@article{SnaebjornssonSchulze2018, author = {Snaebjornsson, Marteinn T and Schulze, Almut}, title = {Non-canonical functions of enzymes facilitate cross-talk between cell metabolic and regulatory pathways}, series = {Experimental \& Molecular Medicine}, volume = {50}, journal = {Experimental \& Molecular Medicine}, doi = {10.1038/s12276-018-0065-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-238763}, pages = {1-16}, year = {2018}, abstract = {The metabolic rewiring that occurs during cell transformation is a hallmark of cancer. It is diverse in different cancers as it reflects different combinations of oncogenic drivers, tumor suppressors, and the microenvironment. Metabolic rewiring is essential to cancer as it enables uncontrolled proliferation and adaptation to the fluctuating availability of nutrients and oxygen caused by poor access to the vasculature due to tumor growth and a foreign microenvironment encountered during metastasis. Increasing evidence now indicates that the metabolic state in cancer cells also plays a causal role in tumor growth and metastasis, for example through the action of oncometabolites, which modulate cell signaling and epigenetic pathways to promote malignancy. In addition to altering the metabolic state in cancer cells, some multifunctional enzymes possess non-metabolic functions that also contribute to cell transformation. Some multifunctional enzymes that are highly expressed in cancer, such as pyruvate kinase M2 (PKM2), have non-canonical functions that are co-opted by oncogenic signaling to drive proliferation and inhibit apoptosis. Other multifunctional enzymes that are frequently downregulated in cancer, such as fructose-bisphosphatase 1 (FBP1), are tumor suppressors, directly opposing mitogenic signaling via their non-canonical functions. In some cases, the enzymatic and non-canonical roles of these enzymes are functionally linked, making the modulation of non-metabolic cellular processes dependent on the metabolic state of the cell.}, language = {en} } @article{SirtlKnollDieuThuyetal.2018, author = {Sirtl, Simon and Knoll, Gertrud and Dieu Thuy, Trinh and Lang, Isabell and Siegmund, Daniela and Gross, Stefanie and Schuler-Thurner, Beatrice and Neubert, Patrick and Jantsch, Jonathan and Wajant, Harald and Ehrenschwender, Martin}, title = {Hypertonicity-enforced BCL-2 addiction unleashes the cytotoxic potential of death receptors}, series = {Oncogene}, volume = {37}, journal = {Oncogene}, doi = {10.1038/s41388-018-0265-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-238327}, pages = {4122-4136}, year = {2018}, abstract = {Attempts to exploit the cytotoxic activity of death receptors (DR) for treating cancer have thus far been disappointing. DR activation in most malignant cells fails to trigger cell death and may even promote tumor growth by activating cell death-independent DR-associated signaling pathways. Overcoming apoptosis resistance is consequently a prerequisite for successful clinical exploitation of DR stimulation. Here we show that hyperosmotic stress in the tumor microenvironment unleashes the deadly potential of DRs by enforcing BCL-2 addiction of cancer cells. Hypertonicity robustly enhanced cytotoxicity of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and other DR ligands in various cancer entities. Initial events in TRAIL DR signaling remained unaffected, but hypertonic conditions unlocked activation of the mitochondrial death pathway and thus amplified the apoptotic signal. Mechanistically, we demonstrate that hyperosmotic stress imposed a BCL-2-addiction on cancer cells to safeguard the integrity of the outer mitochondrial membrane (OMM), essentially exhausting the protective capacity of BCL-2-like pro-survival proteins. Deprivation of these mitochondrial safeguards licensed DR-generated truncated BH3-interacting domain death agonist (tBID) to activate BCL-2-associated X protein (BAX) and initiated mitochondrial outer membrane permeabilization (MOMP). Our work highlights that hyperosmotic stress in the tumor environment primes mitochondria for death and lowers the threshold for DR-induced apoptosis. Beyond TRAIL-based therapies, our findings could help to strengthen the efficacy of other apoptosis-inducing cancer treatment regimens.}, language = {en} } @article{StegmannReichertsAndreattaetal.2019, author = {Stegmann, Yannik and Reicherts, Philipp and Andreatta, Marta and Pauli, Paul and Wieser, Matthias J.}, title = {The effect of trait anxiety on attentional mechanisms in combined context and cue conditioning and extinction learning}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-45239-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239394}, year = {2019}, abstract = {Sensory processing and attention allocation are shaped by threat, but the role of trait-anxiety in sensory processing as a function of threat predictability remains incompletely understood. Therefore, we measured steady-state visual evoked potentials (ssVEPs) as an index of sensory processing of predictable and unpredictable threat cues in 29 low (LA) and 29 high (HA) trait-anxious participants during a modified NPU-paradigm followed by an extinction phase. Three different contextual cues indicated safety (N), predictable (P) or unpredictable threat (U), while foreground cues signalled shocks in the P-condition only. All participants allocated increased attentional resources to the central P-threat cue, replicating previous findings. Importantly, LA individuals exhibited larger ssVEP amplitudes to contextual threat (U and P) than to contextual safety cues, while HA individuals did not differentiate among contextual cues in general. Further, HA exhibited higher aversive ratings of all contexts compared to LA. These results suggest that high trait-anxious individuals might be worse at discriminating contextual threat stimuli and accordingly overestimate the probability and aversiveness of unpredictable threat. These findings support the notion of aberrant sensory processing of unpredictable threat in anxiety disorders, as this processing pattern is already evident in individuals at risk of these disorders.}, language = {en} } @article{SommerfeldSenfBumaetal.2018, author = {Sommerfeld, Andreas and Senf, Cornelius and Buma, Brian and D'Amato, Anthony W. and Despr{\´e}s, Tiphaine and D{\´i}az-Hormaz{\´a}bal, Ignacio and Fraver, Shawn and Frelich, Lee E. and Guti{\´e}rrez, {\´A}lvaro G. and Hart, Sarah J. and Harvey, Brian J. and He, Hong S. and Hl{\´a}sny, Tom{\´a}š and Holz, Andr{\´e}s and Kitzberger, Thomas and Kulakowski, Dominik and Lindenmayer, David and Mori, Akira S. and M{\"u}ller, J{\"o}rg and Paritsis, Juan and Perry, George L. W. and Stephens, Scott L. and Svoboda, Miroslav and Turner, Monica G. and Veblen, Thomas T. and Seidl, Rupert}, title = {Patterns and drivers of recent disturbances across the temperate forest biome}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-06788-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239157}, year = {2018}, abstract = {Increasing evidence indicates that forest disturbances are changing in response to global change, yet local variability in disturbance remains high. We quantified this considerable variability and analyzed whether recent disturbance episodes around the globe were consistently driven by climate, and if human influence modulates patterns of forest disturbance. We combined remote sensing data on recent (2001-2014) disturbances with in-depth local information for 50 protected landscapes and their surroundings across the temperate biome. Disturbance patterns are highly variable, and shaped by variation in disturbance agents and traits of prevailing tree species. However, high disturbance activity is consistently linked to warmer and drier than average conditions across the globe. Disturbances in protected areas are smaller and more complex in shape compared to their surroundings affected by human land use. This signal disappears in areas with high recent natural disturbance activity, underlining the potential of climate-mediated disturbance to transform forest landscapes.}, language = {en} } @article{ShumilovaLutoevIsaenkoetal.2018, author = {Shumilova, T. G. and Lutoev, V. P. and Isaenko, S. I. and Kovalchuk, N. S. and Makeev, B. A. and Lysiuk, A. Yu. and Zubov, A. A. and Ernstson, K.}, title = {Spectroscopic features of ultrahigh-pressure impact glasses of the Kara astrobleme}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-25037-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237983}, year = {2018}, abstract = {The state of substances under ultrahigh pressures and temperatures (UHPHT) now raises a special interest as a matter existing under extreme conditions and as potential new material. Under laboratory conditions only small amounts of micrometer-sized matter are produced at a pressure up to 100 GPa and at room temperature. Simultaneous combination of ultrahigh pressures and temperatures in a lab still requires serious technological effort. Here we describe the composition and structure of the UHPHT vein-like impact glass discovered by us in 2015 on the territory of the Kara astrobleme (Russia) and compare its properties with impact glass from the Ries crater (Germany). A complex of structural and spectroscopic methods presents unusual high pressure marks of structural elements in 8-fold co-ordination that had been described earlier neither in synthetic nor natural glasses. The Kara natural UHPHT glasses being about 70 Ma old have well preserved initial structure, presenting some heterogeneity as a result of partial liquation and crystallization differentiation where an amorphous component is proposed to originate from low level polymerization. Homogeneous parts of the UHPHT glasses can be used to deepened fundamental investigation of a substance under extreme PT conditions and to technological studies for novel material creations.}, language = {en} } @article{SolimandoBrandlMattenheimeretal.2018, author = {Solimando, A G and Brandl, A and Mattenheimer, K and Graf, C and Ritz, M and Ruckdeschel, A and St{\"u}hmer, T and Mokhtari, Z and Rudelius, M and Dotterweich, J and Bittrich, M and Desantis, V and Ebert, R and Trerotoli, P and Frassanito, M A and Rosenwald, A and Vacca, A and Einsele, H and Jakob, F and Beilhack, A}, title = {JAM-A as a prognostic factor and new therapeutic target in multiple myeloma}, series = {Leukemia}, volume = {32}, journal = {Leukemia}, doi = {10.1038/leu.2017.287}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239069}, pages = {736-743}, year = {2018}, abstract = {Cell adhesion in the multiple myeloma (MM) microenvironment has been recognized as a major mechanism of MM cell survival and the development of drug resistance. Here we addressed the hypothesis that the protein junctional adhesion molecule-A (JAM-A) may represent a novel target and a clinical biomarker in MM. We evaluated JAM-A expression in MM cell lines and in 147 MM patient bone marrow aspirates and biopsies at different disease stages. Elevated JAM-A levels in patient-derived plasma cells were correlated with poor prognosis. Moreover, circulating soluble JAM-A (sJAM-A) levels were significantly increased in MM patients as compared with controls. Notably, in vitro JAM-A inhibition impaired MM migration, colony formation, chemotaxis, proliferation and viability. In vivo treatment with an anti-JAM-A monoclonal antibody (αJAM-A moAb) impaired tumor progression in a murine xenograft MM model. These results demonstrate that therapeutic targeting of JAM-A has the potential to prevent MM progression, and lead us to propose JAM-A as a biomarker in MM, and sJAM-A as a serum-based marker for clinical stratification.}, language = {en} } @article{SoltamovKasperPoshakinskiyetal.2019, author = {Soltamov, V. A. and Kasper, C. and Poshakinskiy, A. V. and Anisimov, A. N. and Mokhov, E. N. and Sperlich, A. and Tarasenko, S. A. and Baranov, P. G. and Astakhov, G. V. and Dyakonov, V.}, title = {Excitation and coherent control of spin qudit modes in silicon carbide at room temperature}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-09429-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239149}, year = {2019}, abstract = {One of the challenges in the field of quantum sensing and information processing is to selectively address and coherently manipulate highly homogeneous qubits subject to external perturbations. Here, we present room-temperature coherent control of high-dimensional quantum bits, the so-called qudits, associated with vacancy-related spins in silicon carbide enriched with nuclear spin-free isotopes. In addition to the excitation of a spectrally narrow qudit mode at the pump frequency, several other modes are excited in the electron spin resonance spectra whose relative positions depend on the external magnetic field. We develop a theory of multipole spin dynamics and demonstrate selective quantum control of homogeneous spin packets with sub-MHz spectral resolution. Furthermore, we perform two-frequency Ramsey interferometry to demonstrate absolute dc magnetometry, which is immune to thermal noise and strain inhomogeneity.}, language = {en} } @article{SiegmundEhrenschwenderWajant2018, author = {Siegmund, Daniela and Ehrenschwender, Martin and Wajant, Harald}, title = {TNFR2 unlocks a RIPK1 kinase activity-dependent mode of proinflammatory TNFR1 signaling}, series = {Cell Death \& Disease}, volume = {9}, journal = {Cell Death \& Disease}, doi = {10.1038/s41419-018-0973-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-238034}, year = {2018}, abstract = {TNF is not only a major effector molecule of PAMP/DAMP-activated macrophages, but also regulates macrophage function and viability. We recently demonstrated that TNFR2 triggers necroptosis in macrophages with compromised caspase activity by two cooperating mechanisms: induction of endogenous TNF with subsequent stimulation of TNFR1 and depletion of cytosolic TRAF2-cIAP complexes. Here we show that TNFR2 activation in caspase-inhibited macrophages results in the production of endogenous TNF and TNFR1 stimulation followed by upregulation of A20, TRAF1, IL-6, and IL-1β. Surprisingly, TNFR1-mediated induction of IL-6 and IL-1β was clearly evident in response to TNFR2 stimulation but occurred not or only weakly in macrophages selectively and directly stimulated via TNFR1. Moreover, TNFR2-induced TNFR1-mediated gene induction was largely inhibited by necrostatin-1, whereas upregulation of A20 and TRAF1 by direct and exclusive stimulation of TNFR1 remained unaffected by this compound. Thus, treatment with TNFR2/ZVAD enables TNFR1 in macrophages to stimulate gene induction via a pathway requiring RIPK1 kinase activity. TNFR2/ZVAD-induced production of IL-6 and IL-1β was largely blocked in necroptosis-resistant MLKL- and RIPK3-deficient macrophages, whereas induction of A20 and TRAF1 remained unaffected. In sum, our results show that in caspase-inhibited macrophages TNFR2 not only triggers TNF/TNFR1-mediated necroptosis but also TNF/TNFR1-mediated RIPK3/MLKL-dependent and -independent gene induction.}, language = {en} } @article{VaethWangEcksteinetal.2019, author = {Vaeth, Martin and Wang, Yin-Hu and Eckstein, Miriam and Yang, Jun and Silverman, Gregg J. and Lacruz, Rodrigo S. and Kannan, Kasthuri and Feske, Stefan}, title = {Tissue resident and follicular Treg cell differentiation is regulated by CRAC channels}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-08959-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232148}, year = {2019}, abstract = {T regulatory (Treg) cells maintain immunological tolerance and organ homeostasis. Activated Treg cells differentiate into effector Treg subsets that acquire tissue-specific functions. Ca2+ influx via Ca2+ release-activated Ca2+ (CRAC) channels formed by STIM and ORAI proteins is required for the thymic development of Treg cells, but its function in mature Treg cells remains unclear. Here we show that deletion of Stim1 and Stim2 genes in mature Treg cells abolishes Ca2+ signaling and prevents their differentiation into follicular Treg and tissue-resident Treg cells. Transcriptional profiling of STIM1/STIM2-deficient Treg cells reveals that Ca2+ signaling regulates transcription factors and signaling pathways that control the identity and effector differentiation of Treg cells. In the absence of STIM1/STIM2 in Treg cells, mice develop a broad spectrum of autoantibodies and fatal multiorgan inflammation. Our findings establish a critical role of CRAC channels in controlling lineage identity and effector functions of Treg cells.}, language = {en} } @article{SulzerCassidyHorgaetal.2018, author = {Sulzer, David and Cassidy, Clifford and Horga, Guillermo and Kang, Un Jung and Fahn, Stanley and Casella, Luigi and Pezzoli, Gianni and Langley, Jason and Hu, Xiaoping P. and Zucca, Fabio A. and Isaias, Ioannis U. and Zecca, Luigi}, title = {Neuromelanin detection by magnetic resonance imaging (MRI) and its promise as a biomarker for Parkinson's disease}, series = {npj Parkinson's Disease}, volume = {4}, journal = {npj Parkinson's Disease}, doi = {10.1038/s41531-018-0047-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240207}, year = {2018}, abstract = {The diagnosis of Parkinson's disease (PD) occurs after pathogenesis is advanced and many substantia nigra (SN) dopamine neurons have already died. Now that therapies to block this neuronal loss are under development, it is imperative that the disease be diagnosed at earlier stages and that the response to therapies is monitored. Recent studies suggest this can be accomplished by magnetic resonance imaging (MRI) detection of neuromelanin (NM), the characteristic pigment of SN dopaminergic, and locus coeruleus (LC) noradrenergic neurons. NM is an autophagic product synthesized via oxidation of catecholamines and subsequent reactions, and in the SN and LC it increases linearly during normal aging. In PD, however, the pigment is lost when SN and LC neurons die. As shown nearly 25 years ago by Zecca and colleagues, NM's avid binding of iron provides a paramagnetic source to enable electron and nuclear magnetic resonance detection, and thus a means for safe and noninvasive measure in living human brain. Recent technical improvements now provide a means for MRI to differentiate between PD patients and age-matched healthy controls, and should be able to identify changes in SN NM with age in individuals. We discuss how MRI detects NM and how this approach might be improved. We suggest that MRI of NM can be used to confirm PD diagnosis and monitor disease progression. We recommend that for subjects at risk for PD, and perhaps generally for older people, that MRI sequences performed at regular intervals can provide a pre-clinical means to detect presymptomatic PD.}, language = {en} } @article{UllrichWeberPostetal.2018, author = {Ullrich, M and Weber, M and Post, A M and Popp, S and Grein, J and Zechner, M and Gonz{\´a}lez, H Guerrero and Kreis, A and Schmitt, A G and {\"U}ҫeyler, N and Lesch, K-P and Schuh, K}, title = {OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency}, series = {Molecular Psychiatry}, volume = {23}, journal = {Molecular Psychiatry}, doi = {10.1038/mp.2016.232}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232096}, pages = {444-458}, year = {2018}, abstract = {Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2\% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD.}, language = {en} } @article{TrautzFrankeBohnertetal.2019, author = {Trautz, Florian and Franke, Heike and Bohnert, Simone and Hammer, Niels and M{\"u}ller, Wolf and Stassart, Ruth and Tse, Rexson and Zwirner, Johann and Dreßler, Jan and Ondruschka, Benjamin}, title = {Survival-time dependent increase in neuronal IL-6 and astroglial GFAP expression in fatally injured human brain tissue}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-48145-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229037}, year = {2019}, abstract = {Knowledge on trauma survival time prior to death following a lethal traumatic brain injury (TBI) may be essential for legal purposes. Immunohistochemistry studies might allow to narrow down this survival interval. The biomarkers interleukin-6 (IL-6) and glial fibrillary acidic protein (GFAP) are well known in the clinical setting for their usability in TBI prediction. Here, both proteins were chosen in forensics to determine whether neuronal or glial expression in various brain regions may be associated with the cause of death and the survival time prior to death following TBI. IL-6 positive neurons, glial cells and GFAP positive astrocytes all concordantly increase with longer trauma survival time, with statistically significant changes being evident from three days post-TBI (p < 0.05) in the pericontusional zone, irrespective of its definite cortical localization. IL-6 staining in neurons increases significantly in the cerebellum after trauma, whereas increasing GFAP positivity is also detected in the cortex contralateral to the focal lesion. These systematic chronological changes in biomarkers of pericontusional neurons and glial cells allow for an estimation of trauma survival time. Higher numbers of IL-6 and GFAP-stained cells above threshold values in the pericontusional zone substantiate the existence of fatal traumatic changes in the brain with reasonable certainty.}, language = {en} } @article{TylekSchillingSchlegelmilchetal.2019, author = {Tylek, Tina and Schilling, Tatjana and Schlegelmilch, Katrin and Ries, Maximilian and Rudert, Maximilian and Jakob, Franz and Groll, J{\"u}rgen}, title = {Platelet lysate outperforms FCS and human serum for co-culture of primary human macrophages and hMSCs}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-40190-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229174}, year = {2019}, abstract = {In vitro co-cultures of different primary human cell types are pivotal for the testing and evaluation of biomaterials under conditions that are closer to the human in vivo situation. Especially co-cultures of macrophages and mesenchymal stem cells (MSCs) are of interest, as they are both present and involved in tissue regeneration and inflammatory reactions and play crucial roles in the immediate inflammatory reactions and the onset of regenerative processes, thus reflecting the decisive early phase of biomaterial contact with the host. A co-culture system of these cell types might thus allow for the assessment of the biocompatibility of biomaterials. The establishment of such a co-culture is challenging due to the different in vitro cell culture conditions. For human macrophages, medium is usually supplemented with human serum (hS), whereas hMSC culture is mostly performed using fetal calf serum (FCS), and these conditions are disadvantageous for the respective other cell type. We demonstrate that human platelet lysate (hPL) can replace hS in macrophage cultivation and appears to be the best option for co-cultivation of human macrophages with hMSCs. In contrast to FCS and hS, hPL maintained the phenotype of both cell types, comparable to that of their respective standard culture serum, as well as the percentage of each cell population. Moreover, the expression profile and phagocytosis activity of macrophages was similar to hS.}, language = {en} } @article{StraubFreudenbergSchleicheretal.2018, author = {Straub, Tobias and Freudenberg, Marina A. and Schleicher, Ulrike and Bogdan, Christian and Gasteiger, Georg and Pircher, Hanspeter}, title = {Bacterial coinfection restrains antiviral CD8 T-cell response via LPS-induced inhibitory NK cells}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-06609-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240075}, year = {2018}, abstract = {Infection of specific pathogen-free mice with lymphocytic choriomeningitis virus (LCMV) is a widely used model to study antiviral T-cell immunity. Infections in the real world, however, are often accompanied by coinfections with unrelated pathogens. Here we show that in mice, systemic coinfection with E. coli suppresses the LCMV-specific cytotoxic T-lymphocyte (CTL) response and virus elimination in a NK cell- and TLR2/4-dependent manner. Soluble TLR4 ligand LPS also induces NK cell-mediated negative CTL regulation during LCMV infection. NK cells in LPS-treated mice suppress clonal expansion of LCMV-specific CTLs by a NKG2D- or NCR1-independent but perforin-dependent mechanism. These results suggest a TLR4-mediated immunoregulatory role of NK cells during viral-bacterial coinfections.}, language = {en} } @article{VujanićGesslerOomsetal.2018, author = {Vujanić, Gordan M. and Gessler, Manfred and Ooms, Ariadne H. A. G. and Collini, Paola and Coulomb-l'Hermine, Aurore and D'Hooghe, Ellen and de Krijger, Ronald R. and Perotti, Daniela and Pritchard-Jones, Kathy and Vokuhl, Christian and van den Heuvel-Eibrink, Marry M. and Graf, Norbert}, title = {The UMBRELLA SIOP-RTSG 2016 Wilms tumour pathology and molecular biology protocol}, series = {Nature Reviews Urology}, volume = {15}, journal = {Nature Reviews Urology}, organization = {International Society of Paediatric Oncology-Renal Tumour Study Group (SIOP-RTSG)}, doi = {10.1038/s41585-018-0100-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233265}, pages = {693-701}, year = {2018}, abstract = {On the basis of the results of previous national and international trials and studies, the Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP-RTSG) has developed a new study protocol for paediatric renal tumours: the UMBRELLA SIOP-RTSG 2016 protocol (the UMBRELLA protocol). Currently, the overall outcomes of patients with Wilms tumour are excellent, but subgroups with poor prognosis and increased relapse rates still exist. The identification of these subgroups is of utmost importance to improve treatment stratification, which might lead to reduction of the direct and late effects of chemotherapy. The UMBRELLA protocol aims to validate new prognostic factors, such as blastemal tumour volume and molecular markers, to further improve outcome. To achieve this aim, large, international, high-quality databases are needed, which dictate optimization and international harmonization of specimen handling and comprehensive sampling of biological material, refine definitions and improve logistics for expert review. To promote broad implementation of the UMBRELLA protocol, the updated SIOP-RTSG pathology and molecular biology protocol for Wilms tumours has been outlined, which is a consensus from the SIOP-RTSG pathology panel.}, language = {en} } @article{TanEloPuskaetal.2018, author = {Tan, Z. B. and Elo, T. and Puska, A. and Sarkar, J. and L{\"a}hteenm{\"a}ki, P. and Duerr, F. and Gould, C. and Molenkamp, L. W. and Nagaev, K. E. and Hakonen, P. J.}, title = {Hanbury-Brown and Twiss exchange and non-equilibrium-induced correlations in disordered, four-terminal graphene-ribbon conductor}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-32777-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240348}, year = {2018}, abstract = {We have investigated current-current correlations in a cross-shaped conductor made of graphene. The mean free path of charge carriers is on the order of the ribbon width which leads to a hybrid conductor where there is diffusive transport in the device arms while the central connection region displays near ballistic transport. Our data on auto and cross correlations deviate from the predictions of Landauer-B{\"u}ttiker theory, and agreement can be obtained only by taking into account contributions from non-thermal electron distributions at the inlets to the semiballistic center, in which the partition noise becomes strongly modified. The experimental results display distinct Hanbury - Brown and Twiss (HBT) exchange correlations, the strength of which is boosted by the non-equilibrium occupation-number fluctuations internal to this hybrid conductor. Our work demonstrates that variation in electron coherence along atomically-thin, two-dimensional conductors has significant implications on their noise and cross correlation properties.}, language = {en} } @article{WoodcockGarrattPowneyetal.2019, author = {Woodcock, B. A. and Garratt, M. P. D. and Powney, G. D. and Shaw, R. F. and Osborne, J. L. and Soroka, J. and Lindstr{\"o}m, S. A. M. and Stanley, D. and Ouvrard, P. and Edwards, M. E. and Jauker, F. and McCracken, M. E. and Zou, Y. and Potts, S. G. and Rundl{\"o}f, M. and Noriega, J. A. and Greenop, A. and Smith, H. G. and Bommarco, R. and van der Werf, W. and Stout, J. C. and Steffan-Dewenter, I. and Morandin, L. and Bullock, J. M. and Pywell, R. F.}, title = {Meta-analysis reveals that pollinator functional diversity and abundance enhance crop pollination and yield}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-09393-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233787}, year = {2019}, abstract = {How insects promote crop pollination remains poorly understood in terms of the contribution of functional trait differences between species. We used meta-analyses to test for correlations between community abundance, species richness and functional trait metrics with oilseed rape yield, a globally important crop. While overall abundance is consistently important in predicting yield, functional divergence between species traits also showed a positive correlation. This result supports the complementarity hypothesis that pollination function is maintained by non-overlapping trait distributions. In artificially constructed communities (mesocosms), species richness is positively correlated with yield, although this effect is not seen under field conditions. As traits of the dominant species do not predict yield above that attributed to the effect of abundance alone, we find no evidence in support of the mass ratio hypothesis. Management practices increasing not just pollinator abundance, but also functional divergence, could benefit oilseed rape agriculture.}, language = {en} } @article{WentSudSpeedyetal.2018, author = {Went, Molly and Sud, Amit and Speedy, Helen and Sunter, Nicola J. and F{\"o}rsti, Asta and Law, Philip J. and Johnson, David C. and Mirabella, Fabio and Holroyd, Amy and Li, Ni and Orlando, Giulia and Weinhold, Niels and van Duin, Mark and Chen, Bowang and Mitchell, Jonathan S. and Mansouri, Larry and Juliusson, Gunnar and Smedby, Karin E and Jayne, Sandrine and Majid, Aneela and Dearden, Claire and Allsup, David J. and Bailey, James R. and Pratt, Guy and Pepper, Chris and Fegan, Chris and Rosenquist, Richard and Kuiper, Rowan and Stephens, Owen W. and Bertsch, Uta and Broderick, Peter and Einsele, Hermann and Gregory, Walter M. and Hillengass, Jens and Hoffmann, Per and Jackson, Graham H. and J{\"o}ckel, Karl-Heinz and Nickel, Jolanta and N{\"o}then, Markus M. and da Silva Filho, Miguel Inacio and Thomsen, Hauke and Walker, Brian A. and Broyl, Annemiek and Davies, Faith E. and Hansson, Markus and Goldschmidt, Hartmut and Dyer, Martin J. S. and Kaiser, Martin and Sonneveld, Pieter and Morgan, Gareth J. and Hemminki, Kari and Nilsson, Bj{\"o}rn and Catovsky, Daniel and Allan, James M. and Houlston, Richard S.}, title = {Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology}, series = {Blood Cancer Journal}, volume = {9}, journal = {Blood Cancer Journal}, doi = {10.1038/s41408-018-0162-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233627}, year = {2018}, abstract = {The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.}, language = {en} } @article{WenFeilWoltersetal.2018, author = {Wen, Lai and Feil, Susanne and Wolters, Markus and Thunemann, Martin and Regler, Frank and Schmidt, Kjestine and Friebe, Andreas and Olbrich, Marcus and Langer, Harald and Gawaz, Meinrad and de Wit, Cor and Feil, Robert}, title = {A shear-dependent NO-cGMP-cGKI cascade in platelets acts as an auto-regulatory brake of thrombosis}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-06638-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233616}, year = {2018}, abstract = {Mechanisms that limit thrombosis are poorly defined. One of the few known endogenous platelet inhibitors is nitric oxide (NO). NO activates NO sensitive guanylyl cyclase (NO-GC) in platelets, resulting in an increase of cyclic guanosine monophosphate (cGMP). Here we show, using cGMP sensor mice to study spatiotemporal dynamics of platelet cGMP, that NO-induced cGMP production in pre-activated platelets is strongly shear-dependent. We delineate a new mode of platelet-inhibitory mechanotransduction via shear-activated NO-GC followed by cGMP synthesis, activation of cGMP-dependent protein kinase I (cGKI), and suppression of Ca2+ signaling. Correlative profiling of cGMP dynamics and thrombus formation in vivo indicates that high cGMP concentrations in shear-exposed platelets at the thrombus periphery limit thrombosis, primarily through facilitation of thrombus dissolution. We propose that an increase in shear stress during thrombus growth activates the NO-cGMP-cGKI pathway, which acts as an auto-regulatory brake to prevent vessel occlusion, while preserving wound closure under low shear.}, language = {en} } @article{WelzEickhoffAbdullahetal.2018, author = {Welz, M. and Eickhoff, S. and Abdullah, Z. and Trebicka, J. and Gartlan, K. H. and Spicer, J. A. and Demetris, A. J. and Akhlaghi, H. and Anton, M. and Manske, K. and Zehn, D. and Nieswandt, B. and Kurts, C. and Trapani, J. A. and Knolle, P. and Wohlleber, D. and Kastenm{\"u}ller, W.}, title = {Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-07213-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233593}, year = {2018}, abstract = {CD8 T cells protect the liver against viral infection, but can also cause severe liver damage that may even lead to organ failure. Given the lack of mechanistic insights and specific treatment options in patients with acute fulminant hepatitis, we develop a mouse model reflecting a severe acute virus-induced CD8 T cell-mediated hepatitis. Here we show that antigen-specific CD8 T cells induce liver damage in a perforin-dependent manner, yet liver failure is not caused by effector responses targeting virus-infected hepatocytes alone. Additionally, CD8 T cell mediated elimination of cross-presenting liver sinusoidal endothelial cells causes endothelial damage that leads to a dramatically impaired sinusoidal perfusion and indirectly to hepatocyte death. With the identification of perforin-mediated killing as a critical pathophysiologic mechanism of liver failure and the protective function of a new class of perforin inhibitor, our study opens new potential therapeutic angles for fulminant viral hepatitis.}, language = {en} } @article{WalkerMavrommatisWardelletal.2019, author = {Walker, Brian A. and Mavrommatis, Konstantinos and Wardell, Christopher P. and Ashby, T. Cody and Bauer, Michael and Davies, Faith and Rosenthal, Adam and Wang, Hongwei and Qu, Pingping and Hoering, Antje and Samur, Mehmet and Towfic, Fadi and Ortiz, Maria and Flynt, Erin and Yu, Zhinuan and Yang, Zhihong and Rozelle, Dan and Obenauer, John and Trotter, Matthew and Auclair, Daniel and Keats, Jonathan and Bolli, Niccolo and Fulciniti, Mariateresa and Szalat, Raphael and Moreau, Phillipe and Durie, Brian and Stewart, A. Keith and Goldschmidt, Hartmut and Raab, Marc S. and Einsele, Hermann and Sonneveld, Pieter and San Miguel, Jesus and Lonial, Sagar and Jackson, Graham H. and Anderson, Kenneth C. and Avet-Loiseau, Herve and Munshi, Nikhil and Thakurta, Anjan and Morgan, Gareth}, title = {A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis}, series = {Leukemia}, volume = {33}, journal = {Leukemia}, doi = {10.1038/s41375-018-0196-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233299}, pages = {159-170}, year = {2019}, abstract = {Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R2 = 18.4\% and 25.2\%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R2 of 34.3\% for PFS and 46.5\% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1\% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches.}, language = {en} } @article{WegertVokuhlCollordetal.2018, author = {Wegert, Jenny and Vokuhl, Christian and Collord, Grace and Del Castillo Velasco-Herrera, Martin and Farndon, Sarah J. and Guzzo, Charlotte and Jorgensen, Mette and Anderson, John and Slater, Olga and Duncan, Catriona and Bausenwein, Sabrina and Streitenberger, Heike and Ziegler, Barbara and Furtw{\"a}ngler, Rhoikos and Graf, Norbert and Stratton, Michael R. and Campbell, Peter J. and Jones, David TW and Koelsche, Christian and Pfister, Stefan M. and Mifsud, William and Sebire, Neil and Sparber-Sauer, Monika and Koscielniak, Ewa and Rosenwald, Andreas and Gessler, Manfred and Behjati, Sam}, title = {Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-04650-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233446}, year = {2018}, abstract = {Soft tissue tumors of infancy encompass an overlapping spectrum of diseases that pose unique diagnostic and clinical challenges. We studied genomes and transcriptomes of cryptogenic congenital mesoblastic nephroma (CMN), and extended our findings to five anatomically or histologically related soft tissue tumors: infantile fibrosarcoma (IFS), nephroblastomatosis, Wilms tumor, malignant rhabdoid tumor, and clear cell sarcoma of the kidney. A key finding is recurrent mutation of EGFR in CMN by internal tandem duplication of the kinase domain, thus delineating CMN from other childhood renal tumors. Furthermore, we identify BRAF intragenic rearrangements in CMN and IFS. Collectively these findings reveal novel diagnostic markers and therapeutic strategies and highlight a prominent role of isolated intragenic rearrangements as drivers of infant tumors.}, language = {en} } @article{WaldherrLundtKlaasetal.2018, author = {Waldherr, Max and Lundt, Nils and Klaas, Martin and Betzold, Simon and Wurdack, Matthias and Baumann, Vasilij and Estrecho, Eliezer and Nalitov, Anton and Cherotchenko, Evgenia and Cai, Hui and Ostrovskaya, Elena A. and Kavokin, Alexey V. and Tongay, Sefaattin and Klembt, Sebastian and H{\"o}fling, Sven and Schneider, Christian}, title = {Observation of bosonic condensation in a hybrid monolayer MoSe2-GaAs microcavity}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-05532-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233280}, year = {2018}, abstract = {Bosonic condensation belongs to the most intriguing phenomena in physics, and was mostly reserved for experiments with ultra-cold quantum gases. More recently, it became accessible in exciton-based solid-state systems at elevated temperatures. Here, we demonstrate bosonic condensation driven by excitons hosted in an atomically thin layer of MoSe2, strongly coupled to light in a solid-state resonator. The structure is operated in the regime of collective strong coupling between a Tamm-plasmon resonance, GaAs quantum well excitons, and two-dimensional excitons confined in the monolayer crystal. Polariton condensation in a monolayer crystal manifests by a superlinear increase of emission intensity from the hybrid polariton mode, its density-dependent blueshift, and a dramatic collapse of the emission linewidth, a hallmark of temporal coherence. Importantly, we observe a significant spin-polarization in the injected polariton condensate, a fingerprint for spin-valley locking in monolayer excitons. Our results pave the way towards highly nonlinear, coherent valleytronic devices and light sources.}, language = {en} } @article{AnnunziatavandeVlekkertWolfetal.2019, author = {Annunziata, Ida and van de Vlekkert, Diantha and Wolf, Elmar and Finkelstein, David and Neale, Geoffrey and Machado, Eda and Mosca, Rosario and Campos, Yvan and Tillman, Heather and Roussel, Martine F. and Weesner, Jason Andrew and Fremuth, Leigh Ellen and Qiu, Xiaohui and Han, Min-Joon and Grosveld, Gerard C. and d'Azzo, Alessandra}, title = {MYC competes with MiT/TFE in regulating lysosomal biogenesis and autophagy through an epigenetic rheostat}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-11568-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221189}, year = {2019}, abstract = {Coordinated regulation of the lysosomal and autophagic systems ensures basal catabolism and normal cell physiology, and failure of either system causes disease. Here we describe an epigenetic rheostat orchestrated by c-MYC and histone deacetylases that inhibits lysosomal and autophagic biogenesis by concomitantly repressing the expression of the transcription factors MiT/TFE and FOXH1, and that of lysosomal and autophagy genes. Inhibition of histone deacetylases abates c-MYC binding to the promoters of lysosomal and autophagy genes, granting promoter occupancy to the MiT/TFE members, TFEB and TFE3, and/or the autophagy regulator FOXH1. In pluripotent stem cells and cancer, suppression of lysosomal and autophagic function is directly downstream of c-MYC overexpression and may represent a hallmark of malignant transformation. We propose that, by determining the fate of these catabolic systems, this hierarchical switch regulates the adaptive response of cells to pathological and physiological cues that could be exploited therapeutically.}, language = {en} } @article{AnanyKreckelFuellsacketal.2018, author = {Anany, Mohamed A. and Kreckel, Jennifer and F{\"u}llsack, Simone and Rosenthal, Alevtina and Otto, Christoph and Siegmund, Daniela and Wajant, Harald}, title = {Soluble TNF-like weak inducer of apoptosis (TWEAK) enhances poly(I:C)-induced RIPK1-mediated necroptosis}, series = {Cell Death \& Disease}, volume = {9}, journal = {Cell Death \& Disease}, doi = {10.1038/s41419-018-1137-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221104}, year = {2018}, abstract = {TNF-like weak inducer of apoptosis (TWEAK) and inhibition of protein synthesis with cycloheximide (CHX) sensitize for poly(I:C)-induced cell death. Notably, although CHX preferentially enhanced poly(I:C)-induced apoptosis, TWEAK enhanced primarily poly(I:C)-induced necroptosis. Both sensitizers of poly(I:C)-induced cell death, however, showed no major effect on proinflammatory poly(I:C) signaling. Analysis of a panel of HeLa-RIPK3 variants lacking TRADD, RIPK1, FADD, or caspase-8 expression revealed furthermore similarities and differences in the way how poly(I:C)/TWEAK, TNF, and TRAIL utilize these molecules for signaling. RIPK1 turned out to be essential for poly(I:C)/TWEAK-induced caspase-8-mediated apoptosis but was dispensable for this response in TNF and TRAIL signaling. TRADD-RIPK1-double deficiency differentially affected poly(I:C)-triggered gene induction but abrogated gene induction by TNF completely. FADD deficiency abrogated TRAIL- but not TNF- and poly(I:C)-induced necroptosis, whereas TRADD elicited protective activity against all three death inducers. A general protective activity against poly(I:C)-, TRAIL-, and TNF-induced cell death was also observed in FLIPL and FLIPS transfectrants.}, language = {en} } @phdthesis{Adhikari2024, author = {Adhikari, Bikash}, title = {Targeted degradation of Myc-interacting oncoproteins}, doi = {10.25972/OPUS-31732}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-317326}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The hallmark oncoprotein Myc is a major driver of tumorigenesis in various human cancer entities. However, Myc's structural features make it challenging to develop small molecules against it. A promising strategy to indirectly inhibit the function of Myc is by targeting its interactors. Many Myc-interacting proteins have reported scaffolding functions which are difficult to target using conventional occupancy- driven inhibitors. Thus, in this thesis, the proteolysis targeting chimera (PROTAC) approach was used to target two oncoproteins interacting with Myc which promote the oncogenicity of Myc, Aurora-A and WDR5. PROTACs are bifunctional small molecules that bind to the target protein with one ligand and recruit a cellular E3- ligase with the other ligand to induce target degradation via the ubiquitin- proteasome system. So far, the most widely used E3-ligases for PROTAC development are Cereblon (CRBN) and von Hippel-Lindau tumor suppressor (VHL). Furthermore, there are cases of incompatibility between some E3-ligases and proteins to bring about degradation. Hence there is a need to explore new E3- ligases and a demand for a tool to predict degradative E3-ligases for the target protein in the PROTAC field. In the first part, a highly specific mitotic kinase Aurora-A degrader, JB170, was developed. This compound utilized Aurora-A inhibitor alisertib as the target ligand and thalidomide as the E3-ligase CRBN harness. The specificity of JB170 and the ternary complex formation was supported by the interactions between Aurora-A and CRBN. The PROTAC-mediated degradation of Aurora-A induced a distinct S- phase defect rather than mitotic arrest, shown by its catalytic inhibition. The finding demonstrates that Aurora-A has a non-catalytic role in the S-phase. Furthermore, the degradation of Aurora-A led to apoptosis in various cancer cell lines. In the second part, two different series of WDR5 PROTACs based on two protein- protein inhibitors of WDR5 were evaluated. The most efficient degraders from both series recruited VHL as a E3-ligase and showed partial degradation of WDR5. In addition, the degradation efficiency of the PROTACs was significantly affected by the linker nature and length, highlighting the importance of linker length and composition in PROTAC design. The degraders showed modest proliferation defects at best in cancer cell lines. However, overexpression of VHL increased the degradation efficiency and the antiproliferative effect of the PROTACs. In the last part, a rapamycin-based assay was developed to predict the degradative E3-ligase for a target. The assay was validated using the WDR5/VHL and Aurora- A/CRBN pairs. The result that WDR5 is degraded by VHL but not CRBN and Aurora-A is degraded by CRBN, matches observations made with PROTACs. This technique will be used in the future to find effective tissue-specific and essential E3-ligases for targeted degradation of oncoproteins using PROTACs. Collectively, the work presented here provides a strategy to improve PROTAC development and a starting point for developing Aurora-A and WDR5 PROTACs for cancer therapy.}, subject = {Degradation}, language = {en} } @phdthesis{Bakirci2024, author = {Bakirci, Ezgi}, title = {Development of \(In\) \(vitro\) Models for Tissue Engineering Applications Using a High-Resolution 3D Printing Technology}, doi = {10.25972/OPUS-25164}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-251645}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In vitro models mimic the tissue-specific anatomy and play essential roles in personalized medicine and disease treatments. As a sophisticated manufacturing technology, 3D printing overcomes the limitations of traditional technologies and provides an excellent potential for developing in vitro models to mimic native tissue. This thesis aims to investigate the potential of a high-resolution 3D printing technology, melt electrowriting (MEW), for fabricating in vitro models. MEW has a distinct capacity for depositing micron size fibers with a defined design. In this thesis, three approaches were used, including 1) extending the MEW polymer library for different biomedical applications, 2) developing in vitro models for evaluation of cell growth and migration toward the different matrices, and 3) studying the effect of scaffold designs and biochemical cues of microenvironments on cells. First, we introduce the MEW processability of (AB)n and (ABAC)n segmented copolymers, which have thermally reversible network formulation based on physical crosslinks. Bisurea segments are combined with hydrophobic poly(dimethylsiloxane) (PDMS) or hydrophilic poly(propylene oxide)-poly(ethylene oxide)-poly(propylene oxide) (PPO-PEG-PPO) segments to form the (AB)n segmented copolymers. (ABAC)n segmented copolymers contain all three segments: in addition to bisurea, both hydrophobic and hydrophilic segments are available in the same polymer chain, resulting in tunable mechanical and biological behaviors. MEW copolymers either support cells attachment or dissolve without cytotoxic side effects when in contact with the polymers at lower concentrations, indicating that this copolymer class has potential in biological applications. The unique biological and surface properties, transparency, adjustable hydrophilicity of these copolymers could be beneficial in several in vitro models. The second manuscript addresses the design and development of a melt electrowritten competitive 3D radial migration device. The approach differs from most of the previous literature, as MEW is not used here to produce cell invasive scaffolds but to fabricate an in vitro device. The device is utilized to systematically determine the matrix which promotes cell migration and growth of glioblastoma cells. The glioblastoma cell migration is tested on four different Matrigel concentrations using a melt electrowritten radial device. The glioblastoma U87 cell growth and migration increase at Matrigel concentrations 6 and 8 mg mL-1 In the development of this radial device, the accuracy, and precision of melt electrowritten circular shapes were investigated. The results show that the printing speed and design diameter are essential parameters for the accuracy of printed constructs. It is the first instance where MEW is used for the production of in vitro devices. The influence of biochemical cues and scaffold designs on astrocytes and glioblastoma is investigated in the last manuscript. A fiber comprising the box and triangle-shaped pores within MEW scaffolds are modified with biochemical cues, including RGD and IKVAV peptides using a reactive NCO-sP(EO-stat-PO) macromer. The results show that astrocytes and glioblastoma cells exhibit different phenotypes on scaffold designs and peptide-coated scaffolds.}, subject = {3D-Druck}, language = {en} } @article{VuralDopplerMeinl2018, author = {Vural, Atay and Doppler, Kathrin and Meinl, Edgar}, title = {Autoantibodies Against the Node of Ranvier in Seropositive Chronic Inflammatory Demyelinating Polyneuropathy: Diagnostic, Pathogenic, and Therapeutic Relevance}, series = {Frontiers in Immunology}, volume = {9}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2018.01029}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233279}, year = {2018}, abstract = {Discovery of disease-associated autoantibodies has transformed the clinical management of a variety of neurological disorders. Detection of autoantibodies aids diagnosis and allows patient stratification resulting in treatment optimization. In the last years, a set of autoantibodies against proteins located at the node of Ranvier has been identified in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). These antibodies target neurofascin, contactin1, or contactin-associated protein 1, and we propose to name CIDP patients with these antibodies collectively as seropositive. They have unique clinical characteristics that differ from seronegative CIDP. Moreover, there is compelling evidence that autoantibodies are relevant for the pathogenesis. In this article, we review the current knowledge on the characteristics of autoantibodies against the node of Ranvier proteins and their clinical relevance in CIDP. We start with a description of the structure of the node of Ranvier followed by a summary of assays used to identify seropositive patients; and then, we describe clinical features and characteristics linked to seropositivity. We review knowledge on the role of these autoantibodies for the pathogenesis with relevance for the emerging concept of nodopathy/paranodopathy and summarize the treatment implications.}, language = {en} } @article{TooKellerSickeletal.2018, author = {Too, Chin Chin and Keller, Alexander and Sickel, Wiebke and Lee, Sui Mae and Yule, Catherine M.}, title = {Microbial Community Structure in a Malaysian Tropical Peat Swamp Forest: The Influence of Tree Species and Depth}, series = {Frontiers in Microbiology}, volume = {9}, journal = {Frontiers in Microbiology}, doi = {10.3389/fmicb.2018.02859}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229000}, year = {2018}, abstract = {Tropical peat swamp forests sequester globally significant stores of carbon in deep layers of waterlogged, anoxic, acidic and nutrient-depleted peat. The roles of microbes in supporting these forests through the formation of peat, carbon sequestration and nutrient cycling are virtually unknown. This study investigated physicochemical peat properties and microbial diversity between three dominant tree species: Shorea uliginosa (Dipterocarpaceae), Koompassia malaccensis (legumes associated with nitrogen-fixing bacteria), Eleiodoxa conferta (palm) and depths (surface, 45 and 90 cm) using microbial 16S rRNA gene amplicon sequencing. Water pH, oxygen, nitrogen, phosphorus, total phenolic contents and C/N ratio differed significantly between depths, but not tree species. Depth also strongly influenced microbial diversity and composition, while both depth and tree species exhibited significant impact on the archaeal communities. Microbial diversity was highest at the surface, where fresh leaf litter accumulates, and nutrient supply is guaranteed. Nitrogen was the core parameter correlating to microbial communities, but the interactive effects from various environmental variables displayed significant correlation to relative abundance of major microbial groups. Proteobacteria was the dominant phylum and the most abundant genus, Rhodoplanes, might be involved in nitrogen fixation. The most abundant methanogens and methanotrophs affiliated, respectively, to families Methanomassiliicoccaceae and Methylocystaceae. Our results demonstrated diverse microbial communities and provide valuable insights on microbial ecology in these extreme ecosystems.}, language = {en} } @article{SiebertCiatoMurakamietal.2019, author = {Siebert, Claudia and Ciato, Denis and Murakami, Masanori and Frei-Stuber, Ludwig and Perez-Rivas, Luis Gustavo and Monteserin-Garcia, Jos{\´e} Luis and N{\"o}lting, Svenja and Maurer, Julian and Feuchtinger, Annette and Walch, Axel K. and Haak, Harm R. and Bertherat, J{\´e}r{\^o}me and Mannelli, Massimo and Fassnacht, Martin and Korpershoek, Esther and Reincke, Martin and Stalla, G{\"u}nter K. and Hantel, Constanze and Beuschlein, Felix}, title = {Heat Shock Protein 90 as a Prognostic Marker and Therapeutic Target for Adrenocortical Carcinoma}, series = {Frontiers in Endocrinology}, volume = {10}, journal = {Frontiers in Endocrinology}, doi = {10.3389/fendo.2019.00487}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-238029}, year = {2019}, abstract = {Background: Adrenocortical carcinoma (ACC) is a rare tumor entity with restricted therapeutic opportunities. HSP90 (Heat Shock Protein 90) chaperone activity is fundamental for cell survival and contributes to different oncogenic signaling pathways. Indeed, agents targeting HSP90 function have shown therapeutic efficacy in several cancer types. We have examined the expression of HSP90 in different adrenal tumors and evaluated the use of HSP90 inhibitors in vitro as possible therapy for ACC. Methods: Immunohistochemical expression of HSP90 isoforms was investigated in different adrenocortical tumors and associated with clinical features. Additionally, a panel of N-terminal (17-allylamino-17-demethoxygeldanamycin (17-AAG), luminespib, and ganetespib) and C-terminal (novobiocin and silibinin) HSP90 inhibitors were tested on various ACC cell lines. Results: Within adrenocortical tumors, ACC samples exhibited the highest expression of HSP90β. Within a cohort of ACC patients, HSP90β expression levels were inversely correlated with recurrence-free and overall survival. In functional assays, among five different compounds tested luminespib and ganetespib induced a significant decrease in cell viability in single as well as in combined treatments with compounds of the clinically used EDP-M scheme (etoposide, doxorubicin, cisplatin, mitotane). Inhibition of cell viability correlated furthermore with a decrease in proliferation, in cell migration and an increase in apoptosis. Moreover, analysis of cancer pathways indicated a modulation of the ERK1/2—and AKT—pathways by luminespib and ganetespib treatment. Conclusions: Our findings emphasize HSP90 as a marker with prognostic impact and promising target with N-terminal HSP90 inhibitors as drugs with potential therapeutic efficacy toward ACC.}, language = {en} } @article{NguyenSaisingTribellietal.2019, author = {Nguyen, Minh-Thu and Saising, Jongkon and Tribelli, Paula Maria and Nega, Mulugeta and Diene, Seydina M. and Fran{\c{c}}ois, Patrice and Schrenzel, Jacques and Spr{\"o}er, Cathrin and Bunk, Boyke and Ebner, Patrick and Hertlein, Tobias and Kumari, Nimerta and H{\"a}rtner, Thomas and Wistuba, Dorothee and Voravuthikunchai, Supayang P. and M{\"a}der, Ulrike and Ohlsen, Knut and G{\"o}tz, Friedrich}, title = {Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureus}, series = {Frontiers in Microbiology}, volume = {10}, journal = {Frontiers in Microbiology}, doi = {10.3389/fmicb.2019.01157}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224117}, year = {2019}, abstract = {Rhodomyrtone (Rom) is an acylphloroglucinol antibiotic originally isolated from leaves of Rhodomyrtus tomentosa. Rom targets the bacterial membrane and is active against a wide range of Gram-positive bacteria but the exact mode of action remains obscure. Here we isolated and characterized a spontaneous Rom-resistant mutant from the model strain Staphylococcus aureus HG001 (RomR) to learn more about the resistance mechanism. We showed that Rom-resistance is based on a single point mutation in the coding region of farR [regulator of fatty acid (FA) resistance] that causes an amino acid change from Cys to Arg at position 116 in FarR, that affects FarR activity. Comparative transcriptome analysis revealed that mutated farR affects transcription of many genes in distinct pathways. FarR represses for example the expression of its own gene (farR), its flanking gene farE (effector of FA resistance), and other global regulators such as agr and sarA. All these genes were consequently upregulated in the RomR clone. Particularly the upregulation of agr and sarA leads to increased expression of virulence genes rendering the RomR clone more cytotoxic and more pathogenic in a mouse infection model. The Rom-resistance is largely due to the de-repression of farE. FarE is described as an efflux pump for linoleic and arachidonic acids. We observed an increased release of lipids in the RomR clone compared to its parental strain HG001. If farE is deleted in the RomR clone, or, if native farR is expressed in the RomR strain, the corresponding strains become hypersensitive to Rom. Overall, we show here that the high Rom-resistance is mediated by overexpression of farE in the RomR clone, that FarR is an important regulator, and that the point mutation in farR (RomR clone) makes the clone hyper-virulent.}, language = {en} } @article{JohnAbrantesPrustyetal.2019, author = {John, Cathy N. and Abrantes, Pedro M. D. S. and Prusty, Bhupesh K. and Ablashi, Dharam V. and Africa, Charlene W. J.}, title = {K21 Compound, a Potent Antifungal Agent: Implications for the Treatment of Fluconazole-Resistant HIV-Associated Candida Species}, series = {Frontiers in Microbiology}, volume = {10}, journal = {Frontiers in Microbiology}, doi = {10.3389/fmicb.2019.01021}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323505}, year = {2019}, abstract = {Background/Objectives: With mucocutaneous candidiasis being highly prevalent in HIV patients, the emergence of fluconazole-resistant Candida species forms a major challenge in treating and eradicating these infections. The objective of this study was to establish the antifungal activity of K21, a membrane-rupturing antimicrobial compound derived from a silica quaternary ammonium compound (SiQAC) with tetraethoxysilane (TEOS). Methods: The study sample included 81 Candida species of which 9 were type strains and 72 were clinical isolates. Minimum inhibitory concentrations, synergy, fractional inhibitory concentration index (FICI), and time kill assays were determined by broth microdilution. Electron microscopy (EM) was used to determine the qualitative changes brought about after treatment with K21. Results: K21 inhibited the growth of all fluconazole-resistant and susceptible Candida strains with only 2 h of exposure required to effectively kill 99.9\% of the inoculum, and a definite synergistic effect was observed with a combination of K21 and fluconazole. EM demonstrated the presence of two forms of extracellular vesicles indicative of biofilm formation and cell lysis. Conclusion: The study established the efficacy of K21 as an antifungal agent and with fluconazole-resistant candidiasis on the increase, the development of K21 can provide a promising alternative to combat acquired drug resistance.}, language = {en} } @article{OPUS4-31268, title = {Search for new phenomena in events with same-charge leptons and b-jets in pp collisions at √\(s\) = 13 TeV with the ATLAS detector}, series = {Journal of High Energy Physics}, volume = {12}, journal = {Journal of High Energy Physics}, number = {39}, organization = {The ATLAS Collaboration}, doi = {10.1007/JHEP12(2018)039}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312681}, pages = {1-55}, year = {2018}, abstract = {A search for new phenomena in events with two same- charge leptons or three leptons and jets identi fi ed as originating from b - quarks in a data sample of 36.1 fb of pp collisions at ps = 13TeV recorded by the ATLAS detector at the Large Hadron Collider is reported. No signi fi cant excess is found and limits are set on vector- like quark, fourtop- quark, and same- sign top- quark pair production. The observed ( expected) 95\% CL mass limits for a vector- like T - and B - quark singlet are mT > 0 : 98 ( 0 : 99) TeV and mB > 1 : 00 ( 1 : 01) TeV respectively. Limits on the production of the vector- like T5=3 - quark are also derived considering both pair and single production; in the former case the lower limit on the mass of the T5=3 - quark is ( expected to be) 1.19 ( 1.21) TeV. The Standard Model fourtop- quark production cross- section upper limit is ( expected to be) 69 ( 29) fb. Constraints are also set on exotic four- top- quark production models. Finally, limits are set on samesign top- quark pair production. The upper limit on uu ! tt production is ( expected to be) 89 ( 59) fb for a mediator mass of 1TeV, and a dark- matter interpretation is also derived, excluding a mediator of 3TeV with a dark- sector coupling of 1.0 and a coupling to ordinary matter above 0.31.}, language = {en} } @phdthesis{Kagerer2024, author = {Kagerer, Philipp Thomas}, title = {Two-Dimensional Ferromagnetism and Topology at the Surface of MnBi\(_2\)Te\(_4\) - Bi\(_2\)Te\(_3\) Heterostructures - MBE Growth, Magnetism and Electronic Properties}, doi = {10.25972/OPUS-36012}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360121}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In this thesis, a model system of a magnetic topological heterostructure is studied, namely a heterosystem consisting of a single ferromagnetic septuple-layer (SL) of \(MnBi_2Te_4\) on the surface of the three-dimensional topological insulator \(Bi_2Te_3\). Using MBE and developing a specialized experimental setup, the first part of this thesis deals with the growth of \(Bi_2Te_3\) and thin films of \(MnBi_2Te_4\) on \(BaF_2\)-substrates by the co-evaporation of its binary constituents. The structural analysis is conducted along several suitable probes such as X-ray diffraction (XRD, XRR), AFM and scanning tunnelling electron microscopy (STEM). It is furthermore found that the growth of a single septuple-layer of \(MnBi_2Te_4\) on the surface of \(Bi_2Te_3\) can be facilitated. By using X-ray absorption and circular magnetic dichroism (XAS, XMCD), the magnetic properties of \(MnBi_2Te_4\) are explored down to the monolayer limit. The layered nature of the vdW crystal and a strong uniaxial magnetocrystalline anisotropy establish stable out-of plane magnetic order at the surface of \(MnBi_2Te_4\), which is stable even down to the 2D limit. Pushing the material system to there, i.e. a single SL \(MnBi_2Te_4\) further allows to study the phase transition of this 2D ferromagnet and extract its critical behaviour with \(T_c \, = \, 14.89~k\) and \(\beta \, = \, 0.484\). Utilizing bulk crystals of the ferromagnetic \(Fe_3GeTe_2\) as substrate allows to influence, enhance and bias the magnetism in the single SL of \(MnBi_2Te_4\). By growing heterostructures of the type \(MnBi_2Te_4\) -- n layer \(Bi_2Te_3\) -- \(Fe_3GeTe_2\)for n between 0 and 2, it is shown, that a considerable magnetic coupling can be introduced between the \(MnBi_2Te_4\) top-layer and the substrate. Finally the interplay between topology and magnetism in the ferromagnetic extension is studied directly by angle-resolved photoemission spectroscopy. The heterostructure is found to host a linearly dispersing TSS at the centre of the Brillouin zone. Using low temperature and high-resolution ARPES a large magnetic gap opening of \(\sim\) 35 meV is found at the Dirac point of the TSS. By following its temperature evolution, it is apparent that the scaling behaviour coincides with the magnetic order parameter of the modified surface.}, subject = {Molekularstrahlepitaxie}, language = {en} } @phdthesis{Koerner2024, author = {K{\"o}rner, Jacob}, title = {Theoretical and numerical analysis of Fokker-Planck optimal control problems by first- and second-order optimality conditions}, doi = {10.25972/OPUS-36299}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362997}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In this thesis, a variety of Fokker--Planck (FP) optimal control problems are investigated. Main emphasis is put on a first-- and second--order analysis of different optimal control problems, characterizing optimal controls, establishing regularity results for optimal controls, and providing a numerical analysis for a Galerkin--based numerical scheme. The Fokker--Planck equation is a partial differential equation (PDE) of linear parabolic type deeply connected to the theory of stochastic processes and stochastic differential equations. In essence, it describes the evolution over time of the probability distribution of the state of an object or system of objects under the influence of both deterministic and stochastic forces. The FP equation is a cornerstone in understanding and modeling phenomena ranging from the diffusion and motion of molecules in a fluid to the fluctuations in financial markets. Two different types of optimal control problems are analyzed in this thesis. On the one hand, Fokker--Planck ensemble optimal control problems are considered that have a wide range of applications in controlling a system of multiple non--interacting objects. In this framework, the goal is to collectively drive each object into a desired state. On the other hand, tracking--type control problems are investigated, commonly used in parameter identification problems or stemming from the field of inverse problems. In this framework, the aim is to determine certain parameters or functions of the FP equation, such that the resulting probability distribution function takes a desired form, possibly observed by measurements. In both cases, we consider FP models where the control functions are part of the drift, arising only from the deterministic forces of the system. Therefore, the FP optimal control problem has a bilinear control structure. Box constraints on the controls may be present, and the focus is on time--space dependent controls for ensemble--type problems and on only time--dependent controls for tracking--type optimal control problems. In the first chapter of the thesis, a proof of the connection between the FP equation and stochastic differential equations is provided. Additionally, stochastic optimal control problems, aiming to minimize an expected cost value, are introduced, and the corresponding formulation within a deterministic FP control framework is established. For the analysis of this PDE--constrained optimal control problem, the existence, and regularity of solutions to the FP problem are investigated. New \$L^\infty\$--estimates for solutions are established for low space dimensions under mild assumptions on the drift. Furthermore, based on the theory of Bessel potential spaces, new smoothness properties are derived for solutions to the FP problem in the case of only time--dependent controls. Due to these properties, the control--to--state map, which associates the control functions with the corresponding solution of the FP problem, is well--defined, Fr{\´e}chet differentiable and compact for suitable Lebesgue spaces or Sobolev spaces. The existence of optimal controls is proven under various assumptions on the space of admissible controls and objective functionals. First--order optimality conditions are derived using the adjoint system. The resulting characterization of optimal controls is exploited to achieve higher regularity of optimal controls, as well as their state and co--state functions. Since the FP optimal control problem is non--convex due to its bilinear structure, a first--order analysis should be complemented by a second--order analysis. Therefore, a second--order analysis for the ensemble--type control problem in the case of \$H^1\$--controls in time and space is performed, and sufficient second--order conditions are provided. Analogous results are obtained for the tracking--type problem for only time--dependent controls. The developed theory on the control problem and the first-- and second--order optimality conditions is applied to perform a numerical analysis for a Galerkin discretization of the FP optimal control problem. The main focus is on tracking-type problems with only time--dependent controls. The idea of the presented Galerkin scheme is to first approximate the PDE--constrained optimization problem by a system of ODE--constrained optimization problems. Then, conditions on the problem are presented such that the convergence of optimal controls from one problem to the other can be guaranteed. For this purpose, a class of bilinear ODE--constrained optimal control problems arising from the Galerkin discretization of the FP problem is analyzed. First-- and second--order optimality conditions are established, and a numerical analysis is performed. A discretization with linear finite elements for the state and co--state problem is investigated, while the control functions are approximated by piecewise constant or piecewise quadratic continuous polynomials. The latter choice is motivated by the bilinear structure of the optimal control problem, allowing to overcome the discrepancies between a discretize--then--optimize and optimize--then--discretize approach. Moreover, second--order accuracy results are shown using the space of continuous, piecewise quadratic polynomials as the discrete space of controls. Lastly, the theoretical results and the second--order convergence rates are numerically verified.}, subject = {Parabolische Differentialgleichung}, language = {en} } @phdthesis{deGraafgebButtler2024, author = {de Graaf [geb. Buttler], Simone Linda}, title = {From Small to Large Data: Leveraging Synthetic Data for Inventory Management}, doi = {10.25972/OPUS-36136}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-361364}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In a world of constant change, uncertainty has become a daily challenge for businesses. Rapidly shifting market conditions highlight the need for flexible responses to unforeseen events. Operations Management (OM) is crucial for optimizing business processes, including site planning, production control, and inventory management. Traditionally, companies have relied on theoretical models from microeconomics, game theory, optimization, and simulation. However, advancements in machine learning and mathematical optimization have led to a new research field: data-driven OM. Data-driven OM uses real data, especially time series data, to create more realistic models that better capture decision-making complexities. Despite the promise of this new research area, a significant challenge remains: the availability of extensive historical training data. Synthetic data, which mimics real data, has been used to address this issue in other machine learning applications. Therefore, this dissertation explores how synthetic data can be leveraged to improve decisions for data-driven inventory management, focusing on the single-period newsvendor problem, a classic stochastic optimization problem in inventory management. The first article, "A Meta Analysis of Data-Driven Newsvendor Approaches", presents a standardized evaluation framework for data-driven prescriptive approaches, tested through a numerical study. Findings suggest model performance is not robust, emphasizing the need for a standardized evaluation process. The second article, "Application of Generative Adversarial Networks in Inventory Management", examines using synthetic data generated by Generative Adversarial Networks (GANs) for the newsvendor problem. This study shows GANs can model complex demand relationships, offering a promising alternative to traditional methods. The third article, "Combining Synthetic Data and Transfer Learning for Deep Reinforcement Learning in Inventory Management", proposes a method using Deep Reinforcement Learning (DRL) with synthetic and real data through transfer learning. This approach trains a generative model to learn demand distributions, generates synthetic data, and fine-tunes a DRL agent on a smaller real dataset. This method outperforms traditional approaches in controlled and practical settings, though further research is needed to generalize these findings.}, subject = {Bestandsmanagement}, language = {en} } @article{GilSepulcreLindnerSchindleretal.2021, author = {Gil-Sepulcre, Marcos and Lindner, Joachim O. and Schindler, Dorothee and Velasco, Luc{\´i}a and Moonshiram, Dooshaye and R{\"u}diger, Olaf and DeBeer, Serena and Stepanenko, Vladimir and Solano, Eduardo and W{\"u}rthner, Frank and Llobet, Antoni}, title = {Surface-promoted evolution of Ru-bda coordination oligomers boosts the efficiency of water oxidation molecular anodes}, series = {Journal of the American Chemical Society}, volume = {143}, journal = {Journal of the American Chemical Society}, number = {30}, doi = {10.1021/jacs.1c04738}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-351514}, pages = {11651-11661}, year = {2021}, abstract = {A new Ru oligomer of formula {[Ru-\(^{II}\)(bda-\(\kappa\)-N\(^2\)O\(^2\))(4,4'-bpy)]\(_{10}\)(4,4'-bpy)}, 10 (bda is [2,2'-bipyridine]-6,6'-dicarbox-ylate and 4,4'-bpy is 4,4'-bipyridine), was synthesized and thoroughly characterized with spectroscopic, X-ray, and electrochemical techniques. This oligomer exhibits strong affinity for graphitic materials through CH-\(\pi\) interactions and thus easily anchors on multiwalled carbon nanotubes (CNT), generating the molecular hybrid material 10@CNT. The latter acts as a water oxidation catalyst and converts to a new species, 10'(H\(_2\)O)\(_2\)@CNT, during the electrochemical oxygen evolution process involving solvation and ligand reorganization facilitated by the interactions of molecular Ru catalyst and the surface. This heterogeneous system has been shown to be a powerful and robust molecular hybrid anode for electrocatalytic water oxidation into molecular oxygen, achieving current densities in the range of 200 mA/cm\(^2\) at pH 7 under an applied potential of 1.45 V vs NHE. The remarkable long-term stability of this hybrid material during turnover is rationalized based on the supramolecular interaction of the catalyst with the graphitic surface.}, language = {en} } @article{GronwaldHoosHottenrott2019, author = {Gronwald, Thomas and Hoos, Olaf and Hottenrott, Kuno}, title = {Effects of Acute Normobaric Hypoxia on Non-linear Dynamics of Cardiac Autonomic Activity During Constant Workload Cycling Exercise}, series = {Frontiers in Physiology}, volume = {10}, journal = {Frontiers in Physiology}, doi = {10.3389/fphys.2019.00999}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369199}, year = {2019}, abstract = {Aim: Measurements of Non-linear dynamics of heart rate variability (HRV) provide new possibilities to monitor cardiac autonomic activity during exercise under different environmental conditions. Using detrended fluctuation analysis (DFA) technique to assess correlation properties of heart rate (HR) dynamics, the present study examines the influence of normobaric hypoxic conditions (HC) in comparison to normoxic conditions (NC) during a constant workload exercise. Materials and Methods: Nine well trained cyclists performed a continuous workload exercise on a cycle ergometer with an intensity corresponding to the individual anaerobic threshold until voluntary exhaustion under both NC and HC (15\% O2). The individual exercise duration was normalized to 10\% sections (10-100\%). During exercise HR and RR-intervals were continuously-recorded. Besides HRV time-domain measurements (meanRR, SDNN), fractal correlation properties using short-term scaling exponent alpha1 of DFA were calculated. Additionally, blood lactate (La), oxygen saturation of the blood (SpO2), and rating of perceived exertion (RPE) were recorded in regular time intervals. Results: We observed significant changes under NC and HC for all parameters from the beginning to the end of the exercise (10\% vs. 100\%) except for SpO2 and SDNN during NC: increases for HR, La, and RPE in both conditions; decreases for SpO2 and SDNN during HC, meanRR and DFA-alpha1 during both conditions. Under HC HR (40-70\%), La (10-90\%), and RPE (50-90\%) were significantly-higher, SpO2 (10-100\%), meanRR (40-70\%), and DFA-alpha1 (20-60\%) were significantly-lower than under NC. Conclusion: Under both conditions, prolonged exercise until voluntary exhaustion provokes a lower total variability combined with a reduction in the amplitude and correlation properties of RR fluctuations which may be attributed to increased organismic demands. Additionally, HC provoked higher demands and loss of correlation properties at an earlier stage during the exercise regime, implying an accelerated alteration of cardiac autonomic regulation.}, language = {en} } @article{FahmyGarciaFarrellWitteBoumaetal.2019, author = {Fahmy-Garcia, Shorouk and Farrell, Eric and Witte-Bouma, Janneke and Robbesom-van den Berge, Iris and Suarez, Melva and Mumcuoglu, Didem and Walles, Heike and Kluijtmans, Sebastiaan G. J. M. and van der Eerden, Bram C. J. and van Osch, Gerjo J. V. M. and van Leeuwen, Johannes P. T. M. and van Driel, Marjolein}, title = {Follistatin Effects in Migration, Vascularization, and Osteogenesis in vitro and Bone Repair in vivo}, series = {Frontiers in Bioengineering and Biotechnology}, volume = {7}, journal = {Frontiers in Bioengineering and Biotechnology}, doi = {10.3389/fbioe.2019.00038}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227617}, year = {2019}, abstract = {The use of biomaterials and signaling molecules to induce bone formation is a promising approach in the field of bone tissue engineering. Follistatin (FST) is a glycoprotein able to bind irreversibly to activin A, a protein that has been reported to inhibit bone formation. We investigated the effect of FST in critical processes for bone repair, such as cell recruitment, osteogenesis and vascularization, and ultimately its use for bone tissue engineering. In vitro, FST promoted mesenchymal stem cell (MSC) and endothelial cell (EC) migration as well as essential steps in the formation and expansion of the vasculature such as EC tube-formation and sprouting. FST did not enhance osteogenic differentiation of MSCs, but increased committed osteoblast mineralization. In vivo, FST was loaded in an in situ gelling formulation made by alginate and recombinant collagen-based peptide microspheres and implanted in a rat calvarial defect model. Two FST variants (FST288 and FST315) with major differences in their affinity to cell-surface proteoglycans, which may influence their effect upon in vivo bone repair, were tested. In vitro, most of the loaded FST315 was released over 4 weeks, contrary to FST288, which was mostly retained in the biomaterial. However, none of the FST variants improved in vivo bone healing compared to control. These results demonstrate that FST enhances crucial processes needed for bone repair. Further studies need to investigate the optimal FST carrier for bone regeneration.}, language = {en} } @article{GalKilenczAlbertetal.2019, author = {G{\´a}l, Bernadett I. and Kilencz, T{\"u}nde and Albert, Anita and Demeter, Ildik{\´o} and Hegedűs, Kl{\´a}ra M{\´a}ria and Janka, Zolt{\´a}n and Csifcs{\´a}k, G{\´a}bor and {\´A}lmos, P{\´e}ter Z.}, title = {Mild Effect of Nalmefene on Alcoholic Cue-Induced Response Invigoration in Alcohol Use Disorder Without Accompanying Changes in Electrophysiological Signatures of Early Visual Processing and Executive Control}, series = {Frontiers in Pharmacology}, volume = {10}, journal = {Frontiers in Pharmacology}, doi = {10.3389/fphar.2019.01087}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369182}, year = {2019}, abstract = {Nalmefene is approved for as-needed pharmacological treatment in alcohol use disorder (AUD) by the European Medicines Agency. While the cellular effects of nalmefene have been thoroughly investigated, data are very limited on how this agent influences neural signals associated with inhibitory control and the visual analysis of environmental cues. This double-blind crossover study assessed the behavioral and neural effects of acute nalmefene administration in patients diagnosed with AUD. In experiment 1, we validated our experimental paradigm (electroencephalography combined with a modified Go/NoGo task using images of alcoholic and nonalcoholic drinks as prime stimuli) in 20 healthy adults to ensure that our protocol is suitable for assessing the behavioral and neural aspects of executive control. In experiment 2, we recruited 19 patients with AUD, and in a double-blind crossover design, we investigated the effects of nalmefene versus placebo on task performance (response accuracy, the sensitivity index, and reaction times), visual responses to appetitive cues (occipital P1, N1, and P2 components), and electrophysiological markers of conflict detection and response inhibition (frontal N2 and P3 waveforms). Under placebo, patients produced faster reaction times to alcohol-primed Go stimuli, an effect that was weak despite being statistically significant. However, the effect of alcoholic cues on the speed of response initiation disappeared after receiving nalmefene. We found no placebo versus nalmefene difference regarding our patients' ability to accurately inhibit responses to NoGo stimuli or for occipital and frontal event-related potentials. Our results suggest that nalmefene might be potent in reducing the vigor to act upon alcoholic cues in AUD patients, but this effect is most probably mediated via subcortical (rather than cortical) neural circuits.}, language = {en} } @article{FrankeConzelmannGruenblattetal.2019, author = {Franke, Maximilian and Conzelmann, Annette and Gr{\"u}nblatt, Edna and Werling, Anna M. and Spieles, Helen and Wewetzer, Christoph and Warnke, Andreas and Romanos, Marcel and Walitza, Susanne and Renner, Tobias J.}, title = {No Association of Variants of the NPY-System With Obsessive-Compulsive Disorder in Children and Adolescents}, series = {Frontiers in Molecular Neuroscience}, volume = {12}, journal = {Frontiers in Molecular Neuroscience}, doi = {10.3389/fnmol.2019.00112}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229051}, year = {2019}, abstract = {Obsessive-compulsive disorder (OCD) causes severe distress and is therefore counted by the World Health Organisation (WHO) as one of the 10 most impairing illnesses. There is evidence for a strong genetic underpinning especially in early onset OCD (eoOCD). Though several genes involved in neurotransmission have been reported as candidates, there is still a need to identify new pathways. In this study, we focussed on genetic variants of the Neuropeptide Y (NPY) system. NPY is one of the most abundant neuropeptides in the human brain with emerging evidence of capacity to modulate stress response, which is of high relevance in OCD. We focussed on tag-SNPs of NPY and its receptor gene NPY1R in a family-based approach. The sample comprised 86 patients (children and adolescents) with eoOCD with both their biological parents. However, this first study on genetic variants of the NPY-system could not confirm the association between the investigated SNPs and eoOCD. Based on the small sample size results have to be interpreted as preliminary and should be replicated in larger samples. However, also in an additional GWAS analysis in a large sample, we could not observe an associations between NPY and OCD. Overall, these preliminary results point to a minor role of NPY on the stress response of OCD.}, language = {en} } @article{GeranUeckerPruessetal.2019, author = {Geran, Rohat and Uecker, Florian C. and Pr{\"u}ss, Harald and Haeusler, Karl Georg and Paul, Friedemann and Ruprecht, Klemens and Harms, Lutz and Schmidt, Felix A.}, title = {Olfactory and Gustatory Dysfunction in Patients With Autoimmune Encephalitis}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, doi = {10.3389/fneur.2019.00480}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232921}, year = {2019}, abstract = {Objective: To test the hypothesis that olfactory (OF) and gustatory function (GF) is disturbed in patients with autoimmune encephalitides (AE). Methods: The orthonasal OF was tested in 32 patients with AE and 32 age- and sex-matched healthy controls (HC) with the standardized Threshold Discrimination Identification (TDI) score. This validated olfactory testing method yields individual scores for olfactory threshold (T), odor discrimination (D), and identification (I), along with a composite TDI score. The GF was determined by the Taste Strip Test (TST). Results: Overall, 24/32 (75\%) of patients with AE, but none of 32 HC (p < 0.001) had olfactory dysfunction in TDI testing. The results of the threshold, discrimination and identification subtests were significantly reduced in patients with AE compared to HC (all p < 0.001). Assessed by TST, 5/19 (26.3\%) of patients with AE, but none of 19 HC presented a significant limitation in GF (p < 0.001). The TDI score was correlated with the subjective estimation of the olfactory capacity on a visual analog scale (VAS; rs = 0.475, p = 0.008). Neither age, sex, modified Rankin Scale nor disease duration were associated with the composite TDI score. Conclusions: This is the first study investigating OF and GF in AE patients. According to unblinded assessment, patients with AE have a reduced olfactory and gustatory capacity compared to HC, suggesting that olfactory and gustatory dysfunction are hitherto unrecognized symptoms in AE. Further studies with larger number of AE patients would be of interest to verify our results.}, language = {en} } @article{JarickMokhtariSchelleretal.2018, author = {Jarick, Katja J. and Mokhtari, Zeinab and Scheller, Lukas and Hartweg, Julia and Thusek, Sina and Le, Duc-Dung and Ranecky, Maria and Shaikh, Haroon and Qureischi, Musga and Heinze, Katrin G. and Beilhack, Andreas}, title = {Photoconversion of Alloreactive T Cells in Murine Peyer's Patches During Acute Graft-Versus-Host Disease: Tracking the Homing Route of Highly Proliferative Cells In Vivo}, series = {Frontiers in Immunology}, volume = {9}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2018.01468}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323309}, year = {2018}, abstract = {The regulation of immune cell migration throughout the body is essential to warrant immunosurveillance and to maintain immune homeostasis. Marking and tracking of these cells has proven important to study mechanisms of immune cell trafficking and cell interaction in vivo. Photoconversion is a well-suited technique for intravital application because it enables contactless time- and location-specific marking of cells in the tissue without surgically manipulating the microenvironment of the cells in question. However, in dividing cells the converted fluorescent protein may decline quickly. Here, we provide a detailed description of the photoconversion technique and its applicability to tracking highly proliferating T cells from the priming site of T cell activation to peripheral target organs of effector function in a preclinical model. Dendra2+ T cells were photoconverted in the Peyer's patches during the initiation phase of acute graft-versus-host disease (GvHD) and tracked through the mesenteric lymph nodes and the peripheral blood to the small intestine with flow cytometry and intravital two-photon microscopy. Photoconverted alloreactive T cells preserved the full proliferative capacity, homing, and migration of alloreactive T cells in the intestinal lamina propria. We conclusively proved that photoconversion of highly proliferative alloreactive T cells in the Peyer's patches is an effective tool to study trafficking of alloreactive T cells under physiologic conditions and to GvHD target tissues. This technique can also be applied to the study of immune cell tracking under inflammatory and non-inflammatory conditions.}, language = {en} } @article{HammerHalderKleihetal.2018, author = {Hammer, Eva M. and Halder, Sebastian and Kleih, Sonja C. and K{\"u}bler, Andrea}, title = {Psychological Predictors of Visual and Auditory P300 Brain-Computer Interface Performance}, series = {Frontiers in Neuroscience}, volume = {12}, journal = {Frontiers in Neuroscience}, doi = {10.3389/fnins.2018.00307}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369207}, year = {2018}, abstract = {Brain-Computer Interfaces (BCIs) provide communication channels independent from muscular control. In the current study we used two versions of the P300-BCI: one based on visual the other on auditory stimulation. Up to now, data on the impact of psychological variables on P300-BCI control are scarce. Hence, our goal was to identify new predictors with a comprehensive psychological test-battery. A total of N = 40 healthy BCI novices took part in a visual and an auditory BCI session. Psychological variables were measured with an electronic test-battery including clinical, personality, and performance tests. The personality factor "emotional stability" was negatively correlated (Spearman's rho = -0.416; p < 0.01) and an output variable of the non-verbal learning test (NVLT), which can be interpreted as ability to learn, correlated positively (Spearman's rho = 0.412; p < 0.01) with visual P300-BCI performance. In a linear regression analysis both independent variables explained 24\% of the variance. "Emotional stability" was also negatively related to auditory P300-BCI performance (Spearman's rho = -0.377; p < 0.05), but failed significance in the regression analysis. Psychological parameters seem to play a moderate role in visual P300-BCI performance. "Emotional stability" was identified as a new predictor, indicating that BCI users who characterize themselves as calm and rational showed worse BCI performance. The positive relation of the ability to learn and BCI performance corroborates the notion that also for P300 based BCIs learning may constitute an important factor. Further studies are needed to consolidate or reject the presented predictors.}, language = {en} } @article{HersterBittnerCodreaetal.2019, author = {Herster, Franziska and Bittner, Zsofia and Codrea, Marius Cosmin and Archer, Nathan K. and Heister, Martin and L{\"o}ffler, Markus W. and Heumos, Simon and Wegner, Joanna and Businger, Ramona and Schindler, Michael and Stegner, David and Sch{\"a}kel, Knut and Grabbe, Stephan and Ghoreschi, Kamran and Miller, Lloyd S. and Weber, Alexander N. R.}, title = {Platelets Aggregate With Neutrophils and Promote Skin Pathology in Psoriasis}, series = {Frontiers in Immunology}, volume = {10}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2019.01867}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320175}, year = {2019}, abstract = {Psoriasis is a frequent systemic inflammatory autoimmune disease characterized primarily by skin lesions with massive infiltration of leukocytes, but frequently also presents with cardiovascular comorbidities. Especially polymorphonuclear neutrophils (PMNs) abundantly infiltrate psoriatic skin but the cues that prompt PMNs to home to the skin are not well-defined. To identify PMN surface receptors that may explain PMN skin homing in psoriasis patients, we screened 332 surface antigens on primary human blood PMNs from healthy donors and psoriasis patients. We identified platelet surface antigens as a defining feature of psoriasis PMNs, due to a significantly increased aggregation of neutrophils and platelets in the blood of psoriasis patients. Similarly, in the imiquimod-induced experimental in vivo mouse model of psoriasis, disease induction promoted PMN-platelet aggregate formation. In psoriasis patients, disease incidence directly correlated with blood platelet counts and platelets were detected in direct contact with PMNs in psoriatic but not healthy skin. Importantly, depletion of circulating platelets in mice in vivo ameliorated disease severity significantly, indicating that both PMNs and platelets may be relevant for psoriasis pathology and disease severity.}, language = {en} } @article{GryszelSchlossarekWuerthneretal.2023, author = {Gryszel, Maciej and Schlossarek, Tim and W{\"u}rthner, Frank and Natali, Mirco and Głowacki, Eric Daniel}, title = {Water-soluble cationic perylene diimide dyes as stable photocatalysts for H\(_2\)O\(_2\) evolution}, series = {ChemPhotoChem}, volume = {7}, journal = {ChemPhotoChem}, number = {9}, issn = {2367-0932}, doi = {10.1002/cptc.202300070}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370250}, year = {2023}, abstract = {Photocatalytic generation of hydrogen peroxide, H\(_2\)O\(_2\), has gained increasing attention in recent years, with applications ranging from solar energy conversion to biophysical research. While semiconducting solid-state materials are normally regarded as the workhorse for photogeneration of H\(_2\)O\(_2\), an intriguing alternative for on-demand H\(_2\)O\(_2\) is the use of photocatalytic organic dyes. Herein we report the use of water-soluble dyes based on perylene diimide molecules which behave as true molecular catalysts for the light-induced conversion of dissolved oxygen to hydrogen peroxide. In particular, we address how to obtain visible-light photocatalysts which are stable with respect to aggregation and photochemical degradation. We report on the factors affecting efficiency and stability, including variable electron donors, oxygen partial pressure, pH, and molecular catalyst structure. The result is a perylene diimide derivative with unprecedented peroxide evolution performance using a broad range of organic donor molecules and operating in a wide pH range.}, language = {en} } @article{KasaragodSchindelin2018, author = {Kasaragod, Vikram B. and Schindelin, Hermann}, title = {Structure-Function Relationships of Glycine and GABAA Receptors and Their Interplay With the Scaffolding Protein Gephyrin}, series = {Frontiers in Molecular Neuroscience}, volume = {11}, journal = {Frontiers in Molecular Neuroscience}, doi = {10.3389/fnmol.2018.00317}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325607}, year = {2018}, abstract = {Glycine and γ-aminobutyric acid (GABA) are the major determinants of inhibition in the central nervous system (CNS). These neurotransmitters target glycine and GABAA receptors, respectively, which both belong to the Cys-loop superfamily of pentameric ligand-gated ion channels (pLGICs). Interactions of the neurotransmitters with the cognate receptors result in receptor opening and a subsequent influx of chloride ions, which, in turn, leads to hyperpolarization of the membrane potential, thus counteracting excitatory stimuli. The majority of glycine receptors and a significant fraction of GABAA receptors (GABAARs) are recruited and anchored to the post-synaptic membrane by the central scaffolding protein gephyrin. This ∼93 kDa moonlighting protein is structurally organized into an N-terminal G-domain (GephG) connected to a C-terminal E-domain (GephE) via a long unstructured linker. Both inhibitory neurotransmitter receptors interact via a short peptide motif located in the large cytoplasmic loop located in between transmembrane helices 3 and 4 (TM3-TM4) of the receptors with a universal receptor-binding epitope residing in GephE. Gephyrin engages in nearly identical interactions with the receptors at the N-terminal end of the peptide motif, and receptor-specific interaction toward the C-terminal region of the peptide. In addition to its receptor-anchoring function, gephyrin also interacts with a rather large collection of macromolecules including different cytoskeletal elements, thus acting as central scaffold at inhibitory post-synaptic specializations. Dysfunctions in receptor-mediated or gephyrin-mediated neurotransmission have been identified in various severe neurodevelopmental disorders. Although biochemical, cellular and electrophysiological studies have helped to understand the physiological and pharmacological roles of the receptors, recent high resolution structures of the receptors have strengthened our understanding of the receptors and their gating mechanisms. Besides that, multiple crystal structures of GephE in complex with receptor-derived peptides have shed light into receptor clustering by gephyrin at inhibitory post-synapses. This review will highlight recent biochemical and structural insights into gephyrin and the GlyRs as well as GABAA receptors, which provide a deeper understanding of the molecular machinery mediating inhibitory neurotransmission.}, language = {en} } @article{SchneiderWiewelhoveRaederetal.2019, author = {Schneider, Christoph and Wiewelhove, Thimo and Raeder, Christian and Flatt, Andrew A. and Hoos, Olaf and Hottenrott, Laura and Schumbera, Oliver and Kellmann, Michael and Meyer, Tim and Pfeiffer, Mark and Ferrauti, Alexander}, title = {Heart Rate Variability Monitoring During Strength and High-Intensity Interval Training Overload Microcycles}, series = {Frontiers in Physiology}, volume = {10}, journal = {Frontiers in Physiology}, doi = {10.3389/fphys.2019.00582}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231515}, year = {2019}, abstract = {Objective: In two independent study arms, we determine the effects of strength training (ST) and high-intensity interval training (HIIT) overload on cardiac autonomic modulation by measuring heart rate (HR) and vagal heart rate variability (HRV). Methods: In the study, 37 well-trained athletes (ST: 7 female, 12 male; HIIT: 9 female, 9 male) were subjected to orthostatic tests (HR and HRV recordings) each day during a 4-day baseline period, a 6-day overload microcycle, and a 4-day recovery period. Discipline-specific performance was assessed before and 1 and 4 days after training. Results: Following ST overload, supine HR, and vagal HRV (Ln RMSSD) were clearly increased and decreased (small effects), respectively, and the standing recordings remained unchanged. In contrast, HIIT overload resulted in decreased HR and increased Ln RMSSD in the standing position (small effects), whereas supine recordings remained unaltered. During the recovery period, these responses were reversed (ST: small effects, HIIT: trivial to small effects). The correlations between changes in HR, vagal HRV measures, and performance were weak or inconsistent. At the group and individual levels, moderate to strong negative correlations were found between HR and Ln RMSSD when analyzing changes between testing days (ST: supine and standing position, HIIT: standing position) and individual time series, respectively. Use of rolling 2-4-day averages enabled more precise estimation of mean changes with smaller confidence intervals compared to single-day values of HR or Ln RMSSD. However, the use of averaged values displayed unclear effects for evaluating associations between HR, vagal HRV measures, and performance changes, and have the potential to be detrimental for classification of individual short-term responses. Conclusion: Measures of HR and Ln RMSSD during an orthostatic test could reveal different autonomic responses following ST or HIIT which may not be discovered by supine or standing measures alone. However, these autonomic changes were not consistently related to short-term changes in performance and the use of rolling averages may alter these relationships differently on group and individual level.}, language = {en} } @article{KervarrecSamimiGuyetantetal.2019, author = {Kervarrec, Thibault and Samimi, Mahtab and Guy{\´e}tant, Serge and Sarma, Bhavishya and Ch{\´e}ret, J{\´e}r{\´e}my and Blanchard, Emmanuelle and Berthon, Patricia and Schrama, David and Houben, Roland and Touz{\´e}, Antoine}, title = {Histogenesis of Merkel Cell Carcinoma: A Comprehensive Review}, series = {Frontiers in Oncology}, volume = {9}, journal = {Frontiers in Oncology}, doi = {10.3389/fonc.2019.00451}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325733}, year = {2019}, abstract = {Merkel cell carcinoma (MCC) is a primary neuroendocrine carcinoma of the skin. This neoplasia features aggressive behavior, resulting in a 5-year overall survival rate of 40\%. In 2008, Feng et al. identified Merkel cell polyomavirus (MCPyV) integration into the host genome as the main event leading to MCC oncogenesis. However, despite identification of this crucial viral oncogenic trigger, the nature of the cell in which MCC oncogenesis occurs is actually unknown. In fact, several hypotheses have been proposed. Despite the large similarity in phenotype features between MCC tumor cells and physiological Merkel cells (MCs), a specialized subpopulation of the epidermis acting as mechanoreceptor of the skin, several points argue against the hypothesis that MCC derives directly from MCs. Alternatively, MCPyV integration could occur in another cell type and induce acquisition of an MC-like phenotype. Accordingly, an epithelial as well as a fibroblastic or B-cell origin of MCC has been proposed mainly based on phenotype similarities shared by MCC and these potential ancestries. The aim of this present review is to provide a comprehensive review of the current knowledge of the histogenesis of MCC.}, language = {en} } @article{NagyvanGeffenStegneretal.2019, author = {Nagy, Magdolna and van Geffen, Johanna P. and Stegner, David and Adams, David J. and Braun, Attila and de Witt, Susanne M. and Elvers, Margitta and Geer, Mitchell J. and Kuijpers, Marijke J. E. and Kunzelmann, Karl and Mori, Jun and Oury, C{\´e}cile and Pircher, Joachim and Pleines, Irina and Poole, Alastair W. and Senis, Yotis A. and Verdoold, Remco and Weber, Christian and Nieswandt, Bernhard and Heemskerk, Johan W. M. and Baaten, Constance C. F. M. J.}, title = {Comparative Analysis of Microfluidics Thrombus Formation in Multiple Genetically Modified Mice: Link to Thrombosis and Hemostasis}, series = {Frontiers in Cardiovascular Medicine}, volume = {6}, journal = {Frontiers in Cardiovascular Medicine}, doi = {10.3389/fcvm.2019.00099}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232194}, year = {2019}, abstract = {Genetically modified mice are indispensable for establishing the roles of platelets in arterial thrombosis and hemostasis. Microfluidics assays using anticoagulated whole blood are commonly used as integrative proxy tests for platelet function in mice. In the present study, we quantified the changes in collagen-dependent thrombus formation for 38 different strains of (genetically) modified mice, all measured with the same microfluidics chamber. The mice included were deficient in platelet receptors, protein kinases or phosphatases, small GTPases or other signaling or scaffold proteins. By standardized re-analysis of high-resolution microscopic images, detailed information was obtained on altered platelet adhesion, aggregation and/or activation. For a subset of 11 mouse strains, these platelet functions were further evaluated in rhodocytin- and laminin-dependent thrombus formation, thus allowing a comparison of glycoprotein VI (GPVI), C-type lectin-like receptor 2 (CLEC2) and integrin α6β1 pathways. High homogeneity was found between wild-type mice datasets concerning adhesion and aggregation parameters. Quantitative comparison for the 38 modified mouse strains resulted in a matrix visualizing the impact of the respective (genetic) deficiency on thrombus formation with detailed insight into the type and extent of altered thrombus signatures. Network analysis revealed strong clusters of genes involved in GPVI signaling and Ca2+ homeostasis. The majority of mice demonstrating an antithrombotic phenotype in vivo displayed with a larger or smaller reduction in multi-parameter analysis of collagen-dependent thrombus formation in vitro. Remarkably, in only approximately half of the mouse strains that displayed reduced arterial thrombosis in vivo, this was accompanied by impaired hemostasis. This was also reflected by comparing in vitro thrombus formation (by microfluidics) with alterations in in vivo bleeding time. In conclusion, the presently developed multi-parameter analysis of thrombus formation using microfluidics can be used to: (i) determine the severity of platelet abnormalities; (ii) distinguish between altered platelet adhesion, aggregation and activation; and (iii) elucidate both collagen and non-collagen dependent alterations of thrombus formation. This approach may thereby aid in the better understanding and better assessment of genetic variation that affect in vivo arterial thrombosis and hemostasis.}, language = {en} } @phdthesis{Glueck2024, author = {Gl{\"u}ck, Valentina}, title = {Habitual avoidance in trait anxiety and anxiety disorders}, doi = {10.25972/OPUS-36022}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360227}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Maladaptive avoidance behaviors can contribute to the maintenance of fear, anxiety, and anxiety disorders. It has been proposed that, throughout anxiety disorder progression, extensively repeated avoidance may become a habit (i.e., habitual avoidance) instead of being controlled by internal threat-related goals (i.e., goal-directed avoidance). However, the process of the acquisition of habitual avoidance in anxiety disorders is not yet well understood. Accordingly, the current thesis aimed to investigate experimentally whether trait anxiety and anxiety disorders are associated with an increased shift from goal-directed to habitual avoidance. The aim of Study 1 was to develop an experimental operationalization of maladaptive habitual avoidance. To this end, we adapted a commonly used action control task, the outcome devaluation paradigm. In this task, habitual avoidance was operationalized as persistent responses after extensive training to avoid an unpleasant stimulus when the aversive outcome was devalued, i.e., when individuals knew the aversive outcome could not occur anymore. We included indicators for costly and low-cost habitual avoidance, whereby habitual avoidance was associated with a monetary cost, while low-cost habitual avoidance was not associated with monetary costs. In Experiment 1 of Study 1, a pronounced costly and non-costly outcome devaluation effect was observed. However, this result may have partly resulted from trial-and-error learning or a better-safe-than-sorry strategy since not instructions about the stimulus-response-outcome contingencies after the outcome devaluation procedure had been provided to the participants. In Experiment 2 of Study 1, instructions on these stimulus-response-outcome contingencies were included to prevent the potential confounders. As a result, we observed no indicators for costly habitual avoidance, but evidence for low-cost habitual avoidance, potentially because competing goal-directed responses could easily be implemented and inhibited costly habitual avoidance tendencies. In Study 2, the strength of habitual avoidance acquisition was compared between participants with and without anxiety disorders, using the experimental task of Experiment 1 in Study 1. The results indicated that costly and low-cost habitual avoidance was not more pronounced in participants with anxiety disorders than in the healthy control group. However, in an exploratory subgroup comparison, panic disorder predicted more substantial habitual avoidance acquisition than social anxiety disorder. In Study 3, we investigated whether trait anxiety as a risk factor for anxiety disorders is associated with a specific increased shift from goal-directed to habitual avoidance and approach. The task from the Experiment 1 of Study 1 was adapted to include parallel versions for operationalizing habitual avoidance and habitual approach responses. Using a within-subjects design, the individuals - pre-screened for high and low trait anxiety - took part in the approach and the avoidance outcome devaluation task version. The results suggested stronger non-costly habitual responses in more highly trait-anxious individuals independent of the task version, and suggested a tendency towards an impact of trait anxiety on costly habitual approach rather than on costly habitual avoidance. In summary, individuals with high trait anxiety or anxiety disorders did not develop habitual avoidance more readily than individuals with low trait anxiety or without anxiety disorders. Therefore, this thesis does not support the assumption that an increased tendency to acquire habitual avoidance contributes to persistent maladaptive avoidance in anxiety disorders. The thesis also contributes to the discourse on the validity of outcome devaluation studies in general by highlighting the impact of task features, such as the instructions after the outcome devaluation procedure or the task difficulty in the test phase, on the experimental results. Such validity issues may partly explain the heterogeneity of findings in research with the outcome devaluation paradigm. We suggest ways towards more valid operationalizations of habitual avoidance in future studies.}, subject = {Gewohnheit}, language = {en} } @phdthesis{Gabel2024, author = {Gabel, Martin Sebastian}, title = {Behavioural resistance to \(Varroa\) \(destructor\) in the Western honeybee \(Apis\) \(mellifera\) - Mechanisms leading to decreased mite reproduction}, doi = {10.25972/OPUS-36053}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360536}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The Western Honeybee (Apis mellifera) is among the most versatile species in the world. Its adaptability is rooted in thousands of the differently specialized individuals acting jointly together. Thus, bees that are able to handle a certain task or condition well can back up other individuals less capable to do so on the colony level. Vice versa, the latter individuals might perform better in other situations. This evolutionary recipe for success ensures the survival of colonies despite challenging habitat conditions. In this context, the ectoparasitic mite Varroa destructor reflects the most pronounced biotic challenge to honeybees worldwide. Without proper treatment, infested colonies rapidly dwindle and ultimately die. Nevertheless, resistance behaviours against this parasite have evolved in some populations through natural selection, enabling colonies to survive untreated. In this, different behaviours appear to be adapted to the respective habitat conditions and may complement each other. Yet, the why and how of this behavioural response to the mite remains largely unknown. My thesis focuses on the biological background of Varroa-resistance traits in honeybees and presents important findings for the comprehension of this complex host-parasite interaction. Based on this, I draw implications for both, applied bee breeding and scientific investigations in the field of Varroa-resistance. Specifically, I focus on two traits commonly found in resistant and, to a lower degree, also mite-susceptible colonies: decreased mite reproduction and the uncapping and subsequent recapping of sealed brood cells. Examining failures in the reproductive success of mites as a primary mechanism of Varroa-resistance, I was able to link them to specific bee behaviours and external factors. Since mite reproduction and the brood rearing of bees are inevitably connected, I first investigated the effects of brood interruption on the reproductive success of mites. Brood interruption decreased the reproductive success of mites both immediately and in the long term. By examining the causes of reproductive failure, I could show that this was mainly due to an increased share of infertile mites. Furthermore, I proved that interruption in brood rearing significantly increased the expression of recapping behaviour. These findings consequently showed a dynamic modulation of mite reproduction and recapping, as well as a direct effect of brood interruption on both traits. To further elucidate the plasticity in the expression of both traits, I studied mite reproduction, recapping behaviour and infestation levels over the course of three years. The resulting extensive dataset unveiled a significant seasonal variation in mite reproduction and recapping. In addition, I show that recapping decreases the reproductive success of mites by increasing delayed developing female offspring and cells lacking male offspring. By establishing a novel picture-based brood investigation method, I could furthermore show that both the removal of brood cells and recapping activity specifically target brood ages in which mite offspring would be expected. Recapping, however, did not cause infertility of mites. Considering the findings of my first study, this points towards complementary mechanisms. This underlines the importance of increased recapping behaviour and decreased mite reproduction as resistance traits, while at the same time emphasising the challenges of reliable data acquisition. To pave the way for a practical application of these findings in breeding, we then investigated the heritability (i.e., the share of genotypic variation on the observed phenotypic variation) of the accounted traits. By elaborating comparable test protocols and compiling data from over 4,000 colonies, we could, for the first time, demonstrate that recapping of infested cells and decreased reproductive success of mites are heritable (and thus selectable) traits in managed honeybee populations. My thesis proves the importance of recapping and decreased mite reproduction as resistance traits and therefore valuable goals for breeding efforts. In this regard, I shed light on the underlying mechanisms of both traits, and present clear evidence for their interaction and heritability.}, subject = {Varroa destructor}, language = {en} } @phdthesis{Dekant2024, author = {Dekant, Raphael H.}, title = {Species-differences in the \(in\) \(vitro\) biotransformation of trifluoroethene (HFO-1123)}, doi = {10.25972/OPUS-31403}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-314035}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {1,1,2-trifluoroethene (HFO-1123) is intended for use as a refrigerant. Inhalation studies on HFO-1123 in rats suggested a low potential for toxicity, with no-observed-adverse-effect levels greater then 20,000 ppm. However, single inhalation exposure of Goettingen Minipigs and New Zealand White Rabbits resulted in mortality. It was assumed that conjugation of HFO-1123 with glutathione, via glutathione S-transferase, gives rise to S-(1,1,2-trifluoroethyl)-L-glutathione (1123-GSH), which is then transformed to the corresponding cysteine S-conjugate (S-(1,1,2-trifluoroethyl)-L-cysteine, 1123-CYS). Subsequent beta-lyase mediated cleavage of 1123-CYS may result in monofluoroacetic acid, a potent inhibitor of aconitase. Species-differences in 1123-GSH formation and 1123-CYS cleavage to MFA may explain species-differences in HFO-1123 toxicity. This study was designed to test the hypothesis, that GSH-dependent biotransformation and subsequent beta-lyase mediated formation of monofluoroacetic acid, a potent inhibitor of aconitase in the citric acid cycle, may play a key role in HFO-1123 toxicity and to evaluate if species-differences in the extent of MFA formation may account for the species-differences in HFO-1123 toxicity. The overall objective was to determine species-differences in HFO-1123 biotransformation in susceptible vs. less susceptible species and humans as a basis for human risk assessment. To this end, in vitro biotransformation of HFO-1123 and 1123-CYS was investigated in renal and hepatic subcellular fractions of mice, rats, humans, Goettingen Minipigs and NZW Rabbits. Furthermore, cytotoxicity and metabolism of 1123-CYS was assessed in cultured renal epithelial cells. Enzyme kinetic parameters for beta-lyase mediated cleavage of 1123-CYS in renal and hepatic cytosolic fractions were determined, and 19F-NMR was used to identify fluorine containing metabolites arising from 1123-CYS cleavage. Quantification of 1123-GSH formation in hepatic S9 fractions after incubation with HFO-1123 was performed by LC-MS/MS and hepatic metabolism of HFO-1123 was monitored by 19F-NMR. Rates of 1123-GSH formation were increased in rat, mouse and NZW Rabbit compared to human and Goettingen hepatic S9, indicating increased GSH dependent biotransformation in rats, mouse and NZW Rabbits. NZW Rabbit hepatic S9 exhibited increased 1123-GSH formation in the presence compared to the absence of acivicin, a specific gamma-GT inhibitor. This indicates increased gamma-GT mediated cleavage of 1123-GSH in NZW Rabbit hepatic S9 compared to the other species. 19F-NMR confirmed formation of 1123-GSH as the main metabolite of GSH mediated biotransformation of HFO-1123 in hepatic S9 fractions next to F-. Increased F- formation was detected in NZW Rabbit and Goettingen Minipig hepatic S9 in the presence of an NADPH regenerating system, indicating a higher rate of CYP-450 mediated metabolism in these species. Based on these findings, it is possible that CYP-450 mediated metabolism may contribute to HFO-1123 toxicity. In contrast to the increased formation of 1123-GSH in rat, mouse and NZW Rabbit hepatic S9 (compared to human and Goettingen Minipig), enzyme kinetic studies revealed a significantly higher beta-lyase activity towards 1123-CYS in renal cytosol of Goettingen Minipigs compared to cytosol from rats, mice, humans and NZW Rabbits. However, beta-lyase cleavage in renal NZW Rabbit cytosol was slightly increased compared to rat, mouse and human renal cytosols. 19F-NMR analysis confirmed increased time-dependent formation of MFA in renal Goettingen Minipig cytosol and NZW Rabbit (compared to human and rat cytosolic fractions). Three structurally not defined MFA-derivatives were detected exclusively in NZW Rabbit and Goettingen Minipig cytosols. Also, porcine kidney cells were more sensitive to cytotoxicity of 1123-CYS compared to rat and human kidney cells. Overall, increased beta-lyase mediate cleavage of 1123-CYS to MFA in Goettingen Minipig and NZW Rabbit kidney (compared to human and rat) may support the hypothesis that enzymatic cleavage by beta-lyases may account for the species-differences in HFO-1123 toxicity. However, the extent of GST mediated biotransformation in the liver as the initial step in HFO-1123 metabolism does not fully agree with this hypothesis, since 1123-GSH formation occurs at higher rates in rat, mouse and NZW Rabbit S9 as compared to the Goettingen Minipig. Based on the inconsistencies between the extent of GST and beta-lyase mediated biotransformation of HFO-1123 obtained by this study, a decisive statement about an increased biotransformation of HFO-1123 in susceptible species with a direct linkage to the species-specific toxicity cannot be drawn. Resulting from this, a clear and reliable conclusion regarding the risk for human health originating from HFO-1123 cannot be made. However, considering the death of Goettingen Minipigs and NZW Rabbits after inhalation exposure of HFO-1123 at concentrations great than 500 ppm and greater than 1250 ppm, respectively, this indicates a health concern for humans under peak exposure conditions. For a successful registration of HFO-1123 and its use as a refrigerant, further in vitro and in vivo investigations addressing uncertainties in the species-specific toxicity of HFO-1123 are urgently needed.}, subject = {Biotransformation}, language = {en} } @phdthesis{Zhang2024, author = {Zhang, Tengyu}, title = {Development of Modified polylysine based antibody conjugated nanoparticles with tumor-restricted, FcγR-independent stimulatory activity by targeting Fn14}, doi = {10.25972/OPUS-35865}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-358650}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In this study, we developed an innovative nanoparticle formulation to facilitate the delivery of antitumor antibodies to tumor sites. The study commenced with the utilization of 13 bispecific antibody fusion proteins, which targeted the Fn14 receptor, thereby validating the pivotal role of crosslinking in Fn14 receptor activation. Subsequently, gold nanoparticles were activated using COOH-PEG-SH in combination with EDC/NHS, and subsequently conjugated with two Fn14-targeting antibodies, PDL192 and 5B6. Following this, a pH-sensitive shell was generated on the outer layer of the antibody-coupled gold nanoparticles through the application of chemically modified polylysine. The resultant complexes, termed MPL-antibody-AuNP, demonstrated a release profile reminiscent of the tumor microenvironment (TME). Notably, these complexes released antibody-AuNPs only in slightly acidic conditions while remaining intact in neutral or basic environments. Functionality analysis further affirmed the pH-sensitive property of MPL-antibody-AuNPs, demonstrating that the antibodies only initiated potent Fn14 activation in slightly acidic environments. This formulation holds potential for applicability to antibodies or ligands targeting the 80 TNFRSF family, given that gold nanoparticles successfully served as platforms for antibody crosslinking, thereby transforming these antibodies into potent agonists. Moreover, the TME disintegration profile of MPL mitigates the potential cytotoxic effects of antibodies, thereby circumventing associated adverse side effects. This study not only showcases the potential of nanoparticle formulations in targeted therapy, but also provides a solid foundation for further investigations on their clinical application in the context of targeting category II TNFRSF receptors with antibodies or ligands.}, subject = {Immuntherapie}, language = {en} } @phdthesis{Geissendoerfer2024, author = {Geißend{\"o}rfer, Lisa}, title = {The Macroeconomic Dimensions of Credit: A Comprehensive Analysis of Finance, Inequality and Growth}, doi = {10.25972/OPUS-37003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370037}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Besonders einflussreich f{\"u}r das moderne Verst{\"a}ndnis zur makro{\"o}konomischen Rolle von Banken und Kredit ist die monet{\"a}re Wachstumstheorie von Schumpeter. Ausgehend von dieser wird in dieser Dissertation die makro{\"o}konomische Rolle des Finanzsystems f{\"u}r die (1) Erzeugung von Wirtschaftswachstum, (2) Lenkung von {\"o}konomischen Ressourcen und (3) Verteilung von Wohlstand untersucht. In Kapitel 3 wird zun{\"a}chst empirisch gezeigt, dass 1.) ein positiver Zusammenhang zwischen dem Wachstum von Krediten und Wirtschaftswachstum besteht, auch f{\"u}r entwickelte L{\"a}nder, 2.) kein empirischer Zusammenhang von Haushaltssparen und Wirtschaftswachstum festgestellt werden kann, und 3.) auf l{\"a}nderspezifischer Ebene sowohl positive, als auch negative und insignifikante Effekte von Kredit auf Wirtschaftswachstum existieren. Damit zeigt sich eine breite empirische Evidenz f{\"u}r Schumpeters monet{\"a}re Hypothesen. Eine besonders interessante Anwendung von Schumpeters Wachstumstheorie zeigt sich in China. Die Ergebnisse der empirischen Analyse legen nahe, dass es generell einen positiven Zusammenhang zwischen Kredit- und Wirtschaftswachstum in China gibt, der aber nicht linear in Bezug auf Regionen, Zeitpunkte und Gr{\"o}ße des Finanzsystems ist. Weiterhin deuten die Ergebnisse darauf hin, dass die kreditfinanzierte Industriepolitik in China zu mehr Investitionen und BIP-Wachstum beigetragen haben k{\"o}nnte, wobei es jedoch Nichtlinearit{\"a}ten zwischen einzelnen Branchen und Unternehmenstypen gibt. Zuletzt wird in Kapitel 5 die Frage aufgeworfen, welche Rolle das Finanzsystem bei der Verteilung des Wohlstands spielt. W{\"a}hrend Kredite an Haushalte und Unternehmen, zusammen mit Indikatoren zum Arbeits- und Sparverhalten, sowie zur Altersstruktur der Bev{\"o}lkerung, die wichtigsten Determinanten von Verm{\"o}gensungleichheit sind, zeigen sich in der Beziehung von Krediten und Verm{\"o}gensungleichheit ebenfalls verschiedene Nichtlinearit{\"a}ten, u.a. im Bezug auf den Entwicklungsstand von Finanzsystemen und Wohneigentumsquoten.}, subject = {Kredit}, language = {en} } @phdthesis{Chen2024, author = {Chen, Xinyu}, title = {How natural walking changes occipital alpha oscillations and concurrently modulates cognitive processes}, doi = {10.25972/OPUS-35295}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-352958}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Humans actively interact with the world through a wide range of body movements. To understand human cognition in its natural state, we need to incorporate ecologically relevant body movement into our account. One fundamental body movement during daily life is natural walking. Despite its ubiquity, the impact of natural walking on brain activity and cognition has remained a realm underexplored. In electrophysiology, previous studies have shown a robust reduction of ongoing alpha power in the parieto-occipital cortex during body movements. However, what causes the reduction of ongoing alpha, namely whether this is due to body movement or prevalent sensory input changes, was unknown. To clarify this, study 1 was performed to test if the alpha reduction is dependent on visual input. I compared the resting state alpha power during natural walking and standing, in both light and darkness. The results showed that natural walking led to decreased alpha activity over the occipital cortex compared to standing, regardless of the lighting condition. This suggests that the movement-induced modulation of occipital alpha activity is not driven by visual input changes during walking. I argue that the observed alpha power reduction reflects a change in the state of the subject based on disinhibition induced by walking. Accordingly, natural walking might enhance visual processing and other cognitive processes that involve occipital cortical activity. I first tested this hypothesis in vision. Study 2 was performed to examine the possible effects of natural walking across visual processing stages by assessing various neural markers during different movement states. The findings revealed an amplified early visual response, while a later visual response remain unaffected. A follow-up study 3 replicated the walking-induced enhancement of the early visual evoked potential and showed that the enhancement was dependent on specific stimulus-related parameters (eccentricity, laterality, distractor presence). Importantly, the results provided evidence that the enhanced early visual responses are indeed linked to the modulation of ongoing occipital alpha power. Walking also modulated the stimulus-induced alpha power. Specifically, it showed that when the target appeared in the fovea area without a distractor, walking exhibited a significantly reduced modulation of alpha power, and showed the largest difference to standing condition. This effect of eccentricity indicates that during later visual processing stages, the visual input in the fovea area is less processed than in peripheral areas while walking. The two visual studies showed that walking leads to an enhancement in temporally early visual processes which can be predicted by the walking-induced change in ongoing alpha oscillation likely marking disinhibition. However, while walking affects neural markers of early sensory processes, it does not necessarily lead to a change in the behavioural outcome of a sensory task. The two visual studies suggested that the behavioural outcome seems to be mainly based on later processing stages. To test the effects of walking outside the visual domain, I turned to audition in study 4. I investigated the influence of walking in a particular path vs. simply stepping on auditory processing. Specifically, the study tested whether enhanced processing due to natural walking can be found in primary auditory brain activity and whether the processing preferences are dependent on the walking path. In addition, I tested whether the changed spatial processing that was reported in previous visual studies can be seen in the auditory domain. The results showed enhanced sensory processing due to walking in the auditory domain, which was again linked to the modulation of occipital alpha oscillation. The auditory processing was further dependent on the walking path. Additionally, enhanced peripheral sensory processing, as found in vision, was also present in audition. The findings outside vision supported the idea of natural walking affecting cognition in a rather general way. Therefore in my study 5, I examined the effect of natural walking on higher cognitive processing, namely divergent thinking, and its correlation with the modulation of ongoing alpha oscillation. I analyzed alpha oscillations and behavioural performance during restricted and unrestricted movement conditions while subjects completed a Guilford's alternate uses test. The results showed that natural walking, as well as missing body restriction, reduces the occipital alpha ongoing power independent of the task phase which goes along with higher test scores. The occipital alpha power reduction can therefore be an indicator of a changed state that allows improved higher cognitive processes. In summary, the research presented in this thesis highlights that natural walking can change different processes in the visual and auditory domain as well as higher cognitive processes. The effect can be attributed to the movement of natural walking itself rather than to changes in sensory input during walking. The results further indicate that the walking-induced modulation of ongoing occipital alpha oscillations drives the cognitive effects. We therefore suggest that walking changes the inhibitory state which can influence awareness and attention. Such a mechanism could facilitate an adaptive enhancement in cognitive processes and thereby optimize movement-related behaviour such as navigation.}, subject = {Walking}, language = {en} } @phdthesis{Hadi2024, author = {Hadi, Naji Said Aboud}, title = {In vitro Studies on the Genotoxicity of Selected Pyrrolizidine Alkaloids}, doi = {10.25972/OPUS-37037}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370376}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Cancer is one of the leading causes of death worldwide. Toxic contaminants in human food or medicinal products, such as substances like pyrrolizidine alkaloids (PAs), have been thought to contribute to cancer incidence. PAs are found in many plant species as secondary metabolites, and they may affect humans through contaminated food sources, herbal medicines, and dietary supplements. Hundreds of compounds belonging to PAs have been identified, differing in their chemical structures, either in their necine base moiety or esterification at their necic acid moiety. PAs undergo hepatic metabolism, and after this process, they can induce hepatotoxicity, genotoxicity, and carcinogenicity. However, the mechanism of inducing genotoxicity and carcinogenicity is still unclear and warrants further investigation. Therefore, the present study aims to investigate the mechanism of genotoxicity induced by selected PAs with different chemical structures in in vitro systems. Primarily, human hepatoma HepG2 cells were utilized, and in co-culture, metabolically active HepG2 cells were combined with non-metabolically active human cervical HeLa H2B-GFP cells. First, the genotoxicity of the PAs europine, lycopsamine, retrorsine, riddelliine, seneciphylline, echimidine, and lasiocarpine was investigated in the cytokinesis-block micronucleus (CBMN) assay. All seven selected PAs caused the formation of micronuclei in a dose-dependent manner, with the maximal increase of micronucleus formation ranging from 1.64 to 2.0 fold. The lowest concentrations at which significant induction of micronuclei was found were 3.2 µM for lasiocarpine and riddelliine, 32 µM for retrorsine and echimidine, and 100 µM for seneciphylline, europine, and lycopsamine. These results confirmed previously published potency rankings in the micronucleus assay. The same PAs, with the exception of seneciphylline, were also investigated in a crosslink-modified comet assay, and reduced tail formation after hydrogen peroxide treatment was found in all diester-type PAs. Meanwhile, an equimolar concentration of the monoesters europine and lycopsamine did not significantly reduce DNA migration. Thus, the crosslinking activity was related to the ester type. Next, the role of metabolic enzymes and membrane transporters in PA-induced genotoxicity was assessed. Ketoconazole (CYP 450-3A4 inhibitor) prevented lasiocarpine-induced micronucleus formation completely, while furafylline (CYP 450-1A2 inhibitor) reduced lasiocarpine-induced micronucleus formation, but did not abolish it completely. This implies that the CYP 450 enzymes play an important role in PA-induced genotoxicity. Carboxylesterase 2 enzyme (CES 2) is commonly known to be involved in the detoxification of xenobiotics. Loperamide (CES 2 inhibitor) yielded an increased formation of lasiocarpine-induced micronuclei, revealing a possible role of CES-mediated detoxification in the genotoxicity of lasiocarpine. Also, intracellular glutathione (GSH) plays an important role in the detoxification of xenobiotics or toxins in the cells. Cells which had been pretreated with L-buthionine sulfoximine (BSO) to reduce GSH content were significantly more sensitive for the induction of micronucleus formation by lasiocarpine revealing the importance of GSH in PA-induced genotoxicity. Quinidine (Q) and nelfinavir (NFR) are OCT1 and OATP1B1 influx transporter inhibitors, respectively, which reduced micronucleus induction by lasiocarpine (only quinidine significantly), but not completely, pointing to a relevance of OCT1 for PA uptake in HepG2 cells. Verapamil (V) and benzbromarone (Bz) are MDR1 and MRP2 efflux transporter inhibitors, respectively, and they caused a slightly increased micronucleus induction by lasiocarpine (significant only for benzbromarone) thus, revealing the role of efflux transporters in PA-induced genotoxicity. The mechanistic approach to PA-induced genotoxicity was further studied based on oxidative stress via the formation of reactive oxygen species (ROS) in HepG2 cells. Overproduction of ROS can cross-link cellular macromolecules such as DNA, leading to genomic damage. An equimolar concentration of 10 µM of lasiocarpine (open-diester PA), riddelliine (cyclic-diester PA), and europine (monoester) significantly induced ROS production, with the highest ROS generation observed after lasiocarpine treatment, followed by riddelliine and then europine. No significant increase in ROS production was found with lycopsamine (10 µM; monoester PA), even at a higher concentration (320 µM). The generation of ROS by these PAs was further analyzed for confirmation by using 5 mM of the thiol radical scavenger antioxidant N-acetyl cysteine (NAC) combined with lasiocarpine, riddelliine, or europine. This analysis yielded a significant decrease in ROS after combining NAC with lasiocarpine, riddelliine, and europine. In addition, lasiocarpine, riddelliine, and europine induced a loss of mitochondrial membrane potential, pointing to mitochondria as the source of ROS generation. In vivo, hepatic sinusoidal epithelial cells (HSECs) are known to be damaged first by PAs after hepatic metabolization, but HSECs themselves do not express the required metabolic enzymes for activation of PAs. To mimic this situation, HepG2 cells were used to metabolically activate PA in a co-culture with HeLa H2B-GFP cells as non-metabolically active neighbours. Due to the green fluorescent GFP label the HeLa cells could be identified easily based in the co-culture. The PAs europine, riddelliine and lasiocarpine induced micronucleus formation in HepG2 cells, and in HeLa H2B-GFP cells co-cultured with HepG2 cells, but not in HeLa H2B-GFP cells cultured alone. Metabolic inhibition of CYP 450 enzymes with ketoconazole abrogated micronucleus formation induced by the same PAs tested in the co-culture. The efflux transporter inhibitors verapamil and benzbromarone reduced the micronucleus formation in the co-culture. Furthermore, mitotic disturbances as an additional genotoxic mechanism of action were observed in HepG2 cells and in HeLa H2B-GFP cells co-cultured with HepG2 cells, but not in HeLa H2B-GFP cells cultured alone. Overall, we were able to show that PAs were activated by HepG2 cells and the metabolites induced genomic damage in co-cultured non-metabolically active green HeLa cells. Finally, in HepG2 cells as well as the co-culture, combinations of PAs lasiocarpine and riddelliine favoured an additive effect rather than synergism. Thus, this study therefore provides support that the assumption of dose-addition can be applied in the characterization of the genotoxicity risk of PAs present in a mixture.}, subject = {Pyrrolizidinalkaloide}, language = {en} } @phdthesis{Schwebs2024, author = {Schwebs, Marie}, title = {Structure and dynamics of the plasma membrane: a single-molecule study in \(Trypanosoma\) \(brucei\)}, doi = {10.25972/OPUS-27569}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-275699}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The unicellular, flagellated parasite Trypanosoma brucei is the causative agent of human African sleeping sickness and nagana in livestock. In the last decades, it has become an established eukaryotic model organism in the field of biology, as well as in the interdisciplinary field of biophysics. For instance, the dense variant surface glycoprotein (VSG) coat offers the possibility to study the dynamics of GPI-anchored proteins in the plasma membrane of living cells. The fluidity of the VSG coat is not only an interesting object of study for its own sake, but is critically important for the survival of the parasite in the mammalian host. In order to maintain the integrity of the coat, the entire VSG coat is recycled within a few minutes. This is surprisingly fast for a purely diffusive process with the flagellar pocket (FP) as the sole site for endo- and exocytosis. Previous studies characterising VSG dynamics using FRAP reported diffusion coefficients that were not sufficient to to enable fast turnover based on passive VSG randomisation on the trypanosome surface. In this thesis, live-cell single-molecule fluorescence microscopy (SMFM) was employed to elucidate whether VSG diffusion coefficients were priorly underestimated or whether directed forces could be involved to bias VSGs towards the entrance of the FP. Embedding the highly motile trypanosomes in thermo-stable hydrogels facilitated the investigation of VSG dynamics on living trypanosomes at the mammalian host's temperature of 37°C. To allow for a spatial correlation of the VSG dynamics to the FP entrance, a cell line was employed harbouring a fluorescently labelled structure as a reference. Sequential two-colour SMFM was then established to allow for recording and registration of the dynamic and static single-molecule information. In order to characterise VSG dynamics, an algorithm to obtain reliable information from short trajectories was adapted (shortTrAn). It allowed for the quantification of the local dynamics in two distinct scenarios: diffusion and directed motion. The adaptation of the algorithm to the VSG data sets required the introduction of an additional projection filter. The algorithm was further extended to take into account the localisation errors inherent to single-particle tracking. The results of the quantification of diffusion and directed motion were presented in maps of the trypanosome surface, including an outline generated from a super-resolved static structure as a reference. Information on diffusion was displayed in one map, an ellipse plot. The colour code represented the local diffusion coefficient, while the shape of the ellipses provided an indication of the diffusion behaviour (aniso- or isotropic diffusion). The eccentricity of the ellipses was used to quantify deviations from isotropic diffusion. Information on directed motion was shown in three maps: A velocity map, representing the amplitude of the local velocities in a colour code. A quiver plot, illustrating the orientation of directed motion, and a third map which indicated the relative standard error of the local velocities colour-coded. Finally, a guideline based on random walk simulations was used to identify which of the two motion scenarios dominated locally. Application of the guideline to the VSG dynamics analysed by shortTrAn yielded supermaps that showed the locally dominant motion mode colour-coded. I found that VSG dynamics are dominated by diffusion, but several times faster than previously determined. The diffusion behaviour was additionally characterised by spatial heterogeneity. Moreover, isolated regions exhibiting the characteristics of round and elongated traps were observed on the cell surface. Additionally, VSG dynamics were studied with respect to the entrance of the FP. VSG dynamics in this region displayed similar characteristics compared to the remainder of the cell surface and forces biasing VSGs into the FP were not found. Furthermore, I investigated a potential interference of the attachment of the cytoskeleton to the plasma membrane with the dynamics of VSGs which are anchored to the outer leaflet of the membrane. Preliminary experiments were conducted on osmotically swollen trypanosomes and trypanosomes depleted for a microtubule-associated protein anchoring the subpellicular microtubule cytoskeleton to the plasma membrane. The measurements revealed a trend that detachment of the cytoskeleton could be associated with a reduction in the VSG diffusion coefficient and a loss of elongated traps. The latter could be an indication that these isolated regions were caused by underlying structures associated with the cytoskeleton. The measurements on cells with an intact cytoskeleton were complemented by random walk simulations of VSG dynamics with the newly determined diffusion coefficient on long time scales not accessible in experiments. Simulations showed that passive VSG randomisation is fast enough to allow for a turnover of the full VSG coat within a few minutes. According to an estimate based on the known rate of endocytosis and the newly determined VSG diffusion coefficient, the majority of exocytosed VSGs could escape from the FP to the cell surface without being immediately re-endocytosed.}, subject = {Trypanosoma brucei}, language = {en} } @phdthesis{Iosip2024, author = {Iosip, Anda-Larisa}, title = {Molecular Mechanosensing Mechanisms of the Carnivorous Plant \(Dionaea\) \(muscipula\)}, doi = {10.25972/OPUS-28764}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-287649}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Plants are able to sense mechanical forces in order to defend themselves against predators, for instance by synthesizing repellent compounds. Very few plants evolved extremely sensitive tactile abilities that allow them to perceive, interpret and respond by rapid movement in the milliseconds range. One such rarity is the charismatic Venus flytrap (Dionaea muscipula) - a carnivorous plant which relies on its spectacular active trapping strategy to catch its prey. The snapping traps are equipped with touch-specialised trigger hairs, that upon bending elicit an action potential (AP). This electrical signal originates within the trigger hairs' mechanosensory cells and further propagates throughout the whole trap, alerting the plant of potential prey. Two APs triggered within thirty seconds will set off the trap and more than five APs will initiate the green stomach formation for prey decomposition and nutrient uptake. Neither the molecular components of the plant's AP nor the Venus flytrap's fast closure mechanism have been fully elucidated yet. Therefore, the general objective of this study is to expound on the molecular basis of touch perception: from AP initiation to trap closure and finally to stomach formation. The typical electrical signal in plants lasts for minutes and its shape is determined by the intensity of the mechanical force applied. In contrast, the Venus flytrap's one-second AP is of all-or-nothing type, similar in shape to the animal AP. In order to gain more insight into the molecular components that give rise to the Venus flytrap's emblematic AP, the transcriptomic landscape of its unique mechanotransducer - the trigger hair - was compared to the rest of the non-specialised tissues and organs. Additionally, the transcriptome of the electrically excitable fully-developed adult trap was compared to non-excitable juvenile traps that are unable to produce sharp APs. Together, the two strategies helped with the identification of electrogenic channels and pumps for each step of the AP as follows: (1) the most specific to the trigger hair was the mechanosensitive channel DmMSL10, making up the best candidate for the initial AP depolarization phase, (2) the K+ outward rectifier DmSKOR could be responsible for repolarisation, (3) further, the proton pump DmAHA4, might kick in during repolarisation and go on with hyperpolarisation and (4) the hyperpolarization- and acid-activated K+ inward rectifier KDM1 might contribute to the re-establishment of electrochemical gradient and the resting potential. Responsible for the AP-associated Ca2+ wave and electrical signal propagation, the glutamate-like receptor DmGLR3.6 was also enriched in the trigger hairs. Together, these findings suggest that the reuse of genes involved in electrical signalling in ordinary plants can give rise to the Venus flytrap's trademark AP. The Venus flytrap has been cultivated ever since its discovery, generating more than one hundred cultivars over the years. Among them, indistinguishable from a normal Venus flytrap at first sight, the 'ERROR' cultivar exhibits a peculiar behaviour: it is unable to snap its traps upon two APs. Nevertheless, it is still able to elicit normal APs. To get a better understanding of the key molecular mechanisms and pathways that are essential for a successful trap closure, the 'ERROR' mutant was compared to the functional wild type. Timelapse photography led to the observation that the 'ERROR' mutants were able to leisurely half close their traps when repeated mechanostimulation was applied (10 minutes after 20 APs, 0.03 Hz). As a result of touch or wounding in non-carnivorous plants, jasmonic acid (JA) is synthesized, alerting the plants of potential predators. Curiously, the JA levels were reduced upon mechanostimulation and completely impaired upon wounding in the 'ERROR' mutant. In search of genes accountable for the 'ERROR' mutant's defects, the transcriptomes of the two phenotypes were compared before and after mechanostimulation (1h after 10 APs, 0.01 Hz). The overall dampened response of the mutant compared to the wild type, was reflected at transcriptomic level as well. Only about 50\% of wild type's upregulated genes after touch stimulation were differentially expressed in 'ERROR' and they manifested only half of the wild type's expression amplitude. Among unresponsive functional categories of genes in 'ERROR' phenotype, there were: cell wall integrity surveilling system, auxin biosynthesis and stress-related transcription factors from the ethylene-responsive AP2/ERF and C2H2-ZF families. Deregulated Ca2+-decoding as well as redox-related elements together with JA-pathway components might also contribute to the malfunctioning of the 'ERROR' mutant. As the mutant does not undergo full stomach formation after mechanical treatment, these missing processes represent key milestones that might mediate growth-defence trade-offs under JA signalling. This confirms the idea that carnivory has evolved by recycling the already available molecular machineries of the ubiquitous plant immune system. To better understand the mutant's defect in the trap snapping mechanism, the ground states (unstimulated traps) of the two phenotypes were compared. In this case, many cell wall-related genes (e.g. expansins) were downregulated in the 'ERROR' mutant. For the first time, these data point to the importance of a special cell wall architecture of the trap, that might confer the mechanical properties needed for a functional buckling system - which amplifies the speed of the trap closure. This study provides candidate channels for each of the AP phases that give rise to and shape the sharp Venus flytrap-specific AP. It further underlines the possible contribution of the cell wall architecture to the metastable ready-to-snap configuration of the trap before stimulation - which might be crucial for the buckling-dependent snapping. And finally, it highlights molecular milestones linked to defence responses that ensure trap morphing into a green stomach after mechanostimulation. Altogether, these processes prove to be interdependent and essential for a successful carnivorous lifestyle.}, subject = {Venusfliegenfalle}, language = {en} } @article{PrustyGulveGovindetal.2018, author = {Prusty, Bhupesh K. and Gulve, Nitish and Govind, Sheila and Krueger, Gerhard R. F. and Feichtinger, Julia and Larcombe, Lee and Aspinall, Richard and Ablashi, Dharam V. and Toro, Carla T.}, title = {Active HHV-6 Infection of Cerebellar Purkinje Cells in Mood Disorders}, series = {Frontiers in Microbiology}, volume = {9}, journal = {Frontiers in Microbiology}, doi = {10.3389/fmicb.2018.01955}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369222}, year = {2018}, abstract = {Early-life infections and associated neuroinflammation is incriminated in the pathogenesis of various mood disorders. Infection with human roseoloviruses, HHV-6A and HHV-6B, allows viral latency in the central nervous system and other tissues, which can later be activated causing cognitive and behavioral disturbances. Hence, this study was designed to evaluate possible association of HHV-6A and HHV-6B activation with three different groups of psychiatric patients. DNA qPCR, immunofluorescence and FISH studies were carried out in post-mortem posterior cerebellum from 50 cases each of bipolar disorder (BPD), schizophrenia, 15 major depressive disorder (MDD) and 50 appropriate control samples obtained from two well-known brain collections (Stanley Medical Research Institute). HHV-6A and HHV-6B late proteins (indicating active infection) and viral DNA were detected more frequently (p < 0.001 for each virus) in human cerebellum in MDD and BPD relative to controls. These roseolovirus proteins and DNA were found less frequently in schizophrenia cases. Active HHV-6A and HHV-6B infection in cerebellar Purkinje cells were detected frequently in BPD and MDD cases. Furthermore, we found a significant association of HHV-6A infection with reduced Purkinje cell size, suggesting virus-mediated abnormal Purkinje cell function in these disorders. Finally, gene expression analysis of cerebellar tissue revealed changes in pathways reflecting an inflammatory response possibly to HHV-6A infection. Our results provide molecular evidence to support a role for active HHV-6A and HHV-6B infection in BPD and MDD.}, language = {en} } @article{TichaMoosWajantetal.2018, author = {Ticha, Olga and Moos, Lukas and Wajant, Harald and Bekeredjian-Ding, Isabelle}, title = {Expression of Tumor Necrosis Factor Receptor 2 Characterizes TLR9-Driven Formation of Interleukin-10-Producing B Cells}, series = {Frontiers in Immunology}, volume = {8}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2017.01951}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241323}, year = {2018}, abstract = {B cell-derived interleukin-10 (IL-10) production has been described as a hallmark for regulatory function in B lymphocytes. However, there is an ongoing debate on the origin of IL-10-secreting B cells and lack of specific surface markers has turned into an important obstacle for studying human B regulatory cells. In this study, we propose that tumor necrosis factor receptor 2 (TNFR2) expression can be used for enrichment of IL-10-secreting B cells. Our data confirm that IL-10 production can be induced by TLR9 stimulation with CpG ODN and that IL-10 secretion accompanies differentiation of peripheral blood B cells into plasma blasts. We further show that CpG ODN stimulation induces TNFR2 expression, which correlates with IL-10 secretion and terminal differentiation. Indeed, flow cytometric sorting of TNFR2+ B cells revealed that TNFR2+ and TNFR2- fractions correspond to IL-10+ and IL-10- fractions, respectively. Furthermore, CpG-induced TNFR2+ B cells were predominantly found in the IgM+ CD27+ B cell subset and spontaneously released immunoglobulin. Finally, our data corroborate the functional impact of TNFR2 by demonstrating that stimulation with a TNFR2 agonist significantly augments IL-10 and IL-6 production in B cells. Altogether, our data highlight a new role for TNFR2 in IL-10-secreting human B lymphocytes along with the potential to exploit this finding for sorting and isolation of this currently ill-defined B cell subset.}, language = {en} } @article{KlotzHigginsSchaubmaretal.2019, author = {Klotz, Peter and Higgins, Paul G. and Schaubmar, Andreas R. and Failing, Klaus and Leidner, Ursula and Seifert, Harald and Scheufen, Sandra and Semmler, Torsten and Ewers, Christa}, title = {Seasonal Occurrence and Carbapenem Susceptibility of Bovine Acinetobacter baumannii in Germany}, series = {Frontiers in Microbiology}, volume = {10}, journal = {Frontiers in Microbiology}, doi = {10.3389/fmicb.2019.00272}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325927}, year = {2019}, abstract = {Acinetobacter baumannii is one of the leading causes of nosocomial infections in humans. To investigate its prevalence, distribution of sequence types (STs), and antimicrobial resistance in cattle, we sampled 422 cattle, including 280 dairy cows, 59 beef cattle, and 83 calves over a 14-month period. Metadata, such as the previous use of antimicrobial agents and feeding, were collected to identify putative determining factors. Bacterial isolates were identified via MALDI-TOF/MS and PCR, antimicrobial susceptibility was evaluated via VITEK2 and antibiotic gradient tests, resistance genes were identified by PCR. Overall, 15.6\% of the cattle harbored A. baumannii, predominantly in the nose (60.3\% of the A. baumannii isolates). It was more frequent in dairy cows (21.1\%) than in beef cattle (6.8\%) and calves (2.4\%). A seasonal occurrence was shown with a peak between May and August. The rate of occurrence of A. baumannii was correlated with a history of use of 3rd generation cephalosporins in the last 6 months prior to sampling Multilocus sequence typing (Pasteur scheme) revealed 83 STs among 126 unique isolates. Nine of the bovine STs have previously been implicated in human infections. Besides known intrinsic resistance of the species, the isolates did not show additional resistance to the antimicrobial substances tested, including carbapenems. Our data suggest that cattle are not a reservoir for nosocomial A. baumannii but carry a highly diverse population of this species. Nevertheless, some STs seem to be able to colonize both cattle and humans.}, language = {en} } @article{SchroeterPawelkeBiseniusetal.2018, author = {Schroeter, Matthias L. and Pawelke, Sarah and Bisenius, Sandrine and Kynast, Jana and Schuemberg, Katharina and Polyakova, Maryna and Anderl-Straub, Sarah and Danek, Adrian and Fassbender, Klaus and Jahn, Holger and Jessen, Frank and Kornhuber, Johannes and Lauer, Martin and Prudlo, Johannes and Schneider, Anja and Uttner, Ingo and Th{\"o}ne-Otto, Angelika and Otto, Markus and Diehl-Schmid, Janine}, title = {A Modified Reading the Mind in the Eyes Test Predicts Behavioral Variant Frontotemporal Dementia Better Than Executive Function Tests}, series = {Frontiers in Aging Neuroscience}, volume = {10}, journal = {Frontiers in Aging Neuroscience}, organization = {FTLD Study Group Germany}, doi = {10.3389/fnagi.2018.00011}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234254}, year = {2018}, abstract = {Behavioral variant frontotemporal dementia (bvFTD) is characterized by deep alterations in behavior and personality. Although revised diagnostic criteria agree for executive dysfunction as most characteristic, impairments in social cognition are also suggested. The study aimed at identifying those neuropsychological and behavioral parameters best discriminating between bvFTD and healthy controls. Eighty six patients were diagnosed with possible or probable bvFTD according to Rascovsky et al. (2011) and compared with 43 healthy age-matched controls. Neuropsychological performance was assessed with a modified Reading the Mind in the Eyes Test (RMET), Stroop task, Trail Making Test (TMT), Hamasch-Five-Point Test (H5PT), and semantic and phonemic verbal fluency tasks. Behavior was assessed with the Apathy Evaluation Scale, Frontal Systems Behavioral Scale, and Bayer Activities of Daily Living Scale. Each test's discriminatory power was investigated by Receiver Operating Characteristic curves calculating the area under the curve (AUC). bvFTD patients performed significantly worse than healthy controls in all neuropsychological tests. Discriminatory power (AUC) was highest in behavioral questionnaires, high in verbal fluency tasks and the RMET, and lower in executive function tests such as the Stroop task, TMT and H5PT. As fluency tasks depend on several cognitive functions, not only executive functions, results suggest that the RMET discriminated better between bvFTD and control subjects than other executive tests. Social cognition should be incorporated into diagnostic criteria for bvFTD in the future, such as in the International Classification of Diseases (ICD)-11, as already suggested in the Diagnostic and Statistical Manual for Mental Disorders (DSM)-5.}, language = {en} } @article{VaahtorantaLenhartSuggateetal.2019, author = {Vaahtoranta, Enni and Lenhart, Jan and Suggate, Sebastian and Lenhard, Wolfgang}, title = {Interactive Elaborative Storytelling: Engaging Children as Storytellers to Foster Vocabulary}, series = {Frontiers in Psychology}, volume = {10}, journal = {Frontiers in Psychology}, doi = {10.3389/fpsyg.2019.01534}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232136}, year = {2019}, abstract = {Positive effects of shared reading for children's language development are boosted by including instruction of word meanings and by increasing interactivity. The effects of engaging children as storytellers on vocabulary development have been less well studied. We developed an approach termed Interactive Elaborative Storytelling (IES), which employs both word-learning techniques and children's storytelling in a shared-reading setting. To systematically investigate potential benefits of children as storytellers, we contrasted this approach to two experimental groups, an Elaborative Storytelling group employing word-learning techniques but no storytelling by children and a Read-Aloud group, excluding any additional techniques. The study was a 3 × 2 pre-posttest randomized design with 126 preschoolers spanning 1 week. Measured outcomes were receptive and expressive target vocabulary, story memory, and children's behavior during story sessions. All three experimental groups made comparable gains on target words from pre- to posttest and there was no difference between groups in story memory. However, in the Elaborative Storytelling group, children were the least restless. Findings are discussed in terms of their contribution to optimizing shared reading as a method of fostering language.}, language = {en} } @article{LangFuellsackWajant2018, author = {Lang, Isabell and F{\"u}llsack, Simone and Wajant, Harald}, title = {Lack of Evidence for a Direct Interaction of Progranulin and Tumor Necrosis Factor Receptor-1 and Tumor Necrosis Factor Receptor-2 From Cellular Binding Studies}, series = {Frontiers in Immunology}, volume = {9}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2018.00793}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236373}, year = {2018}, abstract = {Progranulin (PGRN) is a secreted anti-inflammatory protein which can be processed by neutrophil proteases to various granulins. It has been reported that at least a significant portion of the anti-inflammatory effects of PGRN is due to direct high affinity binding to tumor necrosis factor receptor-1 (TNFR1) and TNFR2 and inhibition of tumor necrosis factor (TNF)-induced TNFR1/2 signaling. Two studies failed to reproduce the interaction of TNFR1 and TNFR2 with PGRN, but follow up reports speculated that this was due to varying experimental circumstances and/or the use of PGRN from different sources. However, even under consideration of these speculations, there is still a striking discrepancy in the literature between the concentrations of PGRN needed to inhibit TNF signaling and the concentrations required to block TNF binding to TNFR1 and TNFR2. While signaling events induced by 0.2-2 nM of TNF have been efficiently inhibited by low, near to equimolar concentrations (0.5-2.5 nM) of PGRN in various studies, the reported inhibitory effects of PGRN on TNF-binding to TNFR1/2 required a huge excess of PGRN (100-1,000-fold). Therefore, we investigated the effect of PGRN on TNF binding to TNFR1 and TNFR2 in highly sensitive cellular binding studies. Unlabeled TNF inhibited >95\% of the specific binding of a Gaussia princeps luciferase (GpL) fusion protein of TNF to TNFR1 and TNFR2 and blocked binding of soluble GpL fusion proteins of TNFR1 and TNFR2 to membrane TNF expressing cells to >95\%, too. Purified PGRN, however, showed in both assays no effect on TNF-TNFR1/2 interaction even when applied in huge excess. To rule out that tags and purification- or storage-related effects compromise the potential ability of PGRN to bind TNF receptors, we directly co-expressed PGRN, and as control TNF, in TNFR1- and TNFR2-expressing cells and looked for binding of GpL-TNF. While expression of TNF strongly inhibited binding of GpL-TNF to TNFR1/2, co-expression of PGRN had not effect on the ability of the TNFR1/2-expressing cells to bind TNF.}, language = {en} } @article{WeissZieglerFliesseretal.2018, author = {Weiss, Esther and Ziegler, Sabrina and Fliesser, Mirjam and Schmitt, Anna-Lena and H{\"u}nniger, Kerstin and Kurzai, Oliver and Morton, Charles-Oliver and Einsele, Hermann and Loeffler, Juergen}, title = {First Insights in NK—DC Cross-Talk and the Importance of Soluble Factors During Infection With Aspergillus fumigatus}, series = {Frontiers in Cellular and Infection Microbiology}, volume = {8}, journal = {Frontiers in Cellular and Infection Microbiology}, doi = {10.3389/fcimb.2018.00288}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233565}, year = {2018}, abstract = {Invasive aspergillosis (IA) is an infectious disease caused by the fungal pathogen Aspergillus fumigatus that mainly affects immunocompromised hosts. To investigate immune cell cross-talk during infection with A. fumigatus, we co-cultured natural killer (NK) cells and dendritic cells (DC) after stimulation with whole fungal structures, components of the fungal cell wall, fungal lysate or ligands for distinct fungal receptors. Both cell types showed activation after stimulation with fungal components and were able to transfer activation signals to the counterpart not stimulated cell type. Interestingly, DCs recognized a broader spectrum of fungal components and thereby initiated NK cell activation when those did not recognize fungal structures. These experiments highlighted the supportive function of DCs in NK cell activation. Furthermore, we focused on soluble DC mediated NK cell activation and showed that DCs stimulated with the TLR2/Dectin-1 ligand zymosan could maximally stimulate the expression of CD69 on NK cells. Thus, we investigated the influence of both receptors for zymosan, Dectin-1 and TLR2, which are highly expressed on DCs but show only minimal expression on NK cells. Specific focus was laid on the question whether Dectin-1 or TLR2 signaling in DCs is important for the secretion of soluble factors leading to NK cell activation. Our results show that Dectin-1 and TLR2 are negligible for NK cell activation. We conclude that besides Dectin-1 and TLR2 other receptors on DCs are able to compensate for the missing signal.}, language = {en} } @article{SchurigHaeuslerGrittneretal.2019, author = {Schurig, Johannes and Haeusler, Karl Georg and Grittner, Ulrike and Nolte, Christian H. and Fiebach, Jochen B. and Audebert, Heinrich J. and Endres, Matthias and Rocco, Andrea}, title = {Frequency of Hemorrhage on Follow Up Imaging in Stroke Patients Treated With rt-PA Depending on Clinical Course}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, doi = {10.3389/fneur.2019.00368}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234947}, year = {2019}, abstract = {Background: According to current guidelines, stroke patients treated with rt-PA should undergo brain imaging to exclude intracerebral bleeding 24 h after thrombolysis, before the start of medical secondary prevention. However, the usefulness of routine follow-up imaging with regard to changes in therapeutic management in patients without neurological deterioration is unclear. We hypothesized that follow up brain imaging solely to exclude bleeding in patients who clinically improved after rt-PA application may not be necessary. Methods: Retrospective single-center analysis including stroke patients treated with rt-PA. Records were reviewed for hemorrhagic transformation one day after systemic thrombolysis and brain imaging-based changes in therapeutic management. Twenty-four hour after thrombolysis patients were divided into four groups: (1) increased NIHSS score; (2) unchanged NIHSS score; (3) improved NIHSS score and; (4) NIHSS score = 0. Results: Out of 188 patients (mean age 73 years, 100 female) receiving rt-PA, 32 (17\%) had imaging-proven hemorrhagic transformation including 11 (6\%) patients with parenchymal hemorrhage. Patients in group (1, 2) more often had hypertension (p = 0.015) and more often had parenchymal hemorrhage (9 vs. 4\%; p < 0.206) compared to group (3, 4) and imaging-based changes in therapeutic management were more frequent (19\% vs. 6\%; p = 0.007). Patients of group (3, 4) had no changes in therapeutic management in 94\% of the cases. Patients in group (4) had no hemorrhagic transformation in routine follow-up brain imaging. Conclusions: Frequency of hemorrhagic transformation in Routine follow-up brain imaging and consecutive changes in therapeutic management were different depending on clinical course measured by NHISS score.}, language = {en} } @article{TreffWinkertSarebanetal.2019, author = {Treff, Gunnar and Winkert, Kay and Sareban, Mahdi and Steinacker, J{\"u}rgen M. and Sperlich, Billy}, title = {The Polarization-Index: A Simple Calculation to Distinguish Polarized From Non-polarized Training Intensity Distributions}, series = {Frontiers in Physiology}, volume = {10}, journal = {Frontiers in Physiology}, doi = {10.3389/fphys.2019.00707}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229040}, year = {2019}, abstract = {The training intensity distribution (TID) of endurance athletes has retrieved substantial scientific interest since it reflects a vital component of training prescription: (i) the intensity of exercise and its distribution over time are essential components for adaptation to endurance training and (ii) the training volume (at least for most endurance disciplines) is already near or at maximum, so optimization of training procedures including TID have become paramount for success. This paper aims to elaborate the polarization-index (PI) which is calculated as log10(Zone 1/Zone 2∗Zone 3∗100), where Zones 1-3 refer to aggregated volume (time or distance) spent with low, mid, or high intensity training. PI allows to distinguish between non-polarized and polarized TID using a cut-off > 2.00 a.U. and to quantify the level of a polarized TID. Within this hypothesis paper, examples from the literature illustrating the usefulness of PI-calculation are discussed as well as its limitations. Further it is elucidated how the PI may contribute to a more precise definition of TID descriptors.}, language = {en} } @phdthesis{CruzdeCasas2024, author = {Cruz de Casas, Paulina}, title = {Sphingolipids as modulators of T cell function}, doi = {10.25972/OPUS-35969}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-359698}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The immune system is responsible for the preservation of homeostasis whenever a given organism is exposed to distinct kinds of perturbations. Given the complexity of certain organisms like mammals, and the diverse types of challenges that they encounter (e.g. infection or disease), the immune system evolved to harbor a great variety of distinct immune cell populations with specialized functions. For instance, the family of T cells is sub-divided into conventional (Tconv) and unconventional T cells (UTCs). Tconv form part of the adaptive arm of the immune system and are comprised of αβ CD4+ or CD8+ cells that differentiate from na{\"i}ve to effector and memory populations upon activation and are essential during infection and cancer. Furthermore, UTCs, which include γδ T cells, NKT and MAIT, are involved in innate and adaptive immune responses, due to their dual mode of activation, through cytokines (innate-like) or TCR (adaptive), and function. Despite our understanding of the basic functions of T cells in several contexts, a great number of open questions related to their basic biology remain. For instance, the mechanism behind the differentiation of na{\"i}ve CD4+ and CD8+ T cells into effector and memory populations is not fully understood. Moreover, the exact function and relevance of distinct UTC subpopulations in a physiological context have not been fully clarified. Here, we investigated the factors mediating na{\"i}ve CD8+ T cell differentiation into effector and memory cells. By using flow cytometry, mass spectrometry, enzymatic assays, and transgenic mouse models, we found that the membrane bound enzyme sphingomyelin-phosphodiesterase acid-like 3b (Smpdl3b) is crucial for the maintenance of memory CD8+ T cells. Our data show that the absence of Smpdl3b leads to diminished CD8+ T cell memory, and a loss of stem-like memory populations due to an aggravated contraction. Our scRNA-seq data suggest that Smpdl3b could be involved in clathrinmediated endocytosis through modulation of Huntingtin interacting protein 1 (Hip1) levels, likely regulating TCR-independent signaling events. Furthermore, in this study we explored the role of UTCs in lymph node-specific immune responses. By using transgenic mouse models for photolabeling, lymph node transplantation models, infection models and flow cytometry, we demonstrate that S1P regulates the migration of tissue-derived UTC from tissues to draining lymph nodes, resulting in heterogeneous immune responses mounted by lymph nodes draining different tissues. Moreover, our unbiased scRNAseq and single lineage-deficient mouse models analysis revealed that all UTC lineages (γδ T cells, NKT and MAIT) are organized in functional units, based on transcriptional homogeneity, shared microanatomical location and migratory behavior, and numerical and functional redundancy. Taken together, our studies describe additional cell intrinsic (Smpdl3b) and extrinsic (S1Pmediated migration) functions of sphingolipid metabolism modulating T cell biology. We propose the S1P/S1PR1/5 signaling axis as the potential survival pathway for Smpdl3b+ memory CD8+ T cells and UTCs, mainly in lymph nodes. Possibly, Smpdl3b regulates S1P/S1PR signaling by balancing ligandreceptor endocytosis, while UTCs migrate to lymph nodes during homeostasis to be exposed to specific levels of S1P that assure their maintenance. Our results are clinically relevant, since several drugs modulating the S1P/S1PR signaling axis or the levels of Smpdl3b are currently used to treat human diseases, such as multiple sclerosis and B cell-mediated diseases. We hope that our discoveries will inspire future studies focusing on sphingolipid metabolism in immune cell biology.}, subject = {T-Lymphozyt}, language = {en} } @phdthesis{Amini2024, author = {Amini, Emad}, title = {How central and peripheral clocks and the neuroendocrine system interact to time eclosion behavior in \(Drosophila\) \(melanogaster\)}, doi = {10.25972/OPUS-36130}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-361309}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {To grow larger, insects must shed their old rigid exoskeleton and replace it with a new one. This process is called molting and the motor behavior that sheds the old cuticle is called ecdysis. Holometabolic insects have pupal stages in between their larval and adult forms, during which they perform metamorphosis. The pupal stage ends with eclosion, i.e., the emergence of the adult from the pupal shell. Insects typically eclose at a specific time during the day, likely when abiotic conditions are at their optimum. A newly eclosed insect is fragile and needs time to harden its exoskeleton. Hence, eclosion is regulated by sophisticated developmental and circadian timing mechanisms. In Drosophila melanogaster, eclosion is limited to a daily time window in the morning, regarded as the "eclosion gate". In a population of laboratory flies entrained by light/dark cycles, most of the flies eclose around lights on. This rhythmic eclosion pattern is controlled by the circadian clock and persists even under constant conditions. Developmental timing is under the control of complex hormonal signaling, including the steroid ecdysone, insulin-like peptides, and prothoracicotropic hormone (PTTH). The interactions of the central circadian clock in the brain and a peripheral clock in the prothoracic gland (PG) that produces ecdysone are important for the circadian timing of eclosion. These two clocks are connected by a bilateral pair of peptidergic PTTH neurons (PTTHn) that project to the PG. Before each molt, the ecdysone level rises and then falls shortly before ecdysis. The falling ecdysone level must fall below a certain threshold value for the eclosion gate to open. The activity of PTTHn is inhibited by short neuropeptide F (sNPF) from the small ventrolateral neurons (sLNvs) and inhibition is thought to lead to a decrease in ecdysone production. The general aim of this thesis is to further the understanding of how the circadian clock and neuroendocrinal pathways are coordinated to drive eclosion rhythmicity and to identify when these endocrinal signaling pathways are active. In Chapter I, a series of conditional PTTHn silencing-based behavioral assays, combined with neuronal activity imaging techniques such as non-invasive ARG-Luc show that PTTH signaling is active and required shortly before eclosion and may serve to phase-adjust the activity of the PG at the end of pupal development. Trans-synaptic anatomical stainings identified the sLNvs, dorsal neurons 1 (DN1), dorsal neurons 2 (DN2), and lateral posterior neurons (LPNs) clock neurons as directly upstream of the PTTHn. Eclosion motor behavior is initiated by Ecdysis triggering hormone (ETH) which activates a pair of ventromedial (Vm) neurons to release eclosion hormone (EH) which positively feeds back to the source of ETH, the endocrine Inka cells. In Chapter II trans-synaptic tracing showed that most clock neurons provide input to the Vm and non-canonical EH neurons. Hence, clock can potentially influence the ETH/EH feedback loop. The activity profile of the Inka cells and Vm neurons before eclosion is described. Vm and Inka cells are active around seven hours before eclosion. Interestingly, all EH neurons appear to be exclusively peptidergic. In Chapter III, using chemoconnectomics, PTTHns were found to express receptors for sNPF, allatostatin A (AstA), allatostatin C (AstC), and myosuppressin (Ms), while EH neurons expressed only Ms and AstA receptors. Eclosion assays of flies with impaired AstA, AstC, or Ms signaling do not show arrhythmicity under constant conditions. However, optogenetic activation of the AstA neurons strongly suppresses eclosion. Chapter IV focuses on peripheral ventral' Tracheal dendrite (v'Td) and class IV dendritic arborization (C4da) neurons. The C4da neurons mediate larval light avoidance through endocrine PTTH signaling. The v'Td neurons mainly receive O2/CO2 input from the trachea and are upstream of Vm neurons but are not required for eclosion rhythmicity. Conditional ablation of the C4da neurons or torso (receptor of PTTH) knock-out in the C4da neurons impaired eclosion rhythmicity. Six to seven hours before eclosion, PTTHn, C4da, and Vm neurons are active based on ARG-Luc imaging. Thus, C4da neurons may indirectly connect the PTTHn to the Vm neurons. In summary, this thesis advances our knowledge of the temporal activity and role of PTTH signaling during pupal development and rhythmic eclosion. It further provides a comprehensive characterization of the synaptic and peptidergic inputs from clock neurons to PTTHn and EH neurons. AstA, AstC, and Ms are identified as potential modulators of eclosion circuits and suggest an indirect effect of PTTH signaling on EH signaling via the peripheral sensory C4da neurons.}, subject = {Neuroendokrines System}, language = {en} } @phdthesis{Dehmer2024, author = {Dehmer, Markus}, title = {A novel USP11-TCEAL1-mediated mechanism protects transcriptional elongation by RNA Polymerase II}, doi = {10.25972/OPUS-36054}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360544}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Deregulated expression of MYC oncoproteins is a driving event in many human cancers. Therefore, understanding and targeting MYC protein-driven mechanisms in tumor biology remain a major challenge. Oncogenic transcription in MYCN-amplified neuroblastoma leads to the formation of the MYCN-BRCA1-USP11 complex that terminates transcription by evicting stalling RNAPII from chromatin. This reduces cellular stress and allows reinitiation of new rounds of transcription. Basically, tumors with amplified MYC genes have a high demand on well orchestration of transcriptional processes-dependent and independent from MYC proteins functions in gene regulation. To date, the cooperation between promoter-proximal termination and transcriptional elongation in cancer cells remains still incomplete in its understanding. In this study the putative role of the dubiquitinase Ubiquitin Specific Protease 11 (USP11) in transcription regulation was further investigated. First, several USP11 interaction partners involved in transcriptional regulation in neuroblastoma cancer cells were identified. In particular, the transcription elongation factor A like 1 (TCEAL1) protein, which assists USP11 to engage protein-protein interactions in a MYCN-dependent manner, was characterized. The data clearly show that TCEAL1 acts as a pro-transcriptional factor for RNA polymerase II (RNAPII)-medi- ated transcription. In detail, TCEAL1 controls the transcription factor S-II (TFIIS), a factor that assists RNAPII to escape from paused sites. The findings claim that TCEAL1 outcompetes the transcription elongation factor TFIIS in a non-catalytic manner on chromatin of highly expressed genes. This is reasoned by the need regulating TFIIS function in transcription. TCEAL1 equili- brates excessive backtracking and premature termination of transcription caused by TFIIS. Collectively, the work shed light on the stoichiometric control of TFIIS demand in transcriptional regulation via the USP11-TCEAL1-USP7 complex. This complex protects RNAPII from TFIIS-mediated termination helping to regulate productive transcription of highly active genes in neuroblastoma.}, subject = {Transkription}, language = {en} } @masterthesis{Mutter2024, type = {Bachelor Thesis}, author = {Mutter, Julian}, title = {Modeling and simulation of a propulsive landing system with 3DOF}, doi = {10.25972/OPUS-36930}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369306}, school = {Universit{\"a}t W{\"u}rzburg}, pages = {77}, year = {2024}, abstract = {In this thesis, a model of the dynamics during the landing phase of an interplanetary lander mission is developed in a 3 DOF approach with the focus lying on landing by propulsive means. Based on this model, a MATLAB simulation was developed with the goal of enabling an estimation of the performance and especially the required fuel amount of a propulsive landing system on Venus. This landing system is modeled to be able to control its descent using thrusters and to perform a stable landing at a specified target location. Using this simulation, the planetary environments of Mars and Venus can be simulated and the impact of wind, atmospheric density and gravity as well as of using different thrusters on the fuel consumption and landing abilities of the simulated landing system can be investigated. The comparability of these results with the behavior of real landing systems is validated in this thesis by simulating the Powered Descent Phase of the Mars 2020 mission and comparing the results to the data the Mars 2020 descent stage has collected during this phase of its landing. Further, based on the simulation, the minimal necessary fuel amount for a successful landing on Venus has been determined for different scenarios. The simulation along with these results are a contribution to the research of this thesis's supervisor Clemens Riegler, M.Sc., who will use them for a comparison of different types of landing systems in the context of his doctoral thesis.}, subject = {Raumfahrt}, language = {en} } @misc{AicheleHeurichMuelleretal.2024, author = {Aichele, Thorsten and Heurich, Tina and M{\"u}ller, Noemi and Odenbreit, Carina and Radičević, Jana and Raith, Sarah and R{\"o}seler, Christoph and Zaus, Petra}, title = {7 + 4. SEED - Scenarios for the Use of ePortfolios in Digital Learning}, doi = {10.25972/OPUS-37009}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370091}, pages = {41}, year = {2024}, abstract = {The SEED project is developing ePortfolios for teaching at the Julius-Maximilians-Universit{\"a}t W{\"u}rzburg. ePortfolios make it possible to further develop teaching and learning in a competence-oriented manner and to strengthen the individual reflection aspect of academic studies to support training professional skills. A total of seven use cases were developed. They provide examples of how ePortfolios can be used in university teaching. Four exam variants help to illustrate both subject-specific and reflective components when examining using ePortfolios.}, subject = {ePortfolio}, language = {en} } @phdthesis{GamboaVargas2024, author = {Gamboa Vargas, Juan Fernando}, title = {Receptors of the TNFSF in the biology and regulation of Tregs}, doi = {10.25972/OPUS-36980}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369801}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In this work we expanded upon a study from our group where a ligand-based TNF-α mutein was developed to engage specifically TNFR2 and not TNFR1 activating Tregs and expanding them, which in an allo-HCT context conferred protection from GvHD. Fusing TNF trimers to the heavy chain of an Fc-dead and mouse irrelevant antibody, a new generation of this agonist was developed called NewSTAR2. It is believed that other members of the TNFSF can also target Tregs, therefore additional agonists against DR3 and GITR were developed under the same principles as for NewSTAR2. Phenotyping analysis of the expression of these three receptors were done to confirm their specificity for Tregs before in vitro and in vivo testings with mice or murine splenic cells. A potent expansion of Tregs was seen with NewSTAR2 and the other agonists as well as upregulation of activation markers on Tregs. Thorough analyses with NewSTAR2-treated mice showed how Tregs in several immune and non-immune organs were expanded and upregulated immunomodulatory receptors. A miniature suppressive assay and other cocultures with responder cells confirmed their enhanced suppression over unstimulated Tregs through contact dependent and independent mechanisms. Despite other myeloid cells also being increased after treatment, no undesired effects were observed under steady-state and prophylactic administration of a single dose of NewSTAR2 improved survival frequencies and lessened development of clinical symptoms. Prophylactic treatment with the other TNFRSF agonists showed similar protection yet Fc(DANA)-muTL1A was superior in in terms of less death events and lower clinical score. It was found that not all the three TNFSF members have redundant functions as development of skin lesions was observed with GITRL-based agonist Fc(DANA)-muGITRL, although its expansion of Tregs in steady-state was remarkable with no apparent adverse effects. Neither agonist had an impact on donor cell engraftment or allorective T cell response, however NewSTAR2-treatmend proved to reduce inflammation in small intestine and liver. This work is proof of concept of the effectivity of selectively engaging TNFSF to activate Tregs and expand them systemically allowing them to control strong and complex immune interactions like those governing GvHD.}, subject = {Regulatorischer T-Lymphozyt}, language = {en} } @phdthesis{Kawan2024, author = {Kawan, Mona}, title = {The membrane trafficking protein myoferlin is a novel interactor of p97}, doi = {10.25972/OPUS-28121}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-281218}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {p97 uses the energy of ATP hydrolysis to unfold and thereby segregate proteins. It is involved in various cellular processes such as proteasomal degradation, DNA damage repair, autophagy, and endo-lysosomal trafficking. The specificity for these processes is controlled by more than 30 regulatory cofactors. Interactions of p97 with cofactors and target proteins are known to be highly dynamic and transient. To identify new interaction partners and to uncover novel cellular functions of p97, the interactome of endogenous p97 was determined by using in cellulo crosslinking followed by immunoprecipitation and mass spectrometry. Myoferlin (MYOF) was identified as a novel interactor of p97 and the interaction was validated in reciprocal immunoprecipitation experiments for different cell lines. The ferlin family member MYOF is a tail-anchored membrane protein containing multiple C2 domains. MYOF is involved in various membrane repair and trafficking processes such as the endocytic recycling of cell surface receptors. The MYOF interactome was determined by mass spectrometry. Among others, the p97 cofactor PLAA, CD71 and Rab14 were identified as common interactors of p97 and MYOF. Immunoprecipitation experiments with PLAA KO cells revealed that the interaction between MYOF and p97 depends on PLAA. Immunofluorescence microscopy showed a co-localization of MYOF with Rab14 and Rab11, which are both involved in endocytic recycling pathways. Furthermore, immunofluoroscence experiments revealed that MYOF and the p97 cofactor PLAA are localized to Rab14- and Rab5-positive endosomal compartments. Using p97 inhibitors and p97 trapping mutants, the presence of p97 at MYOF-positive and Rab14-positive structures could be demonstrated. Consistent with this finding, the endocytic recycling of transferrin was delayed upon inhibition of p97. Taken together, this work identified MYOF as a novel interactor of p97 and suggests a role for p97 in the recycling of endocytic cargo.}, subject = {Endosom}, language = {en} } @phdthesis{Fohmann2024, author = {Fohmann, Ingo}, title = {The Role of Sphingosine 1-phosphate and S1PR1-3 in the Pathophysiology of Meningococcal Meningitis}, doi = {10.25972/OPUS-36976}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369764}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Neisseria meningitidis (N. meningitidis) is an obligate human pathogen which causes live-threatening sepsis and meningitis. The fatality rate after meningococcal infection is high and surviving patients often suffer from severe sequelae. To cause meningitis, N. meningitidis must overcome the endothelium of the blood-brain barrier. The bacterium achieves this through the interaction with endothelial surface receptors leading to alternations of the cellular metabolism and signaling, which lastly results in cellular uptake and barrier traversal of N. meningitidis. Sphingosine 1-phosphate (S1P) is a lipid mediator that belongs to the class of sphingolipids and regulates the integrity of the blood-brain barrier through the interaction with its cognate receptors S1P receptors 1-3 (S1PR1-3). In this study, high performance liquid chromatography coupled with mass spectrometry (LC-MS/MS) was used to generate a time-resolved picture of the sphingolipid metabolism in a brain endothelial cell line (hCMEC/D3) upon meningococcal infection. Among various changes, S1P was elevated in the cellular compartment as well as in the supernatant of infected hCMEC/D3s. Analysis of mRNA expression in infected hCMEC/D3s with quantitative real-time polymerase chain reaction (RT-qPCR) revealed that the increase in S1P could be attributed to the enhanced expression of the S1P-generating enzyme sphingosine kinase 1 (SphK1). Antibody-based detection of SphK1 protein or phosphorylation at SphK1 residue Serine 225 in hCMEC/D3 plasma membrane fractions via Western Blot revealed that N. meningitidis also induced SphK1 phospho-activation and recruitment to the plasma membrane. Importantly, recruitment of SphK1 to the plasma membrane increases the probability of substrate encounter, thus elevating SphK activity. Enhanced SphK activity was also reflected on a functional level, as detected by a commercially available ATP depletion assay used for measuring the enzymatic activity of SphK. Infection of hCMEC/D3 cells with pilus-deficient mutants resulted in a lower SphK activation compared to the N. meningitidis wild type strain. hCMEC/D3 treatment with pilus-enriched protein fractions showed SphK activation similar to the infection with living bacteria and could be ascribed to pilus interaction with the membrane-proximal domain of cellular surface receptor CD147. Inhibition of SphK1 or SphK2 through pre-treatment with specific inhibitors or RNA interference reduced uptake of N. meningitidis into hCMEC/D3 cells, as measured with Gentamicin protection assays. Released S1P induced the phospho-activation of epidermal growth factor receptor (EGFR) via S1PR2 activation, whose expression was also increasing during infection. Furthermore, S1PR2 blockage had a preventive effect on bacterial invasion into hCMEC/D3 cells. On the contrary, activation of S1PR1+3 also reduced bacterial uptake, indicating an opposing regulatory role of S1PR1+3 and S1PR2 during N. meningitidis uptake. Moreover, SphK2 inhibition prevented inflammatory cytokine expression as well as release of interleukin-8 after N. meningitidis infection. Taken together, this study demonstrates the central role of S1P and its cognate receptors S1PR1-3 in the pathophysiology of meningococcal meningitis.}, subject = {Blut-Hirn-Schranke}, language = {en} } @phdthesis{Franken2024, author = {Franken, Robert}, title = {Precision Predictions for \(\mathrm W^+ \mathrm W^-\) Scattering at the LHC}, doi = {10.25972/OPUS-36944}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369445}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In this thesis we examine the vector boson scattering (VBS) process \(\mathrm p \mathrm p \to \mathrm e^+ \nu_\mathrm e\mu^-\bar\nu_\mu\mathrm j\mathrm j +X\) (short: \(\mathrm W^+\mathrm W^-\) scattering) at NLO accuracy in two experimental setups by performing a Monte Carlo analysis of a \(13\,\mathrm{TeV}\) LHC run. \(\mathrm W^+\mathrm W^-\) scattering shows similarities and differences compared to the scattering of other vector bosons. We present a detailed description of the types of appearing subprocesses and background processes. We give insight into our code which solves the problems we are faced within \(\mathrm W^+\mathrm W^-\) scattering. This is especially the presence of the Higgs-boson resonance in the fiducial phase-space region. Particular attention is dedicated to the permutation of resonances. The integrated signal cross section at LO \(\mathcal O(\alpha^6)\) amounts to \(2.6988(3)\,\mathrm{fb}\) and \(1.5322(2)\,\mathrm{fb}\), respectively, in the two experimental setups. The LO QCD-induced background of \(\mathcal O(\alpha_\mathrm s^2\alpha^4)\) amounts to \(6.9115(9)\,\mathrm{fb}\) and \(1.6923(3)\,\mathrm{fb}\). The EW corrections to the signal are \(-11.4\\%\) and \(-6.7\\%\), the QCD corrections amount to \(-5.2\\%\) and \(-23.0\\%\). The EW corrections to the background are \(-8.3\\%\) and \(-5.3\\%\), the QCD corrections amount to \(-30.3\\%\) and \(-77.6\\%\). Our results for the QCD corrections and the QCD-induced background include a large uncertainty from varying the renormalisation and factorisation scale, and we discuss improvements for future calculations. We show the differential cross sections with unique features of \(\mathrm W^+\mathrm W^-\) scattering compared to other VBS processes and investigate in particular the subprocess of Higgs-boson production by using a modified version of our setups.}, subject = {W-Boson}, language = {en} } @phdthesis{Baumann2024, author = {Baumann, Johannes}, title = {Induced Superconductivity in HgTe Quantum Point Contacts}, doi = {10.25972/OPUS-36940}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369405}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In this thesis, the Josephson effect in mercury telluride based superconducting quantum point contacts (SQPCs) is studied. Implementing such confined structures into topological superconductors has been proposed as a means to detect and braid Majorana fermions. For the successful realization of such experiments though, coherent transport across the constriction is essential. By demonstrating the Josephson effect in a confined topological system, the presented experiments lay the foundation for future quantum devices that can be used for quantum computation. In addition, the experiments also provide valuable insights into the behavior of the Josephson effect in the low-channel limit (N<20). Due to the confinement of the weak link, we can also study the Josephson effect in a topological insulator, where the edge modes interact. In conclusion, this thesis discusses the fabrication of, and low-temperature measurements on mercury telluride quantum point contacts embedded within Josephson junctions. We find that the merging of the currently used fabrication methods for mercury telluride quantum point contacts and Josephson junctions does not yield a good enough device quality to resolve subbands of the quantum point contact as quantization effects in the transport properties. As we attribute this to the long dry etching time that is necessary for a top-contact, the fabrication process was adapted to reduce the defect density at the superconductor-semiconductor interface. Employing a technique that involves side contacting the mercury telluride quantum well and reducing the size of the mercury telluride mesa to sub-micrometer dimensions yields a quantized supercurrent across the junction. The observed supercurrent per mode is in good agreement with theoretical predictions for ballistic, one-dimensional modes that are longer than the Josephson penetration depth. Moreover, we find that oscillatory features superimpose the plateaus of the supercurrent and the conductance. The strength of these oscillatory features are sample-dependent and complicate the identification of plateaus. We suggest that the oscillatory features originate mainly from local defects and the short gate electrode. Additionally, resonances are promoted within the weak link if the transparency of the superconductor-HgTe interface differs from one. Furthermore, the research explores the regimes of the quantum spin Hall effect and the 0.5 anomaly. Notably, a small yet finite supercurrent is detected in the QSH regime. In samples fabricated from thick mercury telluride quantum wells, the supercurrent appears to vanish when the quantum point contact is tuned into the regime of the 0.5 anomaly. For samples fabricated from thin mercury telluride quantum wells, the conductance as well as the supercurrent vanish for strong depopulation. In these samples though, the supercurrent remains detectable even for conductance values significantly below 2 e²/h. Numerical calculation reproduce the transport behavior of the superconducting quantum point contacts. Additionally, the topological nature of the weak link is thoroughly investigated using the supercurrent diffraction pattern and the absorption of radio frequency photons. The diffraction pattern reveals a gate independent, monotonous decay of \$I_\text{sw}(B)\$, which is associated with the quantum interference of Andreev bound states funneled through the quantum point contact. Interestingly, the current distribution in the weak link appears unaffected as the quantum point contact is depleted. In the RF measurements, indications of a 4π periodic supercurrent are observed as a suppression of odd Shapiro steps. The ratio of the 4π periodic current to the 2π periodic current appears to decrease for smaller supercurrents, as odd Shapiro steps are exclusively suppressed for large supercurrents. Additionally, considering the observation that the supercurrent is small when the bulk modes in the quantum point contact are fully depleted, we suggest that the re-emerging of odd Shapiro steps is a consequence of the group velocity of the edge modes being significantly suppressed when the bulk modes are absent. Consequently, the topological nature of the superconducting quantum point contact is only noticeable in the transport properties when bulk modes are transmitted through the superconducting quantum point contact. The shown experiments are the first demonstration of mercury telluride superconducting quantum point contacts that exhibit signatures of quantization effects in the conductance as well as the supercurrent. Moreover, the experiments suggest that the regime of interacting topological edge channels is also accessible in mercury telluride superconducting quantum point contacts. This is potentially relevant for the realization of Majorana fermions and their application in the field of quantum computation.}, subject = {Topologischer Isolator}, language = {en} } @phdthesis{Waltmann2024, author = {Waltmann, Maria}, title = {Neurocognitive mechanisms of loss of control in Binge Eating Disorder}, doi = {10.25972/OPUS-36430}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-364300}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Binge Eating Disorder (BED) is a common, early-onset mental health condition characterised by uncontrollable episodes of overeating followed by negative emotions such as guilt and shame. An improved understanding of the neurocognitive mechanisms underlying BED is central to the development of more targeted and effective treatments. This thesis comprises a systematic review and three empirical studies contributing to this endeavour. BED can be thought of as a disorder of cognitive-behavioural control. Indeed, self-report evidence points towards enhanced impulsivity and compulsivity in BED. However, retrospective self-reports do not capture the mechanisms underlying impulsive and compulsive lapses of control in the moment. The systematic review therefore focussed on the experimental literature on impulsivity and compulsivity in BED. The evidence was very mixed, although there was some indication of altered goal-directed control and behavioural flexibility in BED. We highlight poor reliability of experimental paradigms and the failure to properly account for weight status as potential reasons for inconsistencies between studies. Moreover, we propose that impulsivity and/or compulsivity may be selectively enhanced in negative mood states in BED and may therefore not be consistently detected in lab-based studies. In the empirical studies, we explored the role of behavioural flexibility in BED using experimental and neuroimaging methods in concert with computational modelling. In the first empirical study, we assessed the reliability of a common measure of behavioural flexibility, the Probabilistic Reversal Learning Task (PRLT). We demonstrate that the behavioural and computational metrics of the PRLT have sufficient reliability to justify past and future applications if calculated using hierarchical modelling. This substantially improves reliability by reducing error variance. The results support the use of the PRLT in the second and third empirical studies on development and BED. Because a majority of patients develop BED as adolescents or young adults, we speculated that it may emerge as a consequence of disrupted or deficient maturation of behavioural flexibility. Little is known about typical development in this domain. We therefore investigated normative development of reversal learning from adolescence to adulthood in the second empirical study. Typically- developing adolescents exhibited less adaptive and more erratic and explorative behaviour than adults. This behaviour was accounted for by reduced sensitivity to positive feedback in a reinforcement learning model, and partially mediated by reduced activation reflecting uncertainty in the medial prefrontal cortex, a region known to mature substantially during adolescence. In the third empirical study, we investigated reversal learning in BED, paying special attention to potential biases associated with learning from wins vs learning from losses. We speculated that negative urgency could make it more difficult for BED patients to learn and make decisions under pressure to avoid losses. To dissociate between effects of excess weight and BED, we collected data from obese individuals with and without BED as well as normal-weight controls. As hypothesised, there were subtle neurocognitive differences between obese participants with and without BED with regard to learning to obtain rewards and to avoid losses. Obese individuals showed relatively impaired learning to obtain rewards, while BED patients showed relatively impaired learning to avoid losses. This was reflected in differential learning signals in the brain and associated with BED symptom severity. In sum, this thesis shows that the evidence on impulsivity and compulsivity in BED is inconsistent and offers potential explanations for this inconsistency. It highlights the need for reliability in interindividual difference research and indicates ways to improve it. Further, it charts the typical development of reversal learning from adolescence to adulthood and underscores the relevance of exploration in the context of learning and decision-making in adolescence. Finally, it demonstrates qualitative differences between BED and obesity, hinting at a pivotal role of aversive states in loss of control in BED.}, subject = {Binge-eating Disorder}, language = {en} } @phdthesis{Steinmueller2024, author = {Steinm{\"u}ller, Sophie Anna Maria}, title = {Benzimidazole-Based Photoswitches and Photoswitchable Cannabinoid 2 Receptor Ligands}, doi = {10.25972/OPUS-34894}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-348943}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The field of photopharmacology has attracted considerable attention due to applying the spatial and temporal precision of light to pharmacological systems. Photoswitchable biologically active compounds have proven useful in the field of G protein-coupled receptors (GPCRs), which are of tremendous therapeutic relevance. Generally, the pharmacology of GPCRs is complex, perhaps even more complex than originally thought. Suitable tools are required to dissect the different signalling pathways and mechanisms and to unravel how they are connected in a holistic image. This is reflected in the enormous scientific interest in CB2R, as the neuroprotective and immunomodulatory effects attributed to CB2R agonists have not yet translated into effective therapeutics. This work focused on the development of a novel photoswitchable scaffold based on the privileged structure of benzimidazole and its application in photoswitchable CB2R ligands as photopharmacological tools for studying the CB2R. The visible-light photoswitchable ligand 10d enables the investigation of CB2R activation with regard to βarr2 bias, exhibiting a unique pharmacological profile as a "cis-on" affinity switch at receptor level and as a "trans-on" efficacy-switch in βarr2-mediated receptor internalization. The novel photoswitchable scaffold developed in this work further serves as a guide for the development of novel photoswitchable GPCR ligands based on the privileged structure of benzimidazole. To obtain a different tool compound for studying CB2R activation and signalling mechanisms, a previously reported putatively dualsteric CB2R ligand was rendered photoswitchable, by linking the orthosteric agonist to a CB2R-selective PAM via photoswitchable azobenzene. Compound 27-para exhibits a desirable "cis-on" behaviour across all investigated assays with >10-fold higher potency compared to its trans-isomer and can be used as an efficacy-switch employing specific concentrations.}, subject = {Cannabinoide}, language = {en} } @phdthesis{Kumar2024, author = {Kumar, Manish}, title = {Structural and compositional effects on tree-water relation}, doi = {10.25972/OPUS-32624}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-326245}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Forests are essential sources of tangible and intangible benefits, but global climate change associated with recurrent extreme drought episodes severely affects forest productivity due to extensive tree die-back. On that, it appeals to an urgency for large-scale reforestation efforts to mitigate the impact of climate change worldwide; however, there is a lack of understanding of drought-effect on sapling growth and survival mechanisms. It is also challenging to anticipate how long trees can survive and when they succumb to drought. Hence, to ensure success of reforestation programs and sustainable forest productivity, it is essential to identify drought-resistant saplings. For that, profound knowledge of hydraulic characteristics is needed. To achieve this, the study was split into two phases which seek to address (1) how the hydraulic and anatomical traits influence the sapling's growth rate under drought stress. (2) how plant water potential regulation and physiological traits are linked to species' water use strategies and their drought tolerance. The dissertation is assembled of two study campaigns carried out on saplings at the Chair of Botany II, University of W{\"u}rzburg, Germany. The first study involved three ecologically important temperate broadleaved tree species — saplings of 18-month (Acer pseudoplatanus, Betula pendula, and Sorbus aucuparia) — grown from seeds in contrasting conditions (inside a greenhouse and outside), with the latter being subjected to severe natural heat waves. In the second study, two additional temperate species (Fagus sylvatica and Tilia cordata) were added. The drying-out event was conducted using a randomised blocked design by monitoring plant water status in a climate-controlled chamber and a greenhouse. In campaign I, I present the result based on analysed data of 82 plants of temperate deciduous species and address the juvenile growth rate trade-off with xylem safety-efficiency. Our results indicate biomass production varies considerably due to the contrasted growing environment. High hydraulic efficiency is necessary for increased biomass production, while safety-efficiency traits are decoupled and species-specific. Furthermore, productivity was linked considerably to xylem safety without revealing a well-defined pattern among species. Moreover, plasticity in traits differed between stressed and non-stressed plants. For example, safety-related characteristics were more static than efficiency-related traits, which had higher intra-specific variation. Moreover, we recorded anatomical and leaf traits adjustments in response to a stress condition, but consistency among species is lacking. In campaign II, I combined different ways to estimate the degree of isohydry based on water potential regulation and connected the iso-anisohydric spectrum (i.e., hydroscape area, HSA) to hydraulic traits to elucidate actual plant performance during drought. We analysed plant water potential regulation (Ψpd and Ψmd) and stomatal conductance of 28-29 month saplings of five species. I used a linear mixed modelling approach that allowed to control individual variations to describe the water potential regulation and tested different conceptual definitions of isohydricity. The combined methods allowed us to estimate species' relative degree of isohydry. Further, we examined the traits coordination, including hydraulic safety margin, HSM; embolism resistance, P88; turgor loss, Ψtlp; stomata closure, Ps90; capacitance, C; cuticular conductance, gmin, to determine time to hydraulic failure (Thf). Thf is the cumulative effect of time to stomata closure (Tsc) and time after stomatal closure to catastrophic hydraulic failure (Tcrit). Our results show the species' HSA matches their stomatal stringency, which confirms the relationship between stomatal response and leaf water potential decline. Species that close stomata at lower water potential notably had a larger HSA. Isohydric behaviour was mostly associated with leaf hydraulic traits and poorly to xylem safety traits. Species' degree of isohydry was also unrelated to the species' time to death during drying-out experiments. This supports the notion that isohydry behaviours are linked to water use rather than drought survival strategies. Further, consistent with our assumptions, more isohydric species had larger internal water storage and lost their leaf turgor at less negative water potentials. Counter to our expectations, neither embolism resistance nor the associated hydraulic safety margins were related to metrics of isohydry. Instead, our results indicate traits associated with plant drought response to cluster along two largely independent axes of variation (i.e., stomatal stringency and xylem safety). Furthermore, on the temporal progression of plant drought responses, stomatal closure is critical in coordinating various traits to determine species' hydraulic strategies. Desiccation avoidance strategy was linked to Tsc and coordinated traits response of Ps90, Ψtlp, and HSA, whereas desiccation tolerance was related to Tcrit and traits such as lower P88 value, high HSM, and lower gmin. Notably, the shoot capacitance (C) is crucial in Thf and exhibits dichotomous behaviour linked to both Tsc and Tcrit. In conclusion, knowledge of growth rate trade-offs with xylem safety-efficiency combined with traits linked to species' hydraulic strategies along the isohydry could substantially enhance our ability to identify drought-resistant saplings to ensure the success of reforestation programs and predicting sensitivity to drought for achieving sustainable forest ecosystems.}, subject = {Wachstumsrate}, language = {en} } @phdthesis{Jorgacevic2024, author = {Jorgacevic, Ivana}, title = {Elucidating the interconnection of GvHD and Western diet-induced atherosclerosis}, doi = {10.25972/OPUS-32579}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325792}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Allogeneic hematopoietic cell transplantation (Allo-HCT) is the main and only treatment for many malignant and non-malignant haematological disorders. Even though the treatment has improved through the years and patient life expectancy has increased, graft versus host disease (GvHD) is still considered the main obstacle and one of the main reasons for increased mortality. Furthermore, improved patient's survival and life expectancy brought into question the late post-HCT complications. The leading cause of late death after allo-HCT is the relapse of primary disease as well as chronic GvHD (cGvHD). However, a clear relationship was also described with pulmonary complications, endocrine dysfunction and infertility, and cataracts in post-HCT patients. In the last years big concern regarding a cumulative cardiovascular incidence in long-term survivors has been raised. Severe cardiovascular disease (CVD) is caused by atherosclerosis which is considered a chronic inflammatory disease of blood vessels. As such, it takes a long time from endothelial damage, as the onset event, and followed plaque formation to a manifestation of severe consequences, such as stroke, coronary heart disease, or peripheral arterial disease. Endothelial damage is well documented in patients post-HCT. In the context of allo-HCT, the endothelial damage is induced by the conditioning regimen with or without total body irradiation (TBI). Furthermore, endothelial cells (ECs) have been documented as a target of GvHD and increased concentration of circulating endothelial cells (CEC) coinciding with an increase in the number of circulating alloreactive T cells. According to 2021 ESC Guidelines on CVD prevention, the main atherosclerotic CVD (ASCVD) risk factors are blood apolipoprotein B (ApoB)-containing lipoproteins (of which low-density lipoprotein (LDL) is the most abundant), high blood pressure, cigarette smoking and diabetes mellitus (DM). GvHD is considered a high-risk factor for the onset of dyslipidaemia, hypertension, and DM. Overall, the risk of premature cardiovascular death is 2.7 fold increased in comparison to the general population, while the cumulative incidence of cardiovascular complications was shown to be up to 47\% at ten years after reduced intensity conditioning (RIC), post-HCT. However, up to date, there are no available studies elucidating the interconnection between GvHD and atherosclerosis. The goal of this study was, therefore, to investigate the involvement of GvHD in the progression of atherosclerosis as well as to elucidate whether cytotoxic, CD8+ T cells that were shown to play a significant role in endothelial damage during the course of skin GvHD on one hand, and inducers of formation of unstable plaque on the other, are involved in this interconnection. For that purpose we established a novel minor histocompatibility anti gens (miHAg) allo-HCT Western diet (WD)-induced atherosclerosis mouse model. We were able to show that GvHD has a significant impact on atherosclerosis development in B6.Ldlr-/- recipient mice even in the absence of overt clinical disease activity. It seems that the impact is at least partly induced by CD8+ T cells, that showed significantly increased infiltration of aortic lesions in mice facing subclinical GvHD. As studies have shown in regular atherosclerotic mouse models as well as in humans, these CD8+ T cells exhibited not only increased expression of genes involved in activation, survival and differentiation to cytotoxic phenotype, but also some genes pointing out their exhaustion, that were absent in CD4+ T cell cluster. When anti-CD8β antibody was applied once per week along with WD feeding for eight weeks, the plaque formation was significantly reduced in aorta and aortic root pointing out the importance of these cells in an alloreactivity induced lesion formation. Furthermore, anti-CD8β treatment led to significantly decreased necrotic core formation followed by overall increase in plaque stability. Strikingly, bone marrow plus T cells (BMT) recipients fed WD showed significantly increased serum cholesterol levels in comparison to bone marrow (BM) (a group lacking alloreactive T cells that induce GvHD). This effect was reversed when anti-CD8β treatment was applied, suggesting, at least partly, an impact of alloreactive CD8+ T cells on cholesterol levels. Expression of genes responsible for lipid metabolism pointed out the tendency of the liver to regulate the increased cholesterol levels, however, the mechanism behind this phenotype still remains to be revealed. On the other hand, the impact of obesity, induced by chronic high-fat diet (HFD) feeding, has been shown to be an independent risk factor for gastrointestinal GvHD. Similarly, in major histocompatibility complex (MHC) disparate allo-HCT mouse model, we have noticed that even short-term WD intake leads to a significant decrease in survival of mice post-HCT. When the concentration of transplanted alloreactive T cells was reduced, the survival was improved, pointing out the involvement of these cells in the pathogenesis. Additionally, bioluminescence imaging (BLI) during initiation and effector phase of acute GvHD (aGvHD) revealed increased infiltration of alloreactive T cells in mice fed WD. Studies in an obesity model, we could confirm the involvement of specifically CD4+ T cells in WD induced impact, as the relative number of these cells was significantly increased in small intestine on day six post-HCT in mice fed WD. This increased intestinal infiltration was preceded by increase in the number of alloreactive T cells expressing intestine homing receptor (α4β7 integrin) in peripheral lymph nodes (LNs). Even though the number of T cells was not changed in the spleen of WD fed mice, the subset of CD4+ and CD8+ T cells that were highly secreting TNFα was increased as well as the expression of genes regulating pro-inflammatory cytokines such as IL-6 and interferon (IFN)γ pointing out significant WD-induced inflammation. Moreover, slight tendency towards increased intestinal permeability and load of translocated luminal bacteria, that we observed, could induce severe endotoxemia and dysregulated systemic immune response that could lead to detrimental induction of cell death. Justifying our speculations, we noted increased levels of transaminases and an increase in lactate dehydrogenase (LDH) levels (pointing out significant tissue damages). However, the exact mechanism behind this detrimental WD impact still remains to be elucidated.}, subject = {Periphere Stammzellentransplantation}, language = {en} } @phdthesis{Kreisz2024, author = {Kreisz, Philipp}, title = {Group S1 bZIP transcription factors regulate sink tissue development by controlling carbon and nitrogen resource allocation in \(Arabidopsis\) \(thaliana\)}, doi = {10.25972/OPUS-32192}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321925}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The evolutionary success of higher plants is largely attributed to their tremendous developmental plasticity, which allows them to cope with adverse conditions. However, because these adaptations require investments of resources, they must be tightly regulated to avoid unfavourable trade-offs. Most of the resources required are macronutrients based on carbon and nitrogen. Limitations in the availability of these nutrients have major effects on gene expression, metabolism, and overall plant morphology. These changes are largely mediated by the highly conserved master kinase SNF1-RELATED PROTEIN KINASE1 (SnRK1), which represses growth and induces catabolic processes. Downstream of SnRK1, a hub of heterodimerising group C and S1 BASIC LEUCINE ZIPPER (bZIP) transcription factors has been identified. These bZIPs act as regulators of nutrient homeostasis and are highly expressed in strong sink tissues, such as flowers or the meristems that initiate lateral growth of both shoots and roots. However, their potential involvement in controlling developmental responses through their impact on resource allocation and usage has been largely neglected so far. Therefore, the objective of this work was to elucidate the impact of particularly S1 bZIPs on gene expression, metabolism, and plant development. Due to the high homology and suspected partial redundancy of S1 bZIPs, higher order loss-of-function mutants were generated using CRISPR-Cas9. The triple mutant bzip2/11/44 showed a variety of robust morphological changes but maintained an overall growth comparable to wildtype plants. In detail however, seedlings exhibited a strong reduction in primary root length. In addition, floral transition was delayed, and siliques and seeds were smaller, indicating a reduced supply of resources to the shoot and root apices. However, lateral root density and axillary shoot branching were increased, suggesting an increased ratio of lateral to apical growth in the mutant. The full group S1 knockout bzip1/2/11/44/53 showed similar phenotypes, albeit far more pronounced and accompanied by growth retardation. Metabolomic approaches revealed that these architectural changes were accompanied by reduced sugar levels in distal sink tissues such as flowers and roots. Sugar levels were also diminished in leaf apoplasts, indicating that long distance transport of sugars by apoplastic phloem loading was impaired in the mutants. In contrast, an increased sugar supply to the proximal axillary buds and elevated starch levels in the leaves were measured. In addition, free amino acid levels were increased in bzip2/11/44 and bzip1/2/11/44/53, especially for the important transport forms asparagine and glutamine. The increased C and N availability in the proximal tissues could be the cause of the increased axillary branching in the mutants. To identify bZIP target genes that might cause the observed shifts in metabolic status, RNAseq experiments were performed. Strikingly, clade III SUGARS WILL EVENTUALLY BE EXPORTED (SWEET) 8 genes were abundant among the differentially expressed genes. As SWEETs are crucial for sugar export to the apoplast and long-distance transport through the phloem, their reduced expression is likely to be the cause of the observed changes in sugar allocation. Similarly, the reduced expression of GLUTAMINE AMIDOTRANSFERASE 1_2.1 (GAT1_2.1), which exhibits glutaminase activity, could be an explanation for the abundance of glutamine in the mutants. Additional experiments (ATAC-seq, DAP� seq, PTA, q-RT-PCR) supported the direct induction of SWEETs and GAT1_2.1 by S1 bZIPs. To confirm the involvement of these target genes in the observed S1 bZIP mutant phenotypes, loss-of-function mutants were obtained, which showed moderately increased axillary branching. At the same time, the induced overexpression of bZIP11 in axillary meristems had the opposite effect. Collectively, a model is proposed for the function of S1 bZIPs in regulating sink tissue development. For efficient long-distance sugar transport, bZIPs may be required to induce the expression of clade III SWEETs. Thus, reduced SWEET expression in the S1 bZIP mutants would lead to a decrease in apoplastic sugar loading and a reduced supply to distal sinks such as shoot or root apices. The reduction in long� distance transport could lead to sugar accumulation in the leaves, which would then increasingly be transported via symplastic routes towards proximal sinks such as axillary branches and lateral roots or sequestered as starch. The reduced GAT1_2.1 levels lead to an abundance of glutamine, a major nitrogen transport form. The combined effect on C and N allocation results in increased nutrient availability in proximal tissues, promoting the formation of lateral plant organs. Alongside emerging evidence highlighting the power of bZIPs to steer nutrient allocation in other species, a novel but evolutionary conserved role for S1 bZIPs as regulators of developmental plasticity is proposed, while the generation of valuable data sets and novel genetic resources will help to gain a deeper understanding of the molecular mechanisms involved}, subject = {Molekularbiologie}, language = {en} }