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Embryonale Stammzellen als Modellsystem für Infektion und Entzündung
(2024) Scharmacher, Jennifer; Sauer, Heinrich
In dieser Arbeit wurde der Einfluss von LPS auf inflammatorische Prozesse in Geweben aus ES der Maus untersucht. LPS sorgt innerhalb der EBs für eine signifikante Zunahme der Schlagfrequenz, ohne dabei die muskuläre Struktur der Kardiomyozyten zu verändern. Es konnte gezeigt werden, dass durch Inkubation mit LPS, Parameter wie ROS und NO in den EBs hochreguliert wurden. Anhand des NADPH-Oxidase Inhibitors Vas 2870 und Western-Blot Analyse konnte nachgewiesen werden, dass die ROS Quelle hauptsächlich die NOX 2 Isoform der NADPH-Oxidase ist. NOX 1 und NOX 4 wurden zwar auch verstärkt exprimiert, scheinen aber eine eher untergeordnete Rolle zu spielen. Durch den TLR 4 Inhibitor Tak-242 konnte gezeigt werden, dass NOX 2 in den LPS behandelten EBs signifikant zur Kontrolle herunterreguliert wird. Dies beweist eine Involvierung des TLR 4 Signalwegs in die LPS-induzierten Veränderungen des intrazellulären Redoxmilieus. Es ist bekannt, dass LPS über verschiedene Signalwege auch die NO-Synthasen stimuliert. In den EBs zeigte sich LPS-vermittelt eine erhöhte NO-Produktion. Eine gesteigerte Expression der p-eNOS und eNOS in den EBs wurde via Western-Blot nachgewiesen. Durch die Koinkubation mit Tak-242 wurde die NO-Generierung in den EBs nahezu gänzlich inhibiert. Weiterhin wurden durch die Koinkubation mit LPS, Makrophagen und andere aktivierte Immunzellen signifikant stärker differenziert. Es konnte zudem eine gesteigerte Expression des NLRP 3-Inflammasoms gezeigt werden, jedoch wurde hier kein signifikanter Unterschied zwischen kardialen und nicht kardialen Bereichen der EBs gefunden. Weiterhin kam es zu einer signifikant höheren Expression des proinflammatorischen Zytokins IL 1β. Tak-242 inhibierte die IL 1β-Expression in den LPS behandelten EBs, außerdem die LPS-induzierte Kontraktionsfrequenz der kardialen Zellen. Dies beweist die Involvierung des TLR 4 Signalwegs in die beobachteten inflammatorischen Vorgänge in EBs und die Veränderungen der Kardiomyozytenfunktion.
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Computational models of rodent hippocampal nerve cells focusing on their morphology, excitability and function
(2023) Mittag, Martin; Heiliger, Christian; Jedlička, Peter
The nerve cells in the mammalian brain come in various shapes and sizes. They constitute a complex system emerging from a complicated interplay of biophysical principles. Functionally, they can be compared to a computing unit transferring input into useful output, leading ultimately to cognitive functions or behaviour. This processing of information is called the input-output (IO) function of a neuron. The focus of this dissertation is on the particular IO function of hippocampal neurons, their underlying structure (morphology) and their intrinsic mechanisms (ion channels). In order to study these nerve cells, computational models offer the advantage of disentangling the involved biophysical mechanisms and their functional effects in a controlled manner. Therefore, I implement biologically realistic computational models of hippocampal neurons to simulate their IO function in several major, complementary \textit{in silico} investigations.Initially, using detailed neuron models that include active ion channels and other dendritic non-linearities, I demonstrate that the neural IO function can be invariant even when the stimulated dendrites of the nerve cells show vastly different morphological structures and sizes. These results reveal a general principle called accordingly "dendritic constancy". Notably, the dendritic constancy principle can have important clinical implications for neurological diseases. For example, it has been suggested that morphological alterations lead to the concurrent increase in excitability of principal hippocampal nerve cells during Alzheimer’s disease (AD). However, in line with the dendritic constancy principle, I show that the dendritic remodeling in AD cells is likely a homeostatic mechanism to maintain the cell IO function and information flow. The simulations instead reveal, that other intrinsic (ion channels) and extrinsic mechanism modifications lead to the excitability increase observed in AD cells in a multi-causal manner. Finally, various expressions of underlying ion channels cannot only affect the altered, pathological behaviour but potentially result in an optimised IO function and information processing. For instance, hippocampal granule cells (GCs) are believed to convert similar inputs into dissimilar outputs (pattern separation) while using as little energy as possible. The findings in this thesis reveal that the experimentally validated GC model seems to be close to optimal among a population of random, but valid, GC models with different ion channel expressions for the simultaneous performance of pattern separation and economy. In summary, by applying computational models in this dissertation I uncover a relationship between the underlying structure and ion channels of various nerve cells and their IO function.
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Maximizing information content of SNP arrays for genomic prediction
(2023) Weber, Sven Ernst; Snowdon, Rod; Frisch, Mathias
Genomic prediction is a promising tool for improving genetic gains in various crops, serving as a valuable tool for plant breeders. SNP arrays are the preferred genotyping tool for breeders of most major crops, however the limited predefined marker number associated with SNP arrays has the potential to impede achievable prediction accuracy in genomic prediction. The objective of this study was to evaluate cost-effective methods for maximizing the information content of SNP arrays. Three methods were explored and their information content was assessed using prediction accuracies from six genomic prediction models across diverse crops and agronomic traits. Independently of the method used to increase the information content of SNP arrays, the applied genomic prediction models consistently demonstrated similar performance in terms of prediction accuracy within traits, making them equally suitable for genomic prediction across a variety of crops and traits. The first method to maximize the information content of SNP arrays involved constructing haplotype blocks with various methods and parameters and utilizing their haplotypes for genomic prediction. Analyzing data from rapeseed, maize, wheat and soybean in genomic prediction models revealed only marginal improvements in genomic prediction accuracy across most traits. Notably, haplotype blocks demonstrated effectiveness in compensating for poorly performing models in scenarios with highly variable prediction accuracies across prediction models. Nevertheless, the absence of a consistent ideal method or parameter for constructing haplotype blocks makes them a hyperparameter requiring careful tuning. Furthermore, failed allele calls from SNP arrays were examined for their information content in genomic prediction of agronomic traits in maize and rapeseed. Two statistical pipelines were developed and tested to filter non-random failed allele calls from random technical errors. Surprisingly, failed allele calls, potentially originating from genome structural variants, exhibited prediction accuracies comparable to genome-wide SNP datasets. However, the combination of SNPs and failed allele calls did not enhance genomic prediction. As an alternative to whole-genome sequencing marker data, imputation of whole-genome sequencing marker data from SNP arrays was explored. While there was a considerable improvement in LD and marker density, no increase in prediction accuracy was observed. This can likely be attributed to erroneous haplotypes and marker calls resulting from imputation errors. A suitable hypothesis to explain this observation is that these errors are introduced by the high complexity and redundancy of crop plant genomes. Across all three methods, relationships emerged as an explanation for the lack of improvement in genomic prediction accuracy. Relationship estimates exhibited a high correlation between those obtained from SNP array data and methods to increase the information content of SNP arrays, contributing predominantly redundant information. Moreover, it can be assumed that markers on arrays generally exhibit sufficient LD with adjacent QTL. In conclusion, SNP arrays were proven to be a reliable genotyping technology, offering a representative sample of the genome for estimating relationships. Furthermore, this study reaffirms the potential of genomic prediction as a breeding tool to improve genetic gain in several crops.
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Molecular diversity and antimicrobial susceptibility of Streptococcus equi ssp. equi isolates from equines
(2023) Rotinsulu, Dordia Anindita; Bauerfeind, Rolf; Ewers, Christa; Kämpfer, Peter; Valentin-Weigand, Peter; Schermuly, Ralph
Streptococcus equi subspecies equi (See) is the causative agent of strangles, a highly infectious disease of equines worldwide. This study utilized various molecular typing methods, including analysis of whole genome sequence (WGS) data, to enlighten the phylogenetic relationships of See isolates obtained from equines in Germany and other countries, as well as to examine the associations between genotype, virulence-associated genes (VAGs), and epidemiological data. Additionally, antimicrobial susceptibilities, biofilm formation in vitro, and the relationship between genotype and biofilm formation were investigated. This study examined 628 non-duplicate putative S. equi isolates obtained from equines between 2001 and 2020, which were confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) as See (n = 265) and Streptococcus equi subspecies zooepidemicus (Sez) (n = 363), respectively. A published Se-mPCR successfully detected the sodA gene in all tested isolates and confirmed their assignment to the species S. equi. All but one isolates identified as See by MALDI-TOF MS (99.2 %) also harboured the See signature locus ICESe2, while none of them carried the ICESz1 locus of Sez. In contrast, only 44.6 % of the Sez isolates harboured the respective PCR target ICESz1. Among the 265 See isolates, analysis of their seM gene revealed a total of 47 different alleles, including 30 novel ones. The seM-9 allele was the most prevalent (87.9%). Multilocus sequence typing (MLST) of 191 See isolates selected for whole genome sequencing confirmed a low phylogenetic diversity of See since only two highly related sequence types (STs) were detected: ST-151 (73.8 %) and ST-179 (26.2 %). The core genome MLST (cgMLST) analysis exhibited 159 core genome (cg)-geno¬types affiliated with three globally recognized BAPS clusters of See: BAPS-2 (94.8 %), BAPS-5 (4.7 %), and BAPS-6 (0.5 %). Spatial-temporal analysis of See isolates from Germany identified some phylogenetically closely related or identical strains within clusters and beyond, suggesting modern horse transportation promotes the distribution of See strains. Comparison of the cgMLST results with those publicly available for 759 other See isolates from around the world revealed that all genotypes of this study fit perfectly into the general phylogenetic tree of See, supporting the hypothesis of a common See ancestor strain and global expansion of its descendants since the late 19th or early 20th century. In silico screening of WGS data from See isolates for known virulence-associated genes (VAGs) revealed 38 VAGs consistently present in all 191 tested isolates, with an additional 29 VAGs occurring only in 5 % to 99 % of the isolates. Differences in VAG combinations made it possible to distinguish 107 virotypes. The study also revealed that all antigens used in the commercial Strangvac® vaccine were highly-conserved in the investigated See isolates, suggesting the efficacy of Strangvac® against the See strains represented. All See isolates proved susceptible to tested beta-lactam antimicrobials, including penicillin G. Thus, penicillin G can be recommended as the first-line antimicrobial for strangles cases where antimicrobial therapy is clinically indicated. Biofilm assays indicated enhanced or diminished biofilm formation by certain See STs and seM allele groups, respectively, implying a role for the SeM protein in biofilm assembly in vitro.