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In situ experiments to manipulate the atomic structure of nanocrystalline carbon monolayers and Pt-nanoclusters on graphene
(Universität Ulm, 2025-01-16) Leist, Christopher; Kaiser, Ute; Khlobystov, Andrei
By observing and manipulating our surroundings, we attempt to explain the universe from the largest to the smallest scale. In that endeavour, high-resolution transmission electron microscopy [HRTEM] opens the way for both observation and manipulation on very small scales. In this work, advanced aberration-correct electron microscopy in the form of the SALVE instrument is used to perform in-situ high-resolution transmission electron microscopy experiments on nanocrystalline graphene (NCG) and Pt-nanoclusters sputtered on a graphene substrate [Pt@SLG]. By merging the TEM’s inherent ability to quickly change the beam flux by spreading and focusing the e-beam, with different available acceleration voltages and local temperature control using MEMS chips, a wide range of parameters are accessible during the experiments. In combination, this is used to investigate the dynamics of these materials under different conditions and explore optimal parameters for their in-situ manipulation. Moreover, neural networks were trained to assist with the evaluation of the enormous amount of data recorded to capture dynamic processes. To best fulfil this task, they were specifically adapted to cope with contamination and illumination gradients.
Stochastic 3D microstructure modeling of twinned polycrystals for investigating the mechanical behavior of 𝛾-TiAl intermetallics
(Universität Ulm, 2024-03-10) Rieder, Philipp; Neumann, Matthias; Monteiro Fernandes, Lucas; Mulard, Aude; Willot, François; Schmidt, Volker
A stochastic 3D microstructure model for polycrystals is introduced which incorporates two types of twin grains, namely neighboring and inclusion twins. They mimic the presence of crystal twins in -TiAl polycrystalline microstructures as observed by 3D imaging techniques. The polycrystal grain morphology is modeled by means of Voronoi and –more generally– Laguerre tessellations. The crystallographic orientation of each grain is either sampled uniformly on the space of orientations or chosen to be in a twinning relation with another grain. The model is used to quantitatively study relationships between morphology and mechanical properties of polycrystalline materials. For this purpose, full-field Fourier-based computations are performed to investigate the combined effect of grain morphology and twinning on the overall elastic response. For -TiAl polycrystallines, the presence of twins is associated with a softer response compared to polycrystalline aggregates without twins. However, when comparing the influence on the elastic response, a statistically different polycrystalline morphology has a much smaller effect than the presence of twin grains. Notably, the bulk modulus is almost insensitive to the grain morphology and exhibits much less sensitivity to the presence of twins compared to the shear modulus. The numerical results are consistent with a two-scale homogenization estimate that utilizes laminate materials to model the interactions of twins.
Time series analysis via maximum variance frames
(Universität Ulm, 2025-01-14) Bonenberger, Christopher; Schwenker, Friedhelm; Ertel, Wolfgang; Voos, Holger
Shift invariance is a central characteristic of time series data. Many methods in signal processing and machine learning exploit the corresponding local dependencies by means of convolutions. In this dissertation, we transfer the idea of shift invariance by convolutions to a basic machine learning setting. In short, we present a generalization of Principal Component Analysis (PCA) towards structured representation learning, to which we refer as Maximum Variance Frames (MVFs). While PCA, a fundamental technique in machine learning and statistics, is based on pointwise correlations, the proposed approach allows to incorporate prior knowledge, foremost that time series data is governed by local dependencies. In this regard, we define a wide class of linear transformations that are based on different modifications of circulant matrices respectively circular convolutions. We state the general problem of learning corresponding structured data representations under the premise of variance maximization and provide analytical solutions to it. Along with the solution, we provide a formalism that consistently implements data transformations based on these structures in the form of a finite frame. Moreover, we examine several possibilities for fast implementations based on the fast Fourier transform. Taking different structures as a basis for this kind of representation learning, the proposed approach allows to model a wide range of different statistical dependencies. In fact, several well-known time series analysis techniques arise as a special case of Maximum Variance Frames. More precisely, we prove that the discrete Fourier transform, Dynamic PCA and Singular Spectrum Analysis are incorporated within the proposed framework that offers exact mathematical descriptions of their relations. In addition, we show that optimization of a certain class of structures implicitly formulates a novel approach to power spectral density estimation and in addition establishes a corresponding estimator. We demonstrate the performance of this estimator by comparing it to several well-known methods of spectral estimation. Moreover, we highlight the tight relations to subspace methods for spectral estimation and moving-average models. Furthermore, the proposed framework is extended towards supervised learning in accordance with linear discriminant analysis. Beyond that, we show how Maximum Variance Frames can be used for image processing and we provide a corresponding nonlinear kernel algorithm analogously to kernel PCA. Finally, the presented framework contributes to a deeper understanding and more effective utilization of machine learning and time series analysis techniques, and provides new approaches for research and practical applications.
Analyst distance and credit rating consistency
(Universität Ulm, 2024-03-07) Altdörfer, Marc; Guettler, Andre; Löffler, Gunter
In this paper, we investigate the effect of analyst distance on the assignment of credit ratings and show that issuers with analysts located in more distant offices obtain more conservative ratings than issuers with analysts located closer. Our results are robust to an analyst home bias and suggest that more distant analysts are subject to an informational disadvantage when conducting their rating analysis. Given an asymmetric reputational cost function that penalizes an overestimation of credit quality more heavily than an underestimation, assigning more conservative ratings is a rational response to the higher levels of information uncertainty that a greater distance can entail.
Mechanisms of aberrant HTT splicing and its implications on RNA homeostasis in Huntington’s disease
(Universität Ulm, 2025-01-10) Hoschek, Franziska; Neueder, Andreas; Kochanek, Stefan; Nguyen, Huu Phuc
Huntington disease (HD) is an autosomal dominant monogenic neurological disorder. The elongation of the CAG repeat in exon 1 of huntingtin (HTT) leads to the production of a short novel HTT isoform called HTT1a. HTT1a is a functional polyadenylated mRNA that contains the sequences of HTT exon 1 and a part of intron 1. Both the HTT1a mRNA as well as the encoded HTT exon 1 protein are known to be toxic. The generation of HTT1a is CAG repeat length dependent but the exact mechanism leading to HTT1a production remains unknown. In addition, it is unclear whether there is a tissue specific expression profile of HTT1a outside of the brain. Thus, a first approach in this study was to detect HTT1a in several different tissues and cell types. In addition to the involvement of the splicing machinery also regulators of transcription like R-loops and epigenetic modifications could contribute to the generation of HTT1a. Therefore, the involvement of DNA methylation, histone H3K27 trimethylations and R-loops at the HTT1a genomic region was analysed. The role of R-loops and epigenetics is not only interesting with regards to the production of HTT1a but also general transcriptional dysregulation in HD. Hence, the genome wide distribution of differentially methylated regions (DMRs), H3K27me3 marks and R-loops was investigated. For the detection of the HTT1a transcript in human peripheral tissues and brain a highly sensitive digital PCR (dPCR) assay was established. The analysis of transcriptional changes, epigenetics and R-loops was performed in primary human fibroblasts derived from healthy controls, adult onset and juvenile onset HD patients. Amplification-free, long read Nanopore sequencing was used for the analysis of the transcriptome and methylome. R-loops and H3K27me3 were detected by the novel method Cleavage under targets and tagmentation (CUT&Tag). Using dPCR, the HTT1a transcript could be detected not only in human post-mortem tissue in several brain regions but also in human muscle tissue, peripheral blood mononuclear cells (PBMCs) and fibroblasts. A significant, positive linear correlation between the expression levels of HTT1a and the CAG repeat length was found in the motor cortex and in PBMCs. Consequently, the measurement of HTT1a levels in easily accessible PBMCs could be a feasible biomarker in studies aiming at HTT lowering. The analysis of DNA methylation, H3K27me3 and R-loops in HTT exon 1 and intron 1 resulted in no significant differences neither between control and adult onset nor control and juvenile onset HD human fibroblasts. Based on the data obtained, the effect of the studied epigenetic factors on the generation of HTT1a in fibroblasts could not be clarified. However, fibroblasts are much less affected by transcriptional and possibly also epigenetic changes in HD than neurons and therefore these factors may well play a role in the generation of HTT1a in neuronal cells. On the genome wide level, the biggest differences in the transcriptome, epigenome and R-loops were found between control and juvenile onset HD fibroblasts. In contrast, HD mutation state was associated with fewer significant differences in the transcriptome, epigenome and R-loops. This was most likely due to the distinct findings in adult and juvenile onset HD fibroblasts. Overall, the number of significant differentially expressed genes or enriched epigenetic/R-loop regions was low. Only a few genes were identified that had a significant differentially enriched region of more than one type. Moreover, the overlap of genes with significant differentially enriched epigenetic or R-loop regions and differentially expressed genes was low. Nevertheless, TBX5 which was found to be significantly upregulated on the transcript level in juvenile onset HD fibroblasts also showed reduced H3K27me3 and DNA methylation, an epigenetic state associated with active transcription, at its transcription start site. TBX5, encoding T-box binding transcription factor 5, is interacting with transcription factors involved in HD pathogenesis. Consequently, TBX5 might be an interesting candidate to study in the context of transcriptional dysregulation in HD. The gene ontology and pathway enrichment analysis of the differentially expressed genes and genes containing at least one DMR or differential H3K27me3 region or R-loop resulted in multiple inconclusive pathways and processes. However, SUZ12 and EZH2 were identified as potential regulators in all juvenile HD onset gene sets. This is especially interesting as they are both part of the polycomb repressive complex 2, which is discussed to play a role in transcriptional dysregulation in HD. To sum up, in this work the CAG length dependent expression of HTT1a in PBMCs was shown which implies the assessment of HTT1a as potential future biomarker in clinical HD studies. Additionally, this study could further broaden the knowledge about transcriptional dysregulation in HD by analysing genome wide changes in epigenetic marks and R-loops.
Alignment of Fabry–Pérot Cavities for optomechanical acceleration measurements
(Universität Ulm, 2024-12-27) Rezinkina, Marina; Braxmaier, Claus
The wave optics processes in a Fabry–Pérot cavity with a length of about tens of millimeters are considered. Such cavities are used, among other applications, in optomechanical accelerometers for precise measurement of displacement of moving elements. A Fabry–Pérot cavity formed by a spherical and flat mirror is considered. The influence of parameters characterizing the alignment of the Fabry–Pérot cavity mirrors and the laser beam on the appearance of the higher order modes is investigated using numerical modeling. It is shown that the angle of inclination of the flat mirror of the cavity greatly affects the occurrence of higher order modes in addition to the fundamental mode. The levels of displacement of the axis of a spherical mirror in the vertical direction which do not cause the emergence of higher order modes is shown. The influence of the degree of displacement of the laser beam axis in the vertical direction relative to the symmetry axis of the Fabry–Pérot cavity is also investigated.
The dispositional essence of proactive social preferences: the dark core of personality vis-à-vis 58 traits
(Universität Ulm, 2023-02) Hilbig, Benjamin E.; Thielmann, Isabel; Zettler, Ingo; Moshagen, Morten
Individuals differ in how they weigh their own utility versus others’. This tendency codefines the dark factor of personality (D), which is conceptualized as the underlying disposition from which all socially and ethically aversive (dark) traits arise as specific, flavored manifestations. We scrutinize this unique theoretical notion by testing, for a broad set of 58 different traits and related constructs, whether any predict how individuals weigh their own versus others’ utility in proactive allocation decisions (i.e., social value orientations) beyond D. These traits and constructs range from broad dimensions (e.g., agreeableness), to aversive traits (e.g., sadism) and beliefs (e.g., normlessness), to prosocial tendencies (e.g., compassion). In a large-scale longitudinal study involving the assessment of consequential choices (median N = 2,270; a heterogeneous adult community sample from Germany), results from several hundred latent model comparisons revealed that no meaningful incremental variance was explained beyond D. Thus, D alone is sufficient to represent the social preferences inherent in socially and ethically aversive personality traits.
Advanced quantum cascade laser infrared attenuated total reflection spectroscopy
(Universität Ulm, 2024-12-20) Teuber, Andrea; Mizaikoff, Boris; Ziegenbalg, Dirk; Kneipp, Janina
The overarching topic of this cumulative thesis is the development and application of next-generation quantum cascade laser (QCL) based infrared attenuated total reflection (IR-ATR) infrared spectroscopy. Cascade lasers (i.e., interband and quantum cascade lasers; ICLs, QCLs) are considered the most advanced mid-infrared light sources, as discussed and exemplified in the introduction section of this dissertation. The characteristic properties of quantum cascade lasers include a broad spectral coverage and tunability in the mid-infrared range (MIR; 3 – 12 µm), well-defined spectral properties, and a high energy density within the emitted spectral band. As a result, spectroscopic information can be obtained based on differentiating molecular signatures. Consequently, the remainder of this cumulative thesis focuses on a variety of analytical applications capitalizing on the unique properties of cascade lasers presented as a series of peer-reviewed research articles. If laser light sources are combined with appropriate transducers, numerous application opportunities arise in a variety of scenarios ranging from environmental monitoring to bioanalytics. Hence, the development of innovative sensor technologies is an important yet challenging topic. The main purpose of the transducer in optical sensors is to ensure reproducible interaction between the sample and the photons, i.e., herein, light emitted by the laser light source. This is of particular interest if optical sensing technologies aim at taking advantage of inherent molecular specificity without additional chem/bio recognition architectures, as is the case for mid-infrared spectroscopic concepts. While the aforementioned scenarios – environmental vs. life science applications – clearly have their specific needs and requirements, both may capitalize on similar fundamental photonic concepts and building blocks, which are at the core of the present thesis, i.e., mid-infrared laser and mid-infrared waveguide technology. Analyzing molecular constituents in real-world environmental scenarios requires measurement techniques that may particularly withstand harsh external conditions while providing robust and reliable analytical data. Only a few infrared spectroscopic systems have been developed for harsh environments with most devices in routine practice being deployed in appropriate research facilities providing for a constant measurement environment without the need for portable or mobile devices. Among the most robust sensing concepts in mid-infrared photonics are transducers/sampling interfaces based on single or multiple reflection waveguides facilitating IR-ATR (i.e., evanescent field absorption) spectroscopy, which are readily adaptable to harsh conditions as shown in the present thesis. To this end, conventional multi-reflection ATR concepts were augmented with substrate-integrated hollow waveguide (iHWG) technology pioneered by our research team yielding an exceedingly robust modular transducer platform. This was achieved by developing an iHWG-based invariant light coupling concept for coupling IR photons to an ATR waveguide without the need for any additional optics in a robust and compact arrangement. This innovative assembly was proven useful for conventional broadband IR spectroscopy using Fourier transform infrared spectrometers, as well as QCLs. In the course of this thesis, a robust MIR sensor system was developed for mobile measurement applications at harsh environmental or process analytical conditions. The versatility of the developed sensor technology was demonstrated by coupling to a variety of light sources, the optional use of MIR fiberoptics, and by investigating a series of relevant analytes. Bioanalytical sensing technologies frequently require addressing exceedingly small sample volumes/quantities or directly addressing live biological specimens or systems. This requires biocompatible and chemically inert transducers when probing samples in life science applications. To this end, diamond is an ideal waveguide material that next to its inertness and biocompatibility provides a broad spectral transmission window that extends well into the MIR regime, which is of particular interest for the present thesis. While conventional diamond ATR crystals with only a few internal reflections readily exist, the present thesis was focused on optimizing frequency-matched thin-film diamond waveguide technology ideally combining with QCL light sources. Using nanocrystalline diamond layers with a thickness of around 20 µm, near single-mode waveguiding behavior has been achieved yielding a homogeneous evanescent field at the waveguide surface rather than hotspots, as encountered via discrete internal reflections using macroscopic ATR waveguides. Thereby, highly miniaturized sensing concepts are facilitated without trading off size against sensitivity. The performance and quantitative analytical capabilities of QCL-based MIR sensors combined with thin-film diamond waveguides were compared to conventional IR-ATR technology for the exemplary analyte caffeine, which is among the most commonly ingested psychoactive substances found in simulating beverages such as tea, coffee, or energy drinks. The utility of the developed sensing concepts was also shown for the analysis of live biological specimens, i.e., model bacteria, whereby biofilm formation processes were studied in molecular detail using QCLs combined with diamond thin-film waveguide technology for the first time. Different growth phases of bacteria were analyzed and compared with conventional IR spectroscopic data confirming the feasibility of IR laser spectroscopy for complex bioanalytical application scenarios. Finally, even though QCLs combined with diamond thin-film waveguide technology gave rise to adequately sensitive measurement concepts, there are analytical scenarios where even more sensitivity is required. Hence, it was shown that the strategy of surface-enhanced infrared absorption (SEIRA) spectroscopy may be readily adapted for harnessing the MIR sensing technologies developed in this thesis, especially by using graphene for amplifying selected infrared signatures. In summary, the results of this cumulative thesis were published within ten peer-reviewed contributions in leading international journals, including seven of them as a first author. A review contribution introduces the fundamentals of cascade lasers and their applications providing selected highlight examples published as a book chapter. The obtained research results address two main areas – environmental/process analytical scenarios and bioanalytics – demonstrating the versatility of waveguide-based laser spectroscopy in the mid-infrared contributing three publications each to robust IR-ATR concepts suitable for harsh environments, and to advanced thin-film diamond waveguide technology for bioanalytical scenarios.
The role of gas movement between xylem conduits in embolism propagation based on modelling and flow-centrifuge experiments
(Universität Ulm, 2024-12-20) Silva, Luciano de Melo; Jansen, Steven; Sayer, Emma
Chapter 1: The review ‘Gas Diffusion Kinetics in Relation to Embolism Formation and Propagation in Angiosperm Xylem: A Mini-Review’ provides an in-depth analysis of the development of models and methods addressing the relationship between gas diffusion and embolism formation in xylem. Previous studies often presented model equations, assumptions, and simplifications in supplementary materials, which, while focusing on the biological significance, may obscure critical information. This paper aimed to clarify these aspects by summarizing the current understanding of gas diffusion kinetics' functional importance in embolism formation and propagation, drawing on experimental and modelling evidence. The development of new methods and models for investigating gas movement through xylem tissue has enabled a comprehensive exploration of the relationship between gas diffusion and embolism propagation in angiosperms. Several studies have suggested that diffusion drives an increase in gas concentration within a recently embolized vessel. This increase in gas concentration is experimentally shown to be closely associated with embolism formation, as the recently embolized vessel may become a source that increases the likelihood of embolism formation in interconnected neighbouring conduits. Given that gas diffusion is influenced by anatomical features such as pit membrane thickness, total intervessel pit membrane area in a vessel, and vessel dimensions, several studies have used these parameters to model radial and axial gas diffusion in various species and attempted to correlate them with embolism resistance. While radial gas diffusion could be considered the primary determinant for embolism initiation as it introduces additional air into the system, axial gas diffusion does not appear to correlate directly with embolism formation. Modelling the mechanistic process of embolism formation has proven to be challenging due to the current lack of a fully comprehensive understanding of this phenomenon. Considering that gas movement may be linked to embolism resistance, modelling gas movement through xylem tissue may be a feasible alternative to investigate the mechanisms of embolism formation. However, some simplifications in these models, such as considering vessels as cylindrical structures connected at their ends, can overestimate the rate of gas diffusion by misrepresenting the actual pathways and overestimating the distances for gas movement. These limitations in the models call for further investigation to provide more accurate insights into embolism dynamics.
Replication competent HIV-guided CRISPR screen identifies novel antiviral factors
(Universität Ulm, 2024-12-20) Prelli Bozzo, Caterina; Kirchhoff, Frank; Sinzger, Christian; Schindler, Michael; Sparrer, Konstantin
Innate defense mechanisms govern the outcome of pathogen exposure. A major part of these mechanisms are host-encoded proteins called restriction factors (RFs), which may inhibit viral pathogens, such as HIV-1, at essentially each step of their replication cycle. Although many antiviral factors have been identified, it has also become clear that some RFs that are limiting HIV-1 transmission and/or are targeted by the viral accessory proteins Vpu, Vpr or Nef remain to be discovered. CRISPR/Cas9 approaches are frequently used to identify novel RFs. However, previous KO screens are either based on transduction with lentiviral vectors co-expressing Cas9 with sgRNAs and subsequent infection with HIV-1 or on particles packaging Cas9 with the virus. Thus, they only allow to analyze single rounds of replication, and often focus on early steps of the viral replication cycle before integration. To overcome these limitations, I established a new method combining the CRISPR/Cas9 technology with the adaptive capacity of replication-competent HIV-1. To this end, I engineered pooled libraries of 1537 replication-competent HIV-1 each expressing a single sgRNAs to target >500 potential RFs thus equipping them with a defined selection advantage. Replication and selection over multiple rounds of replication thus allows enrichment of HIV-1 clones that target RFs, enabling their virus-driven identification. Screening of recombinant HIV-1 libraries in CD4+ T cells stably expressing Cas9 revealed that viruses expressing sgRNAs targeting several candidate RFs, including GRN, CIITA, EHMT2, CEACAM3, CC2D1B and RHOA were efficiently selected over multiple rounds of viral replication. The inhibitory impact of PGRN, CIITA and CEACAM3 was confirmed in primary CD4+ T cells. Functional analysis revealed that PGRN and CIITA suppress viral transcription whereas CC2D1B inhibits viral particle release. RhoA causes a cell cycle arrest in the G2/M phase which may be beneficial for the replication of the virus. To identify factors which are targeted by the accessory protein Nef, I disrupted the nef gene in the HIV-1 NL4-3 backbone. Lack of the accessory nef gene increased selection of sgRNAs targeting SERINC5, a well-known Nef target, confirming that the system works. Surprisingly, this approach also identified IFI16 as a new Nef target. Subsequent functional studies confirmed that Nef counteracts the inhibitory effects of IFI16. In summary, I established an innovative, robust, highly versatile and sensitive approach that allows the virus-guided identification of relevant antiviral factors by turning HIV-1 into “traitors” revealing their cellular opponents. This groundbreaking technique, allows the identification of new antiviral factors and opens a wide range of possibilities to dissect and understand virus-host interactions.
A direct fuel-cell-based hybrid system for airborne applications
(Universität Ulm, 2024-12-19) Willich, Caroline
The work presented in this book concerns the development of a direct hybrid based on a fuel cell and a battery. It examines its behaviour under different operating conditions and various other relevant aspects for its application as a power train for an electric aircraft. At first the fundamentals of fuel cells and batteries are explained on cell as well as on system level and different fuel cell and battery types are introduced. For both technologies the pressure dependency of the respective technology is addressed. The next section introduces the concept of hybridisation in general as well as various possible architectures. The concept of the direct hybrid and its characteristic performance and current-voltage relationship is explained. The next chapters then examine the influence that hybrid ratio, battery state of charge as well as the operation at low ambient pressure have on the current-voltage characteristics of the direct hybrid. A newly developed power management module is presented next, that enables to control the direct hybrid by choosing operating modes in which the power required for propulsion either comes from the fuel cell, the battery, or both at the same time when working together as a hybrid. When switching from one mode to the other certain limitations and procedures for transitioning from one mode to the other must be defined and observed during operation, which is explained in a separate chapter. The examined dependencies of the hybrid behaviour have to be considered when determining the size of the fuel cell and battery for the power requirement of a given flight profile. A method for optimising the sizes of both the fuel cell and the battery is presented in chapter 4.5, which takes into account the impact of fuel cell and battery behaviour that were examined in the previous chapters. The second part of the book introduces the concept of pressurising the fuel cell at high altitudes, to mitigate the lower power output from the fuel cell at low ambient pressures. Possible compression technologies are compared and assessed for their suitability for the target application. Since electrical turbo-compressors currently show the highest potential for the application their functioning principle and characteristics are explained in more detail. Since the output pressure of turbo-compressors varies with the inlet conditions (temperature and pressure), the performance of a Rotrex EK10AA compressor at low inlet pressures and varying temperature is examined in detail and the influence of low inlet pressures on a power limit that is imposed by the inverter of the electric motor driving the compressor is described. When pressurising a fuel cell its power output increases, but the energy required for compression in an electrical turbocharger increases almost linearly with its pressure ratio. Therefore, the optimum pressure, above which a further increase in pressurisation does not provide any additional benefit and would only make the system larger and heavier, is examined, as well as the influence of altitude (low inlet pressures) and pressure losses on this value. When combining a fuel cell and an electric turbo-compressor the dynamic control of the system is also a challenge. To ensure a stable and safe operation, instable operating conditions, like compressor surge, must be avoided and a strategy for surge avoidance is introduced. At the end an outlook for further research challenges and opportunities is given.
Native and artificial miRNAs as versatile tools for glycoengineering in CHO production cells
(Universität Ulm, 2024-12-19) Schlossbauer, Patrick; Hesse, Friedemann; Niessing, Dierk
Market analysis clearly shows that the biopharmaceutical industry is growing rapidly, and with the increasing demand for biosimilars, and the introduction of tailor-made therapies the need for new technologies to modulate complex molecules emerges simultaneously. Monoclonal antibodies (mAbs) produced in Chinese hamster ovary (CHO) cells still reflect approximately 50 % of newly approved biologicals in the last decade. As the effector function of mAbs is highly sensitive to changes in the glycosylation pattern attached to the protein, this modification has been subject to numerous engineering approaches. Standard methods like radical gene knockout or energy consuming overexpression, however, often fail to meet moderate effector functions. Therefore, the present work aimed to elucidate the possibilities to use microRNAs (miRNAs) as fine-tuning regulators of mAb glycosylation in CHO cells. MiRNAs were identified regulating mAb fucosylation and galactosylation in transient experiments and in stable miRNA overexpressing CHO production cell lines. Here, strategies for the overexpression of miRNAs were tested with subsequent analysis of regulation on transcript and glycosylation level and potentially bioprocessing relevant parameters. Furthermore, artificial miRNAs (amiRNAs) which reflect improved synthetic variants of their native counterparts, were designed and applied in stable cell line development. Thereby, basic principles of efficient amiRNA regulation and potential pitfalls were identified. The experiments were accompanied by miRNA target prediction, which served as a valuable tool to hint at potential regulations and was evaluated by the generated data. Summarized, numerous cell lines with varying fucosylation and galactosylation properties could be generated which clearly demonstrated the applicability of miRNAs or tailor-made amiRNAs as versatile engineering tools in cell line development to generate moderate phenotypic changes required in biosimilar production.
Theoretische Untersuchungen zur Stickstoffreduktion an Kupferoxid Oberflächen
(Universität Ulm, 2024-12-19) Bogenrieder, Stefanie; Jacob, Timo; Groß, Axel
Das Ziel der vorliegenden Arbeit besteht darin zum grundlegenden Verständnis der Kupferoxide und deren Oberflächen beizutragen sowie Einblicke in die Stickstoffreduktion an Kupferoxid Oberflächen auf atomarer Ebene zu ermöglichen. Im Rahmen dieser Arbeit wurden daher die Kupferoxide Cu2O und CuO, deren niedrig indizierten (100), (110) und (111) Oberflächen sowie die Stickstoffreduktion an CuO(111) Oberflächen mittels PBE+U untersucht. Dabei wurde unter anderem eine Korrelation zwischen der Oberflächenstruktur und dem Oberflächenmagnetismus von Kupferoxiden festgestellt. Daneben konnte gezeigt werden, dass die Stickstoffreduktion an den untersuchten Kupferoxid Oberflächen generell bevorzugt an koordinativ ungesättigten Cu-Atomen stattfindet und an den unterschiedlichen CuO(111) Oberflächen verschiedene Mechanismen thermodynamisch bevorzugt werden. Zudem konnte abgeleitet werden, dass die untersuchte Oberfläche mit einem O-Defekt für die Stickstoffreduktion besonders vielversprechend ist. Auf Grundlage dieser Arbeit könnten daher Kupferoxid Oberflächen mit verschiedenen Sauerstoff-Defekten für zukünftige Studien von besonderem Interesse sein.
From structure to electrochemistry: the influence of transition metal ordering on Na+/vacancy orderings in P2-type NaxMO2 cathode materials for sodium-ion batteries†
(Universität Ulm, 2024-11-28) Pfeiffer, Lukas Fridolin; Dillenz, Manuel; Burgard, Nora; Beran, Premysl; Roscher, Daniel; Zarrabeitia, Maider; Drews, Paul; Hervoches, Charles; Mikhailova, Daria; Omar, Ahmad; Baran, Volodymyr; Paul, Neelima; Sotoudeh, Mohsen; Busch, Michael; Wohlfahrt-Mehrens, Margret; Groß, Axel; Passerini, Stefano; Axmann, Peter
P2-type layered oxides are attractive cathode active materials for sodium-ion batteries, however, these materials typically suffer from detrimental Na+/vacancy orderings. In this work, we investigate the origin as well as the influence of the transition metal ratio on Na+/vacancy orderings in P2-type cathode materials. A combination of X-ray diffraction (XRD), neutron diffraction, advanced electrochemical methods, operando XRD and DFT calculations is applied to study Na+/vacancy orderings in P2-NaxNi1/3Mn2/3O2 and P2-NaxMn3/4Ni1/4O2. In P2-NaxNi1/3Mn2/3O2, a honeycomb Ni/Mn superstructure leads to charge ordering within the transition metal slab and pronounced Na+/vacancy orderings, causing distinct voltage jumps at specific sodium contents (x = 2/3, 1/2 and 1/3). For P2-Na0.60Mn3/4Ni1/4O2, the Ni/Mn superstructure is disrupted, resulting in more complex charge orderings within the transition metal slab, partially suppressed Na+/vacancy orderings and an overall smoother potential profile. Based on our findings, guidelines to suppress Na+/vacancy orderings in P2-type cathode materials for sodium-ion batteries are postulated and discussed with respect to electrochemical measurements of various transition metal compositions. These guidelines can serve to predict the tendency towards Na+/vacancy orderings for a given cathode composition or to design new cathode compositions for enhanced cycle life based on the absence of Na+/vacancy orderings.
Advanced materials for the extraction, purification and filtration of adenovirus type 5
(Universität Ulm, 2024-12-18) Dietl, Sandra; Mizaikoff, Boris; Walther, Paul
The binding of viruses to materials is of importance for a wide variety of applications. These include for example the separation of viral contaminants from biotechnological products such as therapeutic proteins and antibodies for biological drugs. For this purpose, suitable separation strategies are required to obtain high-purity end products. The requirements for the applied materials are substantial, as they should be sufficiently robust in order to perform at harsh conditions such as high pressures. In addition, they need to bind the target virus with high capacity. On the other hand, such scavenger materials should be easy and inexpensive to produce in order to save time and cost during synthesis. Since the use of natural receptors is usually expensive and complex, this thesis focuses on the development and optimization of synthetic polymer materials that provide the demanded properties for scavenging adenovirus. The developed materials are based on silica core particles providing chemical and mechanical stability next to simple synthesis routes. The particles were then coated with an organosilane polymer layer yielding robust core-shell particles with tailorable functionalities that may be readily incubated with biotechnologically relevant solutions followed by efficient removal from the suspensions via centrifugation. Human adenovirus type 5 is a human pathogen capable of causing infections in the human body and was used as the exemplary target species during this study. Infections include respiratory diseases, gastrointestinal tract infections, and ocular diseases. Hence, efficient removal of adenovirus from biological samples or waters is therefore an important protection against diseases. Conversely, adenovirus is among the most promising candidates serving as viral vectors in gene therapy, e.g., against cancer. For this purpose, the purification of such viruses after biotechnological production ensuring efficient separation from other cell lysate components is essential. Therefore, the devised polymer materials ideally should cater to both application scenarios and allow for scalable production. To maximize the specificity for binding a selected virus, the first part of this thesis deals with the synthesis of molecularly imprinted polymers for adenovirus type 5. Hereby, adenovirus served as a template species that is spatially fixed via functional monomers and crosslinkers polymerized into a binding matrix. After removal of the template, binding sites are created that correspond to the template in size, shape, and functionalities and ideally specifically rebind the target species. However, large templates such as viruses pose several challenges for imprinting strategies given the plethora of potential unspecific interactions resulting from the vast number of functional groups provided by the capsid proteins. This is evident when comparing virus binding to the imprinted polymers with the binding efficiency to non-imprinted control polymers. To overcome this challenge, a so-called ‘epitope imprinting strategy’ was applied. Here, a peptide fragment is selected that is characteristic for a prevalent surface protein and then used as a template during the imprinting process. Subsequently, the entire viruses may be rebound via molecular recognition of the surface-protein-specific peptides with the correspondingly created binding moieties. Using these polymer particles, the second part of the thesis focused on developing a method to purify adenovirus from cell lysate supernatant via an incubation-elution approach. As in such scenarios only one virus species is present, selectivity is not the main criterium but binding capacity for efficiently harvesting the produced virus and efficient clean-up. Hence, in essence non-imprinted polymer particles were synthesized that are in composition similar to the approach discussed above, yet, only relying on the pronounced interactions between the virus surface and the functional groups at the particles resulting in substantial virus scavenging properties. This approach allowed for an efficient harvesting strategy with almost the entire amount of the virus present in an incubation solution being bound to the particle surface while the majority of the matrix proteins were separated after elution. In the last part of this thesis, virus binding and removal using innovative acrylate-based materials was tested and successfully applied. The polymer materials were fabricated via 3D printing of porous polymer structures and then used as syringe inserts facilitating a flow-through centrifugation strategy for virus retention within the material. In summary, the developed methods have the common goal of simplified binding and removal of adenovirus without using bioreceptors and are entirely based on synthetic scavenger materials, which are in essence universally applicable, i.e., tailorable to other kinds of viral species. For the example of adenovirus, it could be shown that they may either be almost entirely scavenged from virus-containing suspensions, or – for the case of a purification method – that they may be eluted after trapping by the developed particles with efficient removal of the other matrix components.
Characterization and pharmaceutical treatment of the Shank3Δ11 knockout mouse model
(Universität Ulm, 2024-12-18) Bauer, Helen Friedericke; Böckers, Tobias M.; Danzer, Karin; Grabrucker, Andreas; Kindler, Stefan
Phelan-McDermid syndrome (PMS) is a rare genetic disorder defined by global developmental delay, intellectual disability, muscular hypotonia, autism spectrum disorders, and various physical, behavioral, and neurological symptoms. It is caused by a deletion of chromosome 22 or mutations in the SHANK3 gene. This gene encodes a protein localized at glutamatergic synapses, functioning as a master scaffolding protein that connects receptors with the actin cytoskeleton at postsynaptic sites. In recent years, several genetic animal models have been developed to study the pathophysiology of SHANK3 haploinsufficiency. This study investigated the development of behavioral phenotypes in the Shank3Δ11 transgenic mouse model, focusing on differences in sex and genotype. Motor functions, social and repetitive behaviors, the two core symptoms of autism, cognitive and memory functions, as well as anxiety and avoidance behavior were examined at two developmental stages corresponding to human adolescence and early adulthood. Both heterozygous and homozygous Shank3 knockout (KO) mice were compared to wildtype (WT) controls. Shank3-KO mice exhibited impaired motor coordination and endurance, while muscle strength remained unaffected. Only minor changes were observed in social behavior, yet the animals showed pronounced stereotypic and repetitive behaviors. They also demonstrated increased avoidance behavior and slightly elevated anxiety. Cognitive flexibility was somewhat impaired, while spatial memory and orientation remained unchanged. The phenotype was generally stable over time, and female mice exhibited similar characteristics to males, though they were less affected in motor function and repetitive behavior. In all tests, heterozygous Shank3-KO mice either displayed normal behavior or a milder phenotype compared to homozygous counterparts. This study supports the face validity of Shank3-KO mice as a model for mimicking PMS pathology. Following phenotypic characterization, the effects of i.n. insulin, lithium, and zinc treatments were investigated in a small cohort of young homozygous Shank3-KO mice. Treatment began in postnatal week four, with behavioral tests conducted in treatment weeks 3 to 5. I.n. insulin did not enhance behavioral alterations in Shank3-KO mice. However, lithium and zinc supplementation positively influenced motor performance in the Rotarod test. This study also involved the validation of various commercial and homemade SHANK3 antibodies, revealing that some antibodies lacked specificity or showed cross-reactivity family members SHANK1 and SHANK2, which share a close homology. One validated antibody was then further used to study SHANK3 isoform-specific expression in the hippocampus, striatum, cerebellum, and cortex of both heterozygous and homozygous Shank3-KO mice, compared to WT levels. A distinct brain region-specific isoform pattern was observed. Despite certain SHANK3 isoforms still being expressed due to the knockout strategy used, we found a brain region- and sex-specific downregulation of some isoforms. Interestingly, heterozygous Shank3-KO mice displayed either intermediate or WT levels of SHANK3, possibly explaining their milder phenotype in most behavior tests. The comprehensive characterization of this mouse model allows to further investigate the pathophysiology and potential pharmaceutical intervention in PMS preclinical, as effective treatment approaches are currently lacking in the clinical settings.
Prediction of deoxynivalenol contamination in wheat via infrared attenuated total reflection spectroscopy and multivariate data analysis
(Universität Ulm, 2024-03-25) Fomina, Polina; Femenias, Antoni; Tafintseva, Valeria; Freitag, Stephan; Sulyok, Michael; Aledda, Miriam; Kohler, Achim; Krska, Rudolf; Mizaikoff, Boris
The climate crisis further exacerbates the challenges for food production. For instance, the increasingly unpredictable growth of fungal species in the field can lead to an unprecedented high prevalence of several mycotoxins, including the most important toxic secondary metabolite produced by Fusarium spp., i.e., deoxynivalenol (DON). The presence of DON in crops may cause health problems in the population and livestock. Hence, there is a demand for advanced strategies facilitating the detection of DON contamination in cereal-based products. To address this need, we introduce infrared attenuated total reflection (IR-ATR) spectroscopy combined with advanced data modeling routines and optimized sample preparation protocols. In this study, we address the limited exploration of wheat commodities to date via IR-ATR spectroscopy. The focus of this study was optimizing the extraction protocol for wheat by testing various solvents aligned with a greener and more sustainable analytical approach. The employed chemometric method, i.e., sparse partial least-squares discriminant analysis, not only facilitated establishing robust classification models capable of discriminating between high vs low DON-contaminated samples adhering to the EU regulatory limit of 1250 μg/kg but also provided valuable insights into the relevant parameters shaping these models.
Social augmented reality: human-based augmentations and their effects on augmenter and augmented
(Universität Ulm, 2024-12-13) Rixen, Jan Ole; Rukzio, Enrico; Gugenheimer, Jan; Feuchtner, Tiare
Smartphones have become ubiquitous, but while offering unprecedented connectivity, their usage has also been associated with various negative consequences. In turn, Augmented Reality (AR), emerging as the ubiquitous technology of the future, is currently in a non-entrenched state where changes to technology and application scenarios are still possible in an efficient way. As previous work has already established that AR can become embedded into the user's social life, we now still possess the opportunity to address potential negative social consequences preemptively before they manifest. This thesis, therefore, explores the potential influences of creating augmentations based on (other) humans, which we call Human-based Augmentations (HBAs). To allow for a targeted exploration, the thesis first defines an application space based on the C.R.U.D. (Create, Read, Update, Delete) operations. Following this, HBAs can manifest as (1) visually adding other humans to the user's context (Create), (2) displaying additional information about them (Read), (3) updating them visually (Update), and (4) visually deleting them from the user's field-of-view (Delete). Through four publications, the thesis uses this theoretical background to investigate the influences of HBAs on users perceiving the augmentations (Augmenters) and the persons being augmented (Augmented) while focusing on differences between the two actors. While showing that HBAs influence both actors, the thesis repeatably finds a gap between the influences of HBAs on Augmenter and Augmented. In light of the results, it argues for a shift from user-centered design processes that only consider the user towards regarding all actors and influences on them. The findings also suggest that contextual factors and situational properties can alter the influence on the actors, emphasizing the importance of context-sensitive adaptation of HBAs. Overall, the thesis contributes to understanding HBAs' potential influences and proposes first development conditions to avoid adverse societal effects.
Acceptance and user experience of in-vehicle technology and an extension by motivation and needs
(Universität Ulm, 2024-12-13) Stiegemeier, Dina ; Baumann, Martin; Franke, Thomas
Along with the trends for digitalization and automation, the interior of passenger cars is subject to major changes as more and more in-vehicle technology is being integrated into the cockpit. Thereby, driver assistance systems offer support in the primary driving task while in-vehicle information systems (IVIS) provide multimedia content, navigation information, or smartphone connectivity during the ride. However, the effectiveness of these technologies depends on user acceptance and regular use. Therefore, there is a large interest in understanding what influences the use and experience of in-vehicle technology. Traditional technology acceptance models emphasize beliefs about a system’s usefulness and ease of use (Davis, 1985). User experience (UX) research, on the other hand, focuses on the experiential and emotional aspects of technology interaction (Hassenzahl et al., 2003). However, the models have not provided a unified view on influencing factors for technology use. Therefore, one goal of this dissertation is to examine reasons to use or not use different types of in-vehicle technology. Further, both domains do not fully account for the motivational processes possibly influencing the technology use. Thereby, initial research suggests that basic psychological needs and motivational regulations proposed in a prominent motivational theory – the Self-Determination Theory (SDT, Deci & Ryan, 2000; Ryan & Deci, 2000) might serve as antecedents for beliefs proposed in acceptance and user experience models (Luqman et al., 2018). Thereby, the satisfaction of the basic psychological needs for autonomy, competence, and relatedness have been shown to result in increased motivation. Further, more autonomous types of motivational regulation can be associated with increased performance and well-being (Ryan & Deci, 2019). Drawing from these three distinct theoretical perspectives, this dissertation develops a new psychological framework investigating social cognitive models of acceptance and UX in the domain of invehicle technology and exploring potential origins within the perspective of the SDT (Deci & Ryan, 2000; Ryan & Deci, 2000). Addressing this, a series of research questions and empirical studies is presented in the four published manuscripts. The first manuscript aimed to provide an understanding of the main reasons for using or not using available in-vehicle technology. Therefore, a qualitative online survey was conducted to identify the usage barriers and subjective reasons for not using different types of in-vehicle technology. It shows that current acceptance models do not cover the subjectively relevant reasons. The second manuscript examines how motivational regulations affect driver acceptance of assistance and navigation systems, and their relation to common acceptance models. Therefore, a quantitative online study was conducted investigating positive and negative experiences with in-vehicle technology. Results show that motivational regulations significantly enhance the prediction of common acceptance models. The third manuscript investigates the role of eleven basic psychological needs in the driver-vehicle interaction, assessing the relationship between needs, motivational regulations, UX assessments, intentions to use, and affective consequences providing further support for the developed framework. To apply the findings to the design of new technologies, the fourth manuscript describes a mock-up experiment in which a gesture interaction system was designed to support autonomy and competence. The autonomy- and competence-supportive design characteristics had a positive effect on need satisfaction, motivation, UX beliefs, and acceptance. Taken together, the outcomes support the presented psychological framework providing new insights into the acceptance and use of in-vehicle technology. It emphasizes the importance of considering motivational factors alongside traditional acceptance and UX factors. Thereby, this work can contribute to a more focused human-centered development as it provides examples for designing in-vehicle technologies that better meet user needs and enhance well-being. Further design guidelines and implications can be derived from the broad empirical basis of the SDT.
NaWuReT colloquium: career pathways and opportunities for reaction engineers in industry
(Universität Ulm, 2024-03-22) Kreitz, Bjarne; Börnhorst, Marion; Friedland, Jens; Moioli, Emanuele
The Nachwuchs Reaktionstechnik (NaWuReT) is an organization of early-career chemical engineers of the DECHEMA/VDI subject division Reaction Engineering. In the spring of 2023, we organized a series of online lectures involving five invited speakers from industry to shed light on different career opportunities. The speakers gave insights into their individual career pathways and presented their current projects, both of which sparked active discussions among speakers and attendees.

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