@phdthesis{Schulz2024, author = {Schulz, Daniel}, title = {Development of Inhibitory Control in Kindergarten Children}, doi = {10.25972/OPUS-35715}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357152}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {This dissertation explores the development and assessment of inhibitory control - a crucial component of executive functions - in young children. Inhibitory control, defined as the ability to suppress inappropriate responses (Verbruggen \& Logan, 2008), is essential for adaptable and goal-oriented behavior. The rapid and non-linear development of this cognitive function in early childhood presents unique challenges for accurate assessment. As children age, they often exhibit a ceiling effect in terms of response accuracy (Petersen et al., 2016), underscoring the need to consider response latency as well. Ideally, combining response latency with accuracy could yield a more precise measure of inhibitory control (e.g., Magnus et al., 2019), facilitating a detailed tracking of developmental changes in inhibitory control across a wider age spectrum. The three studies of this dissertation collectively aim to clarify the relationship between response accuracy, response latency, and inhibitory control across different stages of child development. Each study utilizes a computerized Pointing Stroop Task (Berger et al., 2000) to measure inhibitory control, examining the task's validity and the integration of dual metrics for a more comprehensive evaluation. The first study focuses on establishing the validity of using both response accuracy and latency as indicators of inhibitory control. Utilizing the framework of explanatory item-response modeling (De Boeck \& Wilson, 2004), the study revealed how the task characteristics congruency and item position influence both the difficulty level and timing aspects in young children's responses in the computerized Pointing Stroop task. Further, this study found that integrating response accuracy with latency, even in a basic manner, provides additional insights. Building upon these findings, the second study investigates the nuances of integrating response accuracy and latency, examining whether this approach can account for age-related differences in inhibitory control. It also explores whether response latencies may contain different information depending on the age and proficiency of the children. The study leverages novel and established methodological perspectives to integrate response accuracy and latency into a single metric, showing the potential applicability of different approaches for assessing inhibitory control development. The third study extends the investigation to a longitudinal perspective, exploring the dynamic relationship between response accuracy, latency, and inhibitory control over time. It assesses whether children who achieve high accuracy at an earlier age show faster improvement in response latency, suggesting a non-linear maturation pathway of inhibitory control. The study also examines if the predictive value of early response latency for later fluid intelligence is dependent on the response accuracy level. Together, these empirical studies contribute to a more robust understanding of the complex interaction between inhibitory control, response accuracy, and response latency, facilitating valid evaluations of cognitive capabilities in children. Moreover, the findings may have practical implications for designing educational strategies and clinical interventions that address the developmental trajectory of inhibitory control. The nuanced approach advocated in this dissertation suggests prioritizing accuracy in assessment and interventions during the early stages of children's cognitive development, gradually shifting the focus to response latency as children mature and secure their inhibitory control abilities.}, subject = {Kognitive Entwicklung}, language = {en} } @phdthesis{Heimberger2024, author = {Heimberger, Kevin}, title = {Regulation pathways of c-MYC under glutamine-starving conditions in colon carcinoma cells}, doi = {10.25972/OPUS-36331}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363316}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Colon carcinomas (CRC) are statistically among the most fatal cancer types and hence one of the top reasons for premature mortality in the developed world. CRC cells are characterized by high proliferation rates caused by deregulation of gene transcription of proto-oncogenes and general chromosomal instability. On macroscopic level, CRC cells show a strongly altered nutrient and energy metabolism. This work presents research to understand general links between the metabolism and transcription alteration. Mainly focussing on glutamine dependency, shown in colon carcinoma cells and expression pathways of the pro-proliferation protein c-MYC. Previous studies showed that a depletion of glutamine in the cultivation medium of colon carcinoma cell lines caused a proliferation arrest and a strong decrease of overall c-MYC levels. Re-addition of glutamine quickly replenished c-MYC levels through an unknown mechanism. Several proteins altering this regulation mechanism were identified and proposed as possible starting point for further in detail studies to unveil the precise biochemical pathway controlling c-MYC translation repression and reactivation in a rapid manner. On a transcriptional level the formation of RNA:DNA hybrids, so called R-loops, was observed under glutamine depleted conditions. The introduction and overexpression of RNaseH1, a R-loop degrading enzyme, in combination with an ectopically expressed c-MYC variant, independent of cellular regulation mechanisms by deleting the regulatory 3'-UTR of the c-MYC gene, lead to a high rate of apoptotic cells in culture. Expression of a functionally inactive variant of RNaseH1 abolished this effect. This indicates a regulatory function of R-loops formed during glutamine starvation in the presence of c-MYC protein in a cell. Degradation of R-loops and high c-MYC levels in this stress condition had no imminent effect on the cell cycle progression is CRC cells but disturbed the nucleotide metabolism. Nucleotide triphosphates were strongly reduced in comparison to starving cells without R-loop degradation and proliferating cells. This study proposes a model of a terminal cycle of transcription termination, unregulated initiation and elongation of transcription leading to a depletion of energy resources of cells. This could finally lead to high apoptosis of the cells. Sequencing experiments to determine a coinciding of termination sites and R-loop formation sides failed so far but show a starting point for further studies in this essential survival mechanism involving R-loop formation and c-MYC downregulation.}, subject = {Myc}, language = {en} } @article{MorimotoShimadaSugimotoOtowaetal.2018, author = {Morimoto, Yoshiro and Shimada-Sugimoto, Mihoko and Otowa, Takeshi and Yoshida, Shintaro and Kinoshita, Akira and Mishima, Hiroyuki and Yamaguchi, Naohiro and Mori, Takatoshi and Imamura, Akira and Ozawa, Hiroki and Kurotaki, Naohiro and Ziegler, Christiane and Domschke, Katharina and Deckert, J{\"u}rgen and Umekage, Tadashi and Tochigi, Mamoru and Kaiya, Hisanobu and Okazaki, Yuji and Tokunaga, Katsushi and Sasaki, Tsukasa and Yoshiura, Koh-ichiro and Ono, Shinji}, title = {Whole-exome sequencing and gene-based rare variant association tests suggest that PLA2G4E might be a risk gene for panic disorder}, series = {Translational Psychiatry}, volume = {8}, journal = {Translational Psychiatry}, doi = {10.1038/s41398-017-0088-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224192}, year = {2018}, abstract = {Panic disorder (PD) is characterized by recurrent and unexpected panic attacks, subsequent anticipatory anxiety, and phobic avoidance. Recent epidemiological and genetic studies have revealed that genetic factors contribute to the pathogenesis of PD. We performed whole-exome sequencing on one Japanese family, including multiple patients with panic disorder, which identified seven rare protein-altering variants. We then screened these genes in a Japanese PD case-control group (384 sporadic PD patients and 571 controls), resulting in the detection of three novel single nucleotide variants as potential candidates for PD (chr15: 42631993, T>C in GANC; chr15: 42342861, G>T in PLA2G4E; chr20: 3641457, G>C in GFRA4). Statistical analyses of these three genes showed that PLA2G4E yielded the lowest p value in gene-based rare variant association tests by Efficient and Parallelizable Association Container Toolbox algorithms; however, the p value did not reach the significance threshold in the Japanese. Likewise, in a German case-control study (96 sporadic PD patients and 96 controls), PLA2G4E showed the lowest p value but again did not reach the significance threshold. In conclusion, we failed to find any significant variants or genes responsible for the development of PD. Nonetheless, our results still leave open the possibility that rare protein-altering variants in PLA2G4E contribute to the risk of PD, considering the function of this gene.}, language = {en} } @article{SchneiderGlazovKornetal.2018, author = {Schneider, Christian and Glazov, Mikhail M. and Korn, Tobias and H{\"o}fling, Sven and Urbaszek, Bernhard}, title = {Two-dimensional semiconductors in the regime of strong light-matter coupling}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-04866-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231295}, year = {2018}, abstract = {The optical properties of transition metal dichalcogenide monolayers are widely dominated by excitons, Coulomb-bound electron-hole pairs. These quasi-particles exhibit giant oscillator strength and give rise to narrow-band, well-pronounced optical transitions, which can be brought into resonance with electromagnetic fields in microcavities and plasmonic nanostructures. Due to the atomic thinness and robustness of the monolayers, their integration in van der Waals heterostructures provides unique opportunities for engineering strong light-matter coupling. We review first results in this emerging field and outline future opportunities and challenges.}, language = {en} } @article{SelkrigMohammadNgetal.2018, author = {Selkrig, Joel and Mohammad, Farhan and Ng, Soon Hwee and Chua, Jia Yi and Tumkaya, Tayfun and Ho, Joses and Chiang, Yin Ning and Rieger, Dirk and Pettersson, Sven and Helfrich-F{\"o}rster, Charlotte and Yew, Joanne Y. and Claridge-Chang, Adam}, title = {The Drosophila microbiome has a limited influence on sleep, activity, and courtship behaviors}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-28764-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235891}, year = {2018}, abstract = {In animals, commensal microbes modulate various physiological functions, including behavior. While microbiota exposure is required for normal behavior in mammals, it is not known how widely this dependency is present in other animal species. We proposed the hypothesis that the microbiome has a major influence on the behavior of the vinegar fly (Drosophila melanogaster), a major invertebrate model organism. Several assays were used to test the contribution of the microbiome on some well-characterized behaviors: defensive behavior, sleep, locomotion, and courtship in microbe-bearing, control flies and two generations of germ-free animals. None of the behaviors were largely influenced by the absence of a microbiome, and the small or moderate effects were not generalizable between replicates and/or generations. These results refute the hypothesis, indicating that the Drosophila microbiome does not have a major influence over several behaviors fundamental to the animal's survival and reproduction. The impact of commensal microbes on animal behaviour may not be broadly conserved.}, language = {en} } @article{NerreterLetschertGoetzetal.2019, author = {Nerreter, Thomas and Letschert, Sebastian and G{\"o}tz, Ralph and Doose, S{\"o}ren and Danhof, Sophia and Einsele, Hermann and Sauer, Markus and Hudecek, Michael}, title = {Super-resolution microscopy reveals ultra-low CD19 expression on myeloma cells that triggers elimination by CD19 CAR-T}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-10948-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232258}, year = {2019}, abstract = {Immunotherapy with chimeric antigen receptor-engineered T-cells (CAR-T) is under investigation in multiple myeloma. There are reports of myeloma remission after CD19 CAR-T therapy, although CD19 is hardly detectable on myeloma cells by flow cytometry (FC). We apply single molecule-sensitive direct stochastic optical reconstruction microscopy (dSTORM), and demonstrate CD19 expression on a fraction of myeloma cells (10.3-80\%) in 10 out of 14 patients (density: 13-5,000 molecules per cell). In contrast, FC detects CD19 in only 2 of these 10 patients, on a smaller fraction of cells. Treatment with CD19 CAR-T in vitro results in elimination of CD19-positive myeloma cells, including those with <100 CD19 molecules per cell. Similar data are obtained by dSTORM analyses of CD20 expression on myeloma cells and CD20 CAR-T. These data establish a sensitivity threshold for CAR-T and illustrate how super-resolution microscopy can guide patient selection in immunotherapy to exploit ultra-low density antigens.}, language = {en} } @article{OdinChaudhuriVolkmannetal.2018, author = {Odin, Per and Chaudhuri, K. Ray and Volkmann, Jens and Antonini, Angelo and Storch, Alexander and Dietrichs, Espen and Pirtošek, Zvezdan and Henriksen, Tove and Horne, Malcolm and Devos, David and Bergquist, Filip}, title = {Viewpoint and practical recommendations from a movement disorder specialist panel on objective measurement in the clinical management of Parkinson's disease}, series = {npj Parkinson's Disease}, volume = {4}, journal = {npj Parkinson's Disease}, doi = {10.1038/s41531-018-0051-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234435}, year = {2018}, abstract = {Motor aspects of Parkinson's disease, such as fluctuations and dyskinesia, can be reliably evaluated using a variety of "wearable" technologies, but practical guidance on objective measurement (OM) and the optimum use of these devices is lacking. Therefore, as a first step, a panel of movement disorder specialists met to provide guidance on how OM could be assessed and incorporated into clinical guidelines. A key aspect of the incorporation of OM into the management of Parkinson's disease (PD) is defining cutoff values that separate "controlled" from "uncontrolled" symptoms that can be modified by therapy and that relate to an outcome that is relevant to the person with PD (such as quality of life). Defining cutoffs by consensus, which can be subsequently tested and refined, is the first step to optimizing OM in the management of PD. OM should be used by all clinicians that treat people with PD but the least experienced may find the most value, but this requires guidance from experts to allow non-experts to apply guidelines. While evidence is gained for devices that produce OM, expert opinion is needed to supplement the evidence base.}, language = {en} } @article{MusselHewig2019, author = {Mussel, Patrick and Hewig, Johannes}, title = {A neural perspective on when and why trait greed comes at the expense of others}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-47372-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231652}, year = {2019}, abstract = {Depending on the point of view, conceptions of greed range from being a desirable and inevitable feature of a well-regulated, well-balanced economy to the root of all evil - radix omnium malorum avaritia (Tim 6.10). Regarding the latter, it has been proposed that greedy individuals strive for obtaining desired goods at all costs. Here, we show that trait greed predicts selfish economic decisions that come at the expense of others in a resource dilemma. This effect was amplified when individuals strived for obtaining real money, as compared to points, and when their revenue was at the expense of another person, as compared to a computer. On the neural level, we show that individuals high, compared to low in trait greed showed a characteristic signature in the EEG, a reduced P3 effect to positive, compared to negative feedback, indicating that they may have a lack of sensitivity to adjust behavior according to positive and negative stimuli from the environment. Brain-behavior relations further confirmed this lack of sensitivity to behavior adjustment as a potential underlying neuro-cognitive mechanism which explains selfish and reckless behavior that may come at the expense of others.}, language = {en} } @article{SchmittMorasBihlmayeretal.2019, author = {Schmitt, Martin and Moras, Paolo and Bihlmayer, Gustav and Cotsakis, Ryan and Vogt, Matthias and Kemmer, Jeannette and Belabbes, Abderrezak and Sheverdyaeva, Polina M. and Kundu, Asish K. and Carbone, Carlo and Bl{\"u}gel, Stefan and Bode, Matthias}, title = {Indirect chiral magnetic exchange through Dzyaloshinskii-Moriya-enhanced RKKY interactions in manganese oxide chains on Ir(100)}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-10515-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230986}, year = {2019}, abstract = {Localized electron spins can couple magnetically via the Ruderman-Kittel-Kasuya-Yosida interaction even if their wave functions lack direct overlap. Theory predicts that spin-orbit scattering leads to a Dzyaloshinskii-Moriya type enhancement of this indirect exchange interaction, giving rise to chiral exchange terms. Here we present a combined spin-polarized scanning tunneling microscopy, angle-resolved photoemission, and density functional theory study of MnO2 chains on Ir(100). Whereas we find antiferromagnetic Mn-Mn coupling along the chain, the inter-chain coupling across the non-magnetic Ir substrate turns out to be chiral with a 120° rotation between adjacent MnO2 chains. Calculations reveal that the Dzyaloshinskii-Moriya interaction results in spin spirals with a periodicity in agreement with experiment. Our findings confirm the existence of indirect chiral magnetic exchange, potentially giving rise to exotic phenomena, such as chiral spin-liquid states in spin ice systems or the emergence of new quasiparticles.}, language = {en} } @article{SchurrSpindlerKurzetal.2019, author = {Schurr, Yvonne and Spindler, Markus and Kurz, Hendrikje and Bender, Markus}, title = {The cytoskeletal crosslinking protein MACF1 is dispensable for thrombus formation and hemostasis}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-44183-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234966}, year = {2019}, abstract = {Coordinated reorganization of cytoskeletal structures is critical for key aspects of platelet physiology. While several studies have addressed the role of microtubules and filamentous actin in platelet production and function, the significance of their crosstalk in these processes has been poorly investigated. The microtubule-actin cross-linking factor 1 (MACF1; synonym: Actin cross-linking factor 7, ACF7) is a member of the spectraplakin family, and one of the few proteins expressed in platelets, which possess actin and microtubule binding domains thereby facilitating actin-microtubule interaction and regulation. We used megakaryocyte- and platelet-specific Macf1 knockout (Macf1fl/fl, Pf4-Cre) mice to study the role of MACF1 in platelet production and function. MACF1 deficient mice displayed comparable platelet counts to control mice. Analysis of the platelet cytoskeletal ultrastructure revealed a normal marginal band and actin network. Platelet spreading on fibrinogen was slightly delayed but platelet activation and clot traction was unaffected. Ex vivo thrombus formation and mouse tail bleeding responses were similar between control and mutant mice. These results suggest that MACF1 is dispensable for thrombopoiesis, platelet activation, thrombus formation and the hemostatic function in mice.}, language = {en} } @article{ScholzCosgareaSuesskindetal.2018, author = {Scholz, S. L. and Cosgarea, I. and S{\"u}ßkind, D. and Murali, R. and M{\"o}ller, I. and Reis, H. and Leonardelli, S. and Schilling, B. and Schimming, T. and Hadaschik, E. and Franklin, C. and Paschen, A. and Sucker, A. and Steuhl, K. P. and Schadendorf, D. and Westekemper, H. and Griewank, K. G.}, title = {NF1 mutations in conjunctival melanoma}, series = {British Journal of Cancer}, volume = {118}, journal = {British Journal of Cancer}, doi = {10.1038/s41416-018-0046-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233329}, pages = {1243-1247}, year = {2018}, abstract = {Background Conjunctival melanoma is a potentially deadly eye tumour. Despite effective local therapies, tumour recurrence and metastasis remain frequent. The genetics of conjunctival melanomas remain incompletely understood. Methods A large cohort of 63 conjunctival melanomas was screened for gene mutations known to be important in other melanoma subtypes by targeted next-generation sequencing. Mutation status was correlated with patient prognosis. Results Frequent mutations in genes activating the MAP kinase pathway were identified. NF1 mutations were most frequent (n = 21, 33\%). Recurrent activating mutations were also identified in BRAF (n = 16, 25\%) and RAS genes (n = 12, 19\%; 11 NRAS and 1 KRAS). Conclusions Similar to cutaneous melanomas, conjunctival melanomas can be grouped genetically into four groups: BRAF-mutated, RAS-mutated, NF1-mutated and triple wild-type melanomas. This genetic classification may be useful for assessment of therapeutic options for patients with metastatic conjunctival melanoma}, language = {en} } @article{SteuerCostaVanderAuweraGlocketal.2019, author = {Steuer Costa, Wagner and Van der Auwera, Petrus and Glock, Caspar and Liewald, Jana F. and Bach, Maximilian and Sch{\"u}ler, Christina and Wabnig, Sebastian and Oranth, Alexandra and Masurat, Florentin and Bringmann, Henrik and Schoofs, Liliane and Stelzer, Ernst H. K. and Fischer, Sabine C. and Gottschalk, Alexander}, title = {A GABAergic and peptidergic sleep neuron as a locomotion stop neuron with compartmentalized Ca2+ dynamics}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-12098-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223273}, year = {2019}, abstract = {Animals must slow or halt locomotion to integrate sensory inputs or to change direction. In Caenorhabditis elegans, the GABAergic and peptidergic neuron RIS mediates developmentally timed quiescence. Here, we show RIS functions additionally as a locomotion stop neuron. RIS optogenetic stimulation caused acute and persistent inhibition of locomotion and pharyngeal pumping, phenotypes requiring FLP-11 neuropeptides and GABA. RIS photoactivation allows the animal to maintain its body posture by sustaining muscle tone, yet inactivating motor neuron oscillatory activity. During locomotion, RIS axonal Ca2+ signals revealed functional compartmentalization: Activity in the nerve ring process correlated with locomotion stop, while activity in a branch correlated with induced reversals. GABA was required to induce, and FLP-11 neuropeptides were required to sustain locomotion stop. RIS attenuates neuronal activity and inhibits movement, possibly enabling sensory integration and decision making, and exemplifies dual use of one cell across development in a compact nervous system.}, language = {en} } @article{CarradecPelletierDaSilvaetal.2018, author = {Carradec, Quentin and Pelletier, Eric and Da Silva, Corinne and Alberti, Adriana and Seeleuthner, Yoann and Blanc-Mathieu, Romain and Lima-Mendez, Gipsi and Rocha, Fabio and Tirichine, Leila and Labadie, Karine and Kirilovsky, Amos and Bertrand, Alexis and Engelen, Stefan and Madoui, Mohammed-Amin and M{\´e}heust, Rapha{\"e}l and Poulain, Julie and Romac, Sarah and Richter, Daniel J. and Yoshikawa, Genki and Dimier, C{\´e}line and Kandels-Lewis, Stefanie and Picheral, Marc and Searson, Sarah and Jaillon, Olivier and Aury, Jean-Marc and Karsenti, Eric and Sullivan, Matthew B. and Sunagawa, Shinichi and Bork, Peer and Not, Fabrice and Hingamp, Pascal and Raes, Jeroen and Guidi, Lionel and Ogata, Hiroyuki and de Vargas, Colomban and Iudicone, Daniele and Bowler, Chris and Wincker, Patrick}, title = {A global ocean atlas of eukaryotic gene}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, organization = {Tara Oceans Coordinators}, doi = {10.1038/s41467-017-02342-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222250}, year = {2018}, abstract = {While our knowledge about the roles of microbes and viruses in the ocean has increased tremendously due to recent advances in genomics and metagenomics, research on marine microbial eukaryotes and zooplankton has benefited much less from these new technologies because of their larger genomes, their enormous diversity, and largely unexplored physiologies. Here, we use a metatranscriptomics approach to capture expressed genes in open ocean Tara Oceans stations across four organismal size fractions. The individual sequence reads cluster into 116 million unigenes representing the largest reference collection of eukaryotic transcripts from any single biome. The catalog is used to unveil functions expressed by eukaryotic marine plankton, and to assess their functional biogeography. Almost half of the sequences have no similarity with known proteins, and a great number belong to new gene families with a restricted distribution in the ocean. Overall, the resource provides the foundations for exploring the roles of marine eukaryotes in ocean ecology and biogeochemistry.}, language = {en} } @article{BrunkSputhDooseetal.2018, author = {Brunk, Michael and Sputh, Sebastian and Doose, S{\"o}ren and van de Linde, Sebastian and Terpitz, Ulrich}, title = {HyphaTracker: An ImageJ toolbox for time-resolved analysis of spore germination in filamentous fungi}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, doi = {10.1038/s41598-017-19103-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221691}, year = {2018}, abstract = {The dynamics of early fungal development and its interference with physiological signals and environmental factors is yet poorly understood. Especially computational analysis tools for the evaluation of the process of early spore germination and germ tube formation are still lacking. For the time-resolved analysis of conidia germination of the filamentous ascomycete Fusarium fujikuroi we developed a straightforward toolbox implemented in ImageJ. It allows for processing of microscopic acquisitions (movies) of conidial germination starting with drift correction and data reduction prior to germling analysis. From the image time series germling related region of interests (ROIs) are extracted, which are analysed for their area, circularity, and timing. ROIs originating from germlings crossing other hyphae or the image boundaries are omitted during analysis. Each conidium/hypha is identified and related to its origin, thus allowing subsequent categorization. The efficiency of HyphaTracker was proofed and the accuracy was tested on simulated germlings at different signal-to-noise ratios. Bright-field microscopic images of conidial germination of rhodopsin-deficient F. fujikuroi mutants and their respective control strains were analysed with HyphaTracker. Consistent with our observation in earlier studies the CarO deficient mutant germinated earlier and grew faster than other, CarO expressing strains.}, language = {en} } @article{ChinaBurrowsWangetal.2018, author = {China, Swarup and Burrows, Susannah M. and Wang, Bingbing and Harder, Tristan H. and Weis, Johannes and Tanarhte, Meryem and Rizzo, Luciana V. and Brito, Joel and Cirino, Glauber G. and Ma, Po-Lun and Cliff, John and Artaxo, Paulo and Gilles, Mary K. and Laskin, Alexander}, title = {Fungal spores as a source of sodium salt particles in the Amazon basin}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-07066-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222492}, year = {2018}, abstract = {In the Amazon basin, particles containing mixed sodium salts are routinely observed and are attributed to marine aerosols transported from the Atlantic Ocean. Using chemical imaging analysis, we show that, during the wet season, fungal spores emitted by the forest biosphere contribute at least 30\% (by number) to sodium salt particles in the central Amazon basin. Hydration experiments indicate that sodium content in fungal spores governs their growth factors. Modeling results suggest that fungal spores account for ~69\% (31-95\%) of the total sodium mass during the wet season and that their fractional contribution increases during nighttime. Contrary to common assumptions that sodium-containing aerosols originate primarily from marine sources, our results suggest that locally-emitted fungal spores contribute substantially to the number and mass of coarse particles containing sodium. Hence, their role in cloud formation and contribution to salt cycles and the terrestrial ecosystem in the Amazon basin warrant further consideration.}, language = {en} } @article{BruchhagenJarickMewisetal.2018, author = {Bruchhagen, Christin and Jarick, Marcel and Mewis, Carolin and Hertlein, Tobias and Niemann, Silke and Ohlsen, Knut and Peters, Georg and Planz, Oliver and Ludwig, Stephan and Ehrhardt, Christina}, title = {Metabolic conversion of CI-1040 turns a cellular MEK-inhibitor into an antibacterial compound}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-27445-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221648}, year = {2018}, abstract = {Influenza virus (IV) infections cause severe respiratory illnesses that can be complicated by bacterial super-infections. Previously, we identified the cellular Raf-MEK-ERK cascade as a promising antiviral target. Inhibitors of MEK, such as CI-1040, showed potent antiviral activity. However, it remained unclear if this inhibitor and its active form, ATR-002, might sensitize host cells to either IV or secondary bacterial infections. To address these questions, we studied the anti-pathogen activity of ATR-002 in comparison to CI-1040, particularly, its impact on Staphylococcus aureus (S. aureus), which is a major cause of IV super-infections. We analysed IV and S. aureus titres in vitro during super-infection in the presence and absence of the drugs and characterized the direct impact of ATR-002 on bacterial growth and phenotypic changes. Importantly, neither CI-1040 nor ATR-002 treatment led to increased bacterial titres during super-infection, indicating that the drug does not sensitize cells for bacterial infection. In contrast, we rather observed reduced bacterial titres in presence of ATR-002. Surprisingly, ATR-002 also led to reduced bacterial growth in suspension cultures, reduced stress- and antibiotic tolerance without resistance induction. Our data identified for the first time that a particular MEK-inhibitor metabolite exhibits direct antibacterial activity, which is likely due to interference with the bacterial PknB kinase/Stp phosphatase signalling system.}, language = {en} } @article{CastilhoHochleitnerWilsonetal.2018, author = {Castilho, Miguel and Hochleitner, Gernot and Wilson, Wouter and van Rietbergen, Bert and Dalton, Paul D. and Groll, J{\"u}rgen and Malda, Jos and Ito, Keita}, title = {Mechanical behavior of a soft hydrogel reinforced with three-dimensional printed microfibre scaffolds}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-19502-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222280}, year = {2018}, abstract = {Reinforcing hydrogels with micro-fibre scaffolds obtained by a Melt-Electrospinning Writing (MEW) process has demonstrated great promise for developing tissue engineered (TE) constructs with mechanical properties compatible to native tissues. However, the mechanical performance and reinforcement mechanism of the micro-fibre reinforced hydrogels is not yet fully understood. In this study, FE models, implementing material properties measured experimentally, were used to explore the reinforcement mechanism of fibre-hydrogel composites. First, a continuum FE model based on idealized scaffold geometry was used to capture reinforcement effects related to the suppression of lateral gel expansion by the scaffold, while a second micro-FE model based on micro-CT images of the real construct geometry during compaction captured the effects of load transfer through the scaffold interconnections. Results demonstrate that the reinforcement mechanism at higher scaffold volume fractions was dominated by the load carrying-ability of the fibre scaffold interconnections, which was much higher than expected based on testing scaffolds alone because the hydrogel provides resistance against buckling of the scaffold. We propose that the theoretical understanding presented in this work will assist the design of more effective composite constructs with potential applications in a wide range of TE conditions.}, language = {en} } @article{CiuchiDiSanteDobrosavljevićetal.2018, author = {Ciuchi, Sergio and Di Sante, Domenico and Dobrosavljević, Vladimir and Fratini, Simone}, title = {The origin of Mooij correlations in disordered metals}, series = {npj Quantum Materials}, volume = {3}, journal = {npj Quantum Materials}, doi = {10.1038/s41535-018-0119-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223148}, year = {2018}, abstract = {Sufficiently disordered metals display systematic deviations from the behavior predicted by semi-classical Boltzmann transport theory. Here the scattering events from impurities or thermal excitations can no longer be considered as additive-independent processes, as asserted by Matthiessen's rule following from this picture. In the intermediate region between the regime of good conduction and that of insulation, one typically finds a change of sign of the temperature coefficient of resistivity, even at elevated temperature spanning ambient conditions, a phenomenology that was first identified by Mooij in 1973. Traditional weak coupling approaches to identify relevant corrections to the Boltzmann picture focused on long-distance interference effects such as "weak localization", which are especially important in low dimensions (1D and 2D) and close to the zero-temperature limit. Here we formulate a strong-coupling approach to tackle the interplay of strong disorder and lattice deformations (phonons) in bulk three-dimensional metals at high temperatures. We identify a polaronic mechanism of strong disorder renormalization, which describes how a lattice locally responds to the relevant impurity potential. This mechanism, which quantitatively captures the Mooij regime, is physically distinct and unrelated to Anderson localization, but realizes early seminal ideas of Anderson himself, concerning the interplay of disorder and lattice deformations.}, language = {en} } @article{AlZabenMedyukhinaDietrichetal.2019, author = {Al-Zaben, Naim and Medyukhina, Anna and Dietrich, Stefanie and Marolda, Alessandra and H{\"u}nniger, Kerstin and Kurzai, Oliver and Figge, Marc Thilo}, title = {Automated tracking of label-free cells with enhanced recognition of whole tracks}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-39725-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221093}, year = {2019}, abstract = {Migration and interactions of immune cells are routinely studied by time-lapse microscopy of in vitro migration and confrontation assays. To objectively quantify the dynamic behavior of cells, software tools for automated cell tracking can be applied. However, many existing tracking algorithms recognize only rather short fragments of a whole cell track and rely on cell staining to enhance cell segmentation. While our previously developed segmentation approach enables tracking of label-free cells, it still suffers from frequently recognizing only short track fragments. In this study, we identify sources of track fragmentation and provide solutions to obtain longer cell tracks. This is achieved by improving the detection of low-contrast cells and by optimizing the value of the gap size parameter, which defines the number of missing cell positions between track fragments that is accepted for still connecting them into one track. We find that the enhanced track recognition increases the average length of cell tracks up to 2.2-fold. Recognizing cell tracks as a whole will enable studying and quantifying more complex patterns of cell behavior, e.g. switches in migration mode or dependence of the phagocytosis efficiency on the number and type of preceding interactions. Such quantitative analyses will improve our understanding of how immune cells interact and function in health and disease.}, language = {en} } @article{DammertBraegelmannOlsenetal.2019, author = {Dammert, Marcel A. and Br{\"a}gelmann, Johannes and Olsen, Rachelle R. and B{\"o}hm, Stefanie and Monhasery, Niloufar and Whitney, Christopher P. and Chalishazar, Milind D. and Tumbrink, Hannah L. and Guthrie, Matthew R. and Klein, Sebastian and Ireland, Abbie S. and Ryan, Jeremy and Schmitt, Anna and Marx, Annika and Ozretić, Luka and Castiglione, Roberta and Lorenz, Carina and Jachimowicz, Ron D. and Wolf, Elmar and Thomas, Roman K. and Poirier, John T. and B{\"u}ttner, Reinhard and Sen, Triparna and Byers, Lauren A. and Reinhardt, H. Christian and Letai, Anthony and Oliver, Trudy G. and Sos, Martin L.}, title = {MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-11371-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223569}, year = {2019}, abstract = {MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients.}, language = {en} } @article{deJongDinizSalomaetal.2018, author = {de Jong, Simone and Diniz, Mateus Jose Abdalla and Saloma, Andiara and Gadelha, Ary and Santoro, Marcos L. and Ota, Vanessa K. and Noto, Cristiano and Curtis, Charles and Newhouse, Stephen J. and Patel, Hamel and Hall, Lynsey S. and O'Reilly, Paul F. and Belangero, Sintia I. and Bressan, Rodrigo A. and Breen, Gerome}, title = {Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder}, series = {Communications Biology}, volume = {1}, journal = {Communications Biology}, organization = {Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium}, doi = {10.1038/s42003-018-0155-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223622}, year = {2018}, abstract = {Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30\% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.}, language = {en} } @article{DekkerDiekstraPulitetal.2019, author = {Dekker, Annelot M. and Diekstra, Frank P. and Pulit, Sara L. and Tazelaar, Gijs H. P. and van der Spek, Rick A. and van Rheenen, Wouter and van Eijk, Kristel R. and Calvo, Andrea and Brunetti, Maura and Van Damme, Philip and Robberecht, Wim and Hardiman, Orla and McLaughlin, Russell and Chi{\`o}, Adriano and Sendtner, Michael and Ludolph, Albert C. and Weishaupt, Jochen H. and Pardina, Jesus S. Mora and van den Berg, Leonard H. and Veldink, Jan H.}, title = {Exome array analysis of rare and low frequency variants in amyotrophic lateral sclerosis}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-42091-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223686}, year = {2019}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects 1 in ~350 individuals. Genetic association studies have established ALS as a multifactorial disease with heritability estimated at ~61\%, and recent studies show a prominent role for rare variation in its genetic architecture. To identify rare variants associated with disease onset we performed exome array genotyping in 4,244 cases and 3,106 controls from European cohorts. In this largest exome-wide study of rare variants in ALS to date, we performed single-variant association testing, gene-based burden, and exome-wide individual set-unique burden (ISUB) testing to identify single or aggregated rare variation that modifies disease risk. In single-variant testing no variants reached exome-wide significance, likely due to limited statistical power. Gene-based burden testing of rare non-synonymous and loss-of-function variants showed NEK1 as the top associated gene. ISUB analysis did not show an increased exome-wide burden of deleterious variants in patients, possibly suggesting a more region-specific role for rare variation. Complete summary statistics are released publicly. This study did not implicate new risk loci, emphasizing the immediate need for future large-scale collaborations in ALS that will expand available sample sizes, increase genome coverage, and improve our ability to detect rare variants associated to ALS.}, language = {en} } @article{DiehlSchmidLicataGoldhardtetal.2019, author = {Diehl-Schmid, Janine and Licata, Abigail and Goldhardt, Oliver and F{\"o}rstl, Hans and Yakushew, Igor and Otto, Markus and Anderl-Straub, Sarah and Beer, Ambros and Ludolph, Albert Christian and Landwehrmeyer, Georg Bernhard and Levin, Johannes and Danek, Adrian and Fliessbach, Klaus and Spottke, Annika and Fassbender, Klaus and Lyros, Epameinondas and Prudlo, Johannes and Krause, Bernd Joachim and Volk, Alexander and Edbauer, Dieter and Schroeter, Matthias Leopold and Drzezga, Alexander and Kornhuber, Johannes and Lauer, Martin and Grimmer, Timo}, title = {FDG-PET underscores the key role of the thalamus in frontotemporal lobar degeneration caused by C9ORF72 mutations}, series = {Translational Psychiatry}, volume = {9}, journal = {Translational Psychiatry}, organization = {FTLDc Study Group}, doi = {10.1038/s41398-019-0381-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225308}, year = {2019}, abstract = {C9ORF72 mutations are the most common cause of familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). MRI studies have investigated structural changes in C9ORF72-associated FTLD (C9FTLD) and provided first insights about a prominent involvement of the thalamus and the cerebellum. Our multicenter, 18F-fluorodeoxyglucose positron-emission tomography study of 22 mutation carriers with FTLD, 22 matched non-carriers with FTLD, and 23 cognitively healthy controls provided valuable insights into functional changes in C9FTLD: compared to non-carriers, mutation carriers showed a significant reduction of glucose metabolism in both thalami, underscoring the key role of the thalamus in C9FTLD. Thalamic metabolism did not correlate with disease severity, duration of disease, or the presence of psychotic symptoms. Against our expectations we could not demonstrate a cerebellar hypometabolism in carriers or non-carriers. Future imaging and neuropathological studies in large patient cohorts are required to further elucidate the central role of the thalamus in C9FTLD.}, language = {en} } @article{DietrichKrugKrastletal.2019, author = {Dietrich, Thomas and Krug, Ralf and Krastl, Gabriel and Tomson, Philip L.}, title = {Restoring the unrestorable! Developing coronal tooth tissue with a minimally invasive surgical extrusion technique}, series = {British Dental Journal}, volume = {226}, journal = {British Dental Journal}, doi = {10.1038/s41415-019-0268-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225333}, pages = {789-793}, year = {2019}, abstract = {Surgical extrusion is a recognised treatment option for teeth that have insufficient coronal tooth structure remaining due to deep caries, resorption or traumatic injury. However, the technique has not been widely adopted, arguably because extraction of a severely compromised tooth may be difficult to achieve in a gentle and predictable way. In this paper, we present our novel approach to surgical extrusion and subsequent management of teeth using a vertical extraction system (Benex), which has become the method of choice in the authors' practice for many teeth that would otherwise be deemed unrestorable. We describe the clinical procedure in detail and discuss the advantages and disadvantages compared to alternative approaches, including surgical crown lengthening and orthodontic extrusion.}, language = {en} } @article{KrahBuentgenSchaeferetal.2019, author = {Krah, Franz-Sebastian and B{\"u}ntgen, Ulf and Schaefer, Hanno and M{\"u}ller, J{\"o}rg and Andrew, Carrie and Boddy, Lynne and Diez, Jeffrey and Egli, Simon and Freckleton, Robert and Gange, Alan C. and Halvorsen, Rune and Heegaard, Einar and Heideroth, Antje and Heibl, Christoph and Heilmann-Clausen, Jacob and H{\o}iland, Klaus and Kar, Ritwika and Kauserud, H{\aa}vard and Kirk, Paul M. and Kuyper, Thomas W. and Krisai-Greilhuber, Irmgard and Norden, Jenni and Papastefanou, Phillip and Senn-Irlet, Beatrice and B{\"a}ssler, Claus}, title = {European mushroom assemblages are darker in cold climates}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-10767-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224815}, year = {2019}, abstract = {Thermal melanism theory states that dark-colored ectotherm organisms are at an advantage at low temperature due to increased warming. This theory is generally supported for ectotherm animals, however, the function of colors in the fungal kingdom is largely unknown. Here, we test whether the color lightness of mushroom assemblages is related to climate using a dataset of 3.2 million observations of 3,054 species across Europe. Consistent with the thermal melanism theory, mushroom assemblages are significantly darker in areas with cold climates. We further show differences in color phenotype between fungal lifestyles and a lifestyle differentiated response to seasonality. These results indicate a more complex ecological role of mushroom colors and suggest functions beyond thermal adaption. Because fungi play a crucial role in terrestrial carbon and nutrient cycles, understanding the links between the thermal environment, functional coloration and species' geographical distributions will be critical in predicting ecosystem responses to global warming.}, language = {en} } @article{HauerPoppSchoelleretal.2018, author = {Hauer, Nadine N. and Popp, Bernt and Schoeller, Eva and Schuhmann, Sarah and Heath, Karen E. and Hisado-Oliva, Alfonso and Klinger, Patricia and Kraus, Cornelia and Trautmann, Udo and Zenker, Martin and Zweier, Christiane and Wiesener, Antje and Jamra, Rami Abou and Kunstmann, Erdmute and Wieczorek, Dagmar and Uebe, Steffen and Ferrazzi, Fulvia and B{\"u}ttner, Christian and Ekici, Arif B. and Rauch, Anita and Sticht, Heinrich and D{\"o}rr, Helmuth-G{\"u}nther and Reis, Andr{\´e} and Thiel, Christian T.}, title = {Clinical relevance of systematic phenotyping and exome sequencing in patients with short stature}, series = {Genetics in Medicine}, volume = {20}, journal = {Genetics in Medicine}, doi = {10.1038/gim.2017.159}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227888}, pages = {630-638}, year = {2018}, abstract = {Purpose Short stature is a common condition of great concern to patients and their families. Mostly genetic in origin, the underlying cause often remains elusive due to clinical and genetic heterogeneity. Methods We systematically phenotyped 565 patients where common nongenetic causes of short stature were excluded, selected 200 representative patients for whole-exome sequencing, and analyzed the identified variants for pathogenicity and the affected genes regarding their functional relevance for growth. Results By standard targeted diagnostic and phenotype assessment, we identified a known disease cause in only 13.6\% of the 565 patients. Whole-exome sequencing in 200 patients identified additional mutations in known short-stature genes in 16.5\% of these patients who manifested only part of the symptomatology. In 15.5\% of the 200 patients our findings were of significant clinical relevance. Heterozygous carriers of recessive skeletal dysplasia alleles represented 3.5\% of the cases. Conclusion A combined approach of systematic phenotyping, targeted genetic testing, and whole-exome sequencing allows the identification of the underlying cause of short stature in at least 33\% of cases, enabling physicians to improve diagnosis, treatment, and genetic counseling. Exome sequencing significantly increases the diagnostic yield and consequently care in patients with short stature.}, language = {en} } @article{KreinbergGrbešićStraussetal.2018, author = {Kreinberg, S{\"o}ren and Grbešić, Tomislav and Strauß, Max and Carmele, Alexander and Emmerling, Monika and Schneider, Christian and H{\"o}fling, Sven and Porte, Xavier and Reitzenstein, Stephan}, title = {Quantum-optical spectroscopy of a two-level system using an electrically driven micropillar laser as a resonant excitation source}, series = {Light: Science \& Applications}, volume = {7}, journal = {Light: Science \& Applications}, doi = {10.1038/s41377-018-0045-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229802}, year = {2018}, abstract = {Two-level emitters are the main building blocks of photonic quantum technologies and are model systems for the exploration of quantum optics in the solid state. Most interesting is the strict resonant excitation of such emitters to control their occupation coherently and to generate close to ideal quantum light, which is of utmost importance for applications in photonic quantum technology. To date, the approaches and experiments in this field have been performed exclusively using bulky lasers, which hinders the application of resonantly driven two-level emitters in compact photonic quantum systems. Here we address this issue and present a concept for a compact resonantly driven single-photon source by performing quantum-optical spectroscopy of a two-level system using a compact high-β microlaser as the excitation source. The two-level system is based on a semiconductor quantum dot (QD), which is excited resonantly by a fiber-coupled electrically driven micropillar laser. We dress the excitonic state of the QD under continuous wave excitation, and trigger the emission of single photons with strong multi-photon suppression (g\(^{(2)}\)(0)=0.02) and high photon indistinguishability (V = 57±9\%) via pulsed resonant excitation at 156 MHz. These results clearly demonstrate the high potential of our resonant excitation scheme, which can pave the way for compact electrically driven quantum light sources with excellent quantum properties to enable the implementation of advanced quantum communication protocols.}, language = {en} } @article{LudwigDelforgeFaconetal.2018, author = {Ludwig, Heinz and Delforge, Michel and Facon, Thierry and Einsele, Hermann and Gay, Francesca and Moreau, Philippe and Avet-Loiseau, Herv{\´e} and Boccadoro, Mario and Hajek, Roman and Mohty, Mohamad and Cavo, Michele and Dimopoulos, Meletios A and San-Miguel, Jes{\´u}s F and Terpos, Evangelos and Zweegman, Sonja and Garderet, Laurent and Mateos, Mar{\´i}a-Victoria and Cook, Gordon and Leleu, Xavier and Goldschmidt, Hartmut and Jackson, Graham and Kaiser, Martin and Weisel, Katja and van de Donk, Niels W. C. J. and Waage, Anders and Beksac, Meral and Mellqvist, Ulf H. and Engelhardt, Monika and Caers, Jo and Driessen, Christoph and Blad{\´e}, Joan and Sonneveld, Pieter}, title = {Prevention and management of adverse events of novel agents in multiple myeloma: a consensus of the European Myeloma Network}, series = {Leukemia}, volume = {32}, journal = {Leukemia}, doi = {10.1038/s41375-018-0040-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237338}, pages = {1542-1560}, year = {2018}, abstract = {During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved the treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drug classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events.}, language = {en} } @article{MilaneseMendePaolietal.2019, author = {Milanese, Alessio and Mende, Daniel R and Paoli, Lucas and Salazar, Guillem and Ruscheweyh, Hans-Joachim and Cuenca, Miguelangel and Hingamp, Pascal and Alves, Renato and Costea, Paul I and Coelho, Luis Pedro and Schmidt, Thomas S. B. and Almeida, Alexandre and Mitchell, Alex L and Finn, Robert D. and Huerta-Cepas, Jaime and Bork, Peer and Zeller, Georg and Sunagawa, Shinichi}, title = {Microbial abundance, activity and population genomic profiling with mOTUs2}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-08844-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224089}, year = {2019}, abstract = {Metagenomic sequencing has greatly improved our ability to profile the composition of environmental and host-associated microbial communities. However, the dependency of most methods on reference genomes, which are currently unavailable for a substantial fraction of microbial species, introduces estimation biases. We present an updated and functionally extended tool based on universal (i.e., reference-independent), phylogenetic marker gene (MG)-based operational taxonomic units (mOTUs) enabling the profiling of >7700 microbial species. As more than 30\% of them could not previously be quantified at this taxonomic resolution, relative abundance estimates based on mOTUs are more accurate compared to other methods. As a new feature, we show that mOTUs, which are based on essential housekeeping genes, are demonstrably well-suited for quantification of basal transcriptional activity of community members. Furthermore, single nucleotide variation profiles estimated using mOTUs reflect those from whole genomes, which allows for comparing microbial strain populations (e.g., across different human body sites).}, language = {en} } @phdthesis{Machwart2024, author = {Machwart, Khaled}, title = {Modulatorischer Einfluss von Levosimendan bei dem Isch{\"a}mie-Reperfusionsschaden auf die myokardiale Mitochondrienfunktion}, doi = {10.25972/OPUS-36102}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-361021}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die vorliegende Studie untersuchte den Effekt von Levosimendan auf die mitochondriale Funktionen im Herzmuskel, insbesondere im Zusammenhang mit dem Isch{\"a}mie/Reperfusions-Schaden. Methoden: In der Studie wurde ein retrogrades Langendorff-Modell verwendet, um die Auswirkungen von Levosimendan, dem Isch{\"a}mie/Reperfusions-Schaden sowie deren Kombination auf die mitochondrialen Funktionen im Herzmuskel zu untersuchen. Dazu wurden vier verschiedene Gruppen von Rattenherzen entsprechend den experimentellen Bedingungen perfundiert, und ihre Funktionen wurden analysiert. Ergebnisse: Der Isch{\"a}mie/Reperfusions-Schaden beeintr{\"a}chtigte die myokardiale Ventrikelfunktion. Zus{\"a}tzlich wurde eine Hypopolarisation des mithochondrialen Membranpotentials in den mit Levosimendan oder Isch{\"a}mie behandelten Gruppen festgestellt. Die ATP-Synthese in den Gruppen mit Levosimendan und Isch{\"a}mie war reduziert. Schlussfolgerung: Levosimendan zeigt signifikante Einfl{\"u}sse auf die Atmungsfunktion der mitochondrialen Komplexe IV und V sowie auf das Membranpotential. Diese Ph{\"a}nomene k{\"o}nnten einem mito-K+ ATP-abh{\"a}ngigen Mechanismus zugrunde liegen. Obwohl Levosimendan w{\"a}hrend des Isch{\"a}mie/Reperfusionsschadens eine protektive Wirkung hinsichtlich einer Ca2+- {\"U}berlastung aufweist, bleibt der kumulative Einfluss der beeintr{\"a}chtigten ATP-Generierung auf die gesamte Myokardfunktion zu kl{\"a}ren.}, subject = {Isch{\"a}mie}, language = {de} } @phdthesis{Schaefer2024, author = {Schaefer, Bastian}, title = {Eigenschaften von synthetischen Bandersatzmaterialien zum MPFL-Ersatz - biomechanische in vitro Studie am porcinen Modell}, doi = {10.25972/OPUS-36139}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-361396}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Der MPFL-Ersatz ist ein g{\"a}ngiges Therapieverfahren zur Behandlung einer patellofemoralen Instabilit{\"a}t. Die Operationstechniken unterscheiden sich zumeist an der patellaren Fixationsmethode und der Auswahl der Transplantate. Biomechanische Studien, welche sich mit den Eigenschaften implantatfreier oss{\"a}rer Fixationsmethoden beim MPFL-Ersatz unter Verwendung k{\"u}nstlicher Transplantate besch{\"a}ftigen gibt es nach aktueller Recherche nicht. Ziel dieser Arbeit war es, die biomechanischen Eigenschaften zweier patellarer Bohrkanalfixationstechniken beim MPFL-Ersatz mit unterschiedlichem k{\"u}nstlichen Bandersatzmaterial zu ermitteln. Die Hypothese war, dass die biomechanischen Eigenschaften in Elongation, Steifigkeit, Prim{\"a}rstabilit{\"a}t und maximaler Ausreißkraft mit denen der bereits etablierten Verfahren und dem nativen MPFL vergleichbar sind. Hierzu wurden 80 porcine Kniescheiben randomisiert in 8 Gruppen aufgeteilt und getestet. In den Gruppen 1-4 wurden parallele, transpatellare Bohrkan{\"a}le mit Tapes der Breiten 2 mm, 3 mm, 4 mm und 5 mm getestet. In den Gruppen 5-8 wurden V-Kanal-Fixationsmethoden mit B{\"a}ndern der Breite von 2 mm, 3 mm, 4 mm und 5 mm untersucht. Zus{\"a}tzlich wurden die biomechanischen Grundeigenschaften der nativen Tapes ermittelt. Alle Tests durchliefen jeweils drei Messabschnitte. Hierbei fand zun{\"a}chst eine Pr{\"a}konditionierung mit 10 Zyklen zwischen 5 N und 20 N statt. Daraufhin folgte eine zyklische Belastung mit 1000 Zyklen zwischen 5 N und 50 N. Am Ende wurde eine maximale Kraftapplikation bis zum Versagen der Fixationskomplexe durchgef{\"u}hrt. Im Rahmen der Messungen wurden Elongation, Steifigkeit, Yield Load und Maximum Load bestimmt. Es konnten Unterschiede zwischen den beiden Fixationsmethoden und den verwendeten Tapes festgestellt werden. Alle acht Gruppen zeigten eine h{\"o}here Prim{\"a}rstabilit{\"a}t als das humane MPFL. Bezogen auf die biomechanischen Eigenschaften und den Versagensmechanismus konnte in dieser Studie ein Vorteil der parallelen transpatellaren Bohrkan{\"a}le gegen{\"u}ber den V- Kanaltechniken festgestellt werden. Die Werte mit der h{\"o}chsten maximalen Ausreißkraft wurden in Gruppe 3 (631,6 ± 83,1 N) und Gruppe 1 (592,9 ± 170,1 N) gemessen. Diese zeigten eine h{\"o}here Prim{\"a}rstabilit{\"a}t mit geringerer Elongation und Steifigkeit im Vergleich zu den in der aktuellen Literatur beschriebenen biomechanischen Studien, welche sich mit unterschiedlichen und teilweise bereits etablierten MPFL-Ersatzverfahren besch{\"a}ftigten. Eine implantatfreie MPFL-Rekonstruktion mit transpatellaren parallelen Bohrkan{\"a}len unter Verwendung eines 2 mm Fiber Tapes (Fa. Arthrex) oder eines 4 mm Tapes (Fa. Topester) k{\"o}nnten dementsprechend eine gute Alternative zur operativen Therapie einer patellofemoralen Instabilit{\"a}t sein.}, subject = {Patellaluxation}, language = {de} } @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} } @phdthesis{Wussmann2024, author = {Wußmann, Maximiliane}, title = {Humane organotypische 3D Modelle des Malignen Melanoms als in vitro Testsystem f{\"u}r die Bewertung der Wirksamkeit von anti-Tumor Therapeutika}, doi = {10.25972/OPUS-36100}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-361005}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Das maligne Melanom, eine der seltensten, aber gleichzeitig auch die t{\"o}dlichste dermatologische Malignit{\"a}t, gekennzeichnet durch die Neigung zu einer fr{\"u}hen Metastasierung sowie die rasche Entwicklung von Therapieresistenzen, z{\"a}hlt zu den Tumorentit{\"a}ten mit dem h{\"o}chsten Anstieg der Inzidenz weltweit. Mausmodelle werden h{\"a}ufig verwendet, um die Melanomagenese zu erforschen und neue effektive therapeutische Strategien zu entwickeln, spiegeln die menschliche Physiologie allerdings nur unzureichend wider. In zweidimensionalen (2D) Zellkulturen mangelt es dagegen an wichtigen Komponenten der Mikroumgebung des Tumors und dem dreidimensionalen Gewebekontext. Um dieses Manko zu beheben und die Entwicklung von auf den Menschen {\"u}bertragbaren Tumormodellen in der onkologischen Forschung voranzutreiben, wurde als Alternative zu Zellkulturen und Tierversuchen humane organotypische dreidimensionale (3D) Melanom-Modelle als in vitro Testsystem f{\"u}r die Bewertung der Wirksamkeit von anti-Tumor Therapeutika entwickelt. Im Zuge dieser Arbeit konnte das in vitro Melanom-Modell entscheidend weiterentwickelt werden. So konnten Modelle unterschiedlichster Komplexit{\"a}t etabliert werden, wobei abh{\"a}ngig von der Fragestellung einfachere epidermale bis hin zu unterschiedlich komplexen Vollhautmodellen Anwendung finden. Durch Simulation der Tumor-Mikroumgebung eignen sich diese zur pr{\"a}klinischen Validierung neuer Tumor-Therapeutika, sowie der Erforschung pathologischer Vorg{\"a}nge, von der Tumor-Formierung bis zur Metastasierung. Zudem konnten erfolgreich unterschiedlichste humane Melanomzelllinien ins Modell integriert werden; dadurch, dass sich diese durch ihre Treibermutationen, die zur Krankheitsentstehung beitragen, unterscheiden, stellen sie unterschiedliche Anspr{\"u}che an potentielle therapeutische Angriffspunkte und erm{\"o}glichen das Widerspiegeln vieler Melanom-Subtypen im Modell. Ferner ist es m{\"o}glich, verschiedene Stadien der Tumor-Entwicklung {\"u}ber die Zugabe von Melanomzellen in Einzelsuspension bzw. von Melanom-Sph{\"a}roiden widerzuspiegeln. Es konnte f{\"u}r bestimmte Therapie-Ans{\"a}tze, wie zielgerichtete Therapien, z.B. die Gabe von sich in der Klinik im Einsatz befindlicher BRAF-/MEK-Inhibitoren, gezeigt werden, dass sich die etablierten Modelle hervorragend als pr{\"a}klinische Testsysteme zur Wirksamkeitsbewertung eignen. Zudem bieten sich einzigartige M{\"o}glichkeiten, um die Interaktion humaner Tumorzellen und gesunder Zellen in einem Gewebeverband zu untersuchen. Ferner konnten drei neue technische Analyse-Verfahren zur nicht-invasiven Detektion der Tumor- Pro- und Regression, Beurteilung der Wirksamkeit von potenziellen Anti-Tumor-Therapien sowie der Evaluierung des Tumor-Metabolismusses implementiert werden. Perspektivisch erm{\"o}glichen immun-kompetente Melanom-Modelle die Austestung neuer Immun- und Zelltherapien in einem voll humanen System; gleichzeitig leisten die etablierten Modelle einen signifikanten Beitrag zur Reduktion von Tierexperimenten.}, subject = {Melanom}, language = {de} } @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} } @techreport{MaennelBorschinskyKayaletal.2024, author = {M{\"a}nnel, Jonathan and Borschinsky, Erik and Kayal, Hakan and Neumann, Tobias and Riegler, Clemens}, title = {SATEX: Extraterrestrik mit Kleinsatelliten - Kurzbericht}, doi = {10.25972/OPUS-36325}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363256}, pages = {42}, year = {2024}, abstract = {Dieser Kurzbericht beleuchtet die Einsatzm{\"o}glichkeiten von Kleinsatelliten in der extraterrestrischen Forschung und zeigt auf welche technologischen Herausforderungen sich bei ihrem Einsatz ergeben. Die pr{\"a}sentierten Ergebnisse sind Teil der SATEX Untersuchung (FKZ 50OO2222). In diesem Dokument werden zun{\"a}chst die allgemeinen Einsatzm{\"o}glichkeiten von Kleinsatelliten in der Extraterrestrik anhand ausgew{\"a}hlter Beispielmissionen beleuchtet. Daraufhin erfolgt die Er{\"o}rterung spezifischer technischer Herausforderungen und Umweltbedingungen bei cislunaren und interplanetaren Kleinsatellitenmissionen, gefolgt von einer kurzen Pr{\"a}sentation von Nutzerw{\"u}nsche aus Deutschland f{\"u}r Missionen zur Erforschung des Weltraums. Zum Abschluss werden zehn konkrete, im Rahmen der Untersuchung ermittelte, Missionsideen vorgestellt und bewertet. Schließlich erfolgt die Zusammenfassung der wichtigsten Erkenntnisse und Empfehlungen.}, subject = {Extraterrestrische Forschung}, language = {de} } @techreport{MaennelBorschinskyKayaletal.2024, author = {M{\"a}nnel, Jonathan and Borschinsky, Erik and Kayal, Hakan and Neumann, Tobias and Riegler, Clemens}, title = {SATEX: Extraterrestrik mit Kleinsatelliten - Kurzbericht}, edition = {korrigierte Version}, doi = {10.25972/OPUS-36979}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369793}, pages = {42}, year = {2024}, abstract = {Dieser Kurzbericht beleuchtet die Einsatzm{\"o}glichkeiten von Kleinsatelliten in der extraterrestrischen Forschung und zeigt auf welche technologischen Herausforderungen sich bei ihrem Einsatz ergeben. Die pr{\"a}sentierten Ergebnisse sind Teil der SATEX Untersuchung (FKZ 50OO2222). In diesem Dokument werden zun{\"a}chst die allgemeinen Einsatzm{\"o}glichkeiten von Kleinsatelliten in der Extraterrestrik anhand ausgew{\"a}hlter Beispielmissionen beleuchtet. Daraufhin erfolgt die Er{\"o}rterung spezifischer technischer Herausforderungen und Umweltbedingungen bei cislunaren und interplanetaren Kleinsatellitenmissionen, gefolgt von einer kurzen Pr{\"a}sentation von Nutzerw{\"u}nsche aus Deutschland f{\"u}r Missionen zur Erforschung des Weltraums. Zum Abschluss werden zehn konkrete, im Rahmen der Untersuchung ermittelte, Missionsideen vorgestellt und bewertet. Schließlich erfolgt die Zusammenfassung der wichtigsten Erkenntnisse und Empfehlungen.}, subject = {Extraterrestrische Forschung}, language = {de} } @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} } @article{LeeLiRuanetal.2019, author = {Lee, Hong-Jen and Li, Chien-Feng and Ruan, Diane and He, Jiabei and Montal, Emily D. and Lorenz, Sonja and Girnun, Geoffrey D. and Chan, Chia-Hsin}, title = {Non-proteolytic ubiquitination of Hexokinase 2 by HectH9 controls tumor metabolism and cancer stem cell expansion}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-10374-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236445}, year = {2019}, abstract = {Enormous efforts have been made to target metabolic dependencies of cancer cells for developing new therapies. However, the therapeutic efficacy of glycolysis inhibitors is limited due to their inability to elicit cell death. Hexokinase 2 (HK2), via its mitochondrial localization, functions as a central nexus integrating glycolysis activation and apoptosis resilience. Here we identify that K63-linked ubiquitination by HectH9 regulates the mitochondrial localization and function of HK2. Through stable isotope tracer approach and functional metabolic analyses, we show that HectH9 deficiency impedes tumor glucose metabolism and growth by HK2 inhibition. The HectH9/HK2 pathway regulates cancer stem cell (CSC) expansion and CSC-associated chemoresistance. Histological analyses show that HectH9 expression is upregulated and correlated with disease progression in prostate cancer. This work uncovers that HectH9 is a novel regulator of HK2 and cancer metabolism. Targeting HectH9 represents an effective strategy to achieve long-term tumor remission by concomitantly disrupting glycolysis and inducing apoptosis.}, language = {en} } @article{LanghauserCasasDaoetal.2018, author = {Langhauser, Friederike and Casas, Ana I. and Dao, Vu-Thao-Vi and Guney, Emre and Menche, J{\"o}rg and Geuss, Eva and Kleikers, Pamela W. M. and L{\´o}pez, Manuela G. and Barab{\´a}si, Albert-L. and Kleinschnitz, Christoph and Schmidt, Harald H. H. W.}, title = {A diseasome cluster-based drug repurposing of soluble guanylate cyclase activators from smooth muscle relaxation to direct neuroprotection}, series = {npj Systems Biology and Applications}, volume = {4}, journal = {npj Systems Biology and Applications}, doi = {10.1038/s41540-017-0039-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236381}, year = {2018}, abstract = {Network medicine utilizes common genetic origins, markers and co-morbidities to uncover mechanistic links between diseases. These links can be summarized in the diseasome, a comprehensive network of disease-disease relationships and clusters. The diseasome has been influential during the past decade, although most of its links are not followed up experimentally. Here, we investigate a high prevalence unmet medical need cluster of disease phenotypes linked to cyclic GMP. Hitherto, the central cGMP-forming enzyme, soluble guanylate cyclase (sGC), has been targeted pharmacologically exclusively for smooth muscle modulation in cardiology and pulmonology. Here, we examine the disease associations of sGC in a non-hypothesis based manner in order to identify possibly previously unrecognized clinical indications. Surprisingly, we find that sGC, is closest linked to neurological disorders, an application that has so far not been explored clinically. Indeed, when investigating the neurological indication of this cluster with the highest unmet medical need, ischemic stroke, pre-clinically we find that sGC activity is virtually absent post-stroke. Conversely, a heme-free form of sGC, apo-sGC, was now the predominant isoform suggesting it may be a mechanism-based target in stroke. Indeed, this repurposing hypothesis could be validated experimentally in vivo as specific activators of apo-sGC were directly neuroprotective, reduced infarct size and increased survival. Thus, common mechanism clusters of the diseasome allow direct drug repurposing across previously unrelated disease phenotypes redefining them in a mechanism-based manner. Specifically, our example of repurposing apo-sGC activators for ischemic stroke should be urgently validated clinically as a possible first-in-class neuroprotective therapy.}, language = {en} } @article{LiaoTtofaliSlotkowskietal.2019, author = {Liao, Chunyu and Ttofali, Fani and Slotkowski, Rebecca A. and Denny, Steven R. and Cecil, Taylor D. and Leenay, Ryan T. and Keung, Albert J. and Beisel, Chase L.}, title = {Modular one-pot assembly of CRISPR arrays enables library generation and reveals factors influencing crRNA biogenesis}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-10747-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236843}, year = {2019}, abstract = {CRISPR-Cas systems inherently multiplex through CRISPR arrays—whether to defend against different invaders or mediate multi-target editing, regulation, imaging, or sensing. However, arrays remain difficult to generate due to their reoccurring repeat sequences. Here, we report a modular, one-pot scheme called CRATES to construct CRISPR arrays and array libraries. CRATES allows assembly of repeat-spacer subunits using defined assembly junctions within the trimmed portion of spacers. Using CRATES, we construct arrays for the single-effector nucleases Cas9, Cas12a, and Cas13a that mediated multiplexed DNA/RNA cleavage and gene regulation in cell-free systems, bacteria, and yeast. CRATES further allows the one-pot construction of array libraries and composite arrays utilized by multiple Cas nucleases. Finally, array characterization reveals processing of extraneous CRISPR RNAs from Cas12a terminal repeats and sequence- and context-dependent loss of RNA-directed nuclease activity via global RNA structure formation. CRATES thus can facilitate diverse multiplexing applications and help identify factors impacting crRNA biogenesis.}, language = {en} } @article{LevyBoulleEmeritetal.2019, author = {Levy, Marion J. F. and Boulle, Fabien and Emerit, Michel Boris and Poilbout, Corinne and Steinbusch, Harry W. M. and Van den Hove, Daniel L. A. and Kenis, Gunter and Lanfumey, Laurence}, title = {5-HTT independent effects of fluoxetine on neuroplasticity}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-42775-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236759}, year = {2019}, abstract = {Selective serotonin reuptake inhibitors are among the most prescribed antidepressants. Fluoxetine is the lead molecule which exerts its therapeutic effects, at least in part, by promoting neuroplasticity through increased brain-derived neurotrophic factor (BDNF)/tropomyosin-related receptor kinase B (TrkB) signalling. It is unclear however, to which extent the neuroplastic effects of fluoxetine are solely mediated by the inhibition of the serotonin transporter (5-HTT). To answer this question, the effects of fluoxetine on neuroplasticity were analysed in both wild type (WT) and 5-Htt knock-out (KO) mice. Using Western blotting and RT-qPCR approaches, we showed that fluoxetine 10 µM activated BDNF/TrkB signalling pathways in both CD1 and C57BL/6J mouse primary cortical neurons. Interestingly, effects on BDNF signalling were observed in primary cortical neurons from both 5-Htt WT and KO mice. In addition, a 3-week in vivo fluoxetine treatment (15 mg/kg/d; i.p.) increased the expression of plasticity genes in brains of both 5-Htt WT and KO mice, and tended to equally enhance hippocampal cell proliferation in both genotypes, without reaching significance. Our results further suggest that fluoxetine-induced neuroplasticity does not solely depend on 5-HTT blockade, but might rely, at least in part, on 5-HTT-independent direct activation of TrkB.}, language = {en} } @article{LeeImhofBergeretal.2018, author = {Lee, Ching Hua and Imhof, Stefan and Berger, Christian and Bayer, Florian and Brehm, Johannes and Molenkamp, Laurens W. and Kiessling, Tobias and Thomale, Ronny}, title = {Topolectrical Circuits}, series = {Communications Physics}, volume = {1}, journal = {Communications Physics}, doi = {10.1038/s42005-018-0035-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236422}, year = {2018}, abstract = {Invented by Alessandro Volta and F{\´e}lix Savary in the early 19th century, circuits consisting of resistor, inductor and capacitor (RLC) components are omnipresent in modern technology. The behavior of an RLC circuit is governed by its circuit Laplacian, which is analogous to the Hamiltonian describing the energetics of a physical system. Here we show that topological insulating and semimetallic states can be realized in a periodic RLC circuit. Topological boundary resonances (TBRs) appear in the impedance read-out of a topolectrical circuit, providing a robust signal for the presence of topological admittance bands. For experimental illustration, we build the Su-Schrieffer-Heeger circuit, where our impedance measurement detects the TBR midgap state. Topolectrical circuits establish a bridge between electrical engineering and topological states of matter, where the accessibility, scalability, and operability of electronics synergizes with the intricate boundary properties of topological phases.}, language = {en} } @article{KuegelKarolakKroenleinetal.2018, author = {K{\"u}gel, Jens and Karolak, Michael and Kr{\"o}nlein, Andreas and Serrate, David and Bode, Matthias and Sangiovanni, Giorgio}, title = {Reversible magnetic switching of high-spin molecules on a giant Rashba surface}, series = {npj Quantum Materials}, volume = {3}, journal = {npj Quantum Materials}, doi = {10.1038/s41535-018-0126-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230866}, year = {2018}, abstract = {The quantum mechanical screening of a spin via conduction electrons depends sensitively on the environment seen by the magnetic impurity. A high degree of responsiveness can be obtained with metal complexes, as the embedding of a metal ion into an organic molecule prevents intercalation or alloying and allows for a good control by an appropriate choice of the ligands. There are therefore hopes to reach an "on demand" control of the spin state of single molecules adsorbed on substrates. Hitherto one route was to rely on "switchable" molecules with intrinsic bistabilities triggered by external stimuli, such as temperature or light, or on the controlled dosing of chemicals to form reversible bonds. However, these methods constrain the functionality to switchable molecules or depend on access to atoms or molecules. Here, we present a way to induce bistability also in a planar molecule by making use of the environment. We found that the particular "habitat" offered by an antiphase boundary of the Rashba system BiAg2 stabilizes a second structure for manganese phthalocyanine molecules, in which the central Mn ion moves out of the molecular plane. This corresponds to the formation of a large magnetic moment and a concomitant change of the ground state with respect to the conventional adsorption site. The reversible spin switch found here shows how we can not only rearrange electronic levels or lift orbital degeneracies via the substrate, but even sway the effects of many-body interactions in single molecules by acting on their surrounding.}, language = {en} } @article{KurabiSchaererNoacketal.2018, author = {Kurabi, Arwa and Schaerer, Daniel and Noack, Volker and Bernhardt, Marlen and Pak, Kwang and Alexander, Thomas and Husseman, Jacob and Nguyen, Quyen and Harris, Jeffrey P. and Ryan, Allen F.}, title = {Active Transport of Peptides Across the Intact Human Tympanic Membrane}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-30031-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230929}, year = {2018}, abstract = {We previously identified peptides that are actively transported across the intact tympanic membrane (TM) of rats with infected middle ears. To assess the possibility that this transport would also occur across the human TM, we first developed and validated an assay to evaluate transport in vitro using fragments of the TM. Using this assay, we demonstrated the ability of phage bearing a TM-transiting peptide to cross freshly dissected TM fragments from infected rats or from uninfected rats, guinea pigs and rabbits. We then evaluated transport across fragments of the human TM that were discarded during otologic surgery. Human trans-TM transport was similar to that seen in the animal species. Finally, we found that free peptide, unconnected to phage, was transported across the TM at a rate comparable to that seen for peptide-bearing phage. These studies provide evidence supporting the concept of peptide-mediated drug delivery across the intact TM and into the middle ears of patients.}, language = {en} } @article{LiuWangSatoetal.2019, author = {Liu, Yuhai and Wang, Zhenjiu and Sato, Toshihiro and Hohenadler, Martin and Wang, Chong and Guo, Wenan and Assaad, Fakher F.}, title = {Superconductivity from the condensation of topological defects in a quantum spin-Hall insulator}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-10372-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237024}, year = {2019}, abstract = {The discovery of quantum spin-Hall (QSH) insulators has brought topology to the forefront of condensed matter physics. While a QSH state from spin-orbit coupling can be fully understood in terms of band theory, fascinating many-body effects are expected if it instead results from spontaneous symmetry breaking. Here, we introduce a model of interacting Dirac fermions where a QSH state is dynamically generated. Our tuning parameter further allows us to destabilize the QSH state in favour of a superconducting state through proliferation of charge-2e topological defects. This route to superconductivity put forward by Grover and Senthil is an instance of a deconfined quantum critical point (DQCP). Our model offers the possibility to study DQCPs without a second length scale associated with the reduced symmetry between field theory and lattice realization and, by construction, is amenable to large-scale fermion quantum Monte Carlo simulations.}, language = {en} } @phdthesis{Starz2024, author = {Starz, Katharina Theresa}, title = {Das Sharenting in der Zivilrechtsdogmatik : zu den Grenzen elterlicher Dispositionsbefugnis {\"u}ber das Pers{\"o}nlichkeitsrecht des Kindes}, publisher = {Mohr Siebeck}, address = {T{\"u}bingen}, doi = {10.25972/OPUS-36966}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369667}, school = {Universit{\"a}t W{\"u}rzburg}, pages = {256}, year = {2024}, abstract = {Im Zeitalter der sozialen Medien ist es f{\"u}r viele Eltern zur Gewohnheit geworden, nicht nur sich selbst, sondern auch das eigene Kind der Internetgemeinschaft zu pr{\"a}sentieren. Diese Praxis wird als "Sharenting" ("to share" + "parenting") bezeichnet. So kommt es, dass mittlerweile ein Großteil der Kinder bereits in sehr jungen Jahren einen - unfreiwilligen - digitalen Fußabdruck hinterl{\"a}sst. Der freiz{\"u}gige Umgang mit den Daten des Kindes bringt zahlreiche rechtliche Probleme mit sich, welche an den Schnittstellen des Rechts zum Schutz der Pers{\"o}nlichkeit, des Datenschutzrechts und des Familienrechts zu verorten sind. Am Beispiel der Plattformen Facebook, Instagram und WhatsApp lotet Katharina Theresa Starz die Grenzen des rechtlich Zul{\"a}ssigen aus und zeigt auf, welche Konsequenzen sich ergeben k{\"o}nnen, wenn ebendiese Grenzen von den Eltern {\"u}berschritten werden.}, language = {de} } @article{LopezKleinheinzAukemaetal.2019, author = {L{\´o}pez, Cristina and Kleinheinz, Kortine and Aukema, Sietse M. and Rohde, Marius and Bernhart, Stephan H. and H{\"u}bschmann, Daniel and Wagener, Rabea and Toprak, Umut H. and Raimondi, Francesco and Kreuz, Markus and Waszak, Sebastian M. and Huang, Zhiqin and Sieverling, Lina and Paramasivam, Nagarajan and Seufert, Julian and Sungalee, Stephanie and Russell, Robert B. and Bausinger, Julia and Kretzmer, Helene and Ammerpohl, Ole and Bergmann, Anke K. and Binder, Hans and Borkhardt, Arndt and Brors, Benedikt and Claviez, Alexander and Doose, Gero and Feuerbach, Lars and Haake, Andrea and Hansmann, Martin-Leo and Hoell, Jessica and Hummel, Michael and Korbel, Jan O. and Lawerenz, Chris and Lenze, Dido and Radlwimmer, Bernhard and Richter, Julia and Rosenstiel, Philip and Rosenwald, Andreas and Schilhabel, Markus B. and Stein, Harald and Stilgenbauer, Stephan and Stadler, Peter F. and Szczepanowski, Monika and Weniger, Marc A. and Zapatka, Marc and Eils, Roland and Lichter, Peter and Loeffler, Markus and M{\"o}ller, Peter and Tr{\"u}mper, Lorenz and Klapper, Wolfram and Hoffmann, Steve and K{\"u}ppers, Ralf and Burkhardt, Birgit and Schlesner, Matthias and Siebert, Reiner}, title = {Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, organization = {ICGC MMML-Seq Consortium}, doi = {10.1038/s41467-019-08578-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237281}, year = {2019}, abstract = {Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.}, language = {en} } @article{LuBoswellBoswelletal.2019, author = {Lu, Yuan and Boswell, Wiliam and Boswell, Mikki and Klotz, Barbara and Kneitz, Susanne and Regneri, Janine and Savage, Markita and Mendoza, Cristina and Postlethwait, John and Warren, Wesley C. and Schartl, Manfred and Walter, Ronald B.}, title = {Application of the Transcriptional Disease Signature (TDSs) to Screen Melanoma-Effective Compounds in a Small Fish Model}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-36656-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237322}, year = {2019}, abstract = {Cell culture and protein target-based compound screening strategies, though broadly utilized in selecting candidate compounds, often fail to eliminate candidate compounds with non-target effects and/or safety concerns until late in the drug developmental process. Phenotype screening using intact research animals is attractive because it can help identify small molecule candidate compounds that have a high probability of proceeding to clinical use. Most FDA approved, first-in-class small molecules were identified from phenotypic screening. However, phenotypic screening using rodent models is labor intensive, low-throughput, and very expensive. As a novel alternative for small molecule screening, we have been developing gene expression disease profiles, termed the Transcriptional Disease Signature (TDS), as readout of small molecule screens for therapeutic molecules. In this concept, compounds that can reverse, or otherwise affect known disease-associated gene expression patterns in whole animals may be rapidly identified for more detailed downstream direct testing of their efficacy and mode of action. To establish proof of concept for this screening strategy, we employed a transgenic strain of a small aquarium fish, medaka (Oryzias latipes), that overexpresses the malignant melanoma driver gene xmrk, a mutant egfr gene, that is driven by a pigment cell-specific mitf promoter. In this model, melanoma develops with 100\% penetrance. Using the transgenic medaka malignant melanoma model, we established a screening system that employs the NanoString nCounter platform to quantify gene expression within custom sets of TDS gene targets that we had previously shown to exhibit differential transcription among xmrk-transgenic and wild-type medaka. Compound-modulated gene expression was identified using an internet-accessible custom-built data processing pipeline. The effect of a given drug on the entire TDS profile was estimated by comparing compound-modulated genes in the TDS using an activation Z-score and Kolmogorov-Smirnov statistics. TDS gene probes were designed that target common signaling pathways that include proliferation, development, toxicity, immune function, metabolism and detoxification. These pathways may be utilized to evaluate candidate compounds for potential favorable, or unfavorable, effects on melanoma-associated gene expression. Here we present the logistics of using medaka to screen compounds, as well as, the development of a user-friendly NanoString data analysis pipeline to support feasibility of this novel TDS drug-screening strategy.}, language = {en} } @article{MercierWolmaransSchubertetal.2019, author = {Mercier, Rebecca and Wolmarans, Annemarie and Schubert, Jonathan and Neuweiler, Hannes and Johnson, Jill L. and LaPointe, Paul}, title = {The conserved NxNNWHW motif in Aha-type co-chaperones modulates the kinetics of Hsp90 ATPase stimulation}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-09299-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224007}, year = {2019}, abstract = {Hsp90 is a dimeric molecular chaperone that is essential for the folding and activation of hundreds of client proteins. Co-chaperone proteins regulate the ATP-driven Hsp90 client activation cycle. Aha-type co-chaperones are the most potent stimulators of the Hsp90 ATPase activity but the relationship between ATPase regulation and in vivo activity is poorly understood. We report here that the most strongly conserved region of Aha-type co-chaperones, the N terminal NxNNWHW motif, modulates the apparent affinity of Hsp90 for nucleotide substrates. The ability of yeast Aha-type co-chaperones to act in vivo is ablated when the N terminal NxNNWHW motif is removed. This work suggests that nucleotide exchange during the Hsp90 functional cycle may be more important than rate of catalysis.}, language = {en} } @article{MeralProvasiPradaGraciaetal.2018, author = {Meral, Derya and Provasi, Davide and Prada-Gracia, Diego and M{\"o}ller, Jan and Marino, Kristen and Lohse, Martin J. and Filizola, Marta}, title = {Molecular details of dimerization kinetics reveal negligible populations of transient µ-opioid receptor homodimers at physiological concentrations}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-26070-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223995}, year = {2018}, abstract = {Various experimental and computational techniques have been employed over the past decade to provide structural and thermodynamic insights into G Protein-Coupled Receptor (GPCR) dimerization. Here, we use multiple microsecond-long, coarse-grained, biased and unbiased molecular dynamics simulations (a total of ~4 milliseconds) combined with multi-ensemble Markov state models to elucidate the kinetics of homodimerization of a prototypic GPCR, the µ-opioid receptor (MOR), embedded in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/cholesterol lipid bilayer. Analysis of these computations identifies kinetically distinct macrostates comprising several different short-lived dimeric configurations of either inactive or activated MOR. Calculated kinetic rates and fractions of dimers at different MOR concentrations suggest a negligible population of MOR homodimers at physiological concentrations, which is supported by acceptor photobleaching fluorescence resonance energy transfer (FRET) experiments. This study provides a rigorous, quantitative explanation for some conflicting experimental data on GPCR oligomerization.}, language = {en} } @article{MedlerNelkeWeisenbergeretal.2019, author = {Medler, Juliane and Nelke, Johannes and Weisenberger, Daniela and Steinfatt, Tim and Rothaug, Moritz and Berr, Susanne and H{\"u}nig, Thomas and Beilhack, Andreas and Wajant, Harald}, title = {TNFRSF receptor-specific antibody fusion proteins with targeting controlled FcγR-independent agonistic activity}, series = {Cell Death \& Disease}, volume = {10}, journal = {Cell Death \& Disease}, doi = {10.1038/s41419-019-1456-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223948}, year = {2019}, abstract = {Antibodies specific for TNFRSF receptors that bind soluble ligands without getting properly activated generally act as strong agonists upon FcγR binding. Systematic analyses revealed that the FcγR dependency of such antibodies to act as potent agonists is largely independent from isotype, FcγR type, and of the epitope recognized. This suggests that the sole cellular attachment, achieved by Fc domain-FcγR interaction, dominantly determines the agonistic activity of antibodies recognizing TNFRSF receptors poorly responsive to soluble ligands. In accordance with this hypothesis, we demonstrated that antibody fusion proteins harboring domains allowing FcγR-independent cell surface anchoring also act as strong agonist provided they have access to their target. This finding defines a general possibility to generate anti-TNFRSF receptor antibodies with FcγR-independent agonism. Moreover, anti-TNFRSF receptor antibody fusion proteins with an anchoring domain promise superior applicability to conventional systemically active agonists when an anchoring target with localized disease associated expression can be addressed.}, language = {en} } @article{LuebckeEbbersVolzkeetal.2019, author = {L{\"u}bcke, Paul M. and Ebbers, Meinolf N. B. and Volzke, Johann and Bull, Jana and Kneitz, Susanne and Engelmann, Robby and Lang, Hermann and Kreikemeyer, Bernd and M{\"u}ller-Hilke, Brigitte}, title = {Periodontal treatment prevents arthritis in mice and methotrexate ameliorates periodontal bone loss}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-44512-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237355}, year = {2019}, abstract = {Recent studies indicate a causal relationship between the periodontal pathogen P. gingivalis and rheumatoid arthritis involving the production of autoantibodies against citrullinated peptides. We therefore postulated that therapeutic eradication P. gingivalis may ameliorate rheumatoid arthritis development and here turned to a mouse model in order to challenge our hypothesis. F1 (DBA/1 x B10.Q) mice were orally inoculated with P. gingivalis before collagen-induced arthritis was provoked. Chlorhexidine or metronidazole were orally administered either before or during the induction phase of arthritis and their effects on arthritis progression and alveolar bone loss were compared to intraperitoneally injected methotrexate. Arthritis incidence and severity were macroscopically scored and alveolar bone loss was evaluated via microcomputed tomography. Serum antibody titres against P. gingivalis were quantified by ELISA and microbial dysbiosis following oral inoculation was monitored in stool samples via microbiome analyses. Both, oral chlorhexidine and metronidazole reduced the incidence and ameliorated the severity of collagen-induced arthritis comparable to methotrexate. Likewise, all three therapies attenuated alveolar bone loss. Relative abundance of Porphyromonadaceae was increased after oral inoculation with P. gingivalis and decreased after treatment. This is the first study to describe beneficial effects of non-surgical periodontal treatment on collagen-induced arthritis in mice and suggests that mouthwash with chlorhexidine or metronidazole may also be beneficial for patients with rheumatoid arthritis and a coexisting periodontitis. Methotrexate ameliorated periodontitis in mice, further raising the possibility that methotrexate may also positively impact on the tooth supporting tissues of patients with rheumatoid arthritis.}, 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{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{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} } @phdthesis{Papay2024, author = {Papay, Marion}, title = {Notwendigkeit der pr{\"a}operativen Reposition von distalen, nach dorsal dislozierten Radiusfrakturen bei bestehender Operationsindikation im Hinblick auf das Schmerzniveau sowie postoperative Ergebnisse}, doi = {10.25972/OPUS-36388}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363882}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die distale Radiusfraktur geh{\"o}rt zu den h{\"a}ufigsten Frakturen in Deutschland mit einem Inzidenzanstieg im Alter unter Betonung des weiblichen Geschlechts. Dabei zeigt sich ein zunehmender Trend in Richtung operative Versorgung, allen voran die Versorgung mittels winkelstabiler Plattensysteme. Instabile, distale Radiusfrakturen werden dabei vor geplanter operativer Versorgung im Rahmen der Initialbehandlung {\"u}blicherweise geschlossen reponiert und im Gipsverband retiniert. Ziel der vorliegenden monozentrischen, prospektiv randomisierten Studie mit zwei Studiengruppen war es herauszufinden, ob sich das Unterlassen der Reposition vor geplanter Operation nachteilig auf das Schmerzniveau in der pr{\"a}operativen Phase auswirkt und ob sich durch die Dislokation Nachteile in Bezug auf den Nervus medianus im Sinne eines Traktionsschadens sowie bez{\"u}glich des klinisch-radiologischen Ausheilungsergebnisses zeigen. Die Studie zeigte, dass das Schmerzempfinden w{\"a}hrend der pr{\"a}operativen Gipsbehandlung unabh{\"a}ngig von einer vorherigen Reposition war. F{\"u}r den prim{\"a}ren Endpunkt an Tag 1 nach der Akutbehandlung konnte statistisch signifikante Nichtunterlegenheit der Gruppe ohne Reposition gegen{\"u}ber der Gruppe mit Reposition nachgewiesen werden. Gleiches galt f{\"u}r Tag 2, sowohl f{\"u}r die absoluten Schmerzniveaus als auch f{\"u}r die Schmerzlinderung. Das Unterlassen der Reposition hatte zudem keine nachteiligen Effekte auf den Nervus medianus. Gleiches zeigte sich f{\"u}r das klinische und radiologische Ausheilungsergebnis. F{\"u}r die funktionellen DASH- und Krimmer-Scores konnte ein Jahr postoperativ ebenfalls statistisch signifikante Nichtunterlegenheit der Gruppe ohne Reposition nachgewiesen werden. Diese Erkenntnisse best{\"a}tigen die in der Literatur vorhandenen Ergebnisse verschiedener Studien dahingehend, dass das Unterlassen der Reposition keine nachteiligen Effekte auf das postoperative Outcome hat. Einige Studien verdeutlichen zudem, dass es nach Reposition, insbesondere bei Vorliegen gewisser Risiko- und Instabilit{\"a}tsfaktoren, ohnehin zur sekund{\"a}ren Dislokation kommt, sodass die generelle Notwendigkeit der Reposition vor Gipsanlage sowohl vor einer operativen als auch vor einer konservativen Weiterbehandlung angezweifelt werden muss.}, subject = {distale Radiusfraktur}, language = {de} } @article{OPUS4-31269, title = {Measurement of prompt photon production in √ s(NN) = 8.16 TeV \(p\) Pb collisions with ATLAS}, series = {Physics letters B}, volume = {796}, journal = {Physics letters B}, organization = {The ATLAS Collaboration}, doi = {10.1016/j.physletb.2019.07.031}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312697}, pages = {230-252}, year = {2019}, abstract = {The inclusive production rates of isolated, prompt photons in p Pb collisions at root s(NN) = 8.16 TeV are studied with the ATLAS detector at the Large Hadron Collider using a dataset with an integrated luminosity of 165 nb(-1) recorded in 2016. The cross-section and nuclear modification factor R-p pb are measured as a function of photon transverse energy from 20 GeV to 550 GeV and in three nucleon-nucleon centre-of-mass pseudorapidity regions, (-2.83, -2.02), (-1.84, 0.91), and (1.09, 1.90). The cross-section and R-p pb values are compared with the results of a next-to-leading-order perturbative QCD calculation, with and without nuclear parton distribution function modifications, and with expectations based on a model of the energy loss of partons prior to the hard scattering. The data disfavour a large amount of energy loss and provide new constraints on the parton densities in nuclei. (C) 2019 The Author. Published by Elsevier B.V.}, language = {en} } @phdthesis{vonderHeide2024, author = {von der Heide, Julia Magdalena}, title = {Ist eine Berechnung der Geometrie der Halswirbelk{\"o}rper anhand ihrer Morphologie im Kindesalter und somit eine Individualisierung der CVM-Methode m{\"o}glich?}, doi = {10.25972/OPUS-36075}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360753}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Ziel der vorliegenden Studie war es zu untersuchen, ob anhand geometrischer Merkmale der HWK im Kindesalter eine sichere individuelle Vorhersage der Morphologie der HWK zum Ende der Entwicklung m{\"o}glich ist. Hierdurch k{\"o}nnte eine Individualisierung der CVM-Methode und somit eine Einsch{\"a}tzung des bereits verstrichenen Wachstums erfolgen. Zu diesem Zweck wurden insgesamt 1377 FRS-Aufnahmen von 267 Patienten - 110 weibliche und 157 m{\"a}nnliche - aus dem Archiv der Poliklinik f{\"u}r Kieferorthop{\"a}die des Universit{\"a}tsklinikums W{\"u}rzburg digitalisiert und untersucht. Die HWK wurden im Programm OnyxCeph (Herst.: Image Instruments GmbH) quantifiziert und die berechneten Werte mit der Software SPSS statistisch ausgewertet. Mittels linearer Regressionen wurde versucht, anhand der Morphologie der Wirbelk{\"o}rper vor dem puberalen Wachstumsschub auf die Geometrie der HWK im Erwachsenenalter zu schließen. Zur Illustrierung wurden Streudiagramm und die dazugeh{\"o}rigen Abfolgen von R{\"o}ntgenbildern dargestellt. Eine Sch{\"a}tzung der Geometrie der HWK im Erwachsenenalter w{\"u}rde bei den separat betrachteten Parametern und bei einer gemeinsamen Betrachtung der Parameter kaum zu korrekten Einsch{\"a}tzungen f{\"u}hren. Die Streudiagramme mit den Bilderabfolgen st{\"u}tzen diese These ebenfalls und illustrieren die m{\"o}gliche Fehleinsch{\"a}tzung der Geometrie. Die Ergebnisse der Studie zeigen erneut, dass die Geometrie der HWK im Erwachsenenalter sehr variabel ist, wie komplex die Entwicklung der HWK ist und dass anhand ihrer Geometrie im Kindesalter keine sichere Einsch{\"a}tzung der skelettalen Reife m{\"o}glich ist. Eine Individualisierung der CVM-Methode ist anhand der in dieser Studie untersuchten Parameter nicht m{\"o}glich. Somit l{\"a}sst sich schlussfolgern, dass die CVM-Methode nicht als alleinige Methode zur pr{\"a}zisen skelettalen Alterseinsch{\"a}tzung verl{\"a}sslich genutzt werden kann, sondern f{\"u}r eine sichere Beurteilung weitere Reifeindikatoren hinzugezogen werden sollten. Allerdings sollten hierzu zus{\"a}tzliche radiologische Untersuchungen, wie beispielsweise die Handr{\"o}ntgenaufnahme, nur dann durchgef{\"u}hrt werden, wenn diese dem ALARA-Prinzip entsprechen.}, subject = {Skelett}, language = {de} } @phdthesis{Roger2024, author = {Roger, Chantal}, title = {Photophysics and Spin Chemistry of Triptycene Bridge Donor-Acceptor-Triads}, doi = {10.25972/OPUS-36303}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363031}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The goal of this thesis was to investigate the influence of rotational restriction between individual parts and of the varying electron density in the bridging unit of D B A systems on the exchange interaction 2J, and thus the electronic coupling between a donor state and an acceptor state. A better understanding of how to influence the underlaying spin dynamics in such donor acceptor systems can open up the door to new technologies, such as modern molecular electronics or optoelectronic devices. Therefore, three series of molecules consisting of a TAA electron donor, a TTC or ATC bridging unit and a PDI electron acceptor were studied. To investigate the influence of rotational restriction on 2J and the electronic coupling, a series of four rotationally hindered triads (chapter 6) was synthesised. The dihedral angle between the TAA and the TTC as well as between the TTC and the PDI was restricted by ortho methyl groups at the phenylene linkers of the connecting ends to the TTC bridge, producing a twist around the linking single bond which minimises the π overlap. The triads exhibit varying numbers of ortho methyl groups and therefore different degrees of rotational restriction. In order to shine light on the influence of varying electron density on 2J and the electronic coupling, a series of four substituted triptycene triads (chapter 7) was synthesised. The electron density in the TTC bridging unit was varied by electron donating and electron withdrawing groups in 12,13 position of the TTC bridging unit and thus varying its HOMO/LUMO energy. The last series of two anthracene bridge triads (chapter 8) connected both approaches by restricting the rotation with ortho methyl groups and simultaneously by varying the bridge energies. In order to obtain the electronic properties, steady state absorption and emission spectra of all triads were investigated (chapter 4). Here, all triads show spectral features associated with the separate absorption bands of TAA and the PDI moiety. The reduced QYs, compared to the unsubstituted PDI acceptor, indicate a non radiative quenching mechanism in all triads. The CV data (chapter 5) were used to calculate the energies of possible CSSs and those results were used to assign the CR dynamics into the different Marcus regions. fs TA measurements reveal that all triads form a CSS upon excitation of the PDI moiety. The lifetimes of the involved states and the rate constants were determined by global exponential fits and global target analysis. The CR dynamics upon depopulation of the CSSs were investigated using external magnetic field dependent ns TA spectroscopy. The ns TA maps show that all triads recombine via CRT pathway populating the local 3PDI state in toluene and provided the respective lifetimes. The approximate QYs of triplet formation were determined using actinometry. The magnetic field dependent ns TA data reveal the exchange interaction 2J between singlet and triplet CSS for each triad. Those magnetic field dependent ns TA data in toluene were furthermore treated using a quantum mechanical simulation (done by U.E. Steiner) to extract the rate constants kT and kS for CRT and CRS, respectively. However, the error margins of kS were rather wide. Finally, the electronic couplings between the donor and the acceptor states were obtained by combining the aforementioned experimental results of the rate constants and applying the Bixon Jortner theoretical description of diabatic ET and Andersons perturbative theory of the exchange coupling. Therefore, the experimentally determined values of 2J and the calculated values of kCS and kT were used. The rate constant kS was calculated based on the electronic coupling V1CSS 1S0. The rotationally hindered triads (chapter 6) show a strong influence of the degree of rotational restriction on the lifetimes and rate constants of the CS processes. The rate constants of CS are increasing with increasing rotational freedom. The magnetic field dependent decay data show that the exchange interactions increase with increasing rotational freedom. Based on the CR dynamics, the calculated electronic couplings of the ET processes reflect the same trend along the series. Here, only singlet couplings turned out to be strongly influenced while the triplet couplings are not. Therefore, this series shows that the ET dynamics of donor acceptor systems can strongly be influenced by restricting the rotational freedom. In the substituted triptycene triads (chapter 7), decreasing electron density in the bridging unit causes a decrease of the CS rate constants. The magnetic field dependent decay data show that with decreasing electron density in the bridge the exchange interaction decreases. The CR dynamics-based rate constants and the electronic couplings follow the same trend as the exchange interaction. This series shows that varying the HOMO/LUMO levels of the connecting bridge between donor and acceptor strongly influences the ET processes. In the anthracene bridge triads (chapter 8), the CS process is slow in both triads. The CR was fast in the anthracene triad and is slowed down in the methoxy substituted anthracene bridge triad. The increase of the exchange interaction with increasing electron density in the bridge was more pronounced than in the substituted triptycene triads. Thus, the variation of electron density in the bridge strongly influences the ET processes even though the rotation is restricted. In this thesis, it was shown that the influence of the rotational hindrance as well as the electron density in a connecting bridge have strong influence on all ET processes and the electronic coupling in donor acceptor systems. These approaches can therefore be used to modify magnetic properties of new materials.}, subject = {Rotation}, language = {en} } @phdthesis{Krings2024, author = {Krings, Moritz}, title = {Universit{\"a}re Psychiatrie um 1900 : Die Anfangsjahre der psychiatrischen Klinik in W{\"u}rzburg}, doi = {10.25972/OPUS-36140}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-361407}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Ende des 19. Jahrhunderts standen sich in Deutschland zwei verschiedene Arten psychiatrischer Institutionen gegen{\"u}ber, die Anstaltspsychiatrien auf der einen, die universit{\"a}ren psychiatrischen Kliniken auf der anderen Seite. Die psychiatriehistorische Forschung widmete sich {\"u}berwiegend psychiatrischen Anstalten w{\"a}hrend Kliniken hier unterrepr{\"a}sentiert sind. Die vorliegende Arbeit m{\"o}chte zur historischen Kenntnis universit{\"a}rer psychiatrischer Einrichtungen beitragen. Hierzu werden die Charakteristika einer psychiatrischen Klinik um 1900 anhand des Beispiels der psychiatrischen Klinik der Universit{\"a}t W{\"u}rzburg betrachtet. Der Fokus liegt hierbei neben Lage und Aufbau der Klinik sowie deren Personal auf den drei Bereichen Patient*innen, Forschung und Lehre.}, subject = {Julius-Maximilians-Universit{\"a}t W{\"u}rzburg}, language = {de} }