technologies in ecological research and communica- tion. By advancing our understanding of how these forces interact with and shape the environment, it provides important frameworks for addressing the multifaceted challenges posed by human activities and technological advancements.
Weniger anzeigenBalancing mutation rates always comes with trade-offs. Often deleterious or even lethal, mutations also produce the necessary genetic diversity to fuel evolution by natural selection. Many factors influence viral mutation rates; however, replicative polymerases play an essential role. Large dsDNA viruses, like herpesviruses, encode a DNA-polymerase with intrinsic 3’-5’ exonuclease (Exo) activity, increasing replication fidelity by orders of magnitude. Abolishing this proofreading consequently yields viral populations with increased mutation rates. Here we described the first successful reconstitution of proofreading deficient herpes simplex type 1 viruses. Although those viruses are initially viable, we found that after a few passages they accumulate huge mutational loads that interfere with productive viral replication. Especially deleterious mutations in major variants map specifically to essential gene sets important for nucleic acid metabolism, structural proteins and others. Notably, mild effects on proofreading conferred by Exo III mutant Y557S (YS) did increase mutation rates but yielded populations with wild type (wt) like replication kinetics. To follow up on the adaptability of mild hypermutators we passaged both wt and YS under antiviral pressure to screen for resistance mutations. We observed faster resistance development in YS by about 5-10 passages. This increase in adaptability is due to 2-3 times more mutations occurring in YS populations compared to wt. Importantly, we could detect no general differences in the underlying evolutionary processes. Furthermore, changing selection pressures shed light on the importance of standing genetic variation, especially in populations that already plateaued in their phenotypes. Finally, within population diversity on a phenotypic and genetic level is vastly increased in YS populations. Taken together we managed to explore the limits of hypermutation in herpes simplex type 1. Marginal increases in their mutation rates lead to greater adaptability which in turn can be employed to speed up evolutionary processes for experimental applications without compromising the underlying mechanism. However, increases beyond that, mediated by abolishing proofreading completely, lead to lethal mutagenesis and suicidal phenotypes. So far lethal mutagenesis is a process exclusively described for RNA virus populations. Defining the circumstances for lethal mutagenesis in herpes simplex virus type 1 might be interesting for future antiviral developments. Especially combination of replicative in concert with Exo inhibitors might yield promising antiviral therapies.
Weniger anzeigenThis thesis presents a detailed analysis of neuropeptide evolution, gene regulation, and function in Blattella germanica and other species of Blattodea. Combining genomic, transcriptomic, and peptidomic methods, I examined neuropeptide diversity and evolutionary origins with a focus on adipokinetic hormones (AKHs) and their receptors, as well as exploring their regulatory functions in cockroach physiology and their potential applications in pest management. In Chapter I, I conducted a comprehensive comparative genomic analysis of neuropeptide precursors across 49 Blattodea species, encompassing a diverse taxonomic range of termites and four cockroach species. The study revealed significant gene loss, duplication, and conservation patterns across different lineages. Notably, I observed the absence of specific neuropeptide genes such as ACP and Gonadulin in several termite families, suggesting potential associations with changes in reproductive strategies or ecological adaptations. In contrast, cockroaches exhibited gene duplications, including duplicates of the AKH gene, indicating diversification of neuropeptide functions within cockroach lineages. Additionally, phylogenetic analyses based on 32 neuropeptide precursors closely aligned with established evolutionary relationships within Blattodea, underscoring the value of neuropeptide genes as molecular markers in evolutionary studies. In Chapter II, I delved into the evolution of AKH ligands and their receptors in Blattodea, uncovering new gene duplication and diversification patterns. Phylogenetic analyses of AKH precursor sequences suggest an ancient AKH gene duplication event in the common ancestor of Blaberoidea, leading to a new set of putative decapeptides specific to this clade. I identified 16 different AKH peptides from 90 species, including the prediction of seven novel decapeptides for the first time. Analysis of AKHR sequences from 18 species reveals highly conserved transmembrane regions characteristic of GPCRs. Phylogenetic analyses based on AKHR sequences support established relationships among termite and cockroach lineages. Additionally, the study investigates predicted post-translational modification sites in AKHRs and finds no significant differences between solitary cockroaches and social termites. In Chapter III, I utilized transcriptomic and peptidomic analyses to carry out a comprehensive analysis of the neuropeptidome of B. germanica. I discovered 69 neuropeptide or neurohormone precursor transcripts in the brain transcriptome, encompassing most of the known insect neuropeptide families. Mass spectrometry confirmed 79 likely bioactive mature neuropeptides and precursor sequences, with many being reported in this species for the first time. Moreover, the bioassay demonstrated that two AKH peptides, including the recently identified novel decapeptide (AKH2), increase carbohydrate levels in both adult male and female B. germanica. Interestingly, females exhibited greater hemolymph carbohydrate mobilization than males when treated with an equal dosage of the AKH peptides, indicating sex-specific metabolic responses. In Chapter IV, I further examined the impact of two distinct AKH peptides on B. germanica at the transcriptome level following the injection of two adipokinetic hormone peptides. RNA sequencing at 3 and 18 hours post-peptide injection revealed significant alterations in metabolic pathways, including enhanced glycolysis, increased tricarboxylic acid cycle activity, and biosynthetic process shifts. I observed distinct transcriptional responses between males and females, indicating potentially differential hormonal regulation, and therefore sexual dimorphism in key physiological traits. Furthermore, I investigated RNA interference-mediated knockdown of AKHR on the host’s response to pathogen infection. I found that knockdown of AKHR led to reduced survival rates upon bacterial infection with Pseudomonas entomophila, underscoring the potential role of AKH signaling in immune defense. In conclusion, this thesis provides a comprehensive exploration of neuropeptide evolution, function, and regulation in Blattodea, with a particular focus on the metabolic roles of AKHs in B. germanica. By integrating genomic, transcriptomic, and peptidomic methodologies, this study enhances our understanding of how neuropeptides contribute to the physiological adaptations of cockroaches and termites. The findings highlight the evolutionary significance of neuropeptide signaling and its potential applications in pest management strategies. This work lays the foundation for future studies on the molecular mechanisms underlying neuropeptide function and their implications for insect ecology and control. Targeting neuropeptide pathways, such as AKH signaling, may offer innovative and sustainable approaches for managing pest populations, thereby mitigating the health risks associated with species like B. germanica.
Weniger anzeigenNeurotransmitter release via synaptic vesicle fusion is essential for fast and reliable neurotransmission in chemical synapses. This process is mediated by the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, composed of Syntaxin-1 (Stx1), Synaptobrevin-2 (Syb2), and Synaptosome-associated protein 25 kDa (SNAP-25), and is further orchestrated by key regulator proteins such as Munc18-1 and Munc13-1. Mutations in SNARE and regulatory proteins are associated with a group of neurological disorders known as SNAREopathies, which present with a range of phenotypes from cognitive impairments to epilepsy. In this work, we investigate the molecular impact of two clinically significant mutations in Syntaxin-1B (Stx1B), E210K and L221P, both of which are associated with distinct epilepsy phenotypes. Despite their clinical relevance, the molecular mechanisms by which these mutations disrupt proper neurotransmission have remained unclear. Our findings reveal that the Stx1BE210K mutant primarily affect the interaction to Munc18-1. The mutation introduces charge repulsion between the Habc domain and the SNARE motif of Stx1B, altering the conformation and significantly reducing its binding affinity to Munc18-1. This alteration can be rescued by charge reversion of the opposing K82 side chain in the Habc domain (Stx1BE210K,K82E), restoring interaction almost to wild type level. In contrast, the L221P mutation directly compromises the structural integrity of the SNARE motif in Stx1B. The substitution of proline affects the helicity of Stx1B, SNARE complex stability and significantly reducing the efficiency and velocity of liposome fusion in vitro. The distinct molecular effects of these two mutations demonstrate how specific alterations within the same SNARE motif can lead to diverse pathophysiological outcomes. In vivo experiments, performed in collaboration with the University of Oslo, using zebrafish models expressing human Stx1B wild-type and mutant constructs display an increased number and duration of seizure events in the mutants, as measured by local field potential recordings. Additionally, the E210K mutant exhibits an impaired touch response. Importantly, both the seizure activity and the altered touch response by Stx1BE210K were rescued in zebrafish expressing the charge-reversion rescue mutant Stx1BE210K,K82E, which partially restored normal local field potential patterns and behavioral responses. These results suggest that the molecular alterations in SNARE complex formation and function are directly linked to the epileptic phenotypes observed in vivo. Additionally, we investigate the interaction of Syb2 with its regulatory partners, Munc18-1 and the MUN domain of Munc13-1, which are crucial for aligning and stabilizing the SNARE motifs of Stx1 and Syb2, ensuring proper SNARE complex assembly. Our findings confirm that Syb2’s juxtamembrane domain (JMD) binds to the C-terminal region of the MUN domain of Munc13-1, with both tryptophan residues in the JMD acting as anchor points. Additionally, cross linking mass spectrometry revealed that the SNARE motif of Syb2 aligns with the concave side of the MUN domain, and an additional binding site for Syb2 was identified in domain 1 of Munc18-1.
Weniger anzeigenDie vorliegende Habilitationsschrift untersucht die Dynamik und Statik des lumbo-sacralen Übergangs sowie die Auswirkungen anatomischer Variationen auf die Rückenfunktion. Der Fokus liegt auf der Validierung klinischer und nicht-invasiver Messmethoden, der Analyse von lumbalen Bewegungsmustern und den muskuloskeletalen Adaptationen bei lumbo-sacralen Übergangsstörungen (LSTV). Die Arbeit zeigt, dass LSTV zu segmentalen Bewegungsveränderungen und erhöhten Degenerationsraten führen können. Sie bietet zudem spezifische Empfehlungen für klinische Diagnostik und Versorgungsstrategien, insbesondere für spino-pelvine Verankerungen. Damit leistet die Arbeit einen Beitrag zum Verständnis und zur Behandlung LSTV-assoziierter Pathologien.
Weniger anzeigenCampylobacter jejuni and Campylobacter coli are considered the primary causative agents of campylobacteriosis in humans, which has significant public health implications worldwide. In Europe, they account for by far the most cases of bacterial gastroenteritis. Particularly feared, though underestimated by the general population, are the long-term consequences of an infection that can occur in rare cases, such as Guillain-Barré syndrome, reactive arthritis, and irritable bowel syndrome. The excessive use of antibiotics in human and veterinary medicine has led to increasing resistance of these bacteria to antimicrobial agents, limiting treatment options. Consequently, the Centers for Disease Control and Prevention (CDC) classifies Campylobacter, especially due to its fluoroquinolone resistance, as a high-priority resistant bacterium and a serious public health threat. This study aimed to compare the antibiotic resistances of Campylobacter isolates from different regions of the world to identify resistance determinants relevant to human medicine and imminent in Europe, which develop under high selection pressure and pose a challenge to global public health. Based on the results of this comparative study, a novel warning tool should be developed that can be used at the molecular level in routine monitoring programs. The results of our comparative study showed differences in the extent of various resistances depending on the origin of the Campylobacter isolates. For example, the isolates from Georgia and Germany showed particularly high resistance to fluoroquinolones and tetracyclines. In contrast, resistance to aminoglycosides and macrolides was less common. The Campylobacter isolates from Vietnam, however, showed nearly complete resistance to fluoroquinolones and tetracyclines, and particularly the Vietnamese C. coli isolates exhibited very high resistance to aminoglycosides and macrolides. These high resistance rates in Vietnam are possibly due to the extensive use of antibiotics in livestock farming. Through the application of whole genome sequencing, phenotypic resistances could be linked to the presence of resistance determinants in the individual isolates. This showed that distinct Campylobacter populations carry different resistance markers and that Vietnamese Campylobacter isolates carried more resistance determinants.
We further investigated to what extent a data analysis based on whole genome data can be used to predict the expression of phenotypic resistance. We found that for the most part, the prediction matched the phenotypic resistance. However, discrepancies between the whole genome sequencing data and the phenotypic resistance profiles were also discovered. Problems included missing or inaccurately annotated AMR genes, detection issues due to multiple gene copies or variants, and novel mutations affecting gene functionality. Additionally, unknown resistance mechanisms were identified, such as resistance to ciprofloxacin without concurrent nalidixic acid resistance. Another resistance mechanism leading to aminoglycoside resistance was deciphered and characterized in the course of this study. By applying natural transformation and analyzing genome data, a point mutation in the 16S rRNA of Campylobacter was identified, which was causally related to aminoglycoside resistance. We were able to show that the stability of the resistance depended on how many of the three copies of the 16S rRNA present in Campylobacter had undergone this mutation. Using Nanopore long-read sequencing technology, combined with short-read data, hybrid assemblies were created for individual isolates. This allowed several isolates to be represented with their fully circular chromosome and, where applicable, additional epichromosomal units (e.g. plasmids). This provided insights into the localization and mode of spread of the identified resistance determinants. Ultimately, based on the whole genome data, it was possible to design new primers and probes and subsequently develop a pentaplex real-time PCR system. This was adequately tested and validated during this study and will be available in the future as a cost-effective alternative to whole genome sequencing to routinely monitor the most important resistance markers such as fluoroquinolone, macrolide, and tetracycline resistances. In conclusion, the great genetic diversity and observed resistances in Campylobacter, especially in regions with intensive antibiotic use, stresses the necessity for continuous monitoring of circulating resistances in a global context to control and contain the spread of resistant strains. Furthermore, this work serves as an incentive to improve public health in the future and raise awareness about reducing antibiotic consumption.
Weniger anzeigenThis dissertation studies (largely American) Science Fiction (SF) texts that are in some way “about” climate change or the anthropocene. While environmentally themed SF has received a significant amount of scholarly attention in the past decade, such academic Science Fiction studies tend to take for granted the political and literary value of writing this kind of SF, trained in scholarly reading practices that conceive of literary texts as imparting valuable knowledge. I propose that contemporary SF is largely written with an acute awareness of what academic readers “do” with such literature, and that academic readings of SF are in fact part of the same literary system as the studied SF itself, sharing the status of being “second-order observations”. In this dissertation I will therefore closely consider what readers and writers of (environmental) SF hope to “do with” texts, studying both how the genre community has defined itself and how two schools of literary analysis – the “suspicious” approach exemplified by Fredric Jameson, and the “post-critical” approach exemplified by Rita Felski – have conceived of the usefulness of literature; it will be my argument that a full analysis of environmental SF as a cultural object must be aware of the fact that such SF is, in turn, already aware of how academics read it. My other contribution to the theory of environmental SF literature will be to argue that more attention must be paid to the implied temporal gap between present and future in such fiction (chapter two). With this in mind, I will then read three moments in environmental SF. I will begin with the emergence of an environmental SF in the second half of the twentieth century, concurrent with the emergence of the environmental sciences and environmental non-fiction; particular attention will be given to science-fictional fantasies of overpopulation around the 1970s, which were used for political purposes by various writers and editors (chapter three). I will also re-read the rather canonical work of cyberpunk author William Gibson (written between 1981 and 2014), arguing that his fiction is not only disinterested in ecology, nature, and climate change, but in fact actively antiecological; written from the perspective of an “end of history”, catastrophic environmental degradation as a historical event becomes unimaginable for the cyberpunk of Gibson (chapter four). Thirdly, I will consider Kim Stanley Robinson’s recent Ministry for the Future (2020) as an example of an ecological SF that is written explicitly concerned both with the temporal gap between present and future, and with the question of how ecological fiction is supposed to effect political change in our non-fictional world (chapter five). In my concluding remarks, I will consider the prominent position of Rachel Carson’s environmental non-fiction text Silent Spring (1962) both in academic history of environmental SF and in two further recent works of environmental writing (chapter six).
Weniger anzeigenThis study investigates how social class differences are recontextualized into pedagogic practices in mathematics classrooms, shaping distinct social consciousnesses across different social groups, and ultimately perpetuating social insulation in subtle ways. The research is situated in secondary schools in Xi’an, the most developed city in Northwest China, in terms of population size and diversity of school types. Three school streams were selected to represent varying levels of social insulation.
The theoretical resource of this study is mainly drawn from Bernstein and Dowling. Bernstein’s theory of pedagogic discourse offers fundamental guidance that instructional discourse in pedagogic practices is governed by underlying regulative discourse like the principle of social class. His concepts like classification and framing, different values of knowledge, and a set of rules of pedagogic discourse, alongside Dowling’s Social Activity Method, which includes domains of practice and distributive strategies, offer concrete analytical instruments for examining the processes of recontextualization. Both quantitative and qualitative methods were used to address different research questions. Quantitative techniques were employed to investigate whether statistical class differences exhibited at the regional level where these samples were located, while qualitative analyses were conducted as tentative and exploratory study.
The thesis comprises three distinct but interconnected sub-studies, each representing a potential pathway of recontextualization. These pathways explore how class distinctions are transformed within pedagogic practices to legitimize and maintain social insulations. As a result, students are interpellated into accepting disparities in school achievements, which serve as indicators for their future roles within different divisions of labour and social positions.
The first part takes various forms of pedagogic communication as a possible way of recontextualization, which carries differentiated power relations. The quality of classroom interactions was extracted as a linking variable between forms of communication and differences in school achievement. The findings reveal that class differences transform into varying durations of peer interactions with a flatter hierarchy, prompting students’ engagement and autonomy. Therefore, social segregation is legitimized at the level of consciousness, as different social groups internalize these power relations through their engagement with specific forms of communication.
The second part explores pedagogic messages and the methods of their transmission by teachers as another pathway for recontextualization. By analyzing class differences in these two dimensions across different school streams, this exploratory study reveals that social class differences are converted in the range of esoteric mathematical knowledge conveyed and the methods used to transmit it. This process covertly legitimizes and reproduces social stratification.
The third part investigates the evaluation criteria contained in the content of teacher feedback and the way it is provided, serving as a further pathway for recontextualization. This sub-study found that class differences are translated in differentiated criteria for school success and in teachers’ perceptions of their students’ abilities, thereby legitimizing and reproducing social segregations through pedagogic practices.
Together, these three pathways provide evidence from different perspectives on how macro-level social class differences are recontextualized into micro-level mathematics pedagogic practices to achieve their legitimizing transmission. The contributions of this study are twofold: first, it extends the cross-cultural applicability of Bernstein and Dowling’s theories; second, it offers empirical support for how the principle of social class is transformed and legitimized in mathematics classrooms. These findings have implications for teacher training programs, particularly in integrating educational equity into three aspects: the arrangement of communication forms, the selection and organization of pedagogic tasks, and the provision of feedback, all aimed at narrowing the achievement gap between students from different social groups. Additionally, this thesis points forward to future research to explore other recontextualized pathways and the role of teachers’ personal backgrounds on the transmission of class differences.
Weniger anzeigenThe motion of salt water through the Earth's geomagnetic field generates characteristic electromagnetic (EM) signals. These ocean-induced EM signals can be observed from outside the ocean by space-borne satellite magnetometers. They depend on oceanic velocities and conductivity (i.e., temperature and salinity) and, therefore, could contribute to observing the ocean heat content or water mass transport. However, the identification of ocean-induced magnetic fields requires a separation from other geomagnetic field contributions (e.g., the core, lithosphere, and ionosphere). In contrast to tidal-induced EM signals, circulation-induced EM signals have not yet been identified in geomagnetic observations.
This thesis developed a novel Kalman-filter-based rescaling of EM signals (KREMS) to detect ocean-circulation-induced magnetic fields. The essential separation from other magnetic field contributions was achieved by predetermining the temporal behavior of the searched EM signal. KREMS was then used to locally rescale the amplitude of this predetermined EM signal by assimilating geomagnetic observations.
An observing system simulation experiment (OSSE) based on synthetic Swarm-like observations demonstrated that KREMS allowed for a global signal identification of circulation-induced EM signals regardless of their complex temporal behavior and low intensity. In an ideal scenario, the uncertainty of the rescaling could be reduced by 70% on average. The best detectability was found in the Indian Ocean basin and in parts of the Southern Ocean. In a more realistic scenario of the OSSE, KREMS performed comparably well as a least-squares approach. Moreover, it was shown that including spatial constraints in KREMS further improved signal identification.
Based on the these findings, KREMS was applied to seven years of real Swarm geomagnetic satellite observations. Compared to the OSSE, the Swarm assimilation results proved to be more ambiguous and strongly dependent on the presumed estimate of the circulation-induced EM signal. The rescaling remained highly uncertain and did not reveal a consistent spatial pattern. In some areas the signal-to-noise ratio turned out to be too low (e.g., the East Pacific Ocean), on others the rescaling indicates substantial discrepancies between the presumed and the true circulation-induced EM signal (e.g., the Southern Indian Ocean).
Finally, a purely observation-based detection of circulation-induced EM signals was considered by estimating the temporal behavior of the EM signal from satellite altimetry. This combination also indicated the potential of KREMS to correct water mass transport estimations (e.g., from satellite altimetry) and suggested the applicability of KREMS not only for examining the detectability of EM signals but also in a broader context of ocean observations.
Weniger anzeigenNanomaterials (NMs) can be manufactured to serve different industrial purposes by fine-tuning their physico-chemical properties. This results in a theoretically unlimited number of NM variants. Thereby, even small variations in the physico-chemical properties of a NM may have substantial influence on their uptake, toxicokinetics as well as (eco-)toxicity. Thus, in theory, risk assessment needs to be performed for all variants and all toxicological endpoint. As this is simply not feasible, grouping and read-across approaches which allow the transfer of information between sufficiently similar NMs are promising alternatives. However, establishing reliable grouping approaches for NMs is not trivial due to the current lack of understanding with respect to the relationship between individual physico-chemical properties and the toxicological profile of NMs. The overall aim of this thesis was to explore how machine learning (ML) approaches can be used to support NM grouping in finding such relationships or underlying patterns. As formulating a reliable grouping hypothesis may largely benefit from mechanistic understanding, the underlying modes-of-action (MoAs) for different NMs were also explored by investigating results from omics approaches. In the first study, the aim was to use ML for identifying the most important physico-chemical properties influencing the toxicity of NMs. Therefore, a dataset of eleven NMs with comprehensive description of their physico-chemical properties was used. These physico-chemical properties were then linked to available in vivo data obtained from short-term inhalation studies (STIS) and in vitro toxicity data measured with the so-called macrophage assay. In both cases, toxicity was represented as binary outcome variable indicating whether a NM was ‘active’ and ‘passive’ in the respective toxicity studies. Unsupervised and supervised ML approaches were trained on this dataset. In the unsupervised model, principal component analysis (PCA) was used to infer information on which physico-chemical properties have the strongest impact in the first two principal components (PCs). Afterwards, k-nearest neighbors (kNN) was applied to compare results to the defined activity levels. In the supervised counterpart, random forest (RF) analysis with and without recursive feature elimination (RFE) was performed. Toxicity classes were thereby directly used as labels in the model building process. Overall, the best model was obtained using RF with RFE. It reached a balanced accuracy of 0.82 and was built on the three parameters zeta potential, redox potential and dissolution rate. This study showed, how ML could support NM grouping approaches. At the same time, it was also obvious that predictive modeling based solely on physico-chemical properties has severe limitations. While this is widely accepted to date and also mentioned in various recommendations, this was not the case at the time of the study. Already with this small set of NMs 5 and compared to other studies a comprehensive description of physico-chemical properties, no perfect separation of ‘active’ and ‘passive’ NMs was possible. The second study, aimed at investigating the oxidative potential (OP) in addition to physico-chemical properties. Different assays for measuring the OP were evaluated with respect to their predictivity for NM toxicity. In addition, one goal was to find out whether or not OP assays could replace each other or whether results from different OP assay in different datasets could be combined. Within this study, four assays have been compared, namely the acellular surface reactivity assays electron spin resonance (ESR) spectroscopy using CPH spin probe and DMPO spin trap and the ferric reduction ability of serum (FRAS) assay as well as the cellular protein carbonylation assay as a marker for oxidative protein damage in NRK-52E cells. The comparison was based on a case study holding OP measurements for 35 NMs. For the four OP assays, mass-based doses were compared to surfacebased ones, correlations and clustering between assays were computed and their predictivity for the same outcome variables as in the first study was assessed for individual assays and all possible combinations of them in a logistic regression model. As a result of those comparisons, surface-based doses were shown to be more predictive than mass-based ones. In addition, correlations between the OP assays were only moderate. Within the logistic regression model, predictivity was highest for protein carbonylation or combinations of assays which include protein carbonylation. Thus, as expected, biological OP assays seem to predict the actual toxicity outcome more reliably. At the same time, combining datasets which used different OP assays for the purpose of building robust ML models based on large datasets is not easily possible as the assays are not highly correlated. Overall, OP seems to be very informative and relevant for NMs in general. However, also other toxicity mechanisms (not directly related to OP) may be triggered by NM treatment, which cannot be reflected by OP assays. The third study focused more generally on elucidating MoAs underlying NM toxicity. Here, proteomics data were to be explored for their potential to unravel MoAs of NMs to support NM grouping. However, as proteomics data for NMs are relatively scarce and interpretation is difficult due to missing reference data, the main idea was to integrate proteomics signatures observed for NMs with those from other traits like chemicals, drugs or diseases. As such meta-analyses are mainly hampered by the lack of standardization for proteomics data, a workflow for harmonized evaluation of public proteomics data and their integration in a meta-analysis setting was developed. The workflow PROTEOMAS aims to make proteomics data FAIR (findable, accessible, interoperable, reusable). In an initial case study, PROTEOMAS was tested on 25 proteomics datasets to investigate the toxicological effects of NMs in relation to those of other traits at the lung level. Proteomic 6 fingerprints and their similarities among the studied traits could be identified. PROTEOMAS was thus useful for meta-analysis of proteomic datasets. In the review article, an overview on the variety of ML models and omics approaches supporting NM grouping available in literature is provided. Corresponding models were collected and some overarching conclusions were drawn from these manuscripts. Especially, data availability and quality are a major concern preventing the development of robust ML models for NM toxicity prediction. In addition, measurements are usually not well-standardized and insufficient metadata is provided and thus datasets cannot be integrated. Overall, there is a strong need for FAIR data in the NM safety community which would then allow development of more reliable models and advancement of in silico tools in a regulatory context. It was also concluded, that recent developments in the field of AI may also greatly support data gap filling and improvement of metadata availability in NM databases as well as linked data concepts. Overall, ML models as well as omics methods were shown to be useful to support NM grouping approaches. However, data availability and standardization of methods are of utmost importance in order to be able to develop reliable models.
Weniger anzeigenWhen animal rights activists enter farms or laboratories, they pose particular challenges for the law. How can the ethical motives of the activists be adequately taken into account in the legal assessment without giving them carte blanche for otherwise unlawful behaviour? This dissertation analyses, evaluates and compares the legislation and jurisprudence in Germany and other jurisdictions, particularly in the United States. In so doing, it incorporates the findings and methods of political theory alongside the legal assessment. The principles developed lay a foundation for a nuanced legal assessment of protest movements and methods on the limits of legality.
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