Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
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RIXS interference in dimers, trimers, and tetramers: bond-directional excitations and quasimolecular wavefunctions
Get PDFIn the quest to realize exotic quantum states of matter, systems with strongly correlated electrons are of particular interest. Such systems may, e.g., form a Mott insulator, with localized magnetic moments. The interactions between these moments depend on the interplay of charge, lattice, orbital, and spin degrees of freedom. Of particular interest are cases where strong spin-orbit coupling leads to spin-orbit entangled j=1/2 magnetic moments, as realized for Ir⁴⁺ ions within an octahedral ligand cage. These moments can give rise to exotic magnetism. In Kitaev materials with, e.g., a honeycomb lattice of edge-sharing IrO₆ octahedra, theory predicts that exchange interactions between j=1/2 moments predominantly have bond-directional nearest-neighbor character, leading to exchange frustration. Ideally, this results in a quantum spin liquid ground state. Direct evidence for quantum spin liquids and bond-directional interactions remains an open experimental challenge. Another route to realizing exotic quantum states is to search for unusual magnetic moments. We investigate these in cluster Mott insulators, where electrons are delocalized over a cluster, such as a dimer, trimer, or tetramer, forming localized quasimolecular magnetic moments.
To probe the excitations in these systems, we use Resonant Inelastic X-ray Scattering (RIXS). This technique allows us to directly measure the energies of spin and orbital excitations and their dependence on exchanged momentum. When the electrons are delocalized over a cluster, like a dimer, trimer, or tetramer, the RIXS intensity exhibits a characteristic periodic modulation as a function of the exchanged momentum. This modulation arises from interference between the RIXS amplitudes from different sites within the cluster. We show that this modulation contains valuable information about bond-directional excitations in Kitaev materials and the quasimolecular wavefunctions in cluster Mott insulators.
Bond-directional magnetic interactions imply the existence of bond-directional magnetic excitations, spin excitations that render crystallographically equivalent directions magnetically inequivalent. We show how to observe the bond-directional character of the magnetic excitations using RIXS at the Ir L₃ edge in the Kitaev materials Na₂IrO₃ and α-Li₂IrO₃. We identify a low-energy spin-conserving excitation (at 10 meV and 15 meV, respectively) and a high-energy spin-flip excitation (at 45 meV and 35 meV, respectively). By exploiting the polarization and exchanged momentum dependence of the RIXS process, we simultaneously determine the bond direction and the spin operator involved in a given excitation, thus proving the bond-directional character of the magnetic excitations.
In cluster Mott insulators, the quasimolecular character can be probed via the modulation of the RIXS intensity. We study Ba₄NbIr₃O₁₂, which contains Ir₃O₁₂ trimers, using RIXS at the Ir L₃ edge. This work represents the first RIXS experimental determination of the quasimolecular electronic structure in a quasimolecular trimer cluster compound. We show that the modulation reveals information about the symmetry of the quasimolecular wavefunctions. The lacunar spinel GaTa₄Se₈ hosts spin-orbit-entangled quasimolecular wavefunctions on Ta₄ tetrahedra. We study the RIXS modulation at the Ta L₃ edge and find that it is sensitive to the wavefunction composition, particularly to the mixing between bonding and antibonding states. This mixing affects the quasimolecular magnetic moment and renormalizes the effective spin-orbit coupling. Accurate modeling was crucial for correct peak assignment and for understanding the tetrahedral quasimolecular magnetic moment
Constructing Knowledge about Voice(s): An Exploration of the Relation between Essentialism and the Stereotyping of Social Categories
Get PDFKnowledge about voice(s) is produced and transmitted in discourses that can be influenced by biases. Both stereotypes and essentialism, or the assumption that there are knowable or discoverable essences defined by necessary traits that exist objectively and mind-independently, have been categorized as biases. Several studies in the field of psychological essentialism indicate a link between the two. The question inhowfar relations between essentialism and stereotypes are present in knowledge about voice(s) is studied on the basis of a theoretical framework that draws from discussions of conceptualizations of relevant terms, namely voice(s), essentialism, knowledge, as well as social categories and stereotypes and an overview over the field of psychological essentialism. Essentialism and stereotypes are shown to share a structural similarity and generic language is discussed as potentially transmitting essentialist and stereotypical ideas about social categories. Case studies that include academic publications as well as (in)formal lessons are analyzed in regard to whether they allow for an essentialist reading. The findings include that generic language regarding social categories can serve as a point of intersection of essentialism and stereotypes, that generic social categories can be used to stand in for specific vocal features that can be more accurately described without reference to social categories, and that essentialism can be strategically used in the context of identity politics. A limitation of this thesis is that it rests on an interpretative approach, wherefore further studies concerning the relation between essentialism and stereotypes in knowledge about voice(s), as people actually experience it, are called for. Through this approach, it emerged that conceptualizations of social categories and their relevance in relation to voice(s) should be made explicit in order to produce and transmit knowledge about voice(s) more accurately and ethically
Investigating interlanguages beyond categorical analyses: Prosodic marking of information status in Italian learners of German
No full textElucidating the regulatory function of LysR-type transcription regulators in Escherichia coli
Get PDFLysR-type transcriptional regulators (LTTRs) constitute the most abundant group of transcription regulators in bacteria. In E. coli K-12, out of the 46 LTTRs, 29 are still partially characterised or completely uncharacterised with respect to their regulatory and functional role. For the majority of these poorly and uncharacterised LTTRs, information regarding the control of the LTTR’s expression and activity, and their target genes remains limited. In this work, I characterized a subset of these partially characterized or uncharacterized LTTRs with a focus on systematic characterization of the LTTR YdcI. Out of the 17 LTTRs selected for this study, 8 LTTRs were shown to be autoregulators and for 4 of them binding to their own promoter regions was shown. A comparative RNA-seq analysis revealed the presumptive target genes of 4 LTTRs (LrhA, YafC, YdcI and YhaJ). Additionally, validation of published ChIP-exo data of YdcI by EMSA identified 10 loci including iraP (responsible for stabilization of stress sigma factor), genes related to transport across the membrane and the TCA cycle as specific targets of this LTTR. A consensus DNA-binding motif for YdcI has also been identified in this work. Another finding of this study elucidates the role of alarmone ppGpp in induction of ydcI gene expression and the role of YdcI possibly acting as an H-NS antagonist for its target, iraP. Hence, this work highights the potential role of YdcI in E. coli in regulating the carbon flux in the TCA cycle in response to stress. Taken together, the findings of this work are of relevance to understand and decipher the complex regulatory network and potential functional implications of the partially characterized LTTRs in E. coli
Genome structure and meiotic recombination in cultivated tomatoes, wild relatives and derived hybrids
Get PDFEvolution, or the adaptation of organisms to survive their ever-changing environments, is facilitated by genetic variation and selection upon it. Genetic information is recombined during meiosis, facilitating the generation of genetic variation. Meiosis is a key feature of sexual reproduction and is a specialized cell division which leads to the production of genetically unique and ploidy-reduced gametes. Meiosis research in plants is often linked with crop improvement as recombination is an important substrate for crop breeders to generate elite genotypes. Increasing recombination rates, e.g. through mutation of anti-CO genes such as RECQ4, and altering recombination distribution has been shown to be possible in the model plant Arabidopsis and has the potential to increase genetic gain in a reduced number of breeding cycles in crops. However, only a limited number of species and genetic contexts have been tested for the discovered approaches. Current advances in DNA sequencing and bioinformatic tools are revolutionizing comparative plant genomics and make it possible to rapidly generate near-complete genome sequences of any plant material of interest where high molecular weight DNA can be extracted.
Here, we aim to increase our understanding of meiosis in tomato species through generation of fundamental genetic and genomic resources that facilitate comparative genomics and have direct potential usage in plant breeding. First, we generated a gap-free de novo chromosome scale assembly of our model tomato species S. lycopersicum cv. Moneyberg-TMV by combining PacBio HiFi and ONT sequencing approaches alone. Our assembly was validated through orthogonal approaches and showed improved statistics compared to gold standard reference genomes. This assembly provided the complete sequence and structure of a 64.1 Mbp introgression from S. peruvianum on chromosome 9 that harbours the Tm-22 TMV resistance gene, which was previously unknown. We suggest the location of the resistance gene on the periphery of pericentromeric heterochromatin together with complex structural variation contributes to the extensive introgression size which has not been reduced despite 60 years of breeding (Chapter II). Second, we selected three more tomato species, including S. lycopersicum cv. Micro-Tom, S. cheesmaniae LA1039 and S. pennellii LA0716, that represent different levels of genetic divergence from Moneyberg-TMV. By generating reference quality chromosome scale de novo genomes we could identify genomic variation including large megabase scale structural variants. Genomic comparison of our S. pennellii and the previous S. pennellii genome shows long-read sequencing technologies greatly improve assembly quality. We performed hybridization of each of these lines with our Moneyberg-TMV model. F1 hybrids were cultivated and used to generate male and female backcross populations. We used parental single nucleotide polymorphisms (SNPs) to identify COs in each of the six backcross populations and found 1) female crossovers recombine at higher rates than male crossovers, and 2) recombination cold-spots directly correlate to large genomic variations (including inversions and regions of high genetic diversity) between the species (Chapter III). Finally, we generated RECQ4 mutants in two previously mentioned interspecific hybrids to increase CO rates. We observed reduced fertility in recq4 mutants and even complete sterility within the S. lycopersicum x S. pennellii F1 background, showing detrimental defects during meiosis. Fertility was restored by whole genome doubling, resulting in viable mutant allotetraploid offspring. Our results suggest RECQ4 is necessary for meiotic progression in divergent hybrids and thereby has different functions compared to Arabidopsis (Chapter IV). By assembling high quality genomes including S. cheesmaniae and S. pennellii genomes, we now have next-generation genomic resources available of the complete tomato clade, allowing for maximal utilization in breeding and research. Combined, our results will further facilitate meiosis research in tomato species and complement that in Arabidopsis to provide a better understanding of how recombination is controlled in plant species alongside direct possible applications in hybrid tomato breeding
Die Primärstabilität von Subscapularissehnennähten in Abhängigkeit der Nahttechnik
Get PDFZahlreiche Single- (SR) und Double Row (DR) Techniken mit einfachen und modifizierten Nähten wurden zur Rekonstruktion des M. subscapularis (SSC) beschrieben, aber es fehlen ausreichend biomechanische und/oder klinische Daten für eindeutige Anwendungsempfehlungen. Ziel dieser biomechanischen Studie war daher die Evaluation der Primärstabilität von SSC-Sehnennähten in Abhängigkeit der Nahttechnik zur Rekonstruktion vollständiger SSC-Rupturen.
Zu den untersuchten Nahttechniken gehörten neben der konventionellen SR- und DR- Technik mit simplen Matratzennähten, die SR-Rekonstruktion mit „modifizierter Mason-Allen“ (MA)-Naht angelehnt an Scheibel und Habermeyer, sowie die modifizierte Lasso-loop (LL)-Naht nach Lafosse et al. Zur biomechanischen Testung wurden 32 Präparate nach Rekonstruktion schrittweise mittels einer Materialprüfmaschine, in einem definierten zyklischen Belastungsprotokoll mit sukzessiver Steigerung der Zuglast bis zu 200 N belastet. Unter Verwendung eines hochauflösenden 3D-Kamerasystem mit digitaler Bildkorrelation wurde die Zyklenzahl bis 3- bzw. 5 mm Lückenbildung zwischen Knochen und Sehne ermittelt. Zusätzlich wurde die maximale Versagenslast erhoben.
Diese Untersuchung zeigte, dass die klassische SR-Rekonstruktion im Vergleich zur DR-Rekonstruktion eine signifikant geringere Zyklenzahl bis zur 3- (p<.001) und 5 mm Lückenbildung (p=.004), sowie eine geringere maximale Versagenslast (p=.015) aufwies. Die SR-Rekonstruktion mit modifizierter LL-Naht hingegen zeigte lediglich eine signifikant geringere Anzahl von Zyklen bis zur 3 mm Lückenbildung (p=.003) im Vergleich zur DR-Rekonstruktion. Die SR-Rekonstruktion mit modifizierter MA-Naht zeigte keine signifikanten Unterschiede im Vergleich zur DR-Rekonstruktion.
Die SR-Rekonstruktion mit modifizierter MA-Naht, die aufgrund der geringeren Anzahl der benötigen Nahtanker vor allem bei verringerter Restlänge und Retraktion der Sehne vorteilhaft sein kann, stellt somit in Hinblick auf ihre biomechanische Potenz eine adäquate Alternative zur Rekonstruktion vollständiger SSC-Rupturen dar
Identification of Novel Regulators of Adrenal Steroidogenesis
Get PDFSteroid hormones are indispensable signaling molecules for organismal homeostasis. Steroid synthesis is known to be regulated by control of the supply of cholesterol to mitochondria where the first steroid in the pathway, pregnenolone, is produced. All other steroids are produced from pregnenolone in reactions taking place in mitochondria and the endoplasmic reticulum. Endolysosomal uptake, de novo synthesis in the endoplasmic reticulum, and mobilization from lipid droplets or plasma membrane can contribute cholesterol for steroidogenesis. How these different organelles coordinate their contributions to steroidogenesis is largely unknown.
Here, I aimed to identify novel mechanisms of steroidogenesis regulation in adrenocortical carcinoma cells. I characterized organellar functions required for steroidogenesis, finding that while mitochondrial energy production is essential, mitochondrial biogenesis and fusion are not required for steroidogenesis. Furthermore, lysosomes and endoplasmic reticulum may support steroidogenesis beyond their known contributions to cholesterol supply and intermediate steroid synthesis.
I also screened changes in the proteomes of mitochondria and the whole cell upon initiation of steroidogenesis for novel regulators of steroidogenesis. The candidates which emerged from this screen have known functions in biogenesis of lysosome-related organelles and insertion of newly translated proteins into the endoplasmic reticulum membrane and lumen, but they had no previously known role in steroidogenesis. Knock-out of these candidates was found to impair steroidogenesis. Specifically, I found the protein BLOC1S6 which is known to regulate biogenesis of lysosome-related organelles is required for production of glucocorticoids in adrenocortical carcinoma cells. This suggests that, in addition to the regulation of steroidogenesis at its initial step of cholesterol supply to mitochondria, the synthesis of downstream glucocorticoids is regulated in a BLOC1S6-dependent manner
Economic Essays on Flexibility in Energy Systems
Get PDFThis dissertation consists of four papers that examine the economic implications of increasing flexibility in energy systems.
Chapter 2 analyzes the interaction of dynamic electricity tariffs and three intervention strategies by the distribution system operator in low-voltage grids. Using an optimization model of EV charging, the chapter evaluates impacts on the number and magnitude of congestion events, flexibility demand, and charging costs. The results show that price signals alone may induce synchronized charging peaks, while temporally and spatially differentiated curtailment strategies can effectively mitigate congestion—approaching the system optimum with limited impact on charging costs.
Chapter 3 quantifies the spatio-temporal potential of flexible EV charging to smooth residual load profiles in Germany. Using region-specific EV diffusion modeled via sigmoid functions and empirically derived location-specific load and flexibility profiles, the analysis examines structural changes in regional and national residual load curves over time. The results highlight a coordination trade-off: regional incentives effectively reduce local peaks but are less efficient at smoothing the national residual load. National incentives effectively smooth the national residual load but may increase strain at the regional level.
Chapter 4 investigates welfare redistribution resulting from flexibility integration. A high-resolution dispatch model simulates multiple flexibility use cases across the transport and heating sectors in Germany in 2030, accounting for heterogeneous user groups. While total system welfare rises modestly, surplus shifts from producers to consumers. On aggregate, consumers benefit regardless of whether they actively provide flexibility, although the extent of these benefits varies considerably across user groups, shaped by consumption profiles and the temporal availability of flexibility.
Chapter 5 examines hydrogen price formation and its relationship with electricity prices. The integrated dispatch of the electricity and hydrogen systems is modeled under future climate-neutral scenarios for 2050. Statistical analysis of shadow prices reveals an average electricity-to-hydrogen price ratio of 0.56. Strong price coupling occurs under low residual load, when electrolysis dominates, while decoupling emerges during high residual load and storage discharge
Development of a New Class of Necroptosis Inhibitors That Bind Allosterically to Human and Mouse MLKL
Get PDFNekroptose ist eine Form des regulierten Zelltods, die zum Platzen der Plasmamembran, und somit zur Freisetzung von Zellbestandteilen und zur Immunantwort führt. Mixed Lineage Kinase domain-like pseudokinase (MLKL) ist das Effektorprotein, das für die Permeabilisierung der Plasmamembran bei der Nekroptose verantwortlich ist. Nekroptose ist mit einer Vielzahl entzündlicher Erkrankungen assoziiert. Aus diesem Grund ist die Inhibierung von MLKL eine attraktive Therapiemöglichkeit, da es das einzige Protein in der Signalkette ist, das ausschließlich mit Nekroptose assoziiert wird. Die Entwicklung neuer MLKL-Inhibitoren steckt jedoch noch in den Anfangsstadien und die existierenden Inhibitoren weisen viele Einschränkungen auf. Im Labor von Prof. Dr. Ana Garcia-Saez wurde eine hydrophobe Tasche in MLKL identifiziert, die als Angriffspunkt für Inhibitoren dienen könnte. Auf dieser Grundlage wurde eine neue Strategie entwickelt, um die Nekroptose gezielt zu regulieren, indem MLKL durch kleine Moleküle, die mit dieser Stelle interagieren, allosterisch gehemmt wird. Zwei Proof-of-Principle Verbindungen (MBA-h1 und MBA-m1) wurden durch in silico Analysen identifiziert. In dieser Arbeit wurden diese beiden Verbindungen in zellbasierten Assays charakterisiert: ihre inhibitorische Wirkung auf die Nekroptose, der Mechanismus, mit dem sie die Aktivierung von MLKL modulieren, und ihre Bindung an MLKL wurden bestimmt. Zusätzlich wurde ihre Wechselwirkung mit rekombinantem MLKL untersucht. Beide MBAs waren in der Lage, MLKL zu binden und die Zelltodkinetik dosisabhängig zu hemmen. Die aus den MBAs gewonnenen Erkenntnisse ermöglichten die Suche nach neuen Verbindungen mit ähnlichem Wirkmechanismus. Darauf aufbauend wurde ein erweitertes In-silico-Screening durchgeführt, bei dem potenzielle Treffer identifiziert und in vitro hinsichtlich ihrer Bindung an MLKL und Inhibierung charakterisiert wurden. Diesem Screening folgten zwei weitere Runden zur Charakterisierung von Analoga der identifizierten Treffer .Die besten Verbindungen übertrafen die bereits existierenden MLKL-Inhibitoren, da sie in der Lage waren, die Nekroptose sowohl in menschlichen als auch in Mauszellen zu hemmen. Zusammenfassend wird in dieser Arbeit ein neuer Ansatz zur Hemmung der Nekroptose vorgeschlagen. Die Hemmung basiert auf einer neu identifizierten intramolekularen Interaktion in MLKL, die für seine Aktivierung essentiell ist
Needs and Challenges of People with Deafblindness/Hearing and Vision Impairment in Working Life
Get PDFDue to a variety of barriers, the opportunities for equal participation in working life are limited for people with deafblindness and combined hearing and vision impairment. Dual sensory impairment (DSI), which is defined as the impairment of both senses, hearing and vision, is usually a progressive condition which encompasses different stages including deafblindness. This often leads employers and medical officers to conclude that further employment is no longer possible, resulting in unwanted early retirement. The EMPLOY project at the University of Cologne (running from April 2021 to July 2025) investigated challenges and conditions conducive to maintaining the employability of people with deafblindness, with DSI. It was funded by the Federal Ministry of Labour and Social Affairs (BMAS) of Germany. The focus was on people with combined hearing and vision impairment and deafblind people who have either been deaf or hard of hearing since birth, or have been blind or visually impaired since birth, and have also experienced another sensory impairment in their lifetime. It also encompassed individuals who have acquired hearing and vision impairment during their lifetime. This project report presents the key outcomes of the project and selected results. It also reflects on the methodological approach taken in the EMPLOY project. The project surveyed the current situation of people with DSI in working life in Germany. Based on the findings, materials were developed to address identified information gaps and limited participation opportunities: a comprehensive information brochure on deafblindness and hearing and vision impairment in working life, published in the REHADAT-Wissen series, and an assessment tool for identifying the participation needs of people with DSI. The concluding chapter presents further needs that emerged during the project which are essential for improving participation in working life and provides recommendations for action to address these needs