JGU-Hochschulschriften

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    Die Hemisphärenlateralisation im Altersvergleich – eine fMRT-Studie
    (2024) Bulheller, Theresa Elisabeth; Tüscher, Oliver
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    Deciphering the role of USH1G/SANS in proteinprotein interactions and nuclear shuttling.
    (2025) Fritze, Jacques Sebastian; Wolfrum, Uwe
    In my thesis I investigated the molecular mechanisms underlying Human Usher syndrome (USH), particularly focusing on the protein USH1G/SANS. Usher syndrome, a clinically and genetically heterogeneous disorder that leads to hearing and vision loss. The USH1G gene encodes the scaffold protein SANS, which is highly expressed in the eye and ear. Recently, SANS has also been found in the cell nucleus, where it participates in the regulation of pre-mRNA splicing. In my thesis I aimed to elucidate the interactions of SANS with splicing-related proteins PRPF31 and PRPF6, as well as the mechanism of SANS’ nuclear-cytoplasmic shuttling. Additionally, I established a method to monitor the nuclear transfer of PRPF31 by live cell imaging. I show that SANS interacts with PRPF31 and PRPF6 at specific sites within its CENTn domain. Using FRET-based interaction assays and AlphaFold2, we identified for PRPF31 and PRPF6 specific binding sites in the CENTn domain of SANS, namely binding to the structured CENTn1 and to the unstructured CENTn2, respectively. In addition, we found evidence for sequential binding of PRPF31 and PRPF6 to the SANS molecule, which might be crucial for role of SANS in splicing processes in the nucleus. To fulfill its nuclear functions, SANS needs to be transported into the nucleus. In my thesis I identified two nuclear localization sequences (NLSs) and two nuclear export sequences (NESs). I highlighted their critical roles in SANS subcellular localization and in nuclear–cytoplasmic shuttling. Comparative analysis with SANS’ paralogue ANKS4B revealed distinct localization patterns, with ANKS4B more confined to the cytoplasm due to a lack of NLS. Using pathogenic variants of USH1G/SANS, we demonstrated altered interactions with the splicing proteins PRPF31 and PRPF6. Additionally, these pathogenic variants displayed subcellular mislocalization, likely impacting SANS’ function in splicing regulation and in the development of USH. Further, I provide data on the nuclear mobility of photoactivatable fluorescencetagged PRPF31 and the rapid transfer of splicing components between nuclear compartments. With these results, I could lay the groundwork for future studies on SANS-dependent molecular dynamics. Collectively, I enlighten the role of SANS in the nucleus. My findings advance the understanding of the molecular functions of SANS and its broader implications for USH1G pathogenesis.
  • ItemDissertationOpen Access
    Antigen specificity of tumor-infiltrating lymphocytes (TILs) in non-small cell lung cancer (NSCLC)
    (2025) Doppler, Christoph Nico
    Increasing the total numbers of tumor-specific lymphocytes among T cell populations used for adoptive cell therapies could dramatically increase overall tumor eradication efficiencies in cancer patients. By analyzing T cell receptor (TCR) repertoires in tumor and adjacent normal tissues of three non-small cell lung cancer patients, this study used an antigen-agnostic approach to identify potentially tumor-specific TCR clonotypes in highly heterogenous tumor-infiltrating lymphocyte (TIL) populations. Hence, TCRs from tumor-enriched and programmed cell death protein 1 (PD-1)-positive TILs were used to generate transgenic TCR-T cells via retroviral transduction of healthy donor lymphocytes. When tested for the recognition of patient-specific neoantigen candidates, three patient P18-derived TCRs specifically recognized a mutated KRASQ61H neoantigen via HLA-A*01:01. Moreover, the three KRASQ61H-specific TCRs formed a specificity cluster exhibiting highly homologous CDR3 antigen recognition motifs. Hence, TCRs from two additional specificity clusters were analyzed that mediated similar reactivity patterns when tested on partially HLA-matched allogeneic cell lines. Consistent with the literature, TCRs of cluster G recognized two pathogen-derived antigens and the non-mutated tumor-associated antigen TMEM161A via HLA-A*02:01. In summary, nine tumor-reactive TCRs were identified either recognizing the KRASQ61H neoantigen or TMEM161A. Therefore, the presented data substantially support the efforts to further develop antigen-agnostic, personalized T cell immunotherapies.
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    The role of alternative splicing of CaV2 channels for synaptic transmission and behavior in Drosophila melanogaster
    (2024) Bell, Christopher; Ryglewski, Stefanie
    In this thesis, I explored the role of alternative splicing of the voltage-gated calcium channel cacophony in Drosophila melanogaster with special focus on its role in synaptic transmission. I could show that the functional diversity of cacophony, which is homologous to the CaV2 channel family in vertebrates, relies heavily on alternative splicing of two splicing sites, one in the voltage sensor and one with a binding site for accessory subunits. My acquired data demonstrate that evoked synaptic vesicle release is possible only with one of the two alternative exons in the voltage sensor of the first homologous repeat, namely IS4B. My data provide evidence that isoforms with the other alternative exon, IS4A, are not required and not sufficient for normal synaptic transmission. Still, animals lacking exon IS4A show a severely impaired behavior and life expectancy is extremely reduced. As for the other investigated splice site, the binding site for accessory subunits in the intracellular loop between homologous repeats I and II, animals with a homozygous loss of either exon are still viable. Although loss of the exon I-IIB results in a reduced synaptic transmission amplitude, this does not result in an effect on motor behavior or life expectancy.
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    Synthese und Untersuchung der physikalischen Eigenschaften von Verbindungen des FeMo1−xVxO4-Typs
    (2025) Osten, Felix Lukas; Möller, Angela; Tremel, Wolfgang
    In der vorliegenden Arbeit wurden die über Festkörperreaktionen zugänglichen Verbindungen des FeMo1−xVxO4-Typs in Hinsicht auf ihre strukturellen und physikalischen Eigenschaften untersucht und beschrieben. Mittels in-situ und ex-situ Röntgendiffraktion an Pulvern, sowie kalorimetrischen Untersuchungen (DSC) konnte das Phasenverhältnis der (α-/β)-FeMoO4 Polymorphe der FeMo1−xVxO4-Substitutionsreihen und dessen Beeinfl usssung durch Temperatur und chemischen Druck mittels Substitution mit FeVO4 beschrieben werden. Das Phasenverhältnis von Tieftemperatur- (α-Phase) zu Hochtemperaturphase (β-Phase) ist mit diesen Parametern vollständig einstellbar. Anhand der röntgenographischen Charakterisierung ergab sich eine Zuordnung zur bevorzugten Substitution der Mo-Lagen durch Vanadium. Der Frage nach der aus Ladungsgründen (MoO4(2−) / VO4(3−) ) folgenden Gemischtvalenz Fe(II,III) wurde mit Hilfe der Mössbauerspektroskopie nachgegangen werden. Hieraus ließ sich eine Zuordnung zu Fe(II,III)-Lagen bestimmen. Aufgrund der Beobachtung einer Ladungsordnung unterhalb von 200 K wurde ein Polaronenmechanismus angenommen, der an Hand magnetischer Untersuchungen näher analysiert wurde. Ausgehend von Suszeptibilitätsdaten konnten Größe und Moment der Polaronen bestimmt und diese der zweidimensionalen Holstein-Klasse eingeordnet werden. Die Leitfähigkeit der Verbindungen FeMo1−xVxO4 (x=0, 0.11, 0.20) wurde mit Hilfe von Widerstandsmessungen untersucht.
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    Posttranslationale Regulation der Transportaktivität humaner kationischer Aminosäuretransporter (human cationic aminoacid transporter: hCATs)
    (2025) Bender-Sigel, Julia; Langguth, Peter; Efferth, Thomas; Closs, Ellen
    Cells depend on transporters for communication, interaction, and the selective uptake of nutrients and other molecules. Despite their importance, the intricate regulatory mecha-nisms that govern transporter activity and surface expression are not fully understood for many of these vital membrane proteins. This work investigated the post-translational regulation of human cationic amino acid transporters (hCATs) by protein kinase C (PKC) involving Rho-GTPases (Cdc42, Rac1, and RhoA) and other potentially involved proteins. The central finding of the work is that both PKC and Rho-GTPases, especially Cdc42, play a crucial role in modulating the transport activity of all four hCAT isoforms. Activation of PKC leads to a significant reduction in arginine uptake by the hCATs. This effect was demonstrated in Xenopus laevis oocytes as a model system and various human cell lines. Interestingly, the reduced arginine uptake is caused by the altered membrane localization of the transporters (induced endocytosis). An important aspect of this work is the investigation of the interplay of Rho-GTPases in regulating hCAT transporters showing the involvement of these GTPases in adapting transporter activity to meet cellular arginine demand. The results suggest that the simul-taneous activation of PKC and Rho-GTPases could lead to complex regulation of hCAT transporters, involving a reduced localization of the transporters in the plasma mem-brane. The importance of membrane localization for the function of hCAT transporters was par-ticularly emphasized in this work. Understanding the mechanisms that regulate mem-brane proteins, especially transporter proteins, is of central importance, as they represent both targets and sensors for the cell's environment. In summary, this research makes an important contribution to understanding the com-plex regulation of amino acid transporters, especially hCATs. The results show that PKC and Rho-GTPases play a crucial role in modulating transport activity and that membrane localization of the transporters is an important factor for their function. The interaction between PKC and Rho-GTPases could represent a finely tuned system that controls amino acid uptake as needed.
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    Reception of anglicisms by beginning readers – an eye tracking study
    (2024) Linsel, Stefanie; Hansen-Schirra, Silvia; Kranich, Svenja; Schaeffer, Moritz
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    Quantum effects in the search for new physics
    (2024) Lo Chiatto, Prisco
    Quantum field theory is the backbone of modern particle physics. As the name implies, it is based on quantum mechanics, of which it is the consistent expansion to include special relativity. However, its quantum nature is not as evident when performing calculations for observables at collider experiments. Indeed, by construction, perturbation theory at leading order coincides with a classical theory, and quantum effect act as a parametrically small correction. Trying to bridge this gap, this thesis explores purely quantum phenomena as a discovery tool for new physics. We start with an account of entanglement at colliders, focusing on the concrete example of 4-fermion scattering in the electroweak theory and including new physics dipole moments. We show that angular correlations of the fermions' decay products can restore (“resurrect”) interference contributions that are otherwise suppressed by small masses in cross sections, thus unlocking a quantum phenomenon. We also critically evaluate the new physics sensitivity of entanglement markers, by interpreting the angular correlations as spin correlation of the parent fermions; we show that there is no advantage in using entanglement markers, and the angular correlations perform equally or better. We then move to a scenario where quantum interference plays an even more dramatic role. We study a new gauge boson that is nearly degenerate with the Standard Model $Z$ boson and show how interference between the two fundamentally alters predictions. We correct inconsistent treatments in older works, which worked in an uncontrolled approximation that suppressed interference. Surprisingly, we find that the quantum Zeno effect is critical to understanding the phenomenology of this system. This effect, which is not widely known in the particle physics community, is due to the mismatch of unitary evolution and the non-unitary nature of particle decay. Finally, we shift our attention to nonrelativistic quantum mechanics, specifically exploring the connection between the quantum vacuum and the classical limit. Here, we uncover a surprising relationship between large-multiplicity scattering amplitudes and tunneling, offering new insights into how quantum effects persist even as systems approach classical behavior. This finding provides a fresh perspective on the interaction between quantum and classical mechanics in high-energy physics.
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    Feasibility studies of an inverse compton scattering based gamma source at MESA
    (2024) Lorey, Christoph Lukas; Meseck, Atoosa
    Recent years saw a number of accelerator projects attempt to utilize Inverse Compton Scattering (ICS) as gamma sources and beam diagnostic tools. With it's low cross section, ICS is a prospective pairing with energy recovery linacs (ERL) as they require low impact experiments for energy recovery efficiency to be high.\\ At the Johannes Gutenberg-University Mainz, the Mainz Energy Recovering Superconducting Linear Accelerator (MESA) is under construction. To investigate the potential of an ICS experiment at MESA, the task was given to conduct a feasibility study for ICS at MESA. In this thesis, the mathematical foundation of ICS as a relativistic particle collision between fermions and photons is summarized and derived. On this foundation, a semi-analytical numerical ICS simulation code named Comparse was written. It's principles and focus on performance are described in a chapter of it's own. Three positions in the accelerator layout possibly suitable for an ICS experiment were identified in the plans and beam line simulations according to which MESA is currently under construction. Using beam parameters in these locations, a number of ICS performance studies were conducted with Comparse. Through various investigated implementation scenarios, a detailed picture of MESA's potential as the driver for a ICS gamma source is formed. We have shown that with minimal effort, MESA can drive a E_ph' > 200 keV or lambda < 6.2 pm photon source with a flux of at least F >14.000 ph/s. At the other end of the scale, assuming moderate modifications to the MESA beamline and an amplified lambda = 193 nm laser, we project the potential for a F > 5*10^8 ph/s gamma source above 1 MeV photon energy. Finally, we present various aspects of ICS experiment that impact the performance, including polarization effects. With this thesis, we have thus provided a rare comprehensive review of the interdependence of the ICS behavior between polarization, scattering and incident angles as well as recoil and momentum distribution.
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