This dissertation consists of four chapters which study how external events influence attitudes, preferences, perceptions, and identities of migrants and natives in different settings. The first chapter examines the effects of the European Refugee Crisis between 2014 and 2015 on the ethnic identity of already resident migrants in Germany. Thereby, I exploit the quasi-experimental setting in Germany, by which refugees are allocated to different counties by state authorities without being able to choose their locations themselves. Doing so, I find that higher shares of refugees in a county increased migrants’ attachment to their home countries, but not their perceived belonging to Germany. Further analyses uncover strong heterogeneities with respect to country of origin and suggest that concerns about xenophobia, experiences of discrimination, and the consumption of foreign media contributed to these effects. Lastly, I find that changes in ethnic identity coincide with the political polarization of migrants. The second chapter looks at the effects of far-right protests in Germany on natives’ attitudes toward migration nationwide. More specifically, we test whether protesters are able to raise support for their concerns, or whether they are perceived as a threat by the public. To do so, we perform a regression discontinuity design approach to estimate short-term effects on natives’ worries about xenophobia and concerns about immigration. Results indicate that protesters were seen as a threat as worries about xenophobia increased while concerns about immigration remained flat after demonstrations took place. Further analyses indicate that media coverage was essential in driving results and that effects were highly dependent on people’s preexisting political views, suggesting that protests had polarizing effects. In the third chapter, we study how unemployment impacts bitterness, which describes a feeling of not having achieved what one deserves compared to others. After finding consistently positive effects using pooled OLS and fixed effects regressions, we identify the causal effect of unemployment on bitterness by exploiting variation from plant closures and firm layoffs in Germany. Combining matching based on entropy balancing with difference-in-differences estimation, we show that unemployment leads to a substantial and significant increase in bitterness. Further analyses uncover evidence that the experience of job loss, the state of being unemployed, and the duration of unemployment contribute separately to overall effects. Lastly, we find some evidence that effects persist over time. In Chapter 4, we analyze how changes in legal status affect perceived discrimination of migrants in Germany. Hereby, we follow two distinct approaches. First, studying the direct impact of naturalization, we estimate a fixed effects model. As this method cannot fully account for all potential sources of endogeneity, we thereafter exploit exogenous variation in residency requirements due to two citizenship reforms in Germany. Overall, we find that while naturalization does appear to reduce perceptions of discrimination overall, these effects are limited to men and immigrants from Eastern European countries. Extending the analysis, we exploit exogenous variation from EU enlargement to show that citizens from countries that became part of the EU experienced a significant reduction in discrimination compared to non-EU immigrants.
View lessThe term Internet use disorders (IUD) covers addictive behaviors related to the use of Internet applications and contents such as online computer games, social networks, online pornography and shopping platforms. Research findings have demonstrated that IUD lead to significant psychological, societal and social impairments. Based on scientific evidence and clinical requirements, Internet Gaming Disorder (IGD) has been included in the 11th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-11). The formal recognition of IGD as a disorder due to behavioral addiction has been highlighted as an achievement regarding the nosological classification and the development of treatment approaches. In addition to IGD, other IUD appear to be of comparable clinical relevance considering their addictive potential and the aversive consequences. Scientific research on interventions for IUD is still at an early stage and further studies are required. Although, systematic reviews and meta-analyses suggest that Cognitive Behavioral Therapy (CBT) may be an effective treatment approach for IUD. Even though the availability of specific interventions for the treatment of IUD is steadily increasing, access barriers and a low utilization of outpatient services lead to shortages of sufficient health care. Digital interventions have the potential to facilitate access to healthcare services and to address treatment barriers.
Based on the current state of research, digital interventions for IUD were investigated in the cumulative dissertation. The research project was embedded in the online short-term therapy of the randomized controlled trial Stepped Care Approach for Problematic Internet use Treatment (SCAPIT; German: Stepped Care Ansatz zur Versorgung Internetbezogener Störungen, SCAVIS). The first study synthesized the systematic evidence for treatment interventions for IUD in order to critically appraise the quality of reporting according to the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) guidelines. The evaluation of systematic reviews and meta-analyses of interventions for IUD revealed considerable heterogeneity in terms of classification of addictive Internet behaviors and treatment approaches. In addition, a lack of studies on IUD manifestations other than IGD was highlighted. The assessment of the quality of reporting indicated deviations from the PRISMA guidelines in terms of missing information on the methodological and scientific approach. The second study was conducted as part of the scientific monitoring of the pilot phase of the online short-term therapy. Baseline data collected from the pilot sample were analyzed to provide preliminary information on clinical characteristics of treatment recipients. A descriptive analysis of sociodemographic data, psychopathological and individual variables was performed and correlations with symptoms of IUD were analyzed. Results of the study revealed that comorbid psychopathologies were associated with INS. The majority of participants reported at least one comorbid mental disorder at the time of inclusion in the online short-term therapy, while affective disorders were most prevalent. In the third study effects of psychopathological symptoms and impairments of functioning on symptom severity of IUD and the duration of Internet use was examined in the sample of patients. Based on a dichotomous classification of the symptom severity of IUD, differences among participants presenting moderate compared to severe addictive Internet behavior were analyzed. Besides psychosocial impairments, depressive, social phobic and somatoform symptoms were assessed. Results of the regression analyses confirmed that psychopathological symptoms and impairments of functioning had a significant effect on symptoms of IUD. Participants with severe addictive Internet behavior exhibited significantly higher psychopathological strains compared to patients with moderate addictive Internet behavior.
In summary, findings of the three studies contribute to the scientific evidence base of digital interventions for IUD. Results of the first study highlight that the current evidence on treatment interventions for IUD is limited by considerable heterogeneity and shortcomings in reporting. Further studies are urgently required to investigate digital treatment approaches. Findings of the second study underline the relevance of studies on certain manifestations of IUD and confirm that those affected commonly exhibit additional psychopathologies in clinical setting. Further, results of the third study imply opportunities for the expansion of the health care system by considering digital interventions as a promising way to minimize access barriers, and to provide evidence-based treatments for those affected. Additional research studies with high methodological quality should be conducted to confirm the findings and to promote the evidence base for digital interventions for the treatment of IUD.
View lessRegardless of our birthplace, culture or language, the body plays a central role in our experiences. In order to understand language learning, it is thus crucial to consider not only aspects of language, but also to understand the interconnections between the brain, body and social interaction. Despite the fundamental role of gestures in human communication and classroom instruction, their impact on second language learning is poorly understood and has rarely been studied in naturalistic instructional settings like schools. Drawing on methods from psycholinguistics, English language teaching and ethnography, this thesis examines the social and cognitive processes that underlie gesture-based L2 learning. In particular, the present work focuses on codified gestures as a teaching tool to support L2 fluency as well as spatial term and grammatical morpheme learning in diverse classrooms. It grapples with the following questions: (1) Can differences in L2 fluency development be observed when employing different teaching methodologies to teach the text of a play—specifically when using methods that employ a gesture for every morpheme of the text without learner access to the written text (CG), and methods that employ gestures for key sentences with learner access to the written text (SL)? (2) Can differences in L2 spatial term development be observed when employing different teaching methodologies to learn the text of a play—specifically when using methods that pair gestures with morphemes (CG), and when using those that pair gestures for key sentences (SL)? (3) When learning English morphosyntactic structures, do different gestures for the third person possessive {-s} and the plural marker {-s} systematically differ from gestures that do not show the specific {-s} meaning? The general methodological approach taken here is to teach learners the same text but to alter the learning process by combining the linguistic units of the text with different gestures. In this way, the effect of different gestures on the learning process can be examined independently of the linguistic forms used to facilitate it. In the first study, L2 oral fluency development was investigated in the context of learning and performing a play. Subjects participated in a picture description task before and after taking part in a theatre project which involved learning the text of a play in a gesture per morpheme (CG) or gesture per sentence (SL) condition. The aim was to compare changes in fluency development between learners. The results show that learning the same text with different instructional methods is associated with a different development in oral fluency. When instructional gestures differ in linguistic units, the initial fluency level of learners is predictive of which learning condition benefits fluency the most. In particular, learners with a lower initial speech rate benefited more from teaching using gestures that are paired with morphemes (CG), whereas the children with a higher initial speech rate benefited more from the condition with gestures at the sentence level (SL). The second study also took place in the context of a theatre project but examined L2 spatial term learning. Subjects participated in a spatial term test before and after learning the text of a play in a CG or SL condition. The finding from experiment one—that learners with a lower initial ability benefited more from gestures that show morphemes (CG), and learners with a higher initial ability benefited more from gestures at the sentence level (SL)—was not replicated. Rather, in experiment two, learners exposed to the one gesture per morpheme condition (CG) showed a more rapid increase in spatial term comprehension and ability. In a third study, subjects were asked to complete word fragments in phrases containing the plural and possessive {-s} in gesture form. The plural and possessive {-s} gestures were presented in both a two-gesture condition with distinct gestures for plural and possessive {-s} and a one gesture condition with a single general {-s} gesture to assess the differences between them. Compared with the single-gesture condition, fragment completion response time after training was found to be faster in the condition with two distinct gestures for plural and possessive {-s}. Notably, the gestures in the two gesture condition in study three were the same as those used in the CG condition in study one and two. In summary, it could be shown that: (i) when instructional gestures differ in linguistic units, the initial fluency level of learners is predictive of which gesture type benefits fluency the most, and children with a lower initial speech rate benefit more from gestures that show morphemes; (ii) gains in understanding and using spatial terms are more immediate for learners exposed to one gesture per morpheme; (iii) seeing different grammatical morphemes for the plural and possessive {-s} in gesture form results in measurable differences in response time when compared to gestures without this distinction; and (iv) contrasting the same and different gestures for the plural and possessive {-s} grammatical morphemes revealed a decrease in response time after instruction for gestures that visually distinguish between grammatical morphemes which differ in meaning but sound the same. Overall, it was demonstrated that learners in this age group benefit from instructional gestures, where one gesture represents a sentence, word, or morpheme, because they can support oral fluency. In the case of gestures at the level of morphology, gestures also help learners to internalize and apply L2 grammar. As a learning tool, gestures bring together our social, physical, and mental experiences. These findings add to the growing literature examining teaching gestures in naturalistic contexts and provide plausible reasons for greater inclusion of codified gestures in L2 instruction in diverse teaching settings.
View lessStreulicht-Nahfeldmikroskopie (s-SNOM) ist eine vielseitige Methode zur Strukturaufklärung, die nicht der Beugungsbegrenzung unterliegt. Somit gelingt, unabhängig von der Wellenlänge der verwendeten Strahlung, die Abbildung von Strukturen auf der Nanometerebene durch die Detektion von Streulicht einer Probe, die sich im optischen Nahfeld einer Sonde befindet. Durch die Verwendung von breitbandigem Licht in Kombination mit einem Michelson-Interferometer können Infrarotspektren von einzelnen Strukturen, die kleiner als 20 nm sind, aufgenommen werden. Die in der vorliegenden Arbeit verwendete Strahlungsquelle für breitbandige IR-Strahlung ist der Elektronenspeicherring Metrology Light Source (MLS) der Physikalisch-Technischen Bundesanstalt (PTB) in Berlin-Adlershof. Es wird Synchrotronstrahlung aus dessen Infrarotstrahlrohr verwendet und als Nahfeldsonde wird die Spitze eines Rasterkraftmikroskops verwendet. Es wird die Entwicklung eines neuen Betriebsmodus‘ für den Speicherring beschrieben, der zur Anpassung der Synchrotronstrahlung an das Mikroskop dient, womit die Empfindlichkeit der nano-FTIRSpektroskopie gesteigert werden kann. Um die langen Messzeiten bei der Aufnahme eines hyperspektralen Datensatzes zu verkürzen, wird die Technik des Compressed Sensing auf s-SNOM angewendet und deren Machbarkeit für eine SiC-Probe untersucht. Es wird die Verwendung einer neuartigen Messmethode beschrieben, bei der die Detektion auf dem thermoelektrischen Effekt beruht. Somit kann auf den ansonsten bei s-SNOM verwendeten, halbleiterbasierten (und mit flüssigem Stickstoff gekühlten) Detektor im Fernfeld der Probe verzichtet werden. Schließlich wird am Beispiel von drei Probensystemen gezeigt, wie Polaritonen ausgenutzt werden können, um die Empfindlichkeit von s-SNOM-basierten Spektroskopiemessungen zu steigern. Beim 2D-Material MoS2 können durch die Kopplung an Phononen des Substrats SiO2 Plasmonen spektroskopisch nachgewiesen werden, die ansonsten nicht zugänglich wären. Beim Probensystem der funktionalisierten Metalloxide SrTiO3/LaAlO3 kann an der Grenzfläche der beiden Perowskite durch den Einfluss der Dicke des Deckmaterials auf die Anwesenheit eines 2D-Elektronengases geschlossen werden. Auf einer Phospholipid-Monolage, welche auf Graphen aufgebracht wurde, kann mittels einer als Plasmonen-Interferometrie bezeichneten Methode eine Kontrastverstärkung erzielt werden. Hierdurch ist es wiederum möglich, Domänenstrukturen des Phospholipids abzubilden, die mittels einfacher Nahfeldmikroskopie nicht zugänglich wären.
View lessThis work explores the potential of supercritical fluid chromatography for the analysis of peptide drugs. The regulatory aspects of peptides are more complex and challenging than for small drug molecules. The same applies to the analytical characterization of peptides. After technical innovations and the introduction of a new instrument generation, supercritical fluid chromatography nowadays is a suitable alternative to reversed-phase chromatography, which is considered the gold standard in peptide analysis. However, the scientific data on the analysis of peptides with supercritical fluid chromatography is limited. In the first part of this thesis, supercritical fluid chromatography is used to develop a method to separate the variety of cyclic and linear peptides characteristic for tyrothricin. A software-based design of experiments approach is utilized to optimize an analytical method that provides superior separation of cyclic peptides compared to the reversed-phase separation. Even isomeric peptide pairs are efficiently separated. Subsequently, the potential of a binary mixture of methanol and acetonitrile combined with additives as the modifier for the separations of other cyclic peptides is investigated. The proportion of the mixture is optimized to improve the resolution and control the elution order of the analytes. Paired with an aromatic stationary phase, this chromatographic parameter offers an effective method optimization opportunity. This knowledge is furthermore extended to larger and more hydrophilic peptides in the following experiment. A single method for the purity analysis of human insulin and six analogs is optimized. A crown ether is also investigated as a promising additive to control the elution order of the insulins in dependence to its concentration. In the last study, the applicability of an established chromatographic modeling software for the in-silico optimization of peptide separations in supercritical fluid chromatography is demonstrated. Optimizing a binary mixture of methanol and acetonitrile serves as an effective parameter of the model. Using such software tools offers enormous time savings and, at the same time, meets the current requirements for analytical method development according to the quality by design concept. These already published studies are finally put into the context of the life cycle concept of analytical methods that will soon be demanded by the ICH Q14 guideline "Analytical procedure development". Existing knowledge, in the form of scientific publications, is employed as the basis for a general risk assessment applicable to peptide separations with supercritical fluid chromatography. From this, a generic method development strategy is derived and presented. This way, the current state of science and technology is taken into account to define an efficient workflow. This is particularly relevant in early pharmaceutical development phases, from where only a small fraction of initial drug candidates reaches market maturity. At the same time, this approach enhances the drug knowledge in early development phases and ultimately serves patient safety. The present work makes an important contribution to demonstrating the potential of supercritical fluid chromatography for the analysis of peptide drugs. It serves as a concise example of how supercritical fluid chromatography can be interpreted as a new technique in the ICH Q14 guideline setting. The approach presented can be easily applied to any other analytical technique or analyte class.
View lessArctic amplification is the phenomenon of accelerated warming of the Arctic polar regions in the context of climate change induced by anthropogenic greenhouse gas emissions. A number of recent cold episodes in midlatitudes in winter have raised the question of whether the Arctic amplification has led to the observed midlatitude cooling. The proposed mechanism of this Arctic-midlatitude linkage involves a stratospheric pathway. Accordingly, the horizontal temperature gradients are decreasing due to the enhanced polar warming at the surface. Consequently, the superjacent winds are weakened which results in slower and more meandering polar jet streams. The enhanced planetary waves propagate into the stratosphere, where they induce strong circulation anomalies, referred to as sudden stratospheric warmings (SSWs). These strong disturbances of the stratospheric polar vortex can potentially exert a downward influence on the troposphere, favouring local cold air outbreaks. Investigating this stratospheric pathway in a climate model requires an accurate representation of the middle atmosphere. Therefore, a comprehensive evaluation using the climate-chemistry model ECHAM/MESSy Atmospheric Chemistry (EMAC) was conducted in this thesis, with the additional aim of examining the impact of ozone chemistry on the stratospheric processes. The suggested steps of the stratospheric pathway were examined using a set of transient simulations and timeslice experiments. Although the Arctic amplification signal continued to rise, no cooling trend or cessation of warming was found in the transient simulations. In contrast, the frequency of SSWs has increased significantly under the influence of climate change. This increase could be attributed to a larger planetary wave input from the troposphere. The primary area of enhanced planetary wave propagation was identified as the Northern Pacific and the region spanning the North Atlantic and Europe. Moreover, the number of events corresponding to strong wave input into the stratosphere increased significantly in a warmer climate. The behaviour of the jet streams was evaluated using a jet detection scheme to determine the exact jet positions. The Eurasian region exhibited an increased occurrence of polar jets, showing a wavier path as well. In contrast, the western hemisphere was characterised by a reduced polar jet frequency. A straightforward connection between the wavier jets and temperature gradients in the lower troposphere was not established in this study. While the modifications in the lower layers imply reduced baroclinic instability and fewer atmospheric waves, an enhanced wave generation became evident in the upper troposphere. However, these anomalies coincide with changes in the static stability and in subtropical temperature changes. The release of additional waves into the stratosphere appears to be related to these upper-tropospheric anomalies. The findings of this thesis suggest that the step linking temperature gradients to upper-tropospheric wave propagation requires further clarification. This is critical for validating the stratospheric pathway. Moreover, an evaluation of the downward influence of SSWs was conducted. Despite more frequent SSWs in a warmer climate, no tendency towards more extreme cold events was found in the most affected regions. While significant cooling anomalies still existed after the SSW events, the temperature anomalies are considerably lower. Finally, the representation of ozone chemistry in the model was determined to have an insignificant impact on the results of the stratospheric pathway.
View lessIn the skin sensitization assessment, the in vivo method, specifically the Local Lymph Node Assay (LLNA), is regarded as the gold standard. However, to adhere to the 3R principle (Reduction, Refinement, Replacement), which advocates for the Reduction, Refinement, and Replacement of animal testing, and to enhance the ethical standards of risk assessment, a greater number of in vitro and in silico testing methods have been developed. While these in vitro and in silico methods offer a higher throughput and a more ethical approach to risk assessment, they each come with their own set of limitations. For instance, most in vitro tests can only be used for a single readout. On the other hand, in silico methods lack physiological and biological feedback. The adverse outcome pathway (AOP) for skin sensitization, as defined by the Organization for Economic Cooperation and Development (OECD) guidelines, involves four key events, which are protein binding (Key Event 1 – KE1), keratinocyte activation (Key Event 2 – KE 2), dendritic cell activation (Key Event 3 – KE 3), and T-lymphocyte activation (Key Event 4 – KE 4) (OECD, 2014). While animal-based assays are reasonably accurate, their skin is physiologically different than human skin. Therefore, this thesis aimed to develop the ‘ImmuSkin-MT’, a 3D-human skin model with immune cells, designed to address the limitations inherent in in vitro skin sensitization assays. The thesis began with 2D co-culture of keratinocytes and immune cells, which have shown to fall short in detecting a skin sensitizer. In parallel to the development of the 2D co-culture assay, the advantages of the autologous in comparison to the allogenic 2D co-culture were investigated. The results indicated that within the donor pool used, allogenic 2D co-culture did not lead to an alloreactive response in the cells. Therefore, whether autologous or allogenic cell pairings were used in the co-culture, they had no impact on the development of the assay. Later, the project progressed and the 'ImmuSkin-MT', created from human hair follicle-derived keratinocytes (HFDK), fibroblasts (HFDF), and immune cells were developed. monocyte-derived Langerhans cells (MoLC) and CD4+ naïve T-lymphocytes were integrated into the reconstructed human skin models (RHS). ImmuSkin-MT were topically exposed to various substances, including non-sensitizers and contact sensitizers. Using the MoLC activation and the stimulation index (SI) of T-lymphocytes, results demonstrate the effectiveness of ImmuSkin-MT in replicating KE 3 and 4 of skin sensitization in response to the skin sensitizers. This model presents a promising alternative to animal testing for contact sensitizers, contributing to more ethical and precise skin sensitization assessment techniques. In conclusion, ImmuSkin-MT represents a significant advancement in skin sensitization assessment by capturing multiple key events simultaneously. The project's findings have the potential to optimize skin sensitization testing methods, providing more accurate, reliable, and ethical alternatives to traditional animal-based assays.
View lessEndogenous retroviruses (ERVs) are repetitive elements that constitute around 10 percent of mammalian genomes. ERVs need to be kept transcriptionally silenced during development and ERV upregulation is linked to loss of pluripotency and mouse embryonic lethality. Precise mechanistic understanding of this process remains incomplete. To investigate effects of ERV derepression, I utilized degradation tag (dTAG) system to acutely deplete endogenous levels of TRIM28, a heterochromatin protein that recruits silencing machinery to ERVs in mouse embryonic stem cells (mESCs). Nascent transcriptome sequencing indicated TRIM28 depletion induces acute transcriptomic changes: upregulation of ERVs and other targets of TRIM28-mediated repression and simultaneous downregulation of key pluripotency super enhancers (SEs) and associated genes. High-resolution microscopy data indicated ERV derepression reduces association of SEs with RNA polymerase II (RNAPII) and Mediator (MED1), the key components of transcriptional condensates. In turn, derepressed ERVs associated with RNAPII and MED1, indicating transcriptional condensate components are redistributed upon TRIM28 depletion. Presence of transcriptional machinery at derepressed ERV loci upregulated nearby genes, including Cthrc1. Ectopic overexpression of pluripotency factors enriched at SEs prevented the reduction in transcriptional condensate association with SEs. ERV knockdown rescued transcriptional condensate localization indicating RNAs produced at ERV play an important in transcriptional condensate redistribution. Evidence presented here shows derepressed ERVs have the capacity to ‘hijack’ transcriptional condensates from key pluripotency genes upon TRIM28 degradation. This may be the molecular mechanism contributing to embryonic lethality associated with ERV derepression in TRIM28 knockout mice.
View lessWe live in a structured world, where objects rarely exist in isolation but are often surrounded by similar environments. When objects consistently co-occur with certain objects and scene contexts, our neural systems can implicitly extract and learn such regularities in real-world environments. Predictive processing theories propose that our brains can use learned statistical regularities to predict the structure of incoming sensory input across space and time during visual processing. The predictions may allow us to efficiently recognize objects and understand scenes, thus forming coherent visual experiences in natural vision. In this dissertation, we conducted three studies to explore how our brains use real-world structures to create coherent visual experiences using neuroimaging techniques (EEG & fMRI) and multivariate pattern analyses (MVPA). Study 1 investigated how scene context affects object processing across time by recording EEG signals while participants viewed semantically consistent or inconsistent objects within scenes. The results reveal that semantically consistent scenes facilitate object representations, but this facilitation is task-dependent rather than automatic. In Study 2, we investigated how cortical feedback mediates the integration of visual information across space by manipulating the spatiotemporal coherence of naturalistic video stimuli shown in both visual hemifields. By analytically combining EEG and fMRI data, we demonstrated that spatial integration of naturalistic visual inputs is mediated by cortical feedback in alpha dynamics that fully traverse the visual hierarchy. In Study 3, we further investigated what level of spatiotemporal coherence is needed to trigger such integration-related alpha dynamics. The findings suggest that integration-related alpha dynamics have some flexibility so that they can accommodate information from videos belonging to the same basic-level category. Together, the dissertation provides multimodal evidence demonstrating that contextual information facilitates object perception and scene integration, highlighting the critical role of predictions related to real-world regularities in constructing coherent visual experiences.
View lessAls eine bisher noch wenig für fremd- und zweitsprachliche Kontexte erarbeitete soziale Kategorie werden in der vorliegenden Arbeit „Zugehörigkeiten“ als lohnender Zugang für den Sprach-, Kultur- und Literaturunterricht vorgeschlagen. Am Beispiel brasilianischer Germanistikstudierender zeigt die Studie, wie die erworbene Zugehörigkeit zur deutschen Sprachgemeinschaft und die bestehende Zugehörigkeit zu Brasilien als fruchtbar und motivierend für fremdsprachliche Lehr-Lern-Prozesse genutzt werden können. Dafür wurde ein Vernetzungsmodell konzipiert, das einzelne Verdichtungspunkte deutsch-brasilianischer Literaturen betrachtet und sie nicht in Bezug auf Nationalphilologien, sondern im Kontext zueinander sieht. Konzeptionell wurde für das Modul die Perspektive einer doppelten Zugehörigkeitsorientierung entwickelt und deren unterrichtliche Ausarbeitung empirisch begleitet: So teilt sich das Konzept in eine subjektorientierte Zugehörigkeitsorientierung, die sich an den Zugehörigkeitskontexten der Teilnehmer*innen in Lehr- und Lernarrangements orientiert und in eine epistemische Zugehörigkeitsorientierung, die die Teilnehmer*innen anleitet, die Zugehörigkeiten von anderen verstärkt wahrzunehmen und die sich somit auf die soziale Verfasstheit unserer Gesellschaften richtet.
View lessResistive random-access memory (RRAM), one of the next-generation non-volatile memory technologies, offers scalability, enhanced performance, and lower power consumption compared to traditional memories, making it a promising solution for future memory architectures. In this work, we study different types of polycrystalline RMnO3 (R = Y, Er) thin films-based RRAM devices. This research starts with the synthesis and characterization of polycrystalline YMnO3 and ErMnO3 thin films with mixed hexagonal and orthorhombic phases. Films are prepared with radio frequency sputtering at room temperature and post-deposition annealing. The orthorhombic phase cannot always be discriminated by X-ray diffraction, as there is an overlap with the peaks of the hexagonal phase and its low volume fraction and the nano-sized grains lead to undetectable peaks. Employing a set of correlative spectroscopy and microscopy techniques, we develop a method to unambiguously identify the presence of the orthorhombic phase, locate it, and quantify it. Subsequently, we investigate different types of memristive devices using polycrystalline thin films with the presence of both hexagonal and orthorhombic phases. First, electrochemical metallization (ECM) memristive devices based on YMnO3 with Al active electrode are studied. These devices exhibit bipolar resistive switching with high ROFF/RON ratios (~ 104), low Set/Reset voltages (VSet ~ 1.7 V and VReset ~ -0.36 V), and good retention. The resistive switching mechanism is ascribed to the formation and rupture of an Al filament along oxygen-deficient boundaries between hexagonal and orthorhombic phases. These localized nanochannels for Al3+ migration effectively remove the randomness of the Al filament formation in the electrolyte. Second, we investigate bipolar resistive switching in Pt/ErMnO3/Ti/Au devices. They exhibit high ROFF/RON ratios (~ 105) and ultra-low resistances (~ 10 ohm) in the low resistance state (RON). The resistive switching is the result of the formation and rupture of an oxygen-vacancy-based conductive filament, which likely occurs either in the orthorhombic phase or at the boundary between the two polymorphs. An increased fraction of the orthorhombic phase strongly reduces the operating voltage in devices (down to VSet ~ -2.07 V) and the variability of VSet. The presence of hexagonal phase prevents large leakage currents in the devices, which otherwise would not show switching behavior. Finally, we present the first demonstration of electroforming-free threshold switching devices with ErMnO3. Pt/ErMnO3/Pt devices exhibit repeatable unipolar threshold switching with a memory window of 0.7 V, characterized by a S-shape current-controlled negative differential resistance (NDR). The devices show a high endurance up to 104 sweeps. We successfully model the threshold switching using Joule-heating-enhanced 3D Poole-Frenkel conduction mechanism. The conducting orthorhombic phase plays a key role in enabling the self-heating mechanism while the hexagonal phase prevents too large electrical and thermal conductivities. Adjusting the conductivity of o-ErMnO3 and engineering the two crystalline phase fractions are key knobs for tuning the threshold switching characteristics. The oscillatory behavior of the NDR devices is demonstrated. This new type of NDR devices based on two polymorphs with different electronic and thermal properties present advantages for tunability of the memory window compared to known NDR devices such as those based on an insulator-to-metal transition (e.g. VO2) or based on the formation of a filament (e.g. NbOx). In all studied devices, the coexistence of the hexagonal and orthorhombic phases of RMnO3 (R = Y, Er) provides unique functionalities. The possibility to engineer these two phases both in conductivity and content through synthesis, provide original routes to design new memristive devices and optimize their properties.
View lessDiese Arbeit untersucht die im Dīwān luġāt at-Turk des Maḥmūd al-Kāšġarī aus dem 11. Jh. n. Chr. verstreuten Angaben zur Sprache der Qïfǰāq mit dem Ziel, die Beziehungen dieser frühesten bekannten kiptschakischen Wörter einschließlich ihrer Lautgestalt zu historischen Vorgänger- und Nachfolgersprachen und bestimmten Sprachregionen der gesamten Turcia herauszuarbeiten und sie so in einen sprachhistorischen Kontext zu stellen. Dazu wurden sämtliche Varietäteneinträge des 637 Manuskriptseiten umfassenden Dīwān luġāt at-Turk neu verzettelt und der so gebildete Auszug des Wortmaterials der Qïfǰāq in alphabetischer Reihenfolge in der Art eines Meta-Wörterbuches aufbereitet. Nach Klärung der Textüberlieferung, Wortherkunft, Wortbildung, Lautstruktur und Bedeutungsspannweite wurde eine Belegsammlung erstellt, die das betreffende Wort in der Gesamtheit seiner Erscheinungsformen in möglichst zahlreichen alttürkischen, mitteltürkischen und neutürkischen Sprachen und Varietäten registriert und die Überlieferungs- und wo möglich Entlehnungswege der spezifisch kiptschakischen Elemente nachzuverfolgen versucht. Im Auswertungsteil wurden die Ergebnisse dieser Nachverfolgung zusammengeführt und verglichen. Besonderes Augenmerk lag darüberhinaus auf der textkritischen Aufarbeitung der Stellen, auf der Rolle des Kopisten und besonders späterer Kommentatoren, auf der Frage nach der Verlässlichkeit der Angaben Maḥmūd al-Kāšġarīs auf dem Hintergrund der so erarbeiteten Daten und auf seinen Angaben zur Verbreitung bestimmter Merkmale im Kiptschakischen zugleich mit anderen Varietäten des 11. Jhs., insbesondere in den Ogusischen Sprachen. Die Nachverfolgung, Lokalisierung und Bewertung charakteristischer sich während der gesamten historischen Zeit ausbreitender Lautwandelerscheinungen erfolgte in einer ergänzenden Untersuchung. Das so gewonnene Bild wurde in einen durch muslimische Geschichtsquellen des 10. bis 12. Jhs. und moderne Untersuchungen an historischem Genmaterial aufgebauten Rahmen eingeordnet. Hier wurde auch versucht, Bezüge zu aus der Geschichtsschreibung bekannten mittelalterlichen Völkerbewegungen herzustellen. Als Arbeitsgrundlage dienten neben dem einzigen erhaltenen Autographen des Dīwān luġāt at-Turk, gelesen nach dem Faksimile von 1990, die Edition des Werks von Dankoff und Kelly (Maḥmūd al-Kāšγarī, Compendium of the Turkic dialects, drei Bände, 1982 bis 1985) und zahlreiche Wörterbücher der alttürkischen, mitteltürkischen und neutürkischen Sprachen, darunter auch historische Wörterbücher, außerdem eine Auswahl an mitteltürkischen literarischen Quellen, Editionen islamischer Geschichtsschreiber und moderne Sekundärliteratur, u.a. zu Geschichte, Klimageschichte und historischer DNA Eurasiens. Als Ergebnis des sprachwissenschaftlichen Teils der Arbeit mit ihrer Untersuchung der von Maḥmūd al-Kāšγarī als kiptschakisch bezeichneten Formen nebst aller anderen Varianten in ihrer zeitlichen und lokalen Verbreitung ergaben sich 68 Wortstammbäume. Diese Wortstammbäume wurden ihrerseits ggf. unter Berücksichtigung interner Kategorien des Dīwān luġāt at-Turk wie Verbreitung in mehreren Türksprachenvarietäten des 11. Jhs. hinsichtlich des Vor- und Weiterlebens der als Kiptschakisch gekennzeichneten Varianten zusammengeführt und ausgewertet und die Ergebnisse ggf. in Gruppen nach Art des Merkmals sortiert und einzeln besprochen. Für einzelne Wörter ergaben sich im Zuge der Aufarbeitung Beiträge zur Lehnwortforschung und Etymologie. Insgesamt konnte die Zweiteilung der kiptschakischen Siedlungsgebiete, wie sie auf der Karte des Dīwān luġāt at-Turk gezeigt ist, durch das Textmaterial bestätigt werden, es ergaben sich jeweils leicht unterschiedliche Bezüge zum West- und Ostalttürkischen. Für das 11. Jh. waren entsprechend charakteristische Sprachvarietätengruppierungen feststellbar. Hier zeichnete sich schwach eine Aufteilung in ein nordtürkisches und ein südtürkisches Sprachareal ab, das allerdings nicht mit dem im Text des Dīwān luġāt at-Turk vorgestellten Nord- und Südriegel der Türkstämme deckungsgleich ist – diese Anordnung im Dīwān luġāt at-Turk stellt eine Momentaufnahme der Wanderbewegungen diverser Türkvölker nach Westen dar. In den Kapiteln zum Erhalt des kiptschakischen Wortmaterials des Dīwān luġāt at-Turk in den mittel- und neutürkischen Sprachen ergaben sich vereinzelt Einblicke in die Entstehungsgeschichte der zeitgenössischen Familie der Kiptschaksprachen. Hierbei waren Überlegungen zu Lautsystemverschiebungen für die Auswertung unerlässlich. Für das 11. Jh. wurde dahingehend eine grobe Dreiteilung der türkischen Sprachgemeinschaft rekonstruiert und diese für die Folgejahrhunderte in ihrer weiteren Entwicklung nachverfolgt. Auch die Vertretung der türkischen Klusile im Altuigurischen von Xinjiang und die Häufigkeit von Frikativen in der Aralo-kaspischen Region spielen in diesem Rahmen eine Rolle. Zwei Kapitel zur Bewertung der Fähigkeiten und Leistungen des Autors Maḥmūd al-Kāšġarī, eines ohne und eines mit Einbeziehung der Ergebnisse der Wortstammbäume, liefern ein mehrschichtiges Profil des Autors und seiner Leistungen. Ein Ergebnis der textkritischen Arbeit ist die versuchte Identifikation des bisher namentlich unbekannten aktivsten nachträglichen Kommentators und Glossenschreibers des Dīwān luġāt at-Turk, "the later hand", mit Aḥmad Ḫaṭīb Dārayyā und damit die Datierung wichtiger Glossen. Schließlich wurde eine Auswertung der muslimischen Quellen zur Geschichte der Kiptschaken mit einer Sichtung historischen genetischen Materials kombiniert und über die aus der sprachwissenschaftlichen Untersuchung gewonnenen Daten geblendet. Im Ergebnis ergaben sich Vermutungen zum Ablauf des mehrphasigen Wanderungsgeschehens der Kiptschaken, Kimäk und Yemäk unter Beteiligung von Bevölkerungsgruppen östlicher (darunter C-Y15550 und C-F12970 unter C-M86) und westlicher (darunter R1b-M73) Herkunft.
View lessTight junctions (TJs) seal the paracellular space between epithelial and endothelial cells, and are essential for tissue compartmentalization and barrier formation. The backbone of the TJ is formed by a group of transmembrane proteins, called claudins. Claudins polymerize into strands and meshes through cis- and trans-interactions, and are expressed in different combinations, based on the needs of the respective tissue. The large protein family can be divided into pore- and barrier-formers claudins, with the former being selectively permeable to ions or water. Structural insight in claudin polymerization is limited; models have been created, but only of a few homopolymers. Recent studies have found only half of the claudin family to form homopolymers, whereas co-expression can promote polymerization of certain claudins. This thesis thus focuses on regulation of claudin polymerization. In the first part of the thesis, intrinsic regulation was examined by a comparison of claudin-3 and claudin-4. These proteins have high sequence homology, yet only claudin-3 polymerizes by itself in fibroblasts. With sequence alignment and molecular dynamics simulations, we predicted a motif in the second extracellular segment key to stable trans-interaction and polymerization. We mutated the two residues in claudin-4 into their claudin-3 equivalents and found that they promote polymerization in fibroblasts. Moreover, the mutated claudin-4 could (partially) rescue TJ localization, as well as the formation of a TJ barrier with ruffled morphology in TJ-deficient epithelial cells. Extrinsic regulation of claudin polymerization, specifically how co-expression of claudins can influence polymerization, was investigated next. Our focus was on claudin-16 and claudin-19, that form a cation-permeable copolymer in the thick ascending limb (TAL) of the kidney. Mutations in either protein cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis, emphasizing their essential role in kidney Ca2+ transport. We also investigated claudin-14, that can block this cation-pore upon its hypercalcemia-induced expression, and is associated with kidney stone formation. It is known that non-polymerizing claudin-16 integrates into the claudin-19 meshwork, but how this is affected by claudin-14 is still poorly understood. Super-resolution microscopy in fibroblasts revealed that claudin-14 can replace claudin-16 in a strand-specific manner. We further validated this in epithelial cells with endogenous claudin-16 and in the TAL of hypercalcemic mice. Claudin-14 expression by transduction in epithelial cells, and in response to hypercalcemia in the mice, again led to claudin-16 replacement. Overall, we have identified a motif that intrinsically regulates claudin polymerization and have shown that claudin-14 replaces claudin-16 to regulate Ca2+ transport in the kidney. These insights form a basis to understand and manipulate claudin polymerization, for instance to improve drug delivery or to prevent pathogen entry. More directly, the knowledge of the claudin-14 regulatory mechanism can be used to develop treatments for kidney stones and other pathologies involving hypercalciuria.
View lessChemotherapy and radiation are standard-of-care cancer treatments, but their effectiveness is often hampered by therapy resistance within the tumor. Numerous studies have demonstrated that tumor cells can evade cell death triggered by genotoxic therapies by activating IKK/NF-κB pathway, thereby preventing apoptosis. The direct targeting of IKKs using pharmacological interventions is not a viable option due to the significant adverse effects caused by the essential role of IKK/NF-κB signaling in various physiological processes. To circumvent this, previous work by our group identified structurally unrelated small molecule inhibitors, MW01 and MW05, that selectively inhibit IKK/NF-κB solely in response to DNA double strand breaks induced by chemotherapy and radiation. Importantly, these compounds do not interfere with IKK/NF-κB activation triggered by other physiological stimuli. Initial work began by confirming the genotoxic stress-specific inhibition by the compounds before moving onto target identification studies. Considering the similar cellular effects of both compounds within the DNA damage-induced NF-κB pathway, comparative target identification studies including kinase assay panels, structural derivatization, and molecular signaling characterization were performed, seeking targets shared between both lead compounds. Common regulators shared by other NF-κB stimuli were first excluded as potential targets of the compounds before investigation of the several identified shared targets revealed a previously unknown regulators of genotoxic stress-induced NF-κB activity, Cdc-like kinases (CLK) 2 and 4, as the functional target of MW01 and MW05. Silencing of the CLK2 and 4 revealed that they are essential for DNA damage-induced NF-κB activity and promote the phosphorylation of IKK at Ser-85, a genotoxic stress specific ATM-dependent phosphosite, critically localizing the CLKs within the cascade between ATM and IKK. CLK2 and 4 were also confirmed as the target of active structural derivatives of MW01 and MW05 and were spared by inactive derivatives, confirming CLK2 and 4’s role in genotoxic stress-induced NF-κB. In addition, CLK inhibitor MU-1210 also inhibited NF-κB following DNA damage, suggesting that CLK inhibitors could be used to potentiate the tumor killing effect of standard cancer treatments. MW01 and MW05 were tested in co-treatment with DNA damaging agents, in the context of on-going DNA damage, and in patient derived glioblastoma cells to assess their potential clinical applications. Critically, neither MW01 nor MW05 exhibit general toxicity; instead, they notably enhance apoptosis specifically in tumor cells following genotoxic stress. In BRCA1-deficient cells and in co-treatment with PARP inhibitor Olaparib, both characterized by on-going DNA damage, MW01 and MW05 potentiated DNA damage and p53 levels, suggesting that the compounds unbalance the NF-κB/p53 axis in favor of apoptosis. This approach introduces a novel therapeutic strategy to curb NF-κB activity induced by DNA damage in cancer cells without impacting its essential functions in healthy cells.
View lessCell-type specification is guided by transcription factors (TFs) that control specificity and activity of transcription by binding to regulatory DNA elements, such as enhancers. TFs are modular proteins, consisting of structured DNA-binding domains, which allow binding to TF-specific DNA motifs, and intrinsically disordered regions (IDRs), which often harbor “minimal activation domains” that control the activity of the TF. Both, DNA-binding specificity and transcriptional activity of TFs have been extensively studied using ChIP-sequencing and activation domain screens. However, the mechanisms by which TFs establish specific gene expression programs remain poorly understood, as TF-binding or the presence of a minimal activation domain within a TF IDR do not necessarily correlate with target gene expression. Recent studies suggest that non-linear sequence features of TF IDRs facilitate the formation of transcriptional condensates, contributing to both the activity and specificity of TFs, thus indicating a relationship between these two features.
In the following, I provide evidence for an evolutionary trade-off between the activity and specificity in human transcription factors encoded as submaximal dispersion of aromatic residues in their IDRs. I identified multiple human TFs that display significant dispersion of aromatic residues in their IDRs, resembling imperfect prion-like sequences. Mutation of dispersed aromatic residues reduced transcriptional activity, while increasing aromatic dispersion in multiple human TFs enhanced transcriptional activity. Furthermore, sequence optimization by increasing aromatic dispersion enhanced in vitro reprogramming efficiency, promoted liquid-like features of condensates formed in vitro, and led to more promiscuous DNA-binding in cells. Together with recent work on enhancer elements, these results suggest an important evolutionary role of suboptimal features in transcriptional control. I propose that engineering of amino acid features that alter condensation may be a strategy to optimize TF-dependent processes, including cellular reprogramming.
View lessVerletzbarkeit als Fähigkeit und als dezidiert politische und feministische Haltung: Diesen Ansatz verfolgt eine Reihe radikal autobiografischer Schreibweisen, die in den letzten Jahren aus den sozialen Medien in den Literaturbetrieb eingezogen sind. Anhand von Beispielen aus dem deutsch-, englisch- und chinesischsprachigen Internet beschreibt Lea Schneider Ästhetiken radikaler Verletzbarkeit, ihre medialen Affordanzen sowie die Wertungskämpfe, die sie beim Eintritt in den etablierten Literaturbetrieb auslösen – bis hin zu einer Neudefinition des Literaturbegriffs selbst.
View lessPolnische Bürgermeister waren eine wichtige Beamtengruppe im Verwaltungsapparat des Generalgouvernements. Gemeinsam mit den deutschen Kreis- und Stadthauptmännern gestalteten sie Kommunalpolitik und waren an der Verfolgung und Ermordung polnischer und europäischer Juden sowie an der Ausbeutung des Generalgouvernements maßgeblich beteiligt. Auf der Grundlage umfangreicher Archivrecherchen und neuer Kontextualisierungen stellt dieses Buch ausgewählte polnische Bürgermeister vor und zeigt, wie diese sich während des Zweiten Weltkriegs verhielten. In die Analyse werden kleine Städte wie Otwock, mittelgroße wie Tschenstochau und Metropolen wie Warschau einbezogen. Mit dieser Studie legt Grzegorz Rossoliński-Liebe ein Standardwerk vor, das eine unverzichtbare Grundlage für die Erforschung von Kommunalverwaltungen im Holocaust darstellt.
View lessThe Internet is a complex system of autonomous but cooperating networks that constitute a critical Infrastructure with a vast socio-economic significance. Any disruption of the Internet and its services has detrimental effects to its users, be it in the private sector or the industry. This is why Internet research aims for observing, mitigating, and ultimately preventing attacks.
In this thesis, we provide methodologies to evaluate and extend the coverage of attack observations, we assess the efficacy of current and emerging attack mitigation solutions, and we identify new opportunities for attack prevention. We do so by utilizing two major vantage point positions, the Internet core and the Internet edge. Our contributions have an operational impact on today's Internet but also its future deployment.
View lessClimate change presents significant challenges for agriculture. The emission of greenhouse gases calls for a reassessment that influences the manufacture and processing of animal feed. Sustainable solutions, such as cultivating domestic grains as protein sources and adopting techniques like grazing livestock on grasslands and agroforestry, will gain importance. However, certain plants that are increasing in significance possess SPM. SPM serve various significant functions and have diverse effects on their surroundings. In addition to benefiting the plant and its environment, the primary motivation for producing these compounds is to provide a growth advantage and protection against herbivore predators, ensuring plant survival and reproduction. Nevertheless, ingestion of plants with SPM still occurs resulting in a possible risk to both animals and consumers if there is a transfer of SPM via feed into food of animal origin, especially into milk.
For some SPM transfer into the milk is already investigated while for others there is still lack of data as summarized in Chapter I.
Chapter I reviews the current literature on two secondary plant metabolites for which there is still a lack of data on their occurrence and possible transfer to milk, although there are indications that transfer may be possible. The QA are naturally occurring alkaloids in Fabaceae. Their best-known representative with a wide range of applications in animal nutrition, due to their beneficial protein content, are lupins, which are subdivided into sweet and bitter lupins depending on their QA content. QAs have multiple toxicological effects that result in a so-called anticholinergic syndrome causing among other coordination disorders, respiratory paralysis, tachyarrhythmia or cardiac arrest. Due to its chemical structure, a transfer into the milk of cows was suspected, but there are no data so far. Sapindaceae, a different botanical family, possesses recognized toxic properties. Within this family, certain SPM, namely HGA, MCPrG, and HGB, have led to significant toxic effects in humans, horses, and wild ruminants. Important representatives of the Sapindaceae are sycamore maple trees, which can be found in meadows and fields with contents on HGA, MCPrG and HGB in their seeds and seedlings. Initial studies suggest that these SPM may be transferred into the milk of mares or cows after ingestion of seeds or seedlings. Nonetheless, thorough research on the effects of these substances and their excretion in milk has not been conducted in dairy cows.
Chapter II therefore explains the aims and hypothesis of the current thesis. The main part of this thesis consists of two published manuscripts summarized in Chapter III and IV. The primary objective was on increasing knowledge on the transfer QA into the milk of dairy cows as well as on the intake of maple toxins HGA, MCPrG and HGB and their subsequent Transfer into the milk of dairy cows. These efforts aimed to provide a more comprehensive assessment of the risks posed to both animals and consumers. Furthermore, a toxicokinetic model was derived to predict the feed to food transfer for QAs (published in Engel et al. 2022, Chapter III).
The first study was conducted as a feeding trial in four Holstein-Friesian dairy cows. During the trial rapeseed meal was switched for either one or two kg of narrow-leafed lupins (L. angustifolius variety Boregine) for seven days as experimental periods with respective depuration periods. During these periods milk was sampled twice daily and analyzed on their respective QA content with an in-house validated novel LC/MS-MS method. Furthermore, milk ingredients were monitored regularly. Based on the data three-compartment toxicokinetic model was derived to predict feed to food transfer. The results reveal that an intake of 1’774 mg QA per cow per day had no effects on animal health. Thereby, the pattern of the used lupin was like those already reported for narrow-leafed lupins even though total QA content was in the upper range of reported QA contents. Already the administration of 1 kg of lupins resulted in a transfer of QA into milk with different transfer rates for all QAs. Administration of twice the number of lupins (2 kg) showed a significant dosedependent transfer of QA into milk. Calculation of individual transfer rates revealed transfer rates differing from 1.05% for isolupanine to 3.74% for multiflorine (Chapter III). With maximum QA contents in milk a preliminary risk assessment was made for high consumers (P95) indicating a potential risk for consumers in this scenario (Chapter III). Nevertheless, data on toxicokinetic and occurrence of QA in feed and food is lacking.
Chapter IV aimed to investigate if there is an intake of sycamore seedlings by dairy cows while grazing and if so, if there is a transfer of their SPM into milk without the occurrence of clinical signs as known for other herbivores like horses after SPM ingestion. For that, five cows were subjected to an observational study over 4 days. Cows had access to a pasture with numerous seedlings growing between grass over a defined period. Additionally, they received a partial mixed ration in the barn ad libitum and concentrate feed suitable for their respective milk yields. Milk of individual cows was sampled twice daily as well as bulk tank milk of the whole herd (n=87) and analyzed on their content of HGA, MCPrG, HGB and their respective metabolites with a novel validated LC/MS-MS method. Experimental plots were placed on the pasture and seedlings were counted and photographed daily before cows were allowed to graze. Additionally, cows were observed by two independent observers and intake was captured if possible. Already on the first day, intake of sycamore maple seedlings was observed in dairy cows as a by-product of grazing. Noteworthily, only respective conjugated metabolites of HGA and MCPrG were measured in milk samples already on day 1 after grazing. Urine samples revealed MCPA-G contents above contents measured in diseased Peré David’s deer without the appearance of clinical symptoms. Statistical analysis revealed an increasing trend in MCPA-G contents in milk. There is still lack of data on toxicological effects of conjugated metabolites, but cows may be in general less susceptible to maple toxin intoxication.
In conclusion, the present thesis highlights that a transfer of the investigated secondary plant metabolites into milk is possible. Current developments in relation to climate change call for a fundamental rethink of the agricultural sector. The significance of local forage and agroforestry methods is increasingly acknowledged. Further investigations are imperative to appraise the potential risk to consumers and to provide suggestions for farm management, feeding, and grazing practices. In the case of lupins, preliminary risk assessment revealed a possible Risk for certain consumer groups. However, the risk to the consumer can be further investigated and reduced by testing the lupins available on the market for their QA content, adapting the recommendations for use and carrying out additional toxicological studies. For SPM found in Sapindaceae including A. pseudoplatanus is remains uncertain whether the conjugated metabolites of HGA and MCPrG found in the milk of individual cows as well as bulk tank milk represent a potential risk to consumers. Nevertheless, both uptake by cows with apparently reduced susceptibility and the possibility of transfer were demonstrated which emphasizes the necessity to produce additional data. To promote sustainable agriculture, it is necessary to enhance the use of indigenous legumes like lupins and pasture farming. This progression necessitates a comprehensive analysis ofthe linked hazards. By establishing these potential threats, we can advance our knowledge of farming and agriculture and create positive environmental impacts that counteract climate change.
View lessIn den letzten Jahrzehnten ist durch gezielte Zucht die Wurfgröße bei Sauen gestiegen und mit dieser Entwicklung hat die Anzahl der Ferkel pro Wurf mit niedrigem Geburtsgewicht (LBW) zugenommen. Höhere Mortalitäts- und geringere Wachstumsraten werden bei LBW-Ferkeln beobachtet. Die hohen Mortalitätsraten werfen Fragen zur ethischen Rechtfertigung der Schweinehaltung auf und stehen im Kontrast zu einer ressourceneffizienten Tierhaltung. Die geringeren Wachstumsraten sind mit ökonomischen Verlusten verbunden und werden mit einer dysfunktionalen Dünndarmentwicklung von LBW-Ferkeln assoziiert. Bei abgesetzten Ferkeln wurden positive Effekte einer Glutamin (Gln)-Supplementierung auf Wachstum und Parameter der intestinalen Entwicklung beschrieben. Da die konditionell essentielle Aminosäure Gln zu einem großen Umfang in den Epithelzellen des Dünndarms verstoffwechselt wird, besteht die Möglichkeit, dass durch Gln die Entwicklung des Dünndarms bei LBW-Ferkeln normalisiert werden könnte.
Ziel dieser Studie war es sowohl die akuten als auch potentielle persistente Effekte einer neonatalen Gln-Supplementierung bei männlichen unkastrierten Ferkeln auf Wachstum und verschiedener Parameter der jejunalen Entwicklung zu untersuchen.
Hierfür wurden männlich unkastrierte Saugferkel in einem Fütterungsversuch untersucht. Die Ferkel von Jungsauen wurden direkt nach der Geburt auf Grund ihres Geburtsgewichtes in Paaren selektiert, wobei die Selektionsgrenzen für LBW bei 0,8-1,2 kg und für normalgewichtige Ferkel (NBW) bei 1,4-1,8 kg lagen. Selektierte Ferkel wurden entweder mit 1 g/kg Körpergewicht (BW) Gln oder der isonitrogenen Menge Alanin (Ala) (1,22 g/kg BW) zwischen dem ersten und dem zwölften Lebenstag oral supplementiert. Durch den Versuchsaufbau ergaben sich vier Versuchsgruppen (LBW-Gln; NBW-Gln; LBW-Ala; NBW-Ala (n =36/Versuchsgruppe)). Die Versuchstiere hatten stets die Möglichkeit, bei der Muttersau zu saugen und erhielten zusätzliches Beifutter ab dem 14. Lebenstag. Das Wachstum der Tiere wurde durch regelmäßiges Wiegen und zusätzliche zootechnische Messungen überwacht. Jeweils ein Drittel einer Versuchsgruppe wurde am fünften, zwölften sowie sechsundzwanzigsten (n=12) Lebenstag euthanasiert und das distale Jejunum inklusive Chymus wurde für weitere Analysen beprobt. Den Tieren aller Versuchsgruppen wurde eine Stunde vor der Euthanasie Bromdesoxyuridin (BrdU) zur Bestimmung der Zellproliferationsrate und L-2H5-Phenylalanin zur Bestimmung der fraktionellen Proteinsyntheserate (FPSR) intraperitoneal verabreicht. Zusätzlich wurde die Milchaufnahme mittels der Deuteriumoxid-Methode am elften bzw. am fünfundzwanzigsten. Lebenstag in entsprechenden Gruppen bestimmt.
Die ausgewerteten Parameter der jejunalen Entwicklung wurden sowohl durch die Gln-Supplementierung als auch durch das niedrige Geburtsgewicht nur geringfügig beeinflusst. Interessanterweise unterschied sich die Konzentration der supplementierten Aminosäuren im beprobten Jejunum-Gewebe und im Chymus zwischen den Supplementierungsgruppen nicht. Entsprechend wurden keine Unterschiede im Gewebe des Jejunums im Hinblick auf Morphologie, Immunzellpopulation und FPSR festgestellt. Weiterhin wurde kein Einfluss von Gln auf mRNA-Abundanz von Genen, welche den Aminosäurentransport, Aminosäurenstoffwechsel und Glutathion-Stoffwechsel regulieren, festgestellt. Für entsprechende Parameter wurden nur geringe Unterschiede zwischen den Geburtsgewichtsgruppen beobachtet. Das Alter der Ferkel hatte den stärksten Einfluss auf die Parameter der jejunalen Entwicklung. Folglich wurden Unterschiede in Bezug auf Morphologie, Aminosäurenmuster, Zellpopulation, Nukleinsäure-Konzentration und mRNA-Abundanz von Genen des Glutathionmetabolismus zwischen den zwölf und fünf Tage alten Ferkeln festgestellt.
Das BW von LBW-Gln-Ferkeln war sowohl während der akuten Supplementierung als auch darüber hinaus höher als bei LBW-Ala-Ferkeln. Jedoch war das BW am 26. Lebenstag zwischen LBW-Gln-Ferkeln und LBW-Ala-Ferkeln nicht unterschiedlich. Das höhere BW der LBW-Gln-Ferkel kann mit einer vergrößerten jejunalen Absorptionsfläche assoziiert werden. Das Wachstum von NBW und folglich das BW waren höher im Vergleich zu LBW. Das schnellere Wachstum beruht dabei nicht auf Unterschieden der intestinalen Entwicklungsparameter, da negative Effekte von einem niedrigen Geburtsgewicht auf die Darmentwicklung aus den gemessenen jejunalen Entwicklungsparametern nicht abzuleiten sind. Es wurden in Bezug auf jejunale Entwicklungsparameter, wie Zellproliferationsrate, Zellpopulation und Morphologie, Unterschiede zwischen den zwölf und 26 Tage alten Ferkeln festgestellt.
Abschließend lässt sich feststellen, dass eine orale Gln-Supplementierung das Wachstum von LBW-Ferkeln nur kurzfristig verbesserte, jedoch nur in sehr geringem Umfang Parameter der jejunalen Entwicklung beeinflusste. Außerdem wurde festgestellt, dass LBW nicht mit einer Entwicklungsstörung des Jejunums assoziiert ist und folglich nicht für das verlangsamte Wachstum verantwortlich ist. Schließlich wurde aufgezeigt, dass besonders ontogenetische Faktoren die Parameter der jejunalen Entwicklung beeinflussen.
View less