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Schriftenreihe
- Frontiers in Psychology (2023) 14:1219915. https://doi.org/10.3389/fpsyg.2023.1219915 (1)
- Frontiers in Public Health (2023) 11:1153088. https://doi.org/10.3389/fpubh.2023.1153088 (1)
- International Archives of the History of Ideas / Archives internationales d’histoire des idées 242 (1)
- Methods in Molecular Biology; 2643 (1)
Sonstige beteiligte Institutionen
- Helmholtz Institute for RNA-based Infection Research (HIRI) (2)
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- Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg (2)
- Anthropology Department University of Tennessee, Knoxville (1)
- CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg (1)
- Carl-Ludwig-Institut für Physiologie, Universität Leipzig (1)
- Chair of Experimental Biomedicine I (1)
- Charles University, Faculty of Mathematics and Physics, Ke Karlovu 5, 121 16 Prague, Czech Republic (1)
- DATE Lab, KITE Research Insititute, University Health Network, Toronto, Canada (1)
- Deutsches Zentrum für Luft- und Raumfahrt (DLR) (1)
Stomata are pores in the leaf surface, formed by pairs of guard cells. The guard cells modulate the aperture of stomata, to balance uptake of CO2 and loss of water vapor to the atmosphere. During drought, the phytohormone abscisic acid (ABA) provokes stomatal closure, via a signaling chain with both Ca2+-dependent and Ca2+-independent branches. Both branches are likely to activate SLAC1-type (Slow Anion Channel Associated 1) anion channels that are essential for initiating the closure of stomata. However, the importance of the Ca2+-dependent signaling branch is still debated, as the core ABA signaling pathway only possesses Ca2+-independent components. Therefore, the aim of this thesis was to address the role of the Ca2+-dependent branch in the ABA signaling pathway of guard cells.
In the first part of the thesis, the relation between ABA-induced Ca2+ signals and stomatal closure was studied, with guard cells that express the genetically encoded Ca2+-indicator R-GECO1-mTurquoise. Ejection of ABA into the guard cell wall rapidly induced stomatal closure, however, only in ¾ of the guard cells ABA evoked a cytosolic Ca2+ signal. A small subset of stomata (¼ of the experiments) closed without Ca2+ signals, showing that the Ca2+ signals are not essential for ABA-induced stomatal closure. However, stomata in which ABA evoked Ca2+ signals closed faster as those in which no Ca2+ signals were detected. Apparently, ABA-induced Ca2+ signals enhance the velocity of stomatal closure. In addition to ABA, hyperpolarizing voltage pulses could also trigger Ca2+ signals in wild type guard cells, which in turn activated S-type anion channels. However, these voltage pulses failed to elicit S-type anion currents in the slac1/slah3 guard cells, suggesting that SLAC1 and SLAH3 contribute to Ca2+-activated conductance. Taken together, our data indicate that ABA-induced Ca2+ signals enhance the activity of S-type anion channels, which accelerates stomatal closure.
The second part of the thesis deals with the signaling pathway downstream of the Ca2+ signals. Two types of Ca2+-dependent protein kinase modules (CPKs and CBL/CIPKs) have been implicated in guard cells. We focused on the protein kinase CIPK23 (CBL-Interacting Protein Kinase 23), which is activated by the Ca2+-dependent protein CBL1 or 9 (Calcineurin B-Like protein 1 or 9) via interacting with the NAF domain of CIPK23. The CBL1/9-CIPK23 complex has been shown to affect stomatal movements, but the underlying molecular mechanisms remain largely unknown. We addressed this topic by using an estrogen-induced expression system, which specifically enhances the expression of wild type CIPK23, a phosphomimic CIPK23T190D and a kinase dead CIPK23K60N in guard cells. Our data show that guard cells expressing CIPK23T190D promoted stomatal opening, while CIPK23K60N enhanced ABA-induced stomatal closure, suggesting that CIPK23 is a negative regulator of stomatal closure. Electrophysiological measurements revealed that the inward K+ channel currents were similar in guard cells that expressed CIPK23, CIPK23T190D or CIPK23K60N, indicating that CIPK23-mediated inward K+ channel AKT1 does not contribute to stomatal movements. Expression of CIPK23K60N, or loss of CIPK23 in guard cells enhanced S-type anion activity, while the active CIPK23T190D inhibited the activity of these anion channels. These results are in line with the detected changes in stomatal movements and thus indicate that CIPK23 regulates stomatal movements by inhibiting S-type anion channels. CIPK23 thus serves as a brake to control anion channel activity. Overall, our findings demonstrate that CIPK23-mediated stomatal movements do not depend on CIPK23-AKT1 module, instead, it is achieved by regulating S-type anion channels SLAC1 and SLAH3.
In sum, the data presented in this thesis give new insights into the Ca2+-dependent branch of ABA signaling, which may help to put forward new strategies to breed plants with enhanced drought stress tolerance, and in turn boost agricultural productivity in the future.
The present thesis introduce different synthetic strategies towards a variety of polycyclic aromatic dicarboximides (PADIs) with highly interesting and diverse properties. This included tetrachlorinated, tetraaryloxy- and tetraaryl-substituted dicarboximides, fused acceptor‒donor(‒acceptor) structures as well as sterically shielded rylene and nanographene dicarboximides. The properties and thus the disclosure of structure‒property relationships of the resulting dyes were investigated in detail among others with UV‒vis absorption spectroscopy, fluorescence spectroscopy, cyclic voltammetry and single crystal X-ray analysis. For instance, some of the fused and substituted PADIs offer strong absorption of visible and near infrared (NIR) light, NIR emission and low-lying LUMO levels. On the contrary, intriguing optical features in the solid-state characterize the rylene dicarboximides with their bulky N-substituents, while the devised sterically enwrapped nanographene host offered remarkable complexation capabilities in solution.
Aging is known to be a risk factor for structural abnormalities and functional decline in the nervous system. Characterizing age-related changes is important to identify putative pathways to overcome deleterious effects and improve life quality for the elderly. In this study, the peripheral nervous system of 24-month-old aged C57BL/6 mice has been investigated and compared to 12-month-old adult mice. Aged mice showed pathological alterations in their peripheral nerves similar to nerve biopsies from elderly human individuals, with nerve fibers showing demyelination and axonal damage. Such changes were lacking in nerves of adult 12-month-old mice and adult, non-aged humans. Moreover, neuromuscular junctions of 24-month-old mice showed increased denervation compared to adult mice. These alterations were accompanied by elevated numbers of macrophages in the peripheral nerves of aged mice. The neuroinflammatory conditions were associated with impaired myelin integrity and with a decline of nerve conduction properties and muscle strength in aged mice.
To determine the pathological impact of macrophages in the aging mice, macrophage depletion was performed in mice by oral administration of CSF-1R specific kinase (c-FMS) inhibitor PLX5622 (300 mg/kg body weight), which reduced the number of macrophages in the peripheral nerves by 70%. The treated mice showed attenuated demyelination, less muscle denervation and preserved muscle strength. This indicates that macrophage-driven inflammation in the peripheral nerves is partially responsible for the age-related neuropathy in mice.
Based on previous observations that systemic inflammation can accelerate disease progression in mouse models of neurodegenerative diseases, it was hypothesized that systemic inflammation can exacerbate the peripheral neuropathy found in aged mice. To investigate this hypothesis, aged C57BL/6 mice were intraperitoneally injected with a single dose of lipopolysaccharide (LPS; 500 μg/kg body weight) to induce systemic inflammation by mimicking bacterial infection, mostly via activation of Toll-like receptors (TLRs). Altered endoneurial macrophage activation, highlighted by Trem2 downregulation, was found in LPS injected aged mice one month after injection. This was accompanied by a so far rarely observed form of axonal perturbation, i.e., the occurrence of “dark axons” characterized by a damaged cytoskeleton and an increased overall electron density of the axoplasm. At the same time, however, LPS injection reduced demyelination and muscle denervation in aged mice. Interestingly, TREM2 deficiency in aged mice led to similar changes to LPS injection. This suggests that LPS injection likely mitigates aging-related demyelination and muscle denervation via Trem2 downregulation.
Taken together, this study reveals the role of macrophage-driven inflammation as a pathogenic mediator in age-related peripheral neuropathy, and that targeting macrophages might be an option to mitigate peripheral neuropathies in aging individuals. Furthermore, this study shows that systemic inflammation may be an ambivalent modifier of age-related nerve damage, leading to a distinct type of axonal perturbation, but in addition to functionally counteracting, dampened demyelination and muscle denervation. Translationally, it is plausible to assume that tipping the balance of macrophage polarization to one direction or the other may determine the functional outcome in the aging peripheral nervous system of the elderly.
Emotional-associative learning processes such as fear conditioning and extinction are highly relevant to not only the development and maintenance of anxiety disorders (ADs), but also to their treatment. Extinction, as the laboratory analogue to behavioral exposure, is assumed a core process underlying the treatment of ADs. Although exposure-based treatments are highly effective for the average patient suffering from an AD, there remains a gap in treatment efficacy with over one third of patients failing to achieve clinically significant symptom relief. There is ergo a pressing need for intensified research regarding the underlying neural mechanisms of aberrant emotional-associative learning processes and the neurobiological moderators of treatment (non-)response in ADs.
The current thesis focuses on different applications of the fundamental principles of fear conditioning and extinction by using two example cases of ADs from two different multicenter trials. First, we targeted alterations in fear acquisition, extinction, and its recall as a function of psychopathology in panic disorder (PD) patients compared to healthy subjects using fMRI. Second, exposure-based therapy and pre-treatment patient characteristics exerting a moderating influence on this essential learning process later on (i.e. treatment outcome) were examined using multimodal functional and structural neuroimaging in spider phobia.
We observed aberrations in emotional-associative learning processes in PD patients compared to healthy subjects indicated by an accelerated fear acquisition and an attenuated extinction recall. Furthermore, pre-treatment differences related to defensive, regulatory, attentional, and perceptual processes may exert a moderating influence on treatment outcome to behavioral exposure in spider phobia. Although the current results need further replication, on an integrative meta level, results point to a hyperactive defensive network system and deficient emotion regulation processes (including extinction processes) and top-down control in ADs. This speaks in favor of transdiagnostic deficits in important functional domains in ADs.
Deficits in transdiagnostic domains such as emotion regulation processes could be targeted by enhancing extinction learning or by means of promising tools like neurofeedback. The detection of pre-treatment clinical response moderators, for instance via machine learning frameworks, may help in supporting clinical decision making on individually tailored treatment approaches or, respectively, to avoid ineffective treatment and its related financial costs. In the long run, the identification of neurobiological markers which are capable of detecting non-responders a priori represents an ultimate goal.
Neurodegeneration plays an essential role in Parkinson’s disease (PD). Several crucial neuronal pro-and antidegeneration markers were described to be altered in disease models accompanied by neurodegeneration. In the AAV1/2-A53T-aSyn PD rat model progressive time-dependent motor impairment and neurodegeneration in the nigrostriatal tract starting from 2 weeks after PD model induction could be found. Downregulation of Nrf2 in SN and nigrostriatal axon localization, a trend of Tau downregulation in SN and upregulation in axon localization in the AAV1/2-A53T-aSyn PD rat model were observed, indicating potential therapeutic value of these two molecular targets in PD. No alterations of SARM1 and NMNAT2 could be detected, indicating little relevance of these two molecules with our AAV1/2-A53T-aSyn rat model.
This thesis identifies how the printing conditions for a high-resolution additive manufacturing technique, melt electrowriting (MEW), needs to be adjusted to process electroactive polymers (EAPs) into microfibers. Using EAPs based on poly(vinylidene difluoride) (PVDF), their ability to be MEW-processed is studied and expands the list of processable materials for this technology.
The StrongPaed study in the paediatric ward of a referral hospital in Mwanza in the lake region of Tanzania showed the prevalence of S. stercoralis, G. lamblia, E. histolytica and E. dispar as well as of other intestinal parasites with various diagnostic methods.
The prevalence of S. stercoralis was 2-10 % depending on the diagnostic methods used. There were no symptomatic infections but only carriage of the nematode. The positive results differed greatly depending on the performed diagnostic methods. None of the diagnostics showed satisfying results, neither in sensitivity and specificity nor in feasibility for this population in an endemic region in sub-Saharan Africa. PCR and microscopy were limited by the low amount of examined stool samples and by the resulting lack of sensitivity. Stool cultures were limited by time-consuming procedures and mainly by the problem of differentiation from hookworm and the resulting lack of specificity. ELISA was limited by the need of blood samples and also by poor specificity in the ELISA used.
The prevalence of G. lamblia was high, but mostly only carriage and not symptomatic infections was seen. No E. histolytica was detected, but 8.5 % samples were positive for E. dispar. Among the performed diagnostics, the rapid test showed sufficient results. It showed better sensitivity than microscopy and is cheaper and more feasible than PCR. Differentiation between E. histolytica and E. dispar was only possible with qPCR performed in Germany.
More children were positive for intestinal parasites from rural than from urban areas. The profession of the parents working as farmers was a risk factor for intestinal parasitic infections. Hygienic living conditions such as access to tap water and flush toilets at home were preventive for intestinal parasitic infections in children.
About 2.4 billion years ago, nature has fundamentally revolutionized life on earth by inventing the multi-subunit protein complex photosystem II, the only molecular machine in nature that catalyzes the thermodynamically demanding photosynthetic splitting of water into oxygen and reducing equivalents. Nature chose a distorted Mn4CaO5 cluster as catalyst, better known as oxygen-evolving complex (OEC), thus recognizing the need for transition metals to achieve high-performance catalysts. The curiosity has always driven mankind to mimic nature’s achievements, but the performance of natural enzymes such as the oxygen-evolving complex in photosystem II remain commonly unmatched. An important role in fine-tuning and regulating the activity of natural enzymes is attributed to the surrounding protein domain, which facilitates substrate preorganization within well-defined nanoenvironments.
In light of growing energy demands and the depletion of fossil fuels, the unparalleled efficiency of natural photosynthesis inspires chemists to artificially mimic its natural counterpart to generate hydrogen as a ‘solar fuel’ through the light-driven splitting of water. As a result, significant efforts have been devoted in recent decades to develop molecular water oxidation catalysts based on earth-abundant transition metals and the discovery of the Ru(bda) (bda: 2,2’ bipyridine-6,6’-dicarboxylate) catalyst family enabled activities comparable to the natural OEC. Similar to the natural archetypes, the design of homogeneous catalysts that interplay judiciously with the second coordination sphere of the outer ligand framework proved to be a promising concept for catalyst design. In this present thesis, novel supramolecular design approaches for enzyme like activation of substrate water molecules for the challenging oxidative water splitting reaction were established via tailor-made engineering of the secondary ligand environment of macrocyclic Ru(bda) catalysts.
All presented studies aimed on the improvement of the quality analysis of already monographed drugs. Thereby different LC methods were applied and coupled to i.e., the UV/VIS detector, the CAD or a hyphenation of these detectors, respectively. The choice of the chromatographic system including the detector was largely dependent on the physicochemical properties of the respective analytes.
With the risk-assessment report on the API cetirizine we presented an exemplary tool, that can help to minimize the risk of the occurrence of unexpected impurities. An in- deep analysis of each step within synthesis pathway by means of reaction matrices of all compounds was performed. It is essential to understand the complete impurity profile of all reactants, solvents, and catalysts and to include them in the matrix. Finally, the API of this synthesis was checked if all impurities are identified by this tool. Of note, a shortcoming of such a targeted approach is that impurities can still occur, but they are not captured. This disadvantage can be partially compensated by non-targeted approaches if they are performed in parallel with the other studies that represent most of the impurities. However, this work also shows that even in a supposedly simple synthesis, potentially hundreds of by-products can be formed. For each of them, it must be decided individually whether their formation is probable or how their quantity can be minimized in order to obtain APIs, that are as pure as possible.
In the dapsone project it was aimed to replace the existing old Ph. Eur. TLC method with a modern RP-HPLC method. This was successful and since Ph. Eur. 10.6, the method developed in this work, became a valid monograph. Within the revision process of the monograph, the individual limits for impurities were tightened. However, this new method needs HPLC instrumentation, suitable to perform gradients. As this is not always available in all control laboratories, we also developed an alternative, more simple method using two different isocratic runs for the impurity analysis. The obtained batch results of both, the new pharmacopoeial method and the more simple one, were in a comparable order of magnitude. Furthermore, within the method development stage of the Ph. Eur. method, we could identify one unknown impurity of the impurity reference by high-resolution MS/MS analysis.
Also, in the baclofen project it was aimed to replace the existing Ph. Eur. method with the introduction of an additional impurity to be quantified. A corresponding method was developed and validated. However, due to the harmonization process of the pharmacopoeias, it is currently not used. In addition, we tried to find further, non- 116
SUMMARY
chromophoric impurities by means of the CAD. However, except for one counterion of an impurity, no further impurities were found. Also, the aforementioned new impurity could not be detected above the reporting threshold in the batches analyzed. As the only individually specified impurity A is also present at a low level, it can be concluded that the examined batches of baclofen are very pure.
The use of universal detectors, such as the CAD can be particularly interesting for compounds with no chromophore or those with only a weak chromophore. Therefore, we decided to take a closer look at the impurity profile of acarbose. Currently, acarbose and its impurities are being studied by low wavelength UV detection at 210 nm. Therefore, the question arose whether there are no other impurities in the API that do not show absorption at this wavelength. CAD, which offers consistent detection properties for all non-volatile compounds, is ideally suited for this purpose. However, it was not so easy to use the CAD together with the UV detector, for example, as a hyphenated detection technique, because the Ph. Eur. method uses phosphate buffers. However, this is non-volatile and therefore inappropriate for the CAD. Therefore, an attempt was made to replace the buffer with a volatile one. However, since this did not lead to satisfactory results and rather the self-degradation process of the stationary phase used could be observed by means of the CAD, it was decided to switch to alternative stationary phases. A column screening also revealed further difficulties with acarbose and its impurities: they show an epimerization reaction at the end of the sugar chain. However, since one wanted to have uniform peaks in the corresponding chromatograms, one had to accelerate this reaction significantly to obtain only one peak for each component. This was best achieved by using two stationary phases: PGC and Amide-HILIC. Impurity-profiling methods could be developed on each of the two phases. In addition, as expected, new impurities could be detected, albeit at a low level. Two of them could even be identified by spiking experiments as the sugar fragments maltose and maltotriose.
Taken together, it can be concluded, that this work has contributed significantly to the improvement of the quality analysis of monographed drugs. In addition to the presented general tool for the identification of potential impurities, one of the methods developed, had already been implemented to the Ph. Eur. In an effort to improve the CAD's universal detection capabilities, additional methods have also been developed. Further, new improved methods for the impurity profiling are ready to use.
Summary
Platelet activation and aggregation at sites of vascular injury is critical to prevent excessive blood loss, but may also lead to life-threatening ischemic disease states, such as myocardial infarction and stroke. Glycoprotein (GP) VI and C type lectin-like receptor 2 (CLEC-2) are essential platelet activating receptors in hemostasis and thrombo-inflammatory disease which signal through a (hem)immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway. The adapter molecules Src-like adapter protein (SLAP) and SLAP2 are involved in the regulation of immune cell receptor surface expression and signaling, but their function in platelets is unknown. As revealed in this thesis, single deficiency of SLAP or SLAP2 in mice had only moderate effects on platelet function, while SLAP/SLAP2 double deficiency resulted in markedly increased signal transduction, integrin activation, granule release, aggregation, procoagulant activity and thrombin generation following (hem)ITAM-coupled, but not G protein-coupled receptor activation. Slap-/-/Slap2-/- mice displayed accelerated occlusive arterial thrombus formation and a dramatically worsened outcome after focal cerebral ischemia. These results establish SLAP and SLAP2 as critical inhibitors of platelet (hem)ITAM signaling in the setting of arterial thrombosis and ischemic stroke.
GPVI has emerged as a promising novel pharmacological target for treatment of thrombotic and inflammatory disease states, but the exact mechanisms of its immunodepletion in vivo are incompletely understood. It was hypothesized that SLAP and SLAP2 may be involved in the control of GPVI down-regulation because of their role in the internalization of immune cell receptors. As demonstrated in the second part of the thesis, SLAP and SLAP2 were dispensable for antibody-induced GPVI down-regulation, but anti-GPVI treatment resulted in prolonged strong thrombocytopenia in Slap-/-/Slap2-/- mice. The profound thrombocytopenia likely resulted from the powerful platelet activation which the anti-GPVI antibody induced in Slap-/-/Slap2-/- platelets, but importantly, not in wild-type platelets. These data indicate that the expression and activation state of key modulators of the GPVI signaling cascade may have important implications for the safety profile and efficacy of anti-GPVI agents.
Small GTPases of the Rho family, such as RhoA and Cdc42, are critically involved in the regulation of cytoskeletal rearrangements during platelet activation, but little is known about the specific roles and functional redundancy of both proteins in platelet biogenesis. As shown in the final part of the thesis, combined deficiency of RhoA and Cdc42 led to marked alterations in megakaryocyte morphology and the generation of platelets of heterogeneous size and granule content. Despite severe hemostatic defects and profound thrombo¬cytopenia, circulating RhoA-/-/Cdc42-/- platelets were still capable of granule secretion and the formation of occlusive thrombi. These results implicate the existence of both distinct and overlapping roles of RhoA and Cdc42 in platelet production and function.
Cardiovascular disease and the acute consequence of myocardial infarc- tion remain one of the most important causes of morbidity and mortality in all western societies. While much progress has been made in mitigating the acute, life-threatening ischemia caused by infarction, heart failure of the damaged my- ocardium remains prevalent. There is mounting evidence for the role of T cells in the healing process after myocardial infarction, but relevant autoantigens, which might trigger and regulate adaptive immune involvement have not been discov- ered in patients.
In this work, we discovered an autoantigenic epitope in the adrenergic receptor beta 1, which is highly expressed in the heart. This autoantigenic epitope causes a pro-inflammatory immune reaction in T cells isolated from pa- tients after myocardial infarction (MI) but not in control patients. This immune reaction was only observed in a subset of MI patients, which carry at least one allele of the HLA-DRB1*13 family. Interestingly, HLA-DRB1*13 was more com- monly expressed in patients in the MI group than in the control group.
Taken together, our data suggests antigen-specific priming of T cells in MI patients, which leads to a pro-inflammatory phenotype. The primed T cells react to a cardiac derived autoantigen ex vivo and are likely to exhibit a similar phenotype in vivo. This immune phenotype was only observed in a certain sub- set of patients sharing a common HLA-allele, which was more commonly ex- pressed in MI patients, suggesting a possible role as a risk factor for cardiovas- cular disease.
While our results are observational and do not have enough power to show strong clinical associations, our discoveries provide an essential tool to further our understanding of involvement of the immune system in cardiovascu- lar disease. We describe the first cardiac autoantigen in the clinical context of MI and provide an important basis for further translational and clinical research in cardiac autoimmunity.
The field of giftedness and gifted education has long been characterized by internal fragmentation and inconsistent definitions of core concepts (e.g., Ambrose et al., 2010; Coleman, 2006; McBee et al., 2012). It was only in recent years that increased efforts have been made to organize available research findings and thereby bring back greater uniformity to the field of giftedness and gifted education. For example, Preckel et al.’s (2020) Talent Development in Achievement Domains (TAD) framework integrates theoretical perspectives and empirical knowledge from different parts of the field. It is general in concept and can be applied to a wide range of achievement domains. By specifically focusing on measurable psychological constructs as well as their relevance at different stages of the talent development process, Preckel et al.’s (2020) TAD framework is well suited as a starting point for generating more domain-specific talent development models.
The present thesis represents one of the first attempts to empirically test the validity of Preckel et al.’s (2020) TAD framework in academic domains using longitudinal data. The longitudinal data came from a sample of former junior students at Julius-Maximilians-Universität (JMU) Würzburg who showed high academic achievement potential.
There were two related research issues: Research Issue 1 first aimed to document in detail how the educational trajectories of former junior students unfold in the years following their Abitur. To this end, a follow-up was conducted among 208 young adults who had participated in the junior study program at JMU Würzburg between the winter semester of 2004/2005 and the summer semester of 2011. The design of the follow-up questionnaire was based on a series of research questions that had emerged from the relevant literature on junior study programs in Germany. The follow-up ran from October 2019 to February 2020. The data were analyzed descriptively and documented as a detailed report. The results of Research Issue 1 revealed that the former junior students continued to be academically (and later professionally) successful long after their school years. For example, at the time of the follow-up, almost all former junior students had earned a bachelor’s and a master’s degree, most often with notable academic successes (e.g., scholarships, awards/prizes). In addition, more than half of those who responded had begun or already completed a doctoral degree, also recording special academic accomplishments (e.g., scientific publications, scholarships). A significant proportion of the former junior students had already entered the workforce at the time of their response. A look at their current professional situation revealed an above-average expression of success indicators (e.g., income, professional status). The clear majority of the former junior students reported that, even in retrospect, they would choose to take part in the junior study program at JMU Würzburg again.
Research Issue 2 aimed to determine the extent to which the structure of Preckel et al.’s (2020) TAD framework could be empirically validated in academic domains. The educational trajectories of 84 former junior students at JMU Würzburg who had chosen a subject from the same subject field in their regular studies as in their junior studies served as the data basis. The educational trajectories were compiled from the former junior students’ follow-up data and from their data on the selection process for the junior study program at JMU Würzburg. Combining the structural assumptions of Preckel et al.’s (2020) TAD framework with relevant insights from individual academic disciplines made it possible to derive hypotheses regarding potential predictors and indicators of the talent development stages aptitude, competence, and expertise in academic domains. Structural equation models were used for data analysis. The results of Research Issue 2 suggested that the talent development stages aptitude, competence, and expertise, while being predictive of each other in their chronological order, could be satisfactorily modeled using framework-compliant indicators in academic domains. In comparison, the talent development stage transformational achievement could not (yet) be modeled based on the longitudinal data. Among the hypothesized predictors, former junior students’ investigative interests and their metacognitive abilities reliably determined the talent development stages competence and expertise, whereas the remaining predictors did not make significant contributions.
Taken together, the results of the present thesis suggest that the validity of Preckel et al.’s (2020) TAD framework can only be partially confirmed in academic domains. Unlike the postulated indicators, the predictors in Preckel et al.’s (2020) TAD framework do not seem to be easily generalizable to academic domains but to be highly specific with regard to the talent domain under consideration. Therefore, a natural progression of the present thesis would be to examine the structure of Preckel et al.’s (2020) TAD framework at the subordinate level of subject fields or even at the level of individual academic disciplines, for example.
Stroke and myocardial infarction are the most prominent and severe consequences of pathological thrombus formation. For prevention and/or treatment of thrombotic events there is a variety of anti-coagulation and antiplatelet medication that all have one side effect in common: the increased risk of bleeding. To design drugs that only intervene in the unwanted aggregation process but do not disturb general hemostasis, it is crucial to decipher the exact clotting pathway which has not been fully understood yet. Platelet membrane receptors play a vital role in the clotting pathway and, thus, the aim of this work is to establish a method to elucidate the interactions, clustering, and reorganization of involved membrane receptors such as GPIIb/IIIa and GPIX as part of the GPIb-IX-V complex. The special challenges regarding visualizing membrane receptor interactions on blood platelets are the high abundancy of the first and the small size of the latter (1—3µm of diameter). The resolution limit of conventional fluorescence microscopy and even super-resolution approaches prevents the successful differentiation of densely packed receptors from one another. Here, this issue is approached with the combination of a recently developed technique called Expansion Microscopy (ExM). The image resolution of a conventional fluorescence microscope is enhanced by simply enlarging the sample physically and thus pulling the receptors apart from each other. This method requires a complex sample preparation and holds lots of obstacles such as variable or anisotropic expansion and low images contrast. To increase ExM accuracy and sensitivity for interrogating blood platelets, it needs optimized sample preparation as well as image analysis pipelines which are the main part of this thesis. The colocalization results show that either fourfold or tenfold expanded, resting platelets allow a clear distinction between dependent, clustered, and independent receptor organizations compared to unexpanded platelets.Combining dual-color Expansion and confocal fluorescence microscopy enables to image in the nanometer range identifying GPIIb/IIIa clustering in resting platelets – a pattern that may play a key role in the clotting pathway
Background
Chronic stress is detrimental to health, and children and young people have had to cope with significantly more stress since the start of the COVID-19 pandemic. In particular, stress at school and in relation to learning is a major problem in this age group. Studies in Germany have indicated that the pandemic has led to a reduced quality of life (QoL) and an increased risk for psychiatric disorders in children and adolescents. Schools are an ideal setting for interventions against stress, which is one of the strongest predictors for the development of psychosocial problems. The present study seeks to address stress by means of a short prevention training programme in schools, including emotion regulation, mindfulness, and self-compassion. In addition to information material for self-study, students should have the opportunity to actively deal with the topic of stress and develop coping strategies within a short space of time. In contrast to very long stress reduction programmes that often last several weeks, the programme is delivered in just 90 min.
Methods
The effectiveness of the short and economical prevention programme LessStress will be examined in a cluster-randomised controlled trial (RCT) encompassing 1894 students. At several measurement time points, students from two groups (intervention and control) will be asked about their subjectively perceived stress levels, among other aspects. Due to the clustered nature of the data, mainly multilevel analyses will be performed.
Discussion
In Germany, there are no nationwide universal prevention programmes for students against stress in schools, and this gap has become more evident since the outbreak of the pandemic. Universal stress prevention in schools may be a starting point to promote resilience. By dealing with stress in a healthy way, mental health can be strengthened and maintained. Moreover, to reach at-risk students at an early stage, we advocate for a stronger networking between child psychiatry and schools.
In the scientific search for truth, the correspondence theory is predominant to decipher what counts as true. In this approach, scientific knowledge becomes empirically demonstrable and thus enclosed to the sphere of immanence. However, in theology’s approach to question the given status of being human and the world’s development as creation, theology does not adhere to answers that are contained within the sphere of demonstrable knowledge or mundanity, and thereby theology presents a fundamentally different conception of truth, Jesus Christ the living truth. In opposition to drawing on empirical proof, I want to reread Christian theology in a Socratic manner that employs irony to question overly simple methodologies and seek further insights what it means to be human and be engaged in the scientific search for truth if the authority of knowledge does not lie within humanity’s grasp. In doing so, theology’s role is an annoying, yet necessary irritation within the field of today’s academia.
Ibrutinib serves as an efficient second-line therapy in relapsed/refractory mantle cell lymphoma. However, resistance to the BTK inhibitor results in a poor prognosis for patients. Since the mechanisms leading to resistance in initially responding tumor cells are poorly understood, this work aimed to decipher acquired features in ibrutinib-surviving cells of a sensitive mantle cell lymphoma cell line and evaluate these potential therapeutic targets in ibrutinib-treated mantle cell lymphoma.
Time-resolved single-cell RNA sequencing was performed to track the transcriptomic evolution of REC-1 cells across 6 and 48 hours of treatment. Single-cell analysis uncovered a subpopulation of REC-1 with potentially greater aggressiveness and survival advantage by benefiting from interaction with the tumor microenvironment. Upregulation of B-cell receptor genes, elevated surface antigen expression of CD52 and metabolic rewiring to higher dependence on oxidative phosphorylation were identified as further potential resistance features of ibrutinib-surviving cells. RNA sequencing after prolonged incubation corroborated the increase in CD52 and oxidative phosphorylation as dominant characteristics of the cells surviving the 4-day treatment, highlighting their potential as therapeutic targets in combination with ibrutinib treatment. Concomitant use of ibrutinib and the oxidative phosphorylation inhibitor IACS-010759 increased toxicity compared to ibrutinib monotherapy due to higher apoptosis and greater inhibition of proliferation. For anti-CD52 therapy, a consecutive approach with ibrutinib pretreatment followed by incubation of surviving cells with a CD52 monoclonal antibody and human serum yielded a synergistic effect, as ibrutinib-surviving mantle cell lymphoma cells were rapidly depleted by complement-dependent cytotoxicity. Regarding the effects on primary tumor cells from mantle cell lymphoma patients, ibrutinib induced upregulation of CD52 in some cases, and increased toxicity of anti-CD52 therapy was observed in ibrutinib-sensitive patient samples after pretreatment with the BTK inhibitor. The likely favorable in vivo efficacy of an anti-CD52 therapy might therefore be restricted to a subgroup of mantle cell lymphoma patients, also in view of the associated side effects.
Given the need for new therapeutic options in mantle cell lymphoma to overcome resistance to ibrutinib, this work highlights the potentially beneficial use of an oxidative phosphorylation inhibitor as add-on therapy. In addition, the findings suggest to further assess the value of anti-CD52 therapy as consolidation to ibrutinib in ibrutinib-sensitive patients with elevated CD52 surface levels on tumor cells to target resistant clones and minimize risk of minimal residual disease and relapse.
The focus of this thesis was to investigate how PCL and PLGA react to the heat exposure that comes with the MEW process over a defined timespan.
To assess the thermal stability of PCL during MEW over 25 d, an automated collection of fibers has been used to determine the CTS on each day of heating for three different temperatures. PCL is exceptionally stable over 25 d at 75 °C, whereas for 85 °C and 95 °C a slight upward trend during the last 10 d could be observed, which is an indication for thermal degradation. Same trend could be observed for diameter of fibers produced at a fixed collector speed. For all temperatures, CTS during the first 5 d decreased due to inhomogeneities of the melt. Physical analysis of the fibers by XRD and mechanical testing showed no significant changes.
To investigate the chemical details of the thermal durability, PCL was artificially aged over 25 d at 75 °C, 85 °C and 95 °C. Data from GPC analysis and rheology revealed that PCL is degrading steadily at all three temperatures. Combined with GC-MS analysis, two different mechanisms for degradation could be observed: random chain scission and unzipping. Additional GPC experiment using a mixture of PCL and a fluorescence labelled PCL showed that PCL was undergoing ester interchange reactions, which could explain its thermal stability.
PLGA was established successfully as material for MEW. GPC results revealed that PLGA degraded heavily in the one-hour preheating period. To reduce the processing temperature, ATEC was blended with PLGA in three mixtures. This slowed down degradation and a processing window of 6 h could be established. Mechanical testing with fibers produced with PLGA and all three blends was performed. PLGA was very brittle, whereas the blends showed an elastic behavior. This could be explained by ester interchange reactions that formed a loosely crosslinked network with ATEC.
This work introduced the reader to all relevant fields to tap into an ultrasound-based state of charge estimation and provides a blueprint for the procedure to achieve and test the fundamentals of such an approach. It spanned from an in-depth electrochemical characterization of the studied battery cells over establishing the measurement technique, digital processing of ultrasonic transmission signals, and characterization of the SoC dependent property changes of those signals to a proof of concept of an ultrasound-based state of charge estimation.
The State of the art & theoretical background chapter focused on the battery section on the mechanical property changes of lithium-ion batteries during operation. The components and the processes involved to manufacture a battery cell were described to establish the fundamentals for later interrogation. A comprehensive summary of methods for state estimation was given and an emphasis was laid on mechanical methods, including a critical review of the most recent research on ultrasound-based state estimation. Afterward, the fundamentals of ultrasonic non-destructive evaluation were introduced, starting with the sound propagation modes in isotropic boundary-free media, followed by the introduction of boundaries and non-isotropic structure to finally approach the class of fluid-saturated porous media, which batteries can be counted to. As the processing of the ultrasonic signals transmitted through lithium-ion battery cells with the aim of feature extraction was one of the main goals of this work, the fundamentals of digital signal processing and methods for the time of flight estimation were reviewed and compared in a separate section.
All available information on the interrogated battery cell and the instrumentation was collected in the Experimental methods & instrumentation chapter, including a detailed step-by-step manual of the process developed in this work to create and attach a sensor stack for ultrasonic interrogation based on low-cost off-the-shelf piezo elements.
The Results & discussion chapter opened with an in-depth electrochemical and post-mortem interrogation to reverse engineer the battery cell design and its internal structure. The combination of inductively coupled plasma-optical emission spectrometry and incremental capacity analysis applied to three-electrode lab cells, constructed from the studied battery cell’s materials, allowed to identify the SoC ranges in which phase transitions and staging occur and thereby directly links changes in the ultrasonic signal properties with the state of the active materials, which makes this work stand out among other studies on ultrasound-based state estimation. Additional dilatometer experiments were able to prove that the measured effect in ultrasonic time of flight cannot originate from the thickness increase of the battery cells alone, as this thickness increase is smaller and in opposite direction to the change in time of flight. Therefore, changes in elastic modulus and density have to be responsible for the observed effect.
The construction of the sensor stack from off-the-shelf piezo elements, its electromagnetic shielding, and attachment to both sides of the battery cells was treated in a subsequent section. Experiments verified the necessity of shielding and its negligible influence on the ultrasonic signals. A hypothesis describing the metal layer in the pouch foil to be the transport medium of an electrical coupling/distortion between sending and receiving sensor was formulated and tested. Impedance spectroscopy was shown to be a useful tool to characterize the resonant behavior of piezo elements and ensure the mechanical coupling of such to the surface of the battery cells. The excitation of the piezo elements by a raised cosine (RCn) waveform with varied center frequency in the range of 50 kHz to 250 kHz was studied in the frequency domain and the influence of the resonant behavior, as identified prior by impedance spectroscopy, on waveform and frequency content was evaluated to be uncritical. Therefore, the forced oscillation produced by this excitation was assumed to be mechanically coupled as ultrasonic waves into the battery cells.
The ultrasonic waves transmitted through the battery cell were recorded by piezo elements on the opposing side. A first inspection of the raw, unprocessed signals identified the transmission of two main wave packages and allowed the identification of two major trends: the time of flight of ultrasonic wave packages decreases with the center frequency of the RCn waveform, and with state of charge. These trends were to be assessed further in the subsequent sections. Therefore, methods for the extraction of features (properties) from the ultrasonic signals were established, compared, and tested in a dedicated section. Several simple and advanced thresholding methods were compared with envelope-based and cross-correlation methods to estimate the time of flight (ToF). It was demonstrated that the envelope-based method yields the most robust estimate for the first and second wave package. This finding is in accordance with the literature stating that an envelope-based method is best suited for dispersive, absorptive media [204], to which lithium-ion batteries are counted. Respective trends were already suggested by the heatmap plots of the raw signals vs. RCn frequency and SoC. To enable such a robust estimate, an FIR filter had to be designed to preprocess the transmitted signals and thereby attenuate frequency components that verifiably lead to a distorted shape of the envelope.
With a robust ToF estimation method selected, the characterization of the signal properties ToF and transmitted energy content (EC) was performed in-depth. A study of cycle-to-cycle variations unveiled that the signal properties are affected by a long rest period and the associated relaxation of the multi-particle system “battery cell” to equilibrium. In detail, during cycling, the signal properties don’t reach the same value at a given SoC in two subsequent cycles if the first of the two cycles follows a long rest period. In accordance with the literature, a break-in period, making up for more than ten cycles post-formation, was observed. During this break-in period, the mechanical properties of the system are said to change until a steady state is reached [25]. Experiments at different C-rate showed that ultrasonic signal properties can sense the non-equilibrium state of a battery cell, characterized by an increasing area between charge and discharge curve of the respective signal property vs. SoC plot. This non-equilibrium state relaxes in the rest period following the discharge after the cut-off voltage is reached. The relaxation in the rest period following the charge is much smaller and shows little C-rate dependency as the state is prepared by constant voltage charging at the end of charge voltage. For a purely statistical SoC estimation approach, as employed in this work, where only instantaneous measurements are taken into account and the historic course of the measurement is not utilized as a source of information, the presence of hysteresis and relaxation leads to a reduced estimation accuracy. Future research should address this issue or even utilize the relaxation to improve the estimation accuracy, by incorporating historic information, e.g., by using the derivative of a signal property as an additional feature. The signal properties were then tested for their correlation with SoC as a function of RCn frequency. This allowed identifying trends in the behavior of the signal properties as a function of RCn frequency and C-rate in a condensed fashion and thereby enabled to predict the frequency range, about 50 kHz to 125 kHz, in which the course of the signal properties is best suited for SoC estimation.
The final section provided a proof of concept of the ultrasound-based SoC estimation, by applying a support vector regression (SVR) to before thoroughly studied ultrasonic signal properties, as well as current and battery cell voltage. The included case study was split into different parts that assessed the ability of an SVR to estimate the SoC in a variety of scenarios. Seven battery cells, prepared with sensor stacks attached to both faces, were used to generate 14 datasets. First, a comparison of self-tests, where a portion of a dataset is used for training and another for testing, and cross-tests, which use the dataset of one cell for training and the dataset of another for testing, was performed. A root mean square error (RMSE) of 3.9% to 4.8% SoC and 3.6% to 10.0% SoC was achieved, respectively. In general, it was observed that the SVR is prone to overestimation at low SoCs and underestimation at high SoCs, which was attributed to the pronounced hysteresis and relaxation of the ultrasonic signal properties in this SoC ranges. The fact that higher accuracy is achieved, if the exact cell is known to the model, indicates that a variation between cells exists. This variation between cells can originate from differences in mechanical properties as a result of production variations or from differences in manual sensor placement, mechanical coupling, or resonant behavior of the ultrasonic sensors. To mitigate the effect of the cell-to-cell variations, a test was performed, where the datasets of six out of the seven cells were combined as training data, and the dataset of the seventh cell was used for testing. This reduced the spread of the RMSE from (3.6 - 10.0)% SoC to (5.9 – 8.5)% SoC, respectively, once again stating that a databased approach for state estimation becomes more reliable with a large data basis. Utilizing self-tests on seven datasets, the effect of additional features on the state estimation result was tested. The involvement of an additional feature did not necessarily improve the estimation accuracy, but it was shown that a combination of ultrasonic and electrical features is superior to the training with these features alone. To test the ability of the model to estimate the SoC in unknown cycling conditions, a test was performed where the C-rate of the test dataset was not included in the training data. The result suggests that for practical applications it might be sufficient to perform training with the boundary of the use cases in a controlled laboratory environment to handle the estimation in a broad spectrum of use cases.
In comparison with literature, this study stands out by utilizing and modifying off-the-shelf piezo elements to equip state-of-the-art lithium-ion battery cells with ultrasonic sensors, employing a range of center frequencies for the waveform, transmitted through the battery cell, instead of a fixed frequency and by allowing the SVR to choose the frequency that yields the best result. The characterization of the ultrasonic signal properties as a function of RCn frequency and SoC and the assignment of characteristic changes in the signal properties to electrochemical processes, such as phase transitions and staging, makes this work unique. By studying a range of use cases, it was demonstrated that an improved SoC estimation accuracy can be achieved with the aid of ultrasonic measurements – thanks to the correlation of the mechanical properties of the battery cells with the SoC.
Background
The role of cytokines in the pathophysiology, diagnosis, and prognosis of small fiber neuropathy (SFN) is incompletely understood. We studied expression profiles of selected pro- and anti-inflammatory cytokines in RNA from white blood cells (WBC) of patients with a medical history and a clinical phenotype suggestive for SFN and compared data with healthy controls.
Methods
We prospectively recruited 52 patients and 21 age- and sex-matched healthy controls. Study participants were characterized in detail and underwent complete neurological examination. Venous blood was drawn for routine and extended laboratory tests, and for WBC isolation. Systemic RNA expression profiles of the pro-inflammatory cytokines interleukin (IL)-1ß, IL-2, IL-8, tumor necrosis factor-alpha (TNF) and the anti-inflammatory cytokines IL-4, IL-10, transforming growth factor beta-1 (TGF) were analyzed. Protein levels of IL-2, IL-8, and TNF were measured in serum of patients and controls. Receiver operating characteristic (ROC)-curve analysis was used to determine the accuracy of IL-2, IL-8, and TNF in differentiating patients and controls. To compare the potential discriminatory efficacy of single versus combined cytokines, equality of different AUCs was tested.
Results
WBC gene expression of IL-2, IL-8, and TNF was higher in patients compared to healthy controls (IL-2: p = 0.02; IL-8: p = 0.009; TNF: p = 0.03) and discriminated between the groups (area under the curve (AUC) ≥ 0.68 for each cytokine) with highest diagnostic accuracy reached by combining the three cytokines (AUC = 0.81, sensitivity = 70%, specificity = 86%). Subgroup analysis revealed the following differences: IL-8 and TNF gene expression levels were higher in female patients compared to female controls (IL-8: p = 0.01; TNF: p = 0.03). The combination of TNF with IL-2 and TNF with IL-2 and IL-8 discriminated best between the study groups. IL-2 was higher expressed in patients with moderate pain compared to those with severe pain (p = 0.02). Patients with acral pain showed higher IL-10 gene expression compared to patients with generalized pain (p = 0.004). We further found a negative correlation between the relative gene expression of IL-2 and current pain intensity (p = 0.02). Serum protein levels of IL-2, IL-8, and TNF did not differ between patients and controls.
Conclusions
We identified higher systemic gene expression of IL-2, IL-8, and TNF in SFN patients than in controls, which may be of potential relevance for diagnostics and patient stratification.