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Schriftenreihe
Sonstige beteiligte Institutionen
- Helmholtz Institute for RNA-based Infection Research (HIRI) (2)
- Interdisziplinäres Zentrum für Klinische Forschung (IZKF) (2)
- Klinische Studienzentrale (Universitätsklinikum) (2)
- 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)
Since the advent of high-throughput sequencing technologies in the mid-2010s, RNA se-
quencing (RNA-seq) has been established as the method of choice for studying gene
expression. In comparison to microarray-based methods, which have mainly been used to
study gene expression before the rise of RNA-seq, RNA-seq is able to profile the entire
transcriptome of an organism without the need to predefine genes of interest. Today,
a wide variety of RNA-seq methods and protocols exist, including dual RNA sequenc-
ing (dual RNA-seq) and multi RNA sequencing (multi RNA-seq). Dual RNA-seq and
multi RNA-seq simultaneously investigate the transcriptomes of two or more species, re-
spectively. Therefore, the total RNA of all interacting species is sequenced together and
only separated in silico. Compared to conventional RNA-seq, which can only investi-
gate one species at a time, dual RNA-seq and multi RNA-seq analyses can connect the
transcriptome changes of the species being investigated and thus give a clearer picture of
the interspecies interactions. Dual RNA-seq and multi RNA-seq have been applied to a
variety of host-pathogen, mutualistic and commensal interaction systems.
We applied dual RNA-seq to a host-pathogen system of human mast cells and Staphylo-
coccus aureus (S. aureus). S. aureus, a commensal gram-positive bacterium, can become
an opportunistic pathogen and infect skin lesions of atopic dermatitis (AD) patients.
Among the first immune cells S. aureus encounters are mast cells, which have previously
been shown to be able to kill the bacteria by discharging antimicrobial products and re-
leasing extracellular traps made of protein and deoxyribonucleic acid (DNA). However,
S. aureus is known to evade the host’s immune response by internalizing within mast
cells. Our dual RNA-seq analysis of different infection settings revealed that mast cells
and S. aureus need physical contact to influence each other’s gene expression. We could
show that S. aureus cells internalizing within mast cells undergo profound transcriptome
changes to adjust their metabolism to survive in the intracellular niche. On the host side,
we found out that infected mast cells elicit a type-I interferon (IFN-I) response in an
autocrine manner and in a paracrine manner to non-infected bystander-cells. Our study
provides the first evidence that mast cells are capable to produce IFN-I upon infection
with a bacterial pathogen.
In this article we offer initial insights into the fairly new interdisciplinary and international domain of robotics in Christian religious practice. We are a group of scholars in media ethics, practical theology/religious education, and human computer interaction, who have been engaged in this discourse since 2017.
A natural starting point is our study of BlessU2, a “blessing robot,” a device which received considerable recognition from the global public at the Wittenberg 500th reformation anniversary in 2017. We thus begin with the results of this study. Secondly, we will briefly address the relevant theses from Gabriele Trovato et al., as presented in their 2019 article on so-called theomorphic robots – followed by our interdisciplinary discussion of their approach. Finally, we draw conclusions for further work on the field of “religious robots.”
Somewhat more carefully: Section 1 offers starting points within the perspectives of Christian religious practice: here, the blessing robot is both cause and occasion for doing religion and theologizing in the context of existential questions (1.1). We continue with perceptions in the field of religion regarding “Discursive Design Theory” (1.2). The interaction of humans with computers as posing questions for theological standardization of religious practice is focused upon in 1.3. Section 2 reconstructs the HRI/HCI-initiative to develop theomorphic robots in a twofold manner, i.e., the idea of developing theomorphic robots (2.1) and the concept of theomorphic robots: Questions and objections (2.2). In this part of the article we raise discussion points concerning the relationship between technology and religion and the need for sharpening the understanding of religion within the research field. Section 3 closes with propositions and alternatives.
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.
Plexus injury often occurs after motor vehicle accidents and results in lifelong disability with severe neuropathic pain. Surgical treatment can partially restore motor functions, but sensory loss and neuropathic pain persist. Regenerative medicine concepts, such as cell replacement therapies for restoring dorsal root ganglia (DRG) function, set high expectations. However, up to now, it is unclear which DRG cell types are affected by nerve injury and can be targeted in regenerative medicine approaches.
This study followed the hypothesis that satellite glial cells (SGCs) might be a suitable endogenous cell source for regenerative medicine concepts in the DRG. SGCs originate from the same neural crest-derived cell lineage as sensory neurons, making them attractive for neural repair strategies in the peripheral nervous system. Our hypothesis was investigated on three levels of experimentation. First, we asked whether adult SGCs have the potential of sensory neuron precursors and can be reprogrammed into sensory neurons in vitro. We found that adult mouse DRG harbor SGC-like cells that can still dedifferentiate into progenitor-like cells. Surprisingly, expression of the early developmental transcription factors Neurog1 and Neurog2 was sufficient to induce neuronal and glial cell phenotypes. In the presence of nerve growth factor, induced neurons developed a nociceptor-like phenotype expressing functional nociceptor markers, such as the ion channels TrpA1, TrpV1 and NaV1.9. In a second set of experiments, we used a rat model for peripheral nerve injury to look for changes in the DRG cell composition. Using an unbiased deep learning-based approach for cell analysis, we found that cellular plasticity responses after nerve injury activate SGCs in the whole DRG. However, neither injury-induced neuronal death nor gliosis was observed. Finally, we asked whether a severe nerve injury changed the cell composition in the human DRG. For this, a cohort of 13 patients with brachial plexus injury was investigated. Surprisingly, in about half of all patients, the injury-affected DRG showed no characteristic DRG tissue. The complete entity of neurons, satellite cells, and axons was lost and fully replaced by mesodermal/connective tissue. In the other half of the patients, the basic cellular entity of the DRG was well preserved. Objective deep learning-based analysis of large-scale bioimages of the “intact” DRG showed no loss of neurons and no signs of gliosis.
This study suggests that concepts for regenerative medicine for restoring DRG function need at least two translational research directions: reafferentation of existing DRG units or full replacement of the entire multicellular DRG structure. For DRG replacement, SGCs of the adult DRG are an attractive endogenous cell source, as the multicellular DRG units could possibly be rebuilt by transdifferentiating neural crest-derived sensory progenitor cells into peripheral sensory neurons and glial cells using Neurog1 and Neurog2.
Various types of cancer involve aberrant cell cycle regulation. Among the pathways responsible for tumor growth, the YAP oncogene, a key downstream effector of the Hippo pathway, is responsible for oncogenic processes including cell proliferation, and metastasis by controlling the expression of cell cycle genes. In turn, the MMB multiprotein complex (which is formed when B-MYB binds to the MuvB core) is a master regulator of mitotic gene expression, which has also been associated with cancer. Previously, our laboratory identified a novel crosstalk between the MMB-complex and YAP. By binding to enhancers of MMB target genes and promoting B-MYB binding to promoters, YAP and MMB co-regulate a set of mitotic and cytokinetic target genes which promote cell proliferation. This doctoral thesis addresses the mechanisms of YAP and MMB mediated transcription, and it characterizes the role of YAP regulated enhancers in transcription of cell cycle genes.
The results reported in this thesis indicate that expression of constitutively active, oncogenic YAP5SA leads to widespread changes in chromatin accessibility in untransformed human MCF10A cells. ATAC-seq identified that newly accessible and active regions include YAP-bound enhancers, while the MMB-bound promoters were found to be already accessible and remain open during YAP induction. By means of CRISPR-interference (CRISPRi) and chromatin immuniprecipitation (ChIP), we identified a role of YAP-bound enhancers in recruitment of CDK7 to MMB-regulated promoters and in RNA Pol II driven transcriptional initiation and elongation of G2/M genes. Moreover, by interfering with the YAP-B-MYB protein interaction, we can show that binding of YAP to B-MYB is also critical for the initiation of transcription at MMB-regulated genes. Unexpectedly, overexpression of YAP5SA also leads to less accessible chromatin regions or chromatin closing. Motif analysis revealed that the newly closed regions contain binding motifs for the p53 family of transcription factors. Interestingly, chromatin closing by YAP is linked to the reduced expression and loss of chromatin-binding of the p53 family member Np63. Furthermore, I demonstrate that downregulation of Np63 following expression of YAP is a key step in driving cellular migration.
Together, the findings of this thesis provide insights into the role of YAP in the chromatin changes that contribute to the oncogenic activities of YAP. The overexpression of YAP5SA not only leads to the opening of chromatin at YAP-bound enhancers which together with the MMB complex stimulate the expression of G2/M genes, but also promotes the closing of chromatin at ∆Np63 -bound regions in order to lead to cell migration.
Companies are expected to act as international players and to use their capabilities to provide customized products and services quickly and efficiently. Today, consumers expect their requirements to be met within a short time and at a favorable price. Order-to-delivery lead time has steadily gained in importance for consumers. Furthermore, governments can use various emissions policies to force companies and customers to reduce their greenhouse gas emissions. This thesis investigates the influence of order-to-delivery lead time and different emission policies on the design of a supply chain. Within this work different supply chain design models are developed to examine these different influences. The first model incorporates lead times and total costs, and various emission policies are implemented to illustrate the trade-off between the different measures. The second model reflects the influence of order-to-delivery lead time sensitive consumers, and different emission policies are implemented to study their impacts. The analysis shows that the share of order-to-delivery lead time sensitive consumers has a significant impact on the design of a supply chain. Demand uncertainty and uncertainty in the design of different emission policies are investigated by developing an appropriate robust mathematical optimization model. Results show that especially uncertainties on the design of an emission policy can significantly impact the total cost of a supply chain. The effects of differently designed emission policies in various countries are investigated in the fourth model. The analyses highlight that both lead times and emission policies can strongly influence companies' offshoring and nearshoring strategies.
Fear and anxiety disorders – interaction of AVP and OXT brain systems with the serotonergic system
(2023)
Anxiety disorders pose a great burden onto society and economy and can have devastating consequences for affected individuals. Treatment options are still limited to psychopharmacotherapy originally developed for the treatment of depression and behavioral therapy. A combination of genetic traits together with aversive events is most likely the cause of these diseases. Gene x environment studies are trying to find a link between genetic traits and specific negative circumstances. In a first study, we focused on social anxiety disorder (SAD), which is the second most-common anxiety disorder after specific phobias. We used a social fear conditioning (SFC) paradigm, which is able to mimic the disease in a mouse model. We wanted to investigate protein levels, as well as mRNA expression of immediate early genes (IEGs), to determine brain areas affected by the paradigm. We also included genes of the vasopressin (AVP)-, oxytocin (OXT)-, neuropeptide Y (NPY)-, and the serotonin system, to investigate the effects of SFC on neurotransmitter gene expression levels in brain regions related to social as well as fear-related behavior. AVP and OXT regulate a lot of different social and anxiety-related behaviors, both positive and negative. Finding a link between different neurotransmitter systems in the development of anxiety disorders could help to identify potential targets for new treatment approaches, which are desperately needed, because the rate of patients not responding to available treatment is very high.
We were able to show altered gene expression of the IEGs cFos and Fosl2, as well as a change in number and density of cFOS-positive cells in the dorsal hippocampus, indicating an influence of SFC on neuronal activity. Our results reveal a possible involvement of anterior dentate gyrus (DG), as well as cornu ammonis area 1 (CA1) and CA3 in the dorsal hippocampus during the expression of social fear. Contrary to our hypothesis, we were not able to see changes in neuronal activity through expression changes of IEGs in the amygdala. Significant higher IEG immunoreactivity and gene expression in the dorsal hippocampus of animals without fear conditioning (SFC-), compared to animals with fear conditioning (SFC+), indicate an involvement of different hippocampal regions in two possible scenarios. Either as elevated gene expression in SFC- animals compared to SFC+ animals or as reduction in SFC+ animals compared to SFC- animals. However, this question cannot be answered without an additional control of basal IEG-activity without social interaction. The NPY system in general and the neuropeptide y receptor type 2 in particular seem to be involved in regulating the response to social fear, mostly through the septum region. In addition to that, a possible role for the induction of social fear response could be identified in the serotonergic system and especially the serotonin receptor 2a of the PVN.
In a second study we focused on changes in the serotonergic system. A polymorphism in the human serotonin transporter (5-HTT) gene is associated with higher risks for the development of anxiety disorders. This makes the 5-HTT a widely used target to study possible causes and the development of anxiety disorders. In mice, a genetically induced knockout of the 5-Htt gene is associated with increased anxiety-like behavior. High amounts of stress during pregnancy, also known as prenatal stress, significantly increase the risk to develop psychiatric disorders for the unborn child. We utilized a prenatal stress paradigm in mice heterozygous for the 5-Htt gene. Some of the animals which had been subjected to prenatal stress showed noticeably “unsocial” interaction behavior towards conspecifics. Again, we were searching for links between the serotonergic system and AVP- and OXT systems. Through quantitative gene expression analysis, we were able to show that both AVP and OXT neuromodulator systems are affected through prenatal stress in female mice, but not in male mice. The 5-Htt genotype seems to be only slightly influential to AVP, OXT or any other neurotransmitter system investigated. Gene expression of AVP and OXT brain systems is highly influenced through the estrous cycle stages of female mice. Additionally, we analyzed the AVP and OXT neuropeptide levels of mice with different 5-Htt genotypes and in both sexes, in order to see whether the production of AVP and OXT is influenced by 5-Htt genotype. On neuropeptide level, we were able to identify a sex difference for vasopressin-immunoreactive (ir) cells in the PVN, with male mice harboring significantly more positive cells than female mice.
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.
Metallic nanostructures possess the ability to support resonances in the visible wavelength regime which are related to localized surface plasmons. These create highly enhanced electric fields in the immediate vicinity of metal surfaces. Nanoparticles with dipolar resonance also radiate efficiently into the far-field and hence serve as antennas for light. Such optical antennas have been explored during the last two decades, however, mainly as standalone units illuminated by external laser beams and more recently as electrically driven point sources, yet merely with basic antenna properties. This work advances the state of the art of locally driven optical antenna systems. As a first instance, the electric driving scheme including inelastic electron tunneling over a nanometer gap is merged with Yagi-Uda theory. The resulting antenna system consists of a suitably wired feed antenna, incorporating a tunnel junction, as well as several nearby parasitic elements whose geometry is optimized using analytical and numerical methods. Experimental evidence of unprecedented directionality of light emission from a nanoantenna is provided. Parallels in the performance between radiofrequency and optical Yagi-Uda arrays are drawn. Secondly, a pair of electrically connected antennas with dissimilar resonances is harnessed as electrodes in an organic light emitting nanodiode prototype. The organic material zinc phthalocyanine, exhibiting asymmetric injection barriers for electrons and holes, in conjunction with the electrode resonances, allows switching and controlling the emitted peak wavelength and directionality as the polarity of the applied voltage is inverted. In a final study, the near-field based transmission-line driving of rod antenna systems is thoroughly explored. Perfect impedance matching, corresponding to zero back-reflection, is achieved when the antenna acts as a generalized coherent perfect absorber at a specific frequency. It thus collects all guided, surface-plasmon mediated input power and transduces it to other nonradiative and radiative dissipation channels. The coherent interplay of losses and interference effects turns out to be of paramount importance for this delicate scenario, which is systematically obtained for various antenna resonances. By means of the here developed semi-analytical toolbox, even more complex nanorod chains, supporting topologically nontrivial localized edge states, are studied. The results presented in this work facilitate the design of complex locally driven antenna systems for optical wireless on-chip communication, subwavelength pixels, and loss-compensated integrated plasmonic nanocircuitry which extends to the realm of topological plasmonics.
Background
Ischemic stroke immediately evokes a strong neuro-inflammatory response within the vascular compartment, which contributes to primary infarct development under vessel occlusion as well as further infarct growth despite recanalization, referred to as ischemia/reperfusion injury. Later, in the subacute phase of stroke (beyond day 1 after recanalization), further inflammatory processes within the brain parenchyma follow. Whether this second wave of parenchymal inflammation contributes to an additional/secondary increase in infarct volumes and bears the potential to be pharmacologically targeted remains elusive. We addressed the role of the NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome in the subacute phase of ischemic stroke.
Methods
Focal cerebral ischemia was induced in C57Bl/6 mice by a 30-min transient middle cerebral artery occlusion (tMCAO). Animals were treated with the NLRP3 inhibitor MCC950 therapeutically 24 h after or prophylactically before tMCAO. Stroke outcome, including infarct size and functional deficits as well as the local inflammatory response, was assessed on day 7 after tMCAO.
Results
Infarct sizes on day 7 after tMCAO decreased about 35% after delayed and about 60% after prophylactic NLRP3 inhibition compared to vehicle. Functionally, pharmacological inhibition of NLRP3 mitigated the local inflammatory response in the ischemic brain as indicated by reduction of infiltrating immune cells and reactive astrogliosis.
Conclusions
Our results demonstrate that the NLRP3 inflammasome continues to drive neuroinflammation within the subacute stroke phase. NLRP3 inflammasome inhibition leads to a better long-term outcome—even when administered with a delay of 1 day after stroke induction, indicating ongoing inflammation-driven infarct progression. These findings may pave the way for eagerly awaited delayed treatment options in ischemic stroke.
This decade saw the development of new high-end light microscopy approaches. These technologies are increasingly used to expand our understanding of cellular function and the molecular mechanisms of life and disease. The precision of state-of-the-art super resolution microscopy is limited by the properties of the applied fluorescent label. Here I describe the synthesis and evaluation of new functional fluorescent probes that specifically stain gephyrin, universal marker of the neuronal inhibitory post-synapse. Selected probe precursor peptides were synthesised using solid phase peptide synthesis and conjugated with selected super resolution capable fluorescent dyes. Identity and purity were defined using chromatography and mass spectrometric methods. To probe the target specificity of the resulting probe variants in cellular context, a high-throughput assay was established. The established semi-automated and parallel workflow was used for the evaluation of three selected probes by defining their co-localization with the expressed fluorescent target protein. My work provided NN1Dc and established the probe as a visualisation tool for essentially background-free visualisation of the synaptic marker protein gephyrin in a cellular context. Furthermore, NN1DA became part of a toolbox for studying the inhibitory synapse ultrastructure and brain connectivity and turned out useful for the development of a label-free, high-throughput protein interaction quantification assay.
This work deals with the acceleration of cardiovascular MRI for the assessment
of functional information in steady-state contrast and for viability assessment
during the inversion recovery of the magnetization. Two approaches
are introduced and discussed in detail. MOCO-MAP uses an exponential
model to recover dynamic image data, IR-CRISPI, with its low-rank plus
sparse reconstruction, is related to compressed sensing.
MOCO-MAP is a successor to model-based acceleration of parametermapping
(MAP) for the application in the myocardial region. To this end, it
was augmented with a motion correction (MOCO) step to allow exponential
fitting the signal of a still object in temporal direction. Iteratively, this
introduction of prior physical knowledge together with the enforcement of
consistency with the measured data can be used to reconstruct an image
series from distinctly shorter sampling time than the standard exam (< 3 s
opposed to about 10 s). Results show feasibility of the method as well as
detectability of delayed enhancement in the myocardium, but also significant
discrepancies when imaging cardiac function and artifacts caused already by
minor inaccuracy of the motion correction.
IR-CRISPI was developed from CRISPI, which is a real-time protocol
specifically designed for functional evaluation of image data in steady-state
contrast. With a reconstruction based on the separate calculation of low-rank
and sparse part, it employs a softer constraint than the strict exponential
model, which was possible due to sufficient temporal sampling density via
spiral acquisition. The low-rank plus sparse reconstruction is fit for the use on
dynamic and on inversion recovery data. Thus, motion correction is rendered
unnecessary with it.
IR-CRISPI was equipped with noise suppression via spatial wavelet filtering.
A study comprising 10 patients with cardiac disease show medical
applicability. A comparison with performed traditional reference exams offer
insight into diagnostic benefits. Especially regarding patients with difficulty
to hold their breath, the real-time manner of the IR-CRISPI acquisition provides
a valuable alternative and an increase in robustness.
In conclusion, especially with IR-CRISPI in free breathing, a major acceleration
of the cardiovascular MR exam could be realized. In an acquisition
of less than 100 s, it not only includes the information of two traditional
protocols (cine and LGE), which take up more than 9.6 min, but also allows
adjustment of TI in retrospect and yields lower artifact level with similar
image quality.
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.
Attention-deficit/hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental disorder described in psychiatry today. ADHD arises during early childhood and is characterized by an age-inappropriate level of inattention, hyperactivity, impulsivity, and partially emotional dysregulation. Besides, substantial psychiatric comorbidity further broadens the symptomatic spectrum. Despite advances in ADHD research by genetic- and imaging studies, the etiopathogenesis of ADHD remains largely unclear. Twin studies suggest a heritability of 70-80 % that, based on genome-wide investigations, is assumed to be polygenic and a mixed composite of small and large, common and rare genetic variants. In recent years the number of genetic risk candidates is continuously increased. However, for most, a biological link to neuropathology and symptomatology of the patient is still missing. Uncovering this link is vital for a better understanding of the disorder, the identification of new treatment targets, and therefore the development of a more targeted and possibly personalized therapy.
The present thesis addresses the issue for the ADHD risk candidates GRM8, FOXP2, and GAD1. By establishing loss of function zebrafish models, using CRISPR/Cas9 derived mutagenesis and antisense oligonucleotides, and studying them for morphological, functional, and behavioral alterations, it provides novel insights into the candidate's contribution to neuropathology and ADHD associated phenotypes. Using locomotor activity as behavioral read-out, the present work identified a genetic and functional implication of Grm8a, Grm8b, Foxp2, and Gad1b in ADHD associated hyperactivity. Further, it provides substantial evidence that the function of Grm8a, Grm8b, Foxp2, and Gad1b in activity regulation involves GABAergic signaling. Preliminary indications suggest that the three candidates interfere with GABAergic signaling in the ventral forebrain/striatum. However, according to present and previous data, via different biological mechanisms such as GABA synthesis, transmitter release regulation, synapse formation and/or transcriptional regulation of synaptic components. Intriguingly, this work further demonstrates that the activity regulating circuit, affected upon Foxp2 and Gad1b loss of function, is involved in the therapeutic effect mechanism of methylphenidate. Altogether, the present thesis identified altered GABAergic signaling in activity regulating circuits in, presumably, the ventral forebrain as neuropathological underpinning of ADHD associated hyperactivity. Further, it demonstrates altered GABAergic signaling as mechanistic link between the genetic disruption of Grm8a, Grm8b, Foxp2, and Gad1b and ADHD symptomatology like hyperactivity. Thus, this thesis highlights GABAergic signaling in activity regulating circuits and, in this context, Grm8a, Grm8b, Foxp2, and Gad1b as exciting targets for future investigations on ADHD etiopathogenesis and the development of novel therapeutic interventions for ADHD related hyperactivity. Additionally, thigmotaxis measurements suggest Grm8a, Grm8b, and Gad1b as interesting candidates for prospective studies on comorbid anxiety in ADHD. Furthermore, expression analysis in foxp2 mutants demonstrates Foxp2 as regulator of ADHD associated gene sets and neurodevelopmental disorder (NDD) overarching genetic and functional networks with possible implications for ADHD polygenicity and comorbidity. Finally, with the characterization of gene expression patterns and the generation and validation of genetic zebrafish models for Grm8a, Grm8b, Foxp2, and Gad1b, the present thesis laid the groundwork for future research efforts, for instance, the identification of the functional circuit(s) and biological mechanism(s) by which Grm8a, Grm8b, Foxp2, and Gad1b loss of function interfere with GABAergic signaling and ultimately induce hyperactivity.
In highly polarized neurons, endoplasmic reticulum (ER) forms a dynamic and continuous network in axons that plays important roles in lipid synthesis, Ca2+ homeostasis and the maintenance of synapses. However, the mechanisms underlying the regulation of axonal ER dynamics and its function in regulation of local translation still remain elusive. In the course of my thesis, I investigated the fast dynamic movements of ER and ribosomes in the growth cone of wildtype motoneurons as well as motoneurons from a mouse model of Spinal Muscular Atrophy (SMA), in response to Brain-derived neurotrophic factor (BDNF) stimulation. Live cell imaging data show that ER extends into axonal growth cone filopodia along actin filaments and disruption of actin cytoskeleton by cytochalasin D treatment impairs the dynamic movement of ER in the axonal filopodia. In contrast to filopodia, ER movements in the growth cone core seem to depend on coordinated actions of the actin and microtubule cytoskeleton. Myosin VI is especially required for ER movements into filopodia and drebrin A mediates actin/microtubule coordinated ER dynamics. Furthermore, we found that BDNF/TrkB signaling induces assembly of 80S ribosomes in growth cones on a time scale of seconds. Activated ribosomes relocate to the presynaptic ER and undergo local translation. These findings describe the dynamic interaction between ER and ribosomes during local translation and identify a novel potential function for the presynaptic ER in intra-axonal synthesis of transmembrane proteins such as the α-1β subunit of N-type Ca2+ channels in motoneurons. In addition, we demonstrate that in Smn-deficient motoneurons, ER dynamic movements are impaired in axonal growth cones that seems to be due to impaired actin cytoskeleton. Interestingly, ribosomes fail to undergo rapid structural changes in Smn-deficient growth cones and do not associate to ER in response to BDNF. Thus, aberrant ER dynamics and ribosome response to extracellular stimuli could affect axonal growth and presynaptic function and maintenance, thereby contributing to the pathology of SMA.
Development, Simulation and Evaluation of Mobile Wireless Networks in Industrial Applications
(2023)
Manyindustrialautomationsolutionsusewirelesscommunicationandrelyontheavail-
ability and quality of the wireless channel. At the same time the wireless medium is
highly congested and guaranteeing the availability of wireless channels is becoming
increasingly difficult. In this work we show, that ad-hoc networking solutions can be
used to provide new communication channels and improve the performance of mobile
automation systems. These ad-hoc networking solutions describe different communi-
cation strategies, but avoid relying on network infrastructure by utilizing the Peer-to-
Peer (P2P) channel between communicating entities.
This work is a step towards the effective implementation of low-range communication
technologies(e.g. VisibleLightCommunication(VLC), radarcommunication, mmWave
communication) to the industrial application. Implementing infrastructure networks
with these technologies is unrealistic, since the low communication range would neces-
sitate a high number of Access Points (APs) to yield full coverage. However, ad-hoc
networks do not require any network infrastructure. In this work different ad-hoc net-
working solutions for the industrial use case are presented and tools and models for
their examination are proposed.
The main use case investigated in this work are Automated Guided Vehicles (AGVs)
for industrial applications. These mobile devices drive throughout the factory trans-
porting crates, goods or tools or assisting workers. In most implementations they must
exchange data with a Central Control Unit (CCU) and between one another. Predicting
if a certain communication technology is suitable for an application is very challenging
since the applications and the resulting requirements are very heterogeneous.
The proposed models and simulation tools enable the simulation of the complex inter-
action of mobile robotic clients and a wireless communication network. The goal is to
predict the characteristics of a networked AGV fleet.
Theproposedtoolswereusedtoimplement, testandexaminedifferentad-hocnetwork-
ing solutions for industrial applications using AGVs. These communication solutions
handle time-critical and delay-tolerant communication. Additionally a control method
for the AGVs is proposed, which optimizes the communication and in turn increases the
transport performance of the AGV fleet. Therefore, this work provides not only tools
for the further research of industrial ad-hoc system, but also first implementations of
ad-hoc systems which address many of the most pressing issues in industrial applica-
tions.
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.
A disturbance in the symbiotic mutualism between the intestinal microbiome and the human host’s organism (syn. dysbiosis) accompanies the development of a variety of inflammatory and metabolic diseases that comprise the Metabolic Syndrome, chronic inflammatory gut diseases like Crohn’s disease, Non-alcoholic fatty liver disease (NAFLD) and cardiovascular diseases, among others. The changed uptake and effectiveness of short chain fatty acids (SCFAs) as well as an increase of the intestinal permeability are common, interdependent disease elements in this regard. Short chain fatty acids are end-products of intestinal bacterial fermentation and affect the mucosal barrier integrity via numerous molecular mechanisms.
There is evidence to suggest, that SCFAs have a modulating influence on Signal transducer and activator of transcription 3 (STAT3) in intestinal epithelial cells. STAT3 is a central gene-transcription factor in signaling pathways of proliferation and inflammation. It can be activated by growth factors and other intercellular signaling molecules like the cytokine Oncostatin M (OSM). The mode of STAT3’s activation exhibits, finally, a decisive influence on the immunological balance at the intestinal mucosa. Therefore, the posttranslational modification of STAT3 under the influence of SCFAs is likely to be a very important factor within the development and -progression of dysbiosis-associated diseases.
In this study, a clear positive in vitro-effect of the short chain fatty acid butyrate on the posttranslational serine727-phosphorylation of STAT3 and its total protein amount in the human adenocarcinoma cell line CACO2 is verified. Moreover, an increased gene expression of the OSM-receptor subunit OSMRβ can be observed after butyrate incubation. Histone deacetylase inhibition is shown to have a predominant role in these effects. Furthermore, a subsequent p38 MAPK-activation by Butyrate is found to be a key molecular mechanism regarding the STAT3-phosphorylation at serine727-residues. To consider the portion of butyrate receptor signaling in this context in future assays, a CACO-2 cell 3D-culture model is introduced in which an improvement of the GPR109A-receptor expression in CACO-2 cells is accomplished.
Mammalian embryonic development is subject to complex biological relationships that need to be understood. However, before the whole structure of development can be put together, the individual building blocks must first be understood in more detail. One of these building blocks is the second cell fate decision and describes the differentiation of cells of the inner cell mass of the embryo into epiblast and primitive endoderm cells. These cells then spatially segregate and form the subsequent bases for the embryo and yolk sac, respectively. In organoids of the inner cell mass, these two types of progenitor cells are also observed to form, and to some extent to spatially separate. This work has been devoted to these phenomena over the past three years. Plenty of studies already provide some insights into the basic mechanics of this cell differentiation, such that the first signs of epiblast and primitive endoderm differentiation, are the expression levels of transcription factors NANOG and GATA6. Here, cells with low expression of GATA6 and high expression of NANOG adopt the epiblast fate. If the expressions are reversed, a primitive endoderm cell is formed. Regarding the spatial segregation of the two cell types, it is not yet clear what mechanism leads to this. A common hypothesis suggests the differential adhesion of cell as the cause for the spatial rearrangement of cells. In this thesis however, the possibility of a global cell-cell communication is investigated. The approach chosen to study these phenomena follows the motto "mathematics is biology's next microscope". Mathematical modeling is used to transform the central gene regulatory network at the heart of this work into a system of equations that allows us to describe the temporal evolution of NANOG and GATA6 under the influence of an external signal. Special attention is paid to the derivation of new models using methods of statistical mechanics, as well as the comparison with existing models. After a detailed stability analysis the advantages of the derived model become clear by the fact that an exact relationship of the model parameters and the formation of heterogeneous mixtures of two cell types was found. Thus, the model can be easily controlled and the proportions of the resulting cell types can be estimated in advance. This mathematical model is also combined with a mechanism for global cell-cell communication, as well as a model for the growth of an organoid. It is shown that the global cell-cell communication is able to unify the formation of checkerboard patterns as well as engulfing patterns based on differently propagating signals. In addition, the influence of cell division and thus organoid growth on pattern formation is studied in detail. It is shown that this is able to contribute to the formation of clusters and, as a consequence, to breathe some randomness into otherwise perfectly sorted patterns.
The aim of this study was to provide a comprehensive overview of the frontal bone in the forensic context with special emphasis on its shape. Analyses on 19th and 20th century Euro-American and German crania were performed in terms of population differences, sexual dimorphism, secular change, and metopism.
It could clearly be seen that the frontal bone on its own already provides a lot of information toward the biological profile of an individual. Overall, using size and shape combined for analyses would always produce the best results, followed by shape only and then size only. Nevertheless, Log_Centroid_Size was the best sex-discriminating variable in the size-shape combined analyses for both populations. Population differences as well as sexual dimorphism could both be assessed (with varying accuracy) using size only and shape only respectively.
Very little secular change between the 19th and 20th century was found for the frontal in both groups respectively, with the secular change that could be seen mostly being shape variation.
Metopism analysis was only performed on German crania, because the presence or absence of a metopic suture was not documented for the Euro-American crania. Unfortunately, the results of these analyses were very limited due to too small sample sizes for the overall low percentage of metopism. The metopic frontal was once again found to be short in relation to its width and presenting a more rounded frontal curvature. The attempt of creating a formula to morphometrically assess the presence of metopism was not successful.
The results of this thesis suggest that forensic case work on skeletal remains would greatly benefit from a broader application of Geometric Morphometrics and consequently from larger databases containing shape data as well as more advanced and user-friendly software for this type of analyses.