@article{LenzPahlHaucketal.2021, author = {Lenz, Dominic and Pahl, Jens and Hauck, Fabian and Alameer, Seham and Balasubramanian, Meena and Baric, Ivo and Boy, Nikolas and Church, Joseph A. and Crushell, Ellen and Dick, Anke and Distelmaier, Felix and Gujar, Jidnyasa and Indolfi, Giuseppe and Lurz, Eberhard and Peters, Bianca and Schwerd, Tobias and Serranti, Daniele and K{\"o}lker, Stefan and Klein, Christoph and Hoffmann, Georg F. and Prokisch, Holger and Greil, Johann and Cerwenka, Adelheid and Giese, Thomas and Staufner, Christian}, title = {NBAS Variants Are Associated with Quantitative and Qualitative NK and B Cell Deficiency}, series = {Journal of Clinical Immunology}, volume = {41}, journal = {Journal of Clinical Immunology}, number = {8}, issn = {0271-9142}, doi = {10.1007/s10875-021-01110-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308362}, pages = {1781-1793}, year = {2021}, abstract = {Purpose Biallelic pathogenic NBAS variants manifest as a multisystem disorder with heterogeneous clinical phenotypes such as recurrent acute liver failure, growth retardation, and susceptibility to infections. This study explores how NBAS-associated disease affects cells of the innate and adaptive immune system. Methods Clinical and laboratory parameters were combined with functional multi-parametric immunophenotyping methods in fifteen NBAS-deficient patients to discover possible alterations in their immune system. Results Our study revealed reduced absolute numbers of mature CD56dim natural killer (NK) cells. Notably, the residual NK cell population in NBAS-deficient patients exerted a lower potential for activation and degranulation in response to K562 target cells, suggesting an NK cell-intrinsic role for NBAS in the release of cytotoxic granules. NBAS-deficient NK cell activation and degranulation was normalized upon pre-activation by IL-2 in vitro, suggesting that functional impairment was reversible. In addition, we observed a reduced number of na{\"i}ve B cells in the peripheral blood associated with hypogammaglobulinemia. Conclusion In summary, we demonstrate that pathogenic biallelic variants in NBAS are associated with dysfunctional NK cells as well as impaired adaptive humoral immunity.}, language = {en} } @article{DanyszDekundyScheschonkaetal.2021, author = {Danysz, Wojciech and Dekundy, Andrzej and Scheschonka, Astrid and Riederer, Peter}, title = {Amantadine: reappraisal of the timeless diamond—target updates and novel therapeutic potentials}, series = {Journal of Neural Transmission}, volume = {128}, journal = {Journal of Neural Transmission}, number = {2}, doi = {10.1007/s00702-021-02306-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-330133}, pages = {127-169}, year = {2021}, abstract = {The aim of the current review was to provide a new, in-depth insight into possible pharmacological targets of amantadine to pave the way to extending its therapeutic use to further indications beyond Parkinson's disease symptoms and viral infections. Considering amantadine's affinities in vitro and the expected concentration at targets at therapeutic doses in humans, the following primary targets seem to be most plausible: aromatic amino acids decarboxylase, glial-cell derived neurotrophic factor, sigma-1 receptors, phosphodiesterases, and nicotinic receptors. Further three targets could play a role to a lesser extent: NMDA receptors, 5-HT3 receptors, and potassium channels. Based on published clinical studies, traumatic brain injury, fatigue [e.g., in multiple sclerosis (MS)], and chorea in Huntington's disease should be regarded potential, encouraging indications. Preclinical investigations suggest amantadine's therapeutic potential in several further indications such as: depression, recovery after spinal cord injury, neuroprotection in MS, and cutaneous pain. Query in the database http://www.clinicaltrials.gov reveals research interest in several further indications: cancer, autism, cocaine abuse, MS, diabetes, attention deficit-hyperactivity disorder, obesity, and schizophrenia.}, language = {en} } @article{FerreiraGamazonAlEjehetal.2019, author = {Ferreira, Manuel A. and Gamazon, Eric R. and Al-Ejeh, Fares and Aittom{\"a}ki, Kristiina and Andrulis, Irene L. and Anton-Culver, Hoda and Arason, Adalgeir and Arndt, Volker and Aronson, Kristan J. and Arun, Banu K. and Asseryanis, Ella and Azzollini, Jacopo and Balma{\~n}a, Judith and Barnes, Daniel R. and Barrowdale, Daniel and Beckmann, Matthias W. and Behrens, Sabine and Benitez, Javier and Bermisheva, Marina and Bialkowska, Katarzyna and Blomqvist, Carl and Bogdanova, Natalia V. and Bojesen, Stig E. and Bolla, Manjeet K. and Borg, Ake and Brauch, Hiltrud and Brenner, Hermann and Broeks, Annegien and Burwinkel, Barbara and Cald{\´e}s, Trinidad and Caligo, Maria A. and Campa, Daniele and Campbell, Ian and Canzian, Federico and Carter, Jonathan and Carter, Brian D. and Castelao, Jose E. and Chang-Claude, Jenny and Chanock, Stephen J. and Christiansen, Hans and Chung, Wendy K. and Claes, Kathleen B. M. and Clarke, Christine L. and Couch, Fergus J. and Cox, Angela and Cross, Simon S. and Czene, Kamila and Daly, Mary B. and de la Hoya, Miguel and Dennis, Joe and Devilee, Peter and Diez, Orland and D{\"o}rk, Thilo and Dunning, Alison M. and Dwek, Miriam and Eccles, Diana M. and Ejlertsen, Bent and Ellberg, Carolina and Engel, Christoph and Eriksson, Mikael and Fasching, Peter A. and Fletcher, Olivia and Flyger, Henrik and Friedman, Eitan and Frost, Debra and Gabrielson, Marike and Gago-Dominguez, Manuela and Ganz, Patricia A. and Gapstur, Susan M. and Garber, Judy and Garc{\´i}a-Closas, Montserrat and Garc{\´i}a-S{\´a}enz, Jos{\´e} A. and Gaudet, Mia M. and Giles, Graham G. and Glendon, Gord and Godwin, Andrew K. and Goldberg, Mark S. and Goldgar, David E. and Gonz{\´a}lez-Neira, Anna and Greene, Mark H. and Gronwald, Jacek and Guen{\´e}l, Pascal and Haimann, Christopher A. and Hall, Per and Hamann, Ute and He, Wei and Heyworth, Jane and Hogervorst, Frans B. L. and Hollestelle, Antoinette and Hoover, Robert N. and Hopper, John L. and Hulick, Peter J. and Humphreys, Keith and Imyanitov, Evgeny N. and Isaacs, Claudine and Jakimovska, Milena and Jakubowska, Anna and James, Paul A. and Janavicius, Ramunas and Jankowitz, Rachel C. and John, Esther M. and Johnson, Nichola and Joseph, Vijai and Karlan, Beth Y. and Khusnutdinova, Elza and Kiiski, Johanna I. and Ko, Yon-Dschun and Jones, Michael E. and Konstantopoulou, Irene and Kristensen, Vessela N. and Laitman, Yael and Lambrechts, Diether and Lazaro, Conxi and Leslie, Goska and Lester, Jenny and Lesueur, Fabienne and Lindstr{\"o}m, Sara and Long, Jirong and Loud, Jennifer T. and Lubiński, Jan and Makalic, Enes and Mannermaa, Arto and Manoochehri, Mehdi and Margolin, Sara and Maurer, Tabea and Mavroudis, Dimitrios and McGuffog, Lesley and Meindl, Alfons and Menon, Usha and Michailidou, Kyriaki and Miller, Austin and Montagna, Marco and Moreno, Fernando and Moserle, Lidia and Mulligan, Anna Marie and Nathanson, Katherine L. and Neuhausen, Susan L. and Nevanlinna, Heli and Nevelsteen, Ines and Nielsen, Finn C. and Nikitina-Zake, Liene and Nussbaum, Robert L. and Offit, Kenneth and Olah, Edith and Olopade, Olufunmilayo I. and Olsson, H{\aa}kan and Osorio, Ana and Papp, Janos and Park-Simon, Tjoung-Won and Parsons, Michael T. and Pedersen, Inge Sokilde and Peixoto, Ana and Peterlongo, Paolo and Pharaoh, Paul D. P. and Plaseska-Karanfilska, Dijana and Poppe, Bruce and Presneau, Nadege and Radice, Paolo and Rantala, Johanna and Rennert, Gad and Risch, Harvey A. and Saloustros, Emmanouil and Sanden, Kristin and Sawyer, Elinor J. and Schmidt, Marjanka K. and Schmutzler, Rita K. and Sharma, Priyanka and Shu, Xiao-Ou and Simard, Jaques and Singer, Christian F. and Soucy, Penny and Southey, Melissa C. and Spinelli, John J. and Spurdle, Amanda B. and Stone, Jennifer and Swerdlow, Anthony J. and Tapper, William J. and Taylor, Jack A. and Teixeira, Manuel R. and Terry, Mary Beth and Teul{\´e}, Alex and Thomassen, Mads and Th{\"o}ne, Kathrin and Thull, Darcy L. and Tischkowitz, Marc and Toland, Amanda E. and Torres, Diana and Truong, Th{\´e}r{\`e}se and Tung, Nadine and Vachon, Celine M. and van Asperen, Christi J. and van den Ouweland, Ans M. W. and van Rensburg, Elizabeth J. and Vega, Ana and Viel, Alexandra and Wang, Qin and Wappenschmidt, Barbara and Weitzel, Jeffrey N. and Wendt, Camilla and Winqvist, Robert and Yang, Xiaohong R. and Yannoukakos, Drakoulis and Ziogas, Argyrios and Kraft, Peter and Antoniou, Antonis C. and Zheng, Wei and Easton, Douglas F. and Milne, Roger L. and Beesley, Jonathan and Chenevix-Trench, Georgia}, title = {Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, organization = {EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, ABCTB Investigators, HEBON Investigators, BCFR Investigators}, doi = {10.1038/s41467-018-08053-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228024}, year = {2019}, abstract = {Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.}, language = {en} } @article{FanEbnerReichertetal.2019, author = {Fan, Sook-Ha and Ebner, Patrick and Reichert, Sebstian and Hertlein, Tobias and Zabel, Susanne and Lankapalli, Aditya Kumar and Nieselt, Kay and Ohlsen, Knut and G{\"o}tz, Friedrich}, title = {MpsAB is important for Staphylococcus aureus virulence and growth at atmospheric CO2 levels}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-11547-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227624}, year = {2019}, abstract = {The mechanisms behind carbon dioxide (CO2) dependency in non-autotrophic bacterial isolates are unclear. Here we show that the Staphylococcus aureus mpsAB operon, known to play a role in membrane potential generation, is crucial for growth at atmospheric CO2 levels. The genes mpsAB can complement an Escherichia coli carbonic anhydrase (CA) mutant, and CA from E. coli can complement the S. aureus delta-mpsABC mutant. In comparison with the wild type, S. aureus mps mutants produce less hemolytic toxin and are less virulent in animal models of infection. Homologs of mpsA and mpsB are widespread among bacteria and are often found adjacent to each other on the genome. We propose that MpsAB represents a dissolved inorganic carbon transporter, or bicarbonate concentrating system, possibly acting as a sodium bicarbonate cotransporter.}, language = {en} } @article{EstradaKrebbersVossetal.2018, author = {Estrada, Veronica and Krebbers, Julia and Voss, Christian and Brazda, Nicole and Blazyca, Heinrich and Illgen, Jennifer and Seide, Klaus and J{\"u}rgens, Christian and M{\"u}ller, J{\"o}rg and Martini, Rudolf and Trieu, Hoc Khiem and M{\"u}ller, Hans Werner}, title = {Low-pressure micro-mechanical re-adaptation device sustainably and effectively improves locomotor recovery from complete spinal cord injury}, series = {Communications Biology}, volume = {1}, journal = {Communications Biology}, doi = {10.1038/s42003-018-0210-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227357}, year = {2018}, abstract = {Traumatic spinal cord injuries result in impairment or even complete loss of motor, sensory and autonomic functions. Recovery after complete spinal cord injury is very limited even in animal models receiving elaborate combinatorial treatments. Recently, we described an implantable microsystem (microconnector) for low-pressure re-adaption of severed spinal stumps in rat. Here we investigate the long-term structural and functional outcome following microconnector implantation after complete spinal cord transection. Re-adaptation of spinal stumps supports formation of a tissue bridge, glial and vascular cell invasion, motor axon regeneration and myelination, resulting in partial recovery of motor-evoked potentials and a thus far unmet improvement of locomotor behaviour. The recovery lasts for at least 5 months. Despite a late partial decline, motor recovery remains significantly superior to controls. Our findings demonstrate that microsystem technology can foster long-lasting functional improvement after complete spinal injury, providing a new and effective tool for combinatorial therapies.}, language = {en} } @article{ElMeseryRosenthalRauertWunderlichetal.2019, author = {El-Mesery, Mohamed and Rosenthal, Tina and Rauert-Wunderlich, Hilka and Schreder, Martin and St{\"u}hmer, Thorsten and Leich, Ellen and Schlosser, Andreas and Ehrenschwender, Martin and Wajant, Harald and Siegmund, Daniela}, title = {The NEDD8-activating enzyme inhibitor MLN4924 sensitizes a TNFR1+ subgroup of multiple myeloma cells for TNF-induced cell death}, series = {Cell Death \& Disease}, volume = {10}, journal = {Cell Death \& Disease}, doi = {10.1038/s41419-019-1860-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226666}, year = {2019}, abstract = {The NEDD8-activating enzyme (NAE) inhibitor MLN4924 inhibits cullin-RING ubiquitin ligase complexes including the SKP1-cullin-F-box E3 ligase βTrCP. MLN4924 therefore inhibits also the βTrCP-dependent activation of the classical and the alternative NFĸB pathway. In this work, we found that a subgroup of multiple myeloma cell lines (e.g., RPMI-8226, MM.1S, KMS-12BM) and about half of the primary myeloma samples tested are sensitized to TNF-induced cell death by MLN4924. This correlated with MLN4924-mediated inhibition of TNF-induced activation of the classical NFκB pathway and reduced the efficacy of TNF-induced TNFR1 signaling complex formation. Interestingly, binding studies revealed a straightforward correlation between cell surface TNFR1 expression in multiple myeloma cell lines and their sensitivity for MLN4924/TNF-induced cell death. The cell surface expression levels of TNFR1 in the investigated MM cell lines largely correlated with TNFR1 mRNA expression. This suggests that the variable levels of cell surface expression of TNFR1 in myeloma cell lines are decisive for TNF/MLN4924 sensitivity. Indeed, introduction of TNFR1 into TNFR1-negative TNF/MLN4924-resistant KMS-11BM cells, was sufficient to sensitize this cell line for TNF/MLN4924-induced cell death. Thus, MLN4924 might be especially effective in myeloma patients with TNFR1+ myeloma cells and a TNFhigh tumor microenvironment.}, language = {en} } @article{DunceMilburnGurusaranetal.2018, author = {Dunce, James M. and Milburn, Amy E. and Gurusaran, Manickam and da Cruz, Irene and Sen, Lee T. and Benavente, Ricardo and Davies, Owen R.}, title = {Structural basis of meiotic telomere attachment to the nuclear envelope by MAJIN-TERB2-TERB1}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-07794-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226416}, year = {2018}, abstract = {Meiotic chromosomes undergo rapid prophase movements, which are thought to facilitate the formation of inter-homologue recombination intermediates that underlie synapsis, crossing over and segregation. The meiotic telomere complex (MAJIN, TERB1, TERB2) tethers telomere ends to the nuclear envelope and transmits cytoskeletal forces via the LINC complex to drive these rapid movements. Here, we report the molecular architecture of the meiotic telomere complex through the crystal structure of MAJIN-TERB2, together with light and X-ray scattering studies of wider complexes. The MAJIN-TERB2 2:2 hetero-tetramer binds strongly to DNA and is tethered through long flexible linkers to the inner nuclear membrane and two TRF1-binding 1:1 TERB2-TERB1 complexes. Our complementary structured illumination microscopy studies and biochemical findings reveal a telomere attachment mechanism in which MAJIN-TERB2-TERB1 recruits telomere-bound TRF1, which is then displaced during pachytene, allowing MAJIN-TERB2-TERB1 to bind telomeric DNA and form a mature attachment plate.}, language = {en} } @article{DubailHuberChantepieetal.2018, author = {Dubail, Johanne and Huber, C{\´e}line and Chantepie, Sandrine and Sonntag, Stephan and T{\"u}ys{\"u}z, Beyhan and Mihci, Ercan and Gordon, Christopher T. and Steichen-Gersdorf, Elisabeth and Amiel, Jeanne and Nur, Banu and Stolte-Dijkstra, Irene and van Eerde, Albertien M. and van Gassen, Koen L. and Breugem, Corstiaan C. and Stegmann, Alexander and Lekszas, Caroline and Maroofian, Reza and Karimiani, Ehsan Ghayoor and Bruneel, Arnaud and Seta, Nathalie and Munnich, Arnold and Papy-Garcia, Dulce and De La Dure-Molla, Muriel and Cormier-Daire, Val{\´e}rie}, title = {SLC10A7 mutations cause a skeletal dysplasia with amelogenesis imperfecta mediated by GAG biosynthesis defects}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-05191-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226377}, year = {2018}, abstract = {Skeletal dysplasia with multiple dislocations are severe disorders characterized by dislocations of large joints and short stature. The majority of them have been linked to pathogenic variants in genes encoding glycosyltransferases, sulfotransferases or epimerases required for glycosaminoglycan synthesis. Using exome sequencing, we identify homozygous mutations in SLC10A7 in six individuals with skeletal dysplasia with multiple dislocations and amelogenesis imperfecta. SLC10A7 encodes a 10-transmembrane-domain transporter located at the plasma membrane. Functional studies in vitro demonstrate that SLC10A7 mutations reduce SLC10A7 protein expression. We generate a Slc10a7-/- mouse model, which displays shortened long bones, growth plate disorganization and tooth enamel anomalies, recapitulating the human phenotype. Furthermore, we identify decreased heparan sulfate levels in Slc10a7-/- mouse cartilage and patient fibroblasts. Finally, we find an abnormal N-glycoprotein electrophoretic profile in patient blood samples. Together, our findings support the involvement of SLC10A7 in glycosaminoglycan synthesis and specifically in skeletal development.}, language = {en} } @article{DostalFennelKochetal.2018, author = {Dost{\´a}l, Jakub and Fennel, Franziska and Koch, Federico and Herbst, Stefanie and W{\"u}rthner, Frank and Brixner, Tobias}, title = {Direct observation of exciton-exciton interactions}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-04884-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226271}, year = {2018}, abstract = {Natural light harvesting as well as optoelectronic and photovoltaic devices depend on efficient transport of energy following photoexcitation. Using common spectroscopic methods, however, it is challenging to discriminate one-exciton dynamics from multi-exciton interactions that arise when more than one excitation is present in the system. Here we introduce a coherent two-dimensional spectroscopic method that provides a signal only in case that the presence of one exciton influences the behavior of another one. Exemplarily, we monitor exciton diffusion by annihilation in a perylene bisimide-based J-aggregate. We determine quantitatively the exciton diffusion constant from exciton-exciton-interaction 2D spectra and reconstruct the annihilation-free dynamics for large pump powers. The latter enables for ultrafast spectroscopy at much higher intensities than conventionally possible and thus improves signal-to-noise ratios for multichromophore systems; the former recovers spatio-temporal dynamics for a broad range of phenomena in which exciton interactions are present.}, language = {en} } @article{DoerkPeterlongoMannermaaetal.2019, author = {D{\"o}rk, Thilo and Peterlongo, Peter and Mannermaa, Arto and Bolla, Manjeet K. and Wang, Qin and Dennis, Joe and Ahearn, Thomas and Andrulis, Irene L. and Anton-Culver, Hoda and Arndt, Volker and Aronson, Kristan J. and Augustinsson, Annelie and Beane Freeman, Laura E. and Beckmann, Matthias W. and Beeghly-Fadiel, Alicia and Behrens, Sabine and Bermisheva, Marina and Blomqvist, Carl and Bogdanova, Natalia V. and Bojesen, Stig E. and Brauch, Hiltrud and Brenner, Hermann and Burwinkel, Barbara and Canzian, Federico and Chan, Tsun L. and Chang-Claude, Jenny and Chanock, Stephen J. and Choi, Ji-Yeob and Christiansen, Hans and Clarke, Christine L. and Couch, Fergus J. and Czene, Kamila and Daly, Mary B. and dos-Santos-Silva, Isabel and Dwek, Miriam and Eccles, Diana M. and Ekici, Arif B. and Eriksson, Mikael and Evans, D. Gareth and Fasching, Peter A. and Figueroa, Jonine and Flyger, Henrik and Fritschi, Lin and Gabrielson, Marike and Gago-Dominguez, Manuela and Gao, Chi and Gapstur, Susan M. and Garc{\´i}a-Closas, Montserrat and Garc{\´i}a-S{\´a}enz, Jos{\´e} A. and Gaudet, Mia M. and Giles, Graham G. and Goldberg, Mark S. and Goldgar, David E. and Guen{\´e}l, Pascal and Haeberle, Lothar and Haimann, Christopher A. and H{\aa}kansson, Niclas and Hall, Per and Hamann, Ute and Hartman, Mikael and Hauke, Jan and Hein, Alexander and Hillemanns, Peter and Hogervorst, Frans B. L. and Hooning, Maartje J. and Hopper, John L. and Howell, Tony and Huo, Dezheng and Ito, Hidemi and Iwasaki, Motoki and Jakubowska, Anna and Janni, Wolfgang and John, Esther M. and Jung, Audrey and Kaaks, Rudolf and Kang, Daehee and Kapoor, Pooja Middha and Khusnutdinova, Elza and Kim, Sung-Won and Kitahara, Cari M. and Koutros, Stella and Kraft, Peter and Kristensen, Vessela N. and Kwong, Ava and Lambrechts, Diether and Le Marchand, Loic and Li, Jingmei and Lindstr{\"o}m, Sara and Linet, Martha and Lo, Wing-Yee and Long, Jirong and Lophatananon, Artitaya and Lubiński, Jan and Manoochehri, Mehdi and Manoukian, Siranoush and Margolin, Sara and Martinez, Elena and Matsuo, Keitaro and Mavroudis, Dimitris and Meindl, Alfons and Menon, Usha and Milne, Roger L. and Mohd Taib, Nur Aishah and Muir, Kenneth and Mulligan, Anna Marie and Neuhausen, Susan L. and Nevanlinna, Heli and Neven, Patrick and Newman, William G. and Offit, Kenneth and Olopade, Olufunmilayo I. and Olshan, Andrew F. and Olson, Janet E. and Olsson, H{\aa}kan and Park, Sue K. and Park-Simon, Tjoung-Won and Peto, Julian and Plaseska-Karanfilska, Dijana and Pohl-Rescigno, Esther and Presneau, Nadege and Rack, Brigitte and Radice, Paolo and Rashid, Muhammad U. and Rennert, Gad and Rennert, Hedy S. and Romero, Atocha and Ruebner, Matthias and Saloustros, Emmanouil and Schmidt, Marjanka K. and Schmutzler, Rita K. and Schneider, Michael O. and Schoemaker, Minouk J. and Scott, Christopher and Shen, Chen-Yang and Shu, Xiao-Ou and Simard, Jaques and Slager, Susan and Smichkoska, Snezhana and Southey, Melissa C. and Spinelli, John J. and Stone, Jennifer and Surowy, Harald and Swerdlow, Anthony J. and Tamimi, Rulla M. and Tapper, William J. and Teo, Soo H. and Terry, Mary Beth and Toland, Amanda E. and Tollenaar, Rob A. E. M. and Torres, Diana and Torres-Mej{\´i}a, Gabriela and Troester, Melissa A. and Truong, Th{\´e}r{\`e}se and Tsugane, Shoichiro and Untch, Michael and Vachon, Celine M. and van den Ouweland, Ans M. W. and van Veen, Elke M. and Vijai, Joseph and Wendt, Camilla and Wolk, Alicja and Yu, Jyh-Cherng and Zheng, Wei and Ziogas, Argyrios and Ziv, Elad and Dunnig, Alison and Pharaoh, Paul D. P. and Schindler, Detlev and Devilee, Peter and Easton, Douglas F.}, title = {Two truncating variants in FANCC and breast cancer risk}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, organization = {ABCTB Investigators, NBCS Collaborators}, doi = {10.1038/s41598-019-48804-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222838}, year = {2019}, abstract = {Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95\%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.}, language = {en} } @article{DindasScherzerRoelfsemaetal.2018, author = {Dindas, Julian and Scherzer, S{\"o}nke and Roelfsema, M. Rob G. and Meyer, Katharina von and M{\"u}ller, Heike M. and Al-Rasheid, K. A. S. and Palme, Klaus and Dietrich, Petra and Becker, Dirk and Bennett, Malcolm J. and Hedrich, Rainer}, title = {AUX1-mediated root hair auxin influx governs SCFTIR1/AFB-type Ca2+ signaling}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-03582-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225368}, year = {2018}, abstract = {Auxin is a key regulator of plant growth and development, but the causal relationship between hormone transport and root responses remains unresolved. Here we describe auxin uptake, together with early steps in signaling, in Arabidopsis root hairs. Using intracellular microelectrodes we show membrane depolarization, in response to IAA in a concentration- and pH-dependent manner. This depolarization is strongly impaired in aux1 mutants, indicating that AUX1 is the major transporter for auxin uptake in root hairs. Local intracellular auxin application triggers Ca2+ signals that propagate as long-distance waves between root cells and modulate their auxin responses. AUX1-mediated IAA transport, as well as IAA- triggered calcium signals, are blocked by treatment with the SCFTIR1/AFB - inhibitor auxinole. Further, they are strongly reduced in the tir1afb2afb3 and the cngc14 mutant. Our study reveals that the AUX1 transporter, the SCFTIR1/AFB receptor and the CNGC14 Ca2+ channel, mediate fast auxin signaling in roots.}, 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{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{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{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{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{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{HellerReiterLeichtetal.2023, author = {Heller, Bianca and Reiter, Florian P. and Leicht, Hans Benno and Fiessler, Cornelia and Bergheim, Ina and Heuschmann, Peter U. and Geier, Andreas and Rau, Monika}, title = {Salt-intake-related behavior varies between sexes and is strongly associated with daily salt consumption in obese patients at high risk for MASLD}, series = {Nutrients}, volume = {15}, journal = {Nutrients}, number = {18}, issn = {2072-6643}, doi = {10.3390/nu15183942}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363107}, year = {2023}, abstract = {Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) imposes a significant burden on Westernized regions. The Western diet, high in salt intake, significantly contributes to disease development. However, there are a lack of data on salt literacy and salt intake among MASLD patients in Germany. Our study aims to analyze daily salt intake and salt-intake-related behavior in MASLD patients. Methods: 234 MASLD patients were prospectively included. Daily salt intake and salt-intake-related behavior were assessed via a food frequency questionnaire (FFQ—DEGS) and a salt questionnaire (SINU). Statistical analyses were performed using SPSS. Results: Mean daily salt intake was higher in men than in women (7.3 ± 5 g/d vs. 5.3 ± 4 g/d; p \< 0.001). There was significant agreement between increased daily salt intake (6 g/d) and the behavioral salt index (SI) (p \< 0.001). Men exhibited higher SI scores compared to women, indicating lower awareness of salt in everyday life. Multivariate analysis identified specific salt-intake-related behaviors impacting daily salt consumption. Conclusions: Our study reveals a strong link between daily salt intake and salt-intake-related behavior, highlighting sex-specific differences in an MASLD cohort. To enhance patient care in high-cardiovascular-risk populations, specific behavioral approaches may be considered, including salt awareness, to improve adherence to lifestyle changes, particularly in male patients.}, language = {en} } @article{WinterSchulzSchmitteretal.2023, author = {Winter, Anna and Schulz, Stefan M. and Schmitter, Marc and M{\"u}ller-Richter, Urs and K{\"u}bler, Alexander and Kasper, Sylvia and Hartmann, Stefan}, title = {Comprehensive geriatric assessment and quality of life aspects in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC)}, series = {Journal of Clinical Medicine}, volume = {12}, journal = {Journal of Clinical Medicine}, number = {17}, issn = {2077-0383}, doi = {10.3390/jcm12175738}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363096}, year = {2023}, abstract = {To define frailty in older cancer patients, the aim of this study was to assess the geriatric status and quality of life (QoL) aspects in patients suffering from recurrent/metastatic head and neck squamous cell carcinoma (r/m HNSCC) under palliative treatment. A comprehensive geriatric assessment (CGA) was performed on 21 r/m HNSCC patients at two defined assessments, and the QoL aspects and the impact of descriptive data were evaluated. The Kolmogorov-Smirnov test, Spearman's rho correlation, and two-way mixed ANOVA were used for statistical analysis. All patients were found to be "frail". Pain, fatigue, and the burden of illness were the highest-rated symptoms. Oral function and orofacial appearance were highly impaired. A significant impact of descriptive data on the CGA and QoL results was found (all p ≤ 0.05). Thus, the CGA results revealed high frailty, severe comorbidities, and high impairments in QoL aspects. The CGA and QoL results were negatively affected by the primary HNSCC treatment approach, the need for prosthetic treatment, and worse oral functional capacity. Therefore, frailty in r/m HNSCC patients seems to be multidimensional. The evaluation of the CGA and QoL aspects in r/m HNSCC patients can be recommended to detect special needs, organize aftercare, and improve the support for frail and vulnerable cancer patients to create a multidisciplinary treatment approach.}, 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{SchneiderSeebauerBeuerleetal.2024, author = {Schneider, Tilman and Seebauer, Florian and Beuerle, Florian and W{\"u}rthner, Frank}, title = {A monodisperse, end-capped Ru(bda) oligomer with outstanding performance in heterogeneous electrochemical water oxidation}, series = {Advanced Materials Technologies}, volume = {9}, journal = {Advanced Materials Technologies}, number = {11}, issn = {2365-709X}, doi = {10.1002/admt.202301721}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363133}, year = {2024}, abstract = {AbstractWater oxidation catalysis is a key step for sustainable fuel production by water splitting into hydrogen and oxygen. The synthesis of a novel coordination oligomer based on four Ru(bda) (bda = 2,2′-bipyridine-6,6′-dicarboxylate) centers, three 4,4′-bipyridine (4,4′-bpy) linkers, and two 4-picoline (4-pic) end caps is reported. The monodispersity of this tetranuclear compound is characterized by NMR techniques. Heterogeneous electrochemical water oxidation after immobilization on multi-walled carbon nanotubes (MWCNTs) shows catalytic performance unprecedented for this compound class, with a turnover frequency (TOF) of 133 s\(^{-1}\) and a turnover number (TON) of 4.89 × 10\(^6\), at a current density of 43.8 mA cm\(^{-2}\) and a potential of 1.45 V versus normal hydrogen electrode (NHE).}, language = {en} } @unpublished{HennigPrustyKauferetal.2022, author = {Hennig, Thomas and Prusty, Archana B. and Kaufer, Benedikt and Whisnant, Adam W. and Lodha, Manivel and Enders, Antje and Thomas, Julius and Kasimir, Francesca and Grothey, Arnhild and Herb, Stefanie and J{\"u}rges, Christopher and Meister, Gunter and Erhard, Florian and D{\"o}lken, Lars and Prusty, Bhupesh K.}, title = {Selective inhibition of miRNA 1 processing by a herpesvirus encoded miRNA}, edition = {accepted version}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267862}, year = {2022}, abstract = {Herpesviruses have mastered host cell modulation and immune evasion to augment productive infection, life-long latency and reactivation thereof 1,2. A long appreciated, yet elusively defined relationship exists between the lytic-latent switch and viral non-coding RNAs 3,4. Here, we identify miRNA-mediated inhibition of miRNA processing as a thus far unknown cellular mechanism that human herpesvirus 6A (HHV-6A) exploits to disrupt mitochondrial architecture, evade intrinsic host defense and drive the lytic-latent switch. We demonstrate that virus-encoded miR-aU14 selectively inhibits the processing of multiple miR-30 family members by direct interaction with the respective pri-miRNA hairpin loops. Subsequent loss of miR-30 and activation of the miR-30/p53/Drp1 axis triggers a profound disruption of mitochondrial architecture. This impairs induction of type I interferons and is necessary for both productive infection and virus reactivation. Ectopic expression of miR-aU14 triggered virus reactivation from latency, identifying viral miR-aU14 as a readily drugable master regulator of the herpesvirus lytic-latent switch. Our results show that miRNA-mediated inhibition of miRNA processing represents a generalized cellular mechanism that can be exploited to selectively target individual members of miRNA families. We anticipate that targeting miR-aU14 provides exciting therapeutic options for preventing herpesvirus reactivations in HHV-6-associated disorders.}, language = {en} } @article{BucheltBloetheKuenzeretal.2023, author = {Buchelt, Sebastian and Bl{\"o}the, Jan Henrik and Kuenzer, Claudia and Schmitt, Andreas and Ullmann, Tobias and Philipp, Marius and Kneisel, Christof}, title = {Deciphering small-scale seasonal surface dynamics of rock glaciers in the Central European Alps using DInSAR time series}, series = {Remote Sensing}, volume = {15}, journal = {Remote Sensing}, number = {12}, issn = {2072-4292}, doi = {10.3390/rs15122982}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362939}, year = {2023}, abstract = {The Essential Climate Variable (ECV) Permafrost is currently undergoing strong changes due to rising ground and air temperatures. Surface movement, forming characteristic landforms such as rock glaciers, is one key indicator for mountain permafrost. Monitoring this movement can indicate ongoing changes in permafrost; therefore, rock glacier velocity (RGV) has recently been added as an ECV product. Despite the increased understanding of rock glacier dynamics in recent years, most observations are either limited in terms of the spatial coverage or temporal resolution. According to recent studies, Sentinel-1 (C-band) Differential SAR Interferometry (DInSAR) has potential for monitoring RGVs at high spatial and temporal resolutions. However, the suitability of DInSAR for the detection of heterogeneous small-scale spatial patterns of rock glacier velocities was never at the center of these studies. We address this shortcoming by generating and analyzing Sentinel-1 DInSAR time series over five years to detect small-scale displacement patterns of five high alpine permafrost environments located in the Central European Alps on a weekly basis at a range of a few millimeters. Our approach is based on a semi-automated procedure using open-source programs (SNAP, pyrate) and provides East-West displacement and elevation change with a ground sampling distance of 5 m. Comparison with annual movement derived from orthophotos and unpiloted aerial vehicle (UAV) data shows that DInSAR covers about one third of the total movement, which represents the proportion of the year suited for DInSAR, and shows good spatial agreement (Pearson R: 0.42-0.74, RMSE: 4.7-11.6 cm/a) except for areas with phase unwrapping errors. Moreover, the DInSAR time series unveils spatio-temporal variations and distinct seasonal movement dynamics related to different drivers and processes as well as internal structures. Combining our approach with in situ observations could help to achieve a more holistic understanding of rock glacier dynamics and to assess the future evolution of permafrost under changing climatic conditions.}, language = {en} } @article{BruennertSeupelGoyaletal.2023, author = {Br{\"u}nnert, Daniela and Seupel, Raina and Goyal, Pankaj and Bach, Matthias and Schraud, Heike and Kirner, Stefanie and K{\"o}ster, Eva and Feineis, Doris and Bargou, Ralf C. and Schlosser, Andreas and Bringmann, Gerhard and Chatterjee, Manik}, title = {Ancistrocladinium A induces apoptosis in proteasome inhibitor-resistant multiple myeloma cells: a promising therapeutic agent candidate}, series = {Pharmaceuticals}, volume = {16}, journal = {Pharmaceuticals}, number = {8}, issn = {1424-8247}, doi = {10.3390/ph16081181}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362887}, year = {2023}, abstract = {The N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A belongs to a novel class of natural products with potent antiprotozoal activity. Its effects on tumor cells, however, have not yet been explored. We demonstrate the antitumor activity of ancistrocladinium A in multiple myeloma (MM), a yet incurable blood cancer that represents a model disease for adaptation to proteotoxic stress. Viability assays showed a potent apoptosis-inducing effect of ancistrocladinium A in MM cell lines, including those with proteasome inhibitor (PI) resistance, and in primary MM cells, but not in non-malignant blood cells. Concomitant treatment with the PI carfilzomib or the histone deacetylase inhibitor panobinostat strongly enhanced the ancistrocladinium A-induced apoptosis. Mass spectrometry with biotinylated ancistrocladinium A revealed significant enrichment of RNA-splicing-associated proteins. Affected RNA-splicing-associated pathways included genes involved in proteotoxic stress response, such as PSMB5-associated genes and the heat shock proteins HSP90 and HSP70. Furthermore, we found strong induction of ATF4 and the ATM/H2AX pathway, both of which are critically involved in the integrated cellular response following proteotoxic and oxidative stress. Taken together, our data indicate that ancistrocladinium A targets cellular stress regulation in MM and improves the therapeutic response to PIs or overcomes PI resistance, and thus may represent a promising potential therapeutic agent.}, language = {en} } @article{EidmannHeinzOberfeldetal.2023, author = {Eidmann, Annette and Heinz, Tizian and Oberfeld, Jan and Weißenberger, Manuel and Rudert, Maximilian and Stratos, Ioannis}, title = {Epidemiology and trends in cartilage surgery of the foot and ankle in Germany: an analysis of national healthcare billing and reporting data from 2006 to 2020}, series = {Medicina}, volume = {59}, journal = {Medicina}, number = {7}, issn = {1648-9144}, doi = {10.3390/medicina59071256}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362835}, year = {2023}, abstract = {Background and objectives: Cartilage surgery constitutes a standard intervention in foot and ankle procedures. Currently, there is a lack of epidemiological data on its frequency, age distribution, and surgical options for cartilage surgery. This study aimed to investigate the current landscape of cartilage surgery in Germany and identify the most common procedures from an epidemiological standpoint. Materials and methods: Medical billing and reporting data from the Federal Statistical Office of Germany, encompassing the period 2006-2020, was examined, including all foot and ankle cartilage surgical procedures (summarized under OPS codes 5-812 and 5-801). The dataset incorporated information on the affected joint, patient age and sex, and surgery type. Each surgical procedure was categorized as "debridement", "regeneration" or "refixation". Linear and nonlinear regression analyses were employed, with a statistical significance threshold of 0.05. Results: From the total of 136,501 procedures conducted during the study period, the most frequently performed interventions were microfracture (58,252) and chondroplasty (56,135), and thus, debridement procedures were in the leading position. The use of acellular membranes was the most used regenerative technique (n = 11,414). At the ankle joint, interventions were mostly arthroscopic and in men, while foot cartilage surgeries were preferably performed via open surgery and mostly in women. Age distribution analysis revealed two primary peaks: the first in the 20-25-year-old group (ankle and foot) and the second in the 45-50-year-old group (ankle) and 55-60-year-old group (foot). Refixation and regenerative procedures were more frequent among younger individuals, while debriding procedures were more frequent among older individuals. Regenerative procedures, particularly in the ankle, significantly increased over time. Conclusions: Cartilage surgery of the foot and ankle was common, with two primary age groups predominantly affected. Notably, recent years have witnessed a considerable rise in cartilage regenerative procedures.}, language = {en} } @article{EwaldFuchsBoegeleinetal.2023, author = {Ewald, Andrea and Fuchs, Andreas and Boegelein, Lasse and Grunz, Jan-Peter and Kneist, Karl and Gbureck, Uwe and Hoelscher-Doht, Stefanie}, title = {Degradation and bone-contact biocompatibility of two drillable magnesium phosphate bone cements in an in vivo rabbit bone defect model}, series = {Materials}, volume = {16}, journal = {Materials}, number = {13}, issn = {1996-1944}, doi = {10.3390/ma16134650}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362824}, year = {2023}, abstract = {The use of bone-cement-enforced osteosynthesis is a growing topic in trauma surgery. In this context, drillability is a desirable feature for cements that can improve fracture stability, which most of the available cement systems lack. Therefore, in this study, we evaluated a resorbable and drillable magnesium-phosphate (MgP)-based cement paste considering degradation behavior and biocompatibility in vivo. Two different magnesium-phosphate-based cement (MPC) pastes with different amounts of phytic acid (IP 6) as setting retarder (MPC 22.5 and MPC 25) were implanted in an orthotopic defect model of the lateral femoral condyle of New Zealand white rabbits for 6 weeks. After explantation, their resorption behavior and material characteristics were evaluated by means of X-ray diffraction (XRD), porosimetry measurement, histological staining, peripheral quantitative computed tomography (pQCT), cone-beam computed tomography (CBCT) and biomechanical load-to-failure tests. Both cement pastes displayed comparable results in mechanical strength and resorption kinetics. Bone-contact biocompatibility was excellent without any signs of inflammation. Initial resorption and bone remodeling could be observed. MPC pastes with IP 6 as setting retardant have the potential to be a valuable alternative in distinct fracture patterns. Drillability, promising resorption potential and high mechanical strength confirm their suitability for use in clinical routine.}, language = {en} } @phdthesis{Swain2024, author = {Swain, Asim}, title = {Helically Twisted Graphene Nanoribbons: Bottom-up Stereospecific Synthesis and Characterization}, doi = {10.25972/OPUS-36016}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360164}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Over the past decade, substantial progress has been made in synthesizing atomically precise carbon nanostructures, with a focus on graphene nanoribbons (NRs) through advanced synthetic techniques. Despite these advancements, precise control over the stereochemistry of twisted NRs remains challenging. This thesis introduces a strategic approach to achieve absolute control over the single-handed helical conformation in a cove-edged NR, utilizing enantiopure [n]helicenes as a molecular wrench to intricately dictate the overall conformation of the NR. Enantiopure [7]helicenes were stitched to the terminal K-regions of a conjugated pyrene NR using a stereospecific and site-selective palladium(II)-catalyzed annulative π-extension (APEX) reaction, resulting in a helically twisted NR with an end-to-end twist of 171°, the second-largest twist reported so far in the literature for twistacenes. The helical end-to-end twist increases with each addition of benzene ring to the central acene core, suggesting that the extra strain induced by the terminal [7]helicenes maintains such a high level of twist. The quantum chemical calculations were conducted to investigate the impact of twisting on the conformational population. At room temperature, the central backbone of the nanoribbon adopts the twisted helicity opposite to that of the attached [7]helicene, constituting around 99\% of the molecular population. For instance, (P)-[7]helicenes produce a left-handed helical nanoribbon, while (M)-[7]helicenes produce a right-handed helical nanoribbon. In the presence of helicenes of opposite chirality, the nanoribbon adopts a waggling conformation. The helically twisted nanoribbons are conformationally robust, as variable temperature chiroptical measurements showed no change in CD and CPL spectra. The proposed strategy, involving the late-stage addition of [n]helicene units through the APEX reaction, appears promising for streamlining the synthesis of diverse cove edge NR variants with desired conformations. In addition to single-handed helically twisted nanoribbons, the symmetry-based functional properties of C2 and C1 symmetric pyrene-fused single and double [n]helicene compounds were studied. Owing to its higher structural rigidity, the C1 symmetric heptagonal ring-containing molecules exhibited exceptional configurational stability along with remarkable chiroptical properties compared to their C2 symmetric as well as pristine helicene congeners.}, subject = {Helicene}, language = {en} } @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{deGraafgebButtler2024, author = {de Graaf [geb. Buttler], Simone Linda}, title = {From Small to Large Data: Leveraging Synthetic Data for Inventory Management}, doi = {10.25972/OPUS-36136}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-361364}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In a world of constant change, uncertainty has become a daily challenge for businesses. Rapidly shifting market conditions highlight the need for flexible responses to unforeseen events. Operations Management (OM) is crucial for optimizing business processes, including site planning, production control, and inventory management. Traditionally, companies have relied on theoretical models from microeconomics, game theory, optimization, and simulation. However, advancements in machine learning and mathematical optimization have led to a new research field: data-driven OM. Data-driven OM uses real data, especially time series data, to create more realistic models that better capture decision-making complexities. Despite the promise of this new research area, a significant challenge remains: the availability of extensive historical training data. Synthetic data, which mimics real data, has been used to address this issue in other machine learning applications. Therefore, this dissertation explores how synthetic data can be leveraged to improve decisions for data-driven inventory management, focusing on the single-period newsvendor problem, a classic stochastic optimization problem in inventory management. The first article, "A Meta Analysis of Data-Driven Newsvendor Approaches", presents a standardized evaluation framework for data-driven prescriptive approaches, tested through a numerical study. Findings suggest model performance is not robust, emphasizing the need for a standardized evaluation process. The second article, "Application of Generative Adversarial Networks in Inventory Management", examines using synthetic data generated by Generative Adversarial Networks (GANs) for the newsvendor problem. This study shows GANs can model complex demand relationships, offering a promising alternative to traditional methods. The third article, "Combining Synthetic Data and Transfer Learning for Deep Reinforcement Learning in Inventory Management", proposes a method using Deep Reinforcement Learning (DRL) with synthetic and real data through transfer learning. This approach trains a generative model to learn demand distributions, generates synthetic data, and fine-tunes a DRL agent on a smaller real dataset. This method outperforms traditional approaches in controlled and practical settings, though further research is needed to generalize these findings.}, subject = {Bestandsmanagement}, language = {en} } @article{HartmannKnierimMaureretal.2023, author = {Hartmann, Nico and Knierim, Maria and Maurer, Wiebke and Dybkova, Nataliya and Hasenfuß, Gerd and Sossalla, Samuel and Streckfuss-B{\"o}meke, Katrin}, title = {Molecular and functional relevance of Na\(_V\)1.8-induced atrial arrhythmogenic triggers in a human SCN10A knock-out stem cell model}, series = {International Journal of Molecular Sciences}, volume = {24}, journal = {International Journal of Molecular Sciences}, number = {12}, issn = {1422-0067}, doi = {10.3390/ijms241210189}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362708}, year = {2023}, abstract = {In heart failure and atrial fibrillation, a persistent Na\(^+\) current (I\(_{NaL}\)) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. We have recently shown that Na\(_V\)1.8 contributes to arrhythmogenesis by inducing a I\(_{NaL}\). Genome-wide association studies indicate that mutations in the SCN10A gene (Na\(_V\)1.8) are associated with increased risk for arrhythmias, Brugada syndrome, and sudden cardiac death. However, the mediation of these Na\(_V\)1.8-related effects, whether through cardiac ganglia or cardiomyocytes, is still a subject of controversial discussion. We used CRISPR/Cas9 technology to generate homozygous atrial SCN10A-KO-iPSC-CMs. Ruptured-patch whole-cell patch-clamp was used to measure the I\(_{NaL}\) and action potential duration. Ca\(^{2+}\) measurements (Fluo 4-AM) were performed to analyze proarrhythmogenic diastolic SR Ca\(^{2+}\) leak. The I\(_{NaL}\) was significantly reduced in atrial SCN10A KO CMs as well as after specific pharmacological inhibition of Na\(_V\)1.8. No effects on atrial APD\(_{90}\) were detected in any groups. Both SCN10A KO and specific blockers of Na\(_V\)1.8 led to decreased Ca\(^{2+}\) spark frequency and a significant reduction of arrhythmogenic Ca\(^{2+}\) waves. Our experiments demonstrate that Na\(_V\)1.8 contributes to I\(_{NaL}\) formation in human atrial CMs and that Na\(_V\)1.8 inhibition modulates proarrhythmogenic triggers in human atrial CMs and therefore Na\(_V\)1.8 could be a new target for antiarrhythmic strategies.}, 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} } @phdthesis{Reissland2024, author = {Reissland, Michaela}, title = {USP10 is a \(de\) \(novo\) tumour-specific regulator of β-Catenin and contributes to cancer stem cell maintenance and tumour progression}, doi = {10.25972/OPUS-31957}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319579}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Colorectal Cancer (CRC) is the third most common cancer in the US. The majority of CRC cases are due to deregulated WNT-signalling pathway. These alterations are mainly caused by mutations in the tumour suppressor gene APC or in CTNNB1, encoding the key effector protein of this pathway, β-Catenin. In canonical WNT-signalling, β-Catenin activates the transcription of several target genes, encoding for proteins involved in proliferation, such as MYC, JUN and NOTCH. Being such a critical regulator of these proto-oncogenes, the stability of β-Catenin is tightly regulated by the Ubiquitin-Proteasome System. Several E3 ligases that ubiquitylate and degrade β-Catenin have been described in the past, but the antagonists, the deubiquitylases, are still unknown. By performing an unbiased siRNA screen, the deubiquitylase USP10 was identified as a de novo positive regulator of β-Catenin stability in CRC derived cells. USP10 has previously been shown in the literature to regulate both mutant and wild type TP53 stability, to deubiquitylate NOTCH1 in endothelial cells and to be involved in the regulation of AMPKα signalling. Overall, however, its role in colorectal tumorigenesis remains controversial. By analysing publicly available protein and gene expression data from colorectal cancer patients, we have shown that USP10 is strongly upregulated or amplified upon transformation and that its expression correlates positively with CTNNB1 expression. In contrast, basal USP10 levels were found in non-transformed tissues, but surprisingly USP10 is upregulated in intestinal stem cells. Endogenous interaction studies in CRC-derived cell lines, with different extend of APCtruncation, revealed an APC-dependent mode of action for both proteins. Furthermore, by utilising CRISPR/Cas9, shRNA-mediated knock-down and overexpression of USP10, we could demonstrate a regulation of β-Catenin stability by USP10 in CRC cell lines. It is widely excepted that 2D cell culture systems do not reflect complexity, architecture and heterogeneity and are therefore not suitable to answer complex biological questions. To overcome this, we established the isolation, cultivation and genetically modification of murine intestinal organoids and utilised this system to study Usp10s role ex vivo. By performing RNA sequencing, dependent on different Usp10 levels, we were able to recapitulate the previous findings and demonstrated Usp10 as important regulator of β-dependent regulation of stem cell homeostasis. Since genetic depletion of USP10 resulted in down-regulation of β-Catenin-dependent transcription, therapeutic intervention of USP10 in colorectal cancer was also investigated. Commercial and newly developed inhibitors were tested for their efficacy against USP10, but failed to significantly inhibit USP10 activity in colorectal cancer cells. To validate the findings from this work also in vivo, development of a novel mouse model for colorectal cancer has begun. By combining CRISPR/Cas9 and classical genetic engineering with viral injection strategies, WT and genetically modified mice could be transformed and, at least in some animals, intestinal lesions were detectable at the microscopic level. The inhibition of USP10, which we could describe as a de novo tumour-specific regulator of β-Catenin, could become a new therapeutic strategy for colorectal cancer patients.}, subject = {Biomedizin}, language = {en} } @article{HeinzWildEidmannetal.2023, author = {Heinz, Tizian and Wild, Moritz and Eidmann, Annette and Weißenberger, Manuel and Rak, Dominik and Nedopil, Alexander Johannes and Rudert, Maximilian and Stratos, Ioannis}, title = {Impact of COVID-19 on fracture incidence in germany: a comparative age and gender analysis of pre- and post-outbreak periods}, series = {Healthcare}, volume = {11}, journal = {Healthcare}, number = {15}, issn = {2227-9032}, doi = {10.3390/healthcare11152139}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362686}, year = {2023}, abstract = {In March 2020, Germany imposed a nationwide lockdown to curb the spread of COVID-19, prompting questions about the impact on the incidence of common fractures. This study examined 15 fracture types in pre-outbreak (2010-2019) and post-outbreak (2020-2021) periods, using data categorized by age (18-64 years, 65 years) and sex (male, female). Linear regression assessed annual growth rates, and mean fracture numbers were compared across periods for significant differences. Results indicated a positive correlation between fracture incidence rates and time for various types, such as cervical, thoracic, lumbar, and pelvic spine fractures, rib fractures, femoral neck, pertrochanteric femur, femoral shaft, and ankle fractures. Frequencies of proximal humerus, distal radius, femoral neck, pertrochanteric femur, femoral shaft, and ankle fractures in 2020 and 2021 were within predicted ranges from previous years. However, rib fractures and spinal fractures (cervical, thoracic, lumbar, and pelvic spine) occurred less frequently during this time. Notably, this study found a consistent decline in most fracture types for individuals aged 18-64 after the pandemic's onset, while the fracture incidence of hip fractures, often referred to as fragility fractures, for those over 65 remained unchanged. Fibula fractures showed the most considerable decrease in both age groups. In conclusion, the COVID-19 pandemic substantially impacted fracture incidence, with lower rates among individuals under 65 and unchanged fragility fractures in the elderly population.}, language = {en} } @article{SchuergerEngel2023, author = {Sch{\"u}rger, Peter and Engel, Volker}, title = {Differential Shannon entropies characterizing electron-nuclear dynamics and correlation: momentum-space versus coordinate-space wave packet motion}, series = {Entropy}, volume = {25}, journal = {Entropy}, number = {7}, issn = {1099-4300}, doi = {10.3390/e25070970}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362670}, year = {2023}, abstract = {We calculate differential Shannon entropies derived from time-dependent coordinate-space and momentum-space probability densities. This is performed for a prototype system of a coupled electron-nuclear motion. Two situations are considered, where one is a Born-Oppenheimer adiabatic dynamics, and the other is a diabatic motion involving strong non-adiabatic transitions. The information about coordinate- and momentum-space dynamics derived from the total and single-particle entropies is discussed and interpreted with the help of analytical models. From the entropies, we derive mutual information, which is a measure for the electron-nuclear correlation. In the adiabatic case, it is found that such correlations are manifested differently in coordinate- and momentum space. For the diabatic dynamics, we show that it is possible to decompose the entropies into state-specific contributions.}, language = {en} } @article{ElsnerKunzWagneretal.2023, author = {Elsner, Clara and Kunz, Andreas Steven and Wagner, Nicole and Huflage, Henner and H{\"u}bner, Stefan and Luetkens, Karsten Sebastian and Bley, Thorsten Alexander and Schmitt, Rainer and Erg{\"u}n, S{\"u}leyman and Grunz, Jan-Peter}, title = {MRI-based evaluation of the flexor digitorum superficialis anatomy: investigating the prevalence and morphometry of the "chiasma antebrachii"}, series = {Diagnostics}, volume = {13}, journal = {Diagnostics}, number = {14}, issn = {2075-4418}, doi = {10.3390/diagnostics13142406}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362631}, year = {2023}, abstract = {Recent dissection studies resulted in the introduction of the term "chiasma antebrachii", which represents an intersection of the flexor digitorum superficialis (FDS) tendons for digits 2 and 3 in the distal third of the forearm. This retrospective investigation aimed to provide an MRI-based morphologic analysis of the chiasma antebrachii. In 89 patients (41 women, 39.3 ± 21.3 years), MRI examinations of the forearm (2010-2021) were reviewed by two radiologists, who evaluated all studies for the presence and length of the chiasma as well as its distance from the distal radioulnar and elbow joint. The chiasma antebrachii was identified in the distal third of the forearm in 88 patients (98.9\%), while one intersection was located more proximally in the middle part. The chiasma had a median length of 28 mm (interquartile range: 24-35 mm). Its distances to the distal radioulnar and elbow joint were 16 mm (8-25 mm) and 215 mm (187-227 mm), respectively. T1-weighted post-contrast sequences were found to be superior to T2- or proton-density-weighted sequences in 71 cases (79.8\%). To conclude, the chiasma antebrachii is part of the standard FDS anatomy. Knowledge of its morphology is important, e.g., in targeted injections of therapeutics or reconstructive surgery.}, language = {en} } @article{LuetkensGrunzKunzetal.2023, author = {Luetkens, Karsten Sebastian and Grunz, Jan-Peter and Kunz, Andreas Steven and Huflage, Henner and Weißenberger, Manuel and Hartung, Viktor and Patzer, Theresa Sophie and Gruschwitz, Philipp and Erg{\"u}n, S{\"u}leyman and Bley, Thorsten Alexander and Feldle, Philipp}, title = {Ultra-high-resolution photon-counting detector CT arthrography of the ankle: a feasibility study}, series = {Diagnostics}, volume = {13}, journal = {Diagnostics}, number = {13}, issn = {2075-4418}, doi = {10.3390/diagnostics13132201}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362622}, year = {2023}, abstract = {This study was designed to investigate the image quality of ultra-high-resolution ankle arthrography employing a photon-counting detector CT. Bilateral arthrograms were acquired in four cadaveric specimens with full-dose (10 mGy) and low-dose (3 mGy) scan protocols. Three convolution kernels with different spatial frequencies were utilized for image reconstruction (ρ\(_{50}\); Br98: 39.0, Br84: 22.6, Br76: 16.5 lp/cm). Seven radiologists subjectively assessed the image quality regarding the depiction of bone, hyaline cartilage, and ligaments. An additional quantitative assessment comprised the measurement of noise and the computation of contrast-to-noise ratios (CNR). While an optimal depiction of bone tissue was achieved with the ultra-sharp Br98 kernel (S ≤ 0.043), the visualization of cartilage improved with lower modulation transfer functions at each dose level (p ≤ 0.014). The interrater reliability ranged from good to excellent for all assessed tissues (intraclass correlation coefficient ≥ 0.805). The noise levels in subcutaneous fat decreased with reduced spatial frequency (p \< 0.001). Notably, the low-dose Br76 matched the CNR of the full-dose Br84 (p 0.999) and superseded Br98 (p \< 0.001) in all tissues. Based on the reported results, a photon-counting detector CT arthrography of the ankle with an ultra-high-resolution collimation offers stellar image quality and tissue assessability, improving the evaluation of miniscule anatomical structures. While bone depiction was superior in combination with an ultra-sharp convolution kernel, soft tissue evaluation benefited from employing a lower spatial frequency.}, language = {en} } @article{BreunFlockFeldheimetal.2023, author = {Breun, Maria and Flock, Katharina and Feldheim, Jonas and Nattmann, Anja and Monoranu, Camelia M. and Herrmann, Pia and Ernestus, Ralf-Ingo and L{\"o}hr, Mario and Hagemann, Carsten and Stein, Ulrike}, title = {Metastasis associated in colorectal cancer 1 (MACC1) mRNA expression is enhanced in sporadic vestibular schwannoma and correlates to deafness}, series = {Cancers}, volume = {15}, journal = {Cancers}, number = {16}, issn = {2072-6694}, doi = {10.3390/cancers15164089}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362543}, year = {2023}, abstract = {Vestibular schwannoma (VS) are benign cranial nerve sheath tumors of the vestibulocochlear nerve. Their incidence is mostly sporadic, but they can also be associated with NF2-related schwannomatosis (NF2), a hereditary tumor syndrome. Metastasis associated in colon cancer 1 (MACC1) is known to contribute to angiogenesis, cell growth, invasiveness, cell motility and metastasis of solid malignant cancers. In addition, MACC1 may be associated with nonsyndromic hearing impairment. Therefore, we evaluated whether MACC1 may be involved in the pathogenesis of VS. Sporadic VS, recurrent sporadic VS, NF2-associated VS, recurrent NF2-associated VS and healthy vestibular nerves were analyzed for MACC1 mRNA and protein expression by quantitative polymerase chain reaction and immunohistochemistry. MACC1 expression levels were correlated with the patients' clinical course and symptoms. MACC1 mRNA expression was significantly higher in sporadic VS compared to NF2-associated VS (p \< 0.001). The latter expressed similar MACC1 concentrations as healthy vestibular nerves. Recurrent tumors resembled the MACC1 expression of the primary tumors. MACC1 mRNA expression was significantly correlated with deafness in sporadic VS patients (p = 0.034). Therefore, MACC1 might be a new molecular marker involved in VS pathogenesis.}, language = {en} } @article{GrunzKunzBaumannetal.2023, author = {Grunz, Jan-Peter and Kunz, Andreas Steven and Baumann, Freerk T. and Hasenclever, Dirk and Sieren, Malte Maria and Heldmann, Stefan and Bley, Thorsten Alexander and Einsele, Hermann and Knop, Stefan and Jundt, Franziska}, title = {Assessing osteolytic lesion size on sequential CT scans is a reliable study endpoint for bone remineralization in newly diagnosed multiple myeloma}, series = {Cancers}, volume = {15}, journal = {Cancers}, number = {15}, issn = {2072-6694}, doi = {10.3390/cancers15154008}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362526}, year = {2023}, abstract = {Multiple myeloma (MM) frequently induces persisting osteolytic manifestations despite hematologic treatment response. This study aimed to establish a biometrically valid study endpoint for bone remineralization through quantitative and qualitative analyses in sequential CT scans. Twenty patients (seven women, 58 ± 8 years) with newly diagnosed MM received standardized induction therapy comprising the anti-SLAMF7 antibody elotuzumab, carfilzomib, lenalidomide, and dexamethasone (E-KRd). All patients underwent whole-body low-dose CT scans before and after six cycles of E-KRd. Two radiologists independently recorded osteolytic lesion sizes, as well as the presence of cortical destruction, pathologic fractures, rim and trabecular sclerosis. Bland-Altman analyses and Krippendorff's α were employed to assess inter-reader reliability, which was high for lesion size measurement (standard error 1.2 mm) and all qualitative criteria assessed (α ≥ 0.74). After six cycles of E-KRd induction, osteolytic lesion size decreased by 22\% (p \< 0.001). While lesion size response did not correlate with the initial lesion size at baseline imaging (Pearson's r = 0.144), logistic regression analysis revealed that the majority of responding osteolyses exhibited trabecular sclerosis (p \< 0.001). The sum of osteolytic lesion sizes on sequential CT scans defines a reliable study endpoint to characterize bone remineralization. Patient level response is strongly associated with the presence of trabecular sclerosis.}, language = {en} } @article{WatzlingKlausWeidemeieretal.2023, author = {Watzling, Martin and Klaus, Lorenz and Weidemeier, Tamara and Horder, Hannes and Ebert, Regina and Blunk, Torsten and Bauer-Kreisel, Petra}, title = {Three-dimensional breast cancer model to investigate CCL5/CCR1 expression mediated by direct contact between breast cancer cells and adipose-derived stromal cells or adipocytes}, series = {Cancers}, volume = {15}, journal = {Cancers}, number = {13}, issn = {2072-6694}, doi = {10.3390/cancers15133501}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362502}, year = {2023}, abstract = {The tumor microenvironment (TME) in breast cancer is determined by the complex crosstalk of cancer cells with adipose tissue-inherent cells such as adipose-derived stromal cells (ASCs) and adipocytes resulting from the local invasion of tumor cells in the mammary fat pad. This leads to heterotypic cellular contacts between these cell types. To adequately mimic the specific cell-to-cell interaction in an in vivo-like 3D environment, we developed a direct co-culture spheroid model using ASCs or differentiated adipocytes in combination with MDA-MB-231 or MCF-7 breast carcinoma cells. Co-spheroids were generated in a well-defined and reproducible manner in a high-throughput process. We compared the expression of the tumor-promoting chemokine CCL5 and its cognate receptors in these co-spheroids to indirect and direct standard 2D co-cultures. A marked up-regulation of CCL5 and in particular the receptor CCR1 with strict dependence on cell-cell contacts and culture dimensionality was evident. Furthermore, the impact of direct contacts between ASCs and tumor cells and the involvement of CCR1 in promoting tumor cell migration were demonstrated. Overall, these results show the importance of direct 3D co-culture models to better represent the complex tumor-stroma interaction in a tissue-like context. The unveiling of tumor-specific markers that are up-regulated upon direct cell-cell contact with neighboring stromal cells, as demonstrated in the 3D co-culture spheroids, may represent a promising strategy to find new targets for the diagnosis and treatment of invasive breast cancer.}, language = {en} } @article{HiewEibeckNguemenietal.2023, author = {Hiew, Shawn and Eibeck, Leila and Nguemeni, Carine and Zeller, Daniel}, title = {The influence of age and physical activity on locomotor adaptation}, series = {Brain Sciences}, volume = {13}, journal = {Brain Sciences}, number = {9}, issn = {2076-3425}, doi = {10.3390/brainsci13091266}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362478}, year = {2023}, abstract = {Background: Aging increases individual susceptibility to falls and injuries, suggesting poorer adaptation of balance responses to perturbation during locomotion, which can be measured with the locomotor adaptation task (LAT). However, it is unclear how aging and lifestyle factors affect these responses during walking. Hence, the present study investigates the relationship between balance and lifestyle factors during the LAT in healthy individuals across the adult lifespan using a correlational design. Methods: Thirty participants aged 20-78 years performed an LAT on a split-belt treadmill (SBT). We evaluated the magnitude and rate of adaptation and deadaptation during the LAT. Participants reported their lifelong physical and cognitive activity. Results: Age positively correlated with gait-line length asymmetry at the late post-adaptation phase (p = 0.007). These age-related effects were mediated by recent physical activity levels (p = 0.040). Conclusion: Our results confirm that locomotor adaptive responses are preserved in aging, but the ability to deadapt newly learnt balance responses is compromised with age. Physical activity mediates these age-related effects. Therefore, gait symmetry post-adaptation could effectively measure the risk of falling, and maintaining physical activity could protect against declines in balance.}, language = {en} } @article{GuederReinFlohretal.2023, author = {G{\"u}der, G{\"u}lmisal and Rein, Eva von and Flohr, Thomas and Weismann, Dirk and Schmitt, Dominik and St{\"o}rk, Stefan and Frantz, Stefan and Kratzer, Vincent and Kendi, Christian}, title = {Motion detectors as additional monitoring devices in the intensive care unit — a proof-of-concept study}, series = {Applied Sciences}, volume = {13}, journal = {Applied Sciences}, number = {16}, issn = {2076-3417}, doi = {10.3390/app13169319}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362404}, year = {2023}, abstract = {Background: Monitoring the vital signs of delirious patients in an intensive care unit (ICU) is challenging, as they might (un-)intentionally remove devices attached to their bodies. In mock-up scenarios, we systematically assessed whether a motion detector (MD) attached to the bed may help in identifying emergencies. Methods: We recruited 15 employees of the ICU and equipped an ICU bed with an MD (IRON Software GmbH, Gr{\"u}nwald, Germany). Participants were asked to replay 22 mock-up scenes of one-minute duration each: 12 scenes with movements and 10 without movements, of which 5 were emergency scenes ("lying dead-still, with no or very shallow breathing"). Blinded recordings were presented to an evaluation panel consisting of an experienced ICU nurse and a physician, who was asked to assess and rate the presence of motions. Results: Fifteen participants (nine women; 173 ± 7.0 cm; 78 ± 19 kg) joined the study. In total, 286 out of 330 scenes (86.7\%) were rated correctly. Ratings were false negative (FN: "no movements detected, but recorded") in 7 out of 180 motion scenes (3.9\%). Ratings were false positive (FP: "movements detected, but not recorded") in 37 out of 150 scenes (24.7\%), more often in men than women (26 out of 60 vs. 11 out of 90, respectively; p \< 0.001). Of note, in 16 of these 37 FP-rated scenes, a vibrating mobile phone was identified as a potential confounder. The emergency scenes were correctly rated in 64 of the 75 runs (85.3\%); 10 of the 11 FP-rated scenes occurred in male subjects. Conclusions: The MD allowed for identifying motions of test subjects with high sensitivity (96\%) and acceptable specificity (75\%). Accuracy might increase further if activities are recorded continuously under real-world conditions.}, language = {en} } @phdthesis{Kagerer2024, author = {Kagerer, Philipp Thomas}, title = {Two-Dimensional Ferromagnetism and Topology at the Surface of MnBi\(_2\)Te\(_4\) - Bi\(_2\)Te\(_3\) Heterostructures - MBE Growth, Magnetism and Electronic Properties}, doi = {10.25972/OPUS-36012}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360121}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In this thesis, a model system of a magnetic topological heterostructure is studied, namely a heterosystem consisting of a single ferromagnetic septuple-layer (SL) of \(MnBi_2Te_4\) on the surface of the three-dimensional topological insulator \(Bi_2Te_3\). Using MBE and developing a specialized experimental setup, the first part of this thesis deals with the growth of \(Bi_2Te_3\) and thin films of \(MnBi_2Te_4\) on \(BaF_2\)-substrates by the co-evaporation of its binary constituents. The structural analysis is conducted along several suitable probes such as X-ray diffraction (XRD, XRR), AFM and scanning tunnelling electron microscopy (STEM). It is furthermore found that the growth of a single septuple-layer of \(MnBi_2Te_4\) on the surface of \(Bi_2Te_3\) can be facilitated. By using X-ray absorption and circular magnetic dichroism (XAS, XMCD), the magnetic properties of \(MnBi_2Te_4\) are explored down to the monolayer limit. The layered nature of the vdW crystal and a strong uniaxial magnetocrystalline anisotropy establish stable out-of plane magnetic order at the surface of \(MnBi_2Te_4\), which is stable even down to the 2D limit. Pushing the material system to there, i.e. a single SL \(MnBi_2Te_4\) further allows to study the phase transition of this 2D ferromagnet and extract its critical behaviour with \(T_c \, = \, 14.89~k\) and \(\beta \, = \, 0.484\). Utilizing bulk crystals of the ferromagnetic \(Fe_3GeTe_2\) as substrate allows to influence, enhance and bias the magnetism in the single SL of \(MnBi_2Te_4\). By growing heterostructures of the type \(MnBi_2Te_4\) -- n layer \(Bi_2Te_3\) -- \(Fe_3GeTe_2\)for n between 0 and 2, it is shown, that a considerable magnetic coupling can be introduced between the \(MnBi_2Te_4\) top-layer and the substrate. Finally the interplay between topology and magnetism in the ferromagnetic extension is studied directly by angle-resolved photoemission spectroscopy. The heterostructure is found to host a linearly dispersing TSS at the centre of the Brillouin zone. Using low temperature and high-resolution ARPES a large magnetic gap opening of \(\sim\) 35 meV is found at the Dirac point of the TSS. By following its temperature evolution, it is apparent that the scaling behaviour coincides with the magnetic order parameter of the modified surface.}, subject = {Molekularstrahlepitaxie}, language = {en} } @phdthesis{Gaballa2024, author = {Gaballa, Abdallah Hatem Hassan Hosny Ahmed}, title = {PAF1c drives MYC-mediated immune evasion in pancreatic ductal adenocarcinoma}, doi = {10.25972/OPUS-36045}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360459}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The expression of the MYC proto-oncogene is elevated in a large proportion of patients with pancreatic ductal adenocarcinoma (PDAC). Previous findings in PDAC have shown that this increased MYC expression mediates immune evasion and promotes S-phase progression. How these functions are mediated and whether a downstream factor of MYC mediates these functions has remained elusive. Recent studies identifying the MYC interactome revealed a complex network of interaction partners, highlighting the need to identify the oncogenic pathway of MYC in an unbiased manner. In this work, we have shown that MYC ensures genomic stability during S-phase and prevents transcription-replication conflicts. Depletion of MYC and inhibition of ATR kinase showed a synergistic effect to induce DNA damage. A targeted siRNA screen targeting downstream factors of MYC revealed that PAF1c is required for DNA repair and S-phase progression. Recruitment of PAF1c to RNAPII was shown to be MYC dependent. PAF1c was shown to be largely dispensable for cell proliferation and regulation of MYC target genes. Depletion of CTR9, a subunit of PAF1c, caused strong tumor regression in a pancreatic ductal adenocarcinoma model, with long-term survival in a subset of mice. This effect was not due to induction of DNA damage, but to restoration of tumor immune surveillance. Depletion of PAF1c resulted in the release of RNAPII with transcription elongation factors, including SPT6, from the bodies of long genes, promoting full-length transcription of short genes. This resulted in the downregulation of long DNA repair genes and the concomitant upregulation of short genes, including MHC class I genes. These data demonstrate that a balance between long and short gene transcription is essential for tumor progression and that interference with PAF1c levels shifts this balance toward a tumor-suppressive transcriptional program. It also directly links MYC-mediated S-phase progression to immune evasion. Unlike MYC, PAF1c has a stable, known folded structure; therefore, the development of a small molecule targeting PAF1c may disrupt the immune evasive function of MYC while sparing its physiological functions in cellular growth.}, subject = {Myc}, language = {en} } @article{OdorferVolkmann2023, author = {Odorfer, Thorsten M. and Volkmann, Jens}, title = {Deep brain stimulation for focal or segmental craniocervical dystonia in patients who have failed botulinum neurotoxin therapy - a narrative review of the literature}, series = {Toxins}, volume = {15}, journal = {Toxins}, number = {10}, issn = {2072-6651}, doi = {10.3390/toxins15100606}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357707}, year = {2023}, abstract = {(1) Background: The first-line treatment for patients with focal or segmental dystonia with a craniocervical distribution is still the intramuscular injection of botulinum neurotoxin (BoNT). However, some patients experience primary or secondary treatment failure from this potential immunogenic therapy. Deep brain stimulation (DBS) may then be used as a backup strategy in this situation. (2) Methods: Here, we reviewed the current study literature to answer a specific question regarding the efficacy and safety of the use of DBS, particularly for cervical dystonia (CD) and Meige syndrome (MS) in patients with documented treatment failure under BoNT. (3) Results: There are only two studies with the highest level of evidence in this area. Despite this clear limitation, in the context of the narrowly defined research question of this paper, it is possible to report 161 patients with CD or MS who were included in studies that were able to show a statistically significant reduction in dystonic symptoms using DBS. Safety and tolerability data appeared adequate. However, much of the information is based on retrospective observations. (4) Conclusions: The evidence base in this area is in need of further scientific investigation. Most importantly, more randomized, controlled and double-blind trials are needed, possibly including a head-to-head comparison of DBS and BoNT.}, language = {en} } @article{MoratinThoeleLangetal.2023, author = {Moratin, Helena and Th{\"o}le, Anna and Lang, Josephine and Ehret Kasemo, Totta and St{\"o}th, Manuel and Hagen, Rudolf and Scherzad, Agmal and Hackenberg, Stephan}, title = {Ag- but not ZnO-nanoparticles disturb the airway epithelial barrier at subtoxic concentrations}, series = {Pharmaceutics}, volume = {15}, journal = {Pharmaceutics}, number = {10}, issn = {1999-4923}, doi = {10.3390/pharmaceutics15102506}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357403}, year = {2023}, abstract = {Inhalation is considered to be the most relevant source of human exposure to nanoparticles (NPs); however, only a few investigations have addressed the influence of exposing the respiratory mucosal barrier to subcytotoxic doses. In the nasal respiratory epithelium, cells of the mucosa represent one of the first contact points of the human organism with airborne NPs. Disruption of the epithelial barrier by harmful materials can lead to inflammation in addition to potential intrinsic toxicity of the particles. The aim of this study was to investigate whether subtoxic concentrations of zinc oxide (ZnO)- and silver (Ag)-NPs have an influence on upper airway barrier integrity. Nasal epithelial cells from 17 donors were cultured at the air-liquid interface and exposed to ZnO- and Ag-NPs. Barrier function, quantified by transepithelial electrical resistance (TEER), decreased after treatment with 10 µg/mL Ag-NPs, but FITC-dextran permeability remained stable and no change in mRNA levels of tight junction proteins and E-cadherin was detected by real-time quantitative PCR (RT-qPCR). The results indicate that subtoxic concentrations of Ag-NPs may already induce damage of the upper airway epithelial barrier in vitro. The lack of similar disruption by ZnO-NPs of similar size suggests a specific effect by Ag-NPs.}, language = {en} } @article{IsraelRiehlButtetal.2023, author = {Israel, Ina and Riehl, Gabriele and Butt, Elke and Buck, Andreas K. and Samnick, Samuel}, title = {Gallium-68-labeled KISS1-54 peptide for mapping KISS1 receptor via PET: initial evaluation in human tumor cell lines and in tumor-bearing mice}, series = {Pharmaceuticals}, volume = {17}, journal = {Pharmaceuticals}, number = {1}, issn = {1424-8247}, doi = {10.3390/ph17010044}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-355898}, year = {2023}, abstract = {Kisspeptins (KPs, KISS1) and their receptor (KISS1R) play a pivotal role as metastasis suppressor for many cancers. Low or lost KP expression is associated with higher tumor grade, increased metastatic potential, and poor prognosis. Therefore, KP expression has prognostic relevance and correlates with invasiveness in cancers. Furthermore, KISS1R represents a very promising target for molecular imaging and therapy for KISS1R-expressing tumors. The goal of this study was to evaluate the developed KISS1-54 derivative, [\(^{68}\)Ga]KISS1-54, as a PET-imaging probe for KISS1R-expressing tumors. The NODAGA-KISS1-54 peptide was labeled by Gallium-68, and the stability of the resulting [\(^{68}\)Ga]KISS1-54 evaluated in injection solution and human serum, followed by an examination in different KISS1R-expressing tumor cell lines, including HepG2, HeLa, MDA-MB-231, MCF7, LNCap, SK-BR-3, and HCT116. Finally, [\(^{68}\)Ga]KISS1-54 was tested in LNCap- and MDA-MB-231-bearing mice, using µ-PET, assessing its potential as an imaging probe for PET. [\(^{68}\)Ga]KISS1-54 was obtained in a 77 ± 7\% radiochemical yield and at a >99\% purity. The [\(^{68}\)Ga]KISS1-54 cell uptake amounted to 0.6-4.4\% per 100,000 cells. Moreover, the accumulation of [\(^{68}\)Ga]KISS1-54 was effectively inhibited by nonradioactive KISS1-54. In [\(^{68}\)Ga]KISS1-54-PET, KISS1R-positive LNCap-tumors were clearly visualized as compared to MDA-MB-231-tumor implant with predominantly intracellular KISS1R expression. Our first results suggest that [\(^{68}\)Ga]KISS1-54 is a promising candidate for a radiotracer for targeting KISS1R-expressing tumors via PET.}, language = {en} } @phdthesis{Glueck2024, author = {Gl{\"u}ck, Valentina}, title = {Habitual avoidance in trait anxiety and anxiety disorders}, doi = {10.25972/OPUS-36022}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360227}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Maladaptive avoidance behaviors can contribute to the maintenance of fear, anxiety, and anxiety disorders. It has been proposed that, throughout anxiety disorder progression, extensively repeated avoidance may become a habit (i.e., habitual avoidance) instead of being controlled by internal threat-related goals (i.e., goal-directed avoidance). However, the process of the acquisition of habitual avoidance in anxiety disorders is not yet well understood. Accordingly, the current thesis aimed to investigate experimentally whether trait anxiety and anxiety disorders are associated with an increased shift from goal-directed to habitual avoidance. The aim of Study 1 was to develop an experimental operationalization of maladaptive habitual avoidance. To this end, we adapted a commonly used action control task, the outcome devaluation paradigm. In this task, habitual avoidance was operationalized as persistent responses after extensive training to avoid an unpleasant stimulus when the aversive outcome was devalued, i.e., when individuals knew the aversive outcome could not occur anymore. We included indicators for costly and low-cost habitual avoidance, whereby habitual avoidance was associated with a monetary cost, while low-cost habitual avoidance was not associated with monetary costs. In Experiment 1 of Study 1, a pronounced costly and non-costly outcome devaluation effect was observed. However, this result may have partly resulted from trial-and-error learning or a better-safe-than-sorry strategy since not instructions about the stimulus-response-outcome contingencies after the outcome devaluation procedure had been provided to the participants. In Experiment 2 of Study 1, instructions on these stimulus-response-outcome contingencies were included to prevent the potential confounders. As a result, we observed no indicators for costly habitual avoidance, but evidence for low-cost habitual avoidance, potentially because competing goal-directed responses could easily be implemented and inhibited costly habitual avoidance tendencies. In Study 2, the strength of habitual avoidance acquisition was compared between participants with and without anxiety disorders, using the experimental task of Experiment 1 in Study 1. The results indicated that costly and low-cost habitual avoidance was not more pronounced in participants with anxiety disorders than in the healthy control group. However, in an exploratory subgroup comparison, panic disorder predicted more substantial habitual avoidance acquisition than social anxiety disorder. In Study 3, we investigated whether trait anxiety as a risk factor for anxiety disorders is associated with a specific increased shift from goal-directed to habitual avoidance and approach. The task from the Experiment 1 of Study 1 was adapted to include parallel versions for operationalizing habitual avoidance and habitual approach responses. Using a within-subjects design, the individuals - pre-screened for high and low trait anxiety - took part in the approach and the avoidance outcome devaluation task version. The results suggested stronger non-costly habitual responses in more highly trait-anxious individuals independent of the task version, and suggested a tendency towards an impact of trait anxiety on costly habitual approach rather than on costly habitual avoidance. In summary, individuals with high trait anxiety or anxiety disorders did not develop habitual avoidance more readily than individuals with low trait anxiety or without anxiety disorders. Therefore, this thesis does not support the assumption that an increased tendency to acquire habitual avoidance contributes to persistent maladaptive avoidance in anxiety disorders. The thesis also contributes to the discourse on the validity of outcome devaluation studies in general by highlighting the impact of task features, such as the instructions after the outcome devaluation procedure or the task difficulty in the test phase, on the experimental results. Such validity issues may partly explain the heterogeneity of findings in research with the outcome devaluation paradigm. We suggest ways towards more valid operationalizations of habitual avoidance in future studies.}, subject = {Gewohnheit}, language = {en} } @article{MichalskiSchloetelburgHartrampfetal.2023, author = {Michalski, Kerstin and Schl{\"o}telburg, Wiebke and Hartrampf, Philipp E. and Kosmala, Aleksander and Buck, Andreas K. and Hahner, Stefanie and Schirbel, Andreas}, title = {Radiopharmaceuticals for treatment of adrenocortical carcinoma}, series = {Pharmaceuticals}, volume = {17}, journal = {Pharmaceuticals}, number = {1}, issn = {1424-8247}, doi = {10.3390/ph17010025}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-355901}, year = {2023}, abstract = {Adrenocortical carcinoma (ACC) represents a rare tumor entity with limited treatment options and usually rapid tumor progression in case of metastatic disease. As further treatment options are needed and ACC metastases are sensitive to external beam radiation, novel theranostic approaches could complement established therapeutic concepts. Recent developments focus on targeting adrenal cortex-specific enzymes like the theranostic twin [\(^{123/131}\)I]IMAZA that shows a good image quality and a promising therapeutic effect in selected patients. But other established molecular targets in nuclear medicine such as the C-X-C motif chemokine receptor 4 (CXCR4) could possibly enhance the therapeutic regimen as well in a subgroup of patients. The aims of this review are to give an overview of innovative radiopharmaceuticals for the treatment of ACC and to present the different molecular targets, as well as to show future perspectives for further developments since a radiopharmaceutical with a broad application range is still warranted.}, language = {en} } @article{KimpelAltieriDischingeretal.2023, author = {Kimpel, Otilia and Altieri, Barbara and Dischinger, Ulrich and Fuss, Carmina Teresa and Kurlbaum, Max and Fassnacht, Martin}, title = {Early detection of recurrence and progress using serum steroid profiling by LC-MS/MS in patients with adrenocortical carcinoma}, series = {Metabolites}, volume = {14}, journal = {Metabolites}, number = {1}, issn = {2218-1989}, doi = {10.3390/metabo14010020}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-355839}, year = {2023}, abstract = {Serum liquid chromatography-tandem mass spectrometry (LC-MS/MS) steroid profiling is used for the diagnosis of adrenocortical carcinoma (ACC). Guidelines recommend endocrine work-up in addition to radiological imaging for follow-up in ACC, but data on this topic are scarce. Patients were included in this retrospective study if pre-therapeutic hormone values, regular tumour evaluation by imaging, steroid measurements by LC-MS/MS, and details on therapies were available. The utility of steroid profiles in detecting recurrence or disease progression was assessed, whereby "endocrine progress" was defined by an elevation of at least 3 of 13 analysed hormones. Cohort A included 47 patients after R0 resection, of whom 15 experienced recurrence and 32 did not. In cohort B, 52 patients with advanced disease (including 7 patients of cohort A with recurrence) could be evaluated on 74 visits when progressive disease was documented. In 20 of 89 cases with documented disease progression, "endocrine progress" was detectable prior to radiological progress. In these cases, recurrence/progression was detected at a median of 32 days earlier by steroid measurement than by imaging, with 11-deoxycortisol and testosterone being the most sensitive markers. Notably, these patients had significantly larger tumour burden. In conclusion, steroid profiling by LC-MS/MS is of value in detecting recurrent/progressive disease in ACC.}, 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} } @article{EngertDollVonaetal.2023, author = {Engert, Jonas and Doll, Julia and Vona, Barbara and Ehret Kasemo, Totta and Spahn, Bjoern and Hagen, Rudolf and Rak, Kristen and Voelker, Johannes}, title = {mRNA abundance of neurogenic factors correlates with hearing capacity in auditory brainstem nuclei of the rat}, series = {Life}, volume = {13}, journal = {Life}, number = {9}, issn = {2075-1729}, doi = {10.3390/life13091858}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357392}, year = {2023}, abstract = {Neural stem cells (NSCs) have previously been described up to the adult stage in the rat cochlear nucleus (CN). A decreasing neurogenic potential was observed with critical changes around hearing onset. A better understanding of molecular factors affecting NSCs and neurogenesis is of interest as they represent potential targets to treat the cause of neurologically based hearing disorders. The role of genes affecting NSC development and neurogenesis in CN over time on hearing capacity has remained unclear. This study investigated the mRNA abundance of genes influencing NSCs and neurogenesis in rats' CN over time. The CN of rats on postnatal days 6, 12, and 24 were examined. Real-time quantitative polymerase chain reaction arrays were used to compare mRNA levels of 84 genes relevant to NSCs and neurogenesis. Age- and hearing-specific patterns of changes in mRNA abundance of neurogenically relevant genes were detected in the rat CN. Additionally, crucial neurogenic factors with significant and relevant influence on neurogenesis were identified. The results of this work should contribute to a better understanding of the molecular mechanisms underlying the neurogenesis of the auditory pathway.}, language = {en} } @article{SteinhardtCejkaChenetal.2024, author = {Steinhardt, Maximilian J. and Cejka, Vladimir and Chen, Mengmeng and B{\"a}uerlein, Sabrina and Sch{\"a}fer, Julia and Adrah, Ali and Ihne-Schubert, Sandra M. and Papagianni, Aikaterini and Kort{\"u}m, K. Martin and Morbach, Caroline and St{\"o}rk, Stefan}, title = {Safety and tolerability of SGLT2 inhibitors in cardiac amyloidosis — a clinical feasibility study}, series = {Journal of Clinical Medicine}, volume = {13}, journal = {Journal of Clinical Medicine}, number = {1}, issn = {2077-0383}, doi = {10.3390/jcm13010283}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-356024}, year = {2024}, abstract = {Sodium-glucose transport protein 2 inhibitors (SGLT2i) slow the progression of renal dysfunction and improve the prognosis of patients with heart failure. Amyloidosis constitutes an important subgroup for which evidence is lacking. Amyloidotic fibrils originating from misfolded transthyretin and light chains are the causal agents in ATTR and AL amyloidosis. In these most frequent subtypes, cardiac involvement is the most common organ manifestation. Because cardiac and renal function frequently deteriorate over time, even under best available treatment, SGLT2i emerge as a promising treatment option due to their reno- and cardioprotective properties. We retrospectively analyzed patients with cardiac amyloidosis, who received either dapagliflozin or empagliflozin. Out of 79 patients, 5.1\% had urinary tract infections; 2 stopped SGLT2i therapy; and 2.5\% died unrelated to the intake of SGLT2i. No genital mycotic infections were observed. As expected, a slight drop in the glomerular filtration rate was noted, while the NYHA functional status, cardiac and hepatic function, as well as the 6 min walk distance remained stable over time. These data provide a rationale for the use of SGLT2i in patients with amyloidosis and concomitant cardiac or renal dysfunction. Prospective randomized data are desired to confirm safety and to prove efficacy in this increasingly important group of patients.}, 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{Gabel2024, author = {Gabel, Martin Sebastian}, title = {Behavioural resistance to \(Varroa\) \(destructor\) in the Western honeybee \(Apis\) \(mellifera\) - Mechanisms leading to decreased mite reproduction}, doi = {10.25972/OPUS-36053}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360536}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The Western Honeybee (Apis mellifera) is among the most versatile species in the world. Its adaptability is rooted in thousands of the differently specialized individuals acting jointly together. Thus, bees that are able to handle a certain task or condition well can back up other individuals less capable to do so on the colony level. Vice versa, the latter individuals might perform better in other situations. This evolutionary recipe for success ensures the survival of colonies despite challenging habitat conditions. In this context, the ectoparasitic mite Varroa destructor reflects the most pronounced biotic challenge to honeybees worldwide. Without proper treatment, infested colonies rapidly dwindle and ultimately die. Nevertheless, resistance behaviours against this parasite have evolved in some populations through natural selection, enabling colonies to survive untreated. In this, different behaviours appear to be adapted to the respective habitat conditions and may complement each other. Yet, the why and how of this behavioural response to the mite remains largely unknown. My thesis focuses on the biological background of Varroa-resistance traits in honeybees and presents important findings for the comprehension of this complex host-parasite interaction. Based on this, I draw implications for both, applied bee breeding and scientific investigations in the field of Varroa-resistance. Specifically, I focus on two traits commonly found in resistant and, to a lower degree, also mite-susceptible colonies: decreased mite reproduction and the uncapping and subsequent recapping of sealed brood cells. Examining failures in the reproductive success of mites as a primary mechanism of Varroa-resistance, I was able to link them to specific bee behaviours and external factors. Since mite reproduction and the brood rearing of bees are inevitably connected, I first investigated the effects of brood interruption on the reproductive success of mites. Brood interruption decreased the reproductive success of mites both immediately and in the long term. By examining the causes of reproductive failure, I could show that this was mainly due to an increased share of infertile mites. Furthermore, I proved that interruption in brood rearing significantly increased the expression of recapping behaviour. These findings consequently showed a dynamic modulation of mite reproduction and recapping, as well as a direct effect of brood interruption on both traits. To further elucidate the plasticity in the expression of both traits, I studied mite reproduction, recapping behaviour and infestation levels over the course of three years. The resulting extensive dataset unveiled a significant seasonal variation in mite reproduction and recapping. In addition, I show that recapping decreases the reproductive success of mites by increasing delayed developing female offspring and cells lacking male offspring. By establishing a novel picture-based brood investigation method, I could furthermore show that both the removal of brood cells and recapping activity specifically target brood ages in which mite offspring would be expected. Recapping, however, did not cause infertility of mites. Considering the findings of my first study, this points towards complementary mechanisms. This underlines the importance of increased recapping behaviour and decreased mite reproduction as resistance traits, while at the same time emphasising the challenges of reliable data acquisition. To pave the way for a practical application of these findings in breeding, we then investigated the heritability (i.e., the share of genotypic variation on the observed phenotypic variation) of the accounted traits. By elaborating comparable test protocols and compiling data from over 4,000 colonies, we could, for the first time, demonstrate that recapping of infested cells and decreased reproductive success of mites are heritable (and thus selectable) traits in managed honeybee populations. My thesis proves the importance of recapping and decreased mite reproduction as resistance traits and therefore valuable goals for breeding efforts. In this regard, I shed light on the underlying mechanisms of both traits, and present clear evidence for their interaction and heritability.}, subject = {Varroa destructor}, language = {en} } @article{SperlichMatzkaHolmberg2023, author = {Sperlich, Billy and Matzka, Manuel and Holmberg, Hans-Christer}, title = {The proportional distribution of training by elite endurance athletes at different intensities during different phases of the season}, series = {Frontiers in Sports and Active Living}, volume = {5}, journal = {Frontiers in Sports and Active Living}, doi = {10.3389/fspor.2023.1258585}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357988}, year = {2023}, abstract = {The present review examines retrospective analyses of training intensity distribution (TID), i.e., the proportion of training at moderate (Zone 1, Z1), heavy (Z2) and severe (Z3) intensity by elite-to-world-class endurance athletes during different phases of the season. In addition, we discuss potential implications of our findings for research in this field, as well as for training by these athletes. Altogether, we included 175 TIDs, of which 120 quantified exercise intensity on the basis of heart rate and measured time-in-zone or employed variations of the session goal approach, with demarcation of zones of exercise intensity based on physiological parameters. Notably, 49\% of the TIDs were single-case studies, predominantly concerning cross-country skiing and/or the biathlon. Eighty-nine TIDs were pyramidal (Z1 > Z2 > Z3), 65 polarized (Z1 > Z3 > Z2) and 8 "threshold" (Z2 > Z1 = Z3). However, these relative numbers varied between sports and the particular phases of the season. In 91\% (n = 160) of the TIDs >60\% of the endurance exercise was of low intensity. Regardless of the approach to quantification or phase of the season, cyclists and swimmers were found to perform a lower proportion of exercise in Z1 (<72\%) and higher proportion in Z2 (>16\%) than athletes involved in the triathlon, speed skating, rowing, running, cross-country skiing or biathlon (>80\% in Z1 and <12\% in Z2 in all these cases). For most of the athletes their proportion of heavy-to-severe exercise was higher during the period of competition than during the preparatory phase, although with considerable variability between sports. In conclusion, the existing literature in this area does not allow general conclusions to be drawn. The methods utilized for quantification vary widely and, moreover, contextual information concerning the mode of exercise, environmental conditions, and biomechanical aspects of the exercise is often lacking. Therefore, we recommend a more comprehensive approach in connection with future investigations on the TIDs of athletes involved in different endurance sports.}, language = {en} } @article{SperlichDuekingLeppichetal.2023, author = {Sperlich, Billy and D{\"u}king, Peter and Leppich, Robert and Holmberg, Hans-Christer}, title = {Strengths, weaknesses, opportunities, and threats associated with the application of artificial intelligence in connection with sport research, coaching, and optimization of athletic performance: a brief SWOT analysis}, series = {Frontiers in Sports and Active Living}, volume = {5}, journal = {Frontiers in Sports and Active Living}, doi = {10.3389/fspor.2023.1258562}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357973}, year = {2023}, abstract = {Here, we performed a non-systematic analysis of the strength, weaknesses, opportunities, and threats (SWOT) associated with the application of artificial intelligence to sports research, coaching and optimization of athletic performance. The strength of AI with regards to applied sports research, coaching and athletic performance involve the automation of time-consuming tasks, processing and analysis of large amounts of data, and recognition of complex patterns and relationships. However, it is also essential to be aware of the weaknesses associated with the integration of AI into this field. For instance, it is imperative that the data employed to train the AI system be both diverse and complete, in addition to as unbiased as possible with respect to factors such as the gender, level of performance, and experience of an athlete. Other challenges include e.g., limited adaptability to novel situations and the cost and other resources required. Opportunities include the possibility to monitor athletes both long-term and in real-time, the potential discovery of novel indicators of performance, and prediction of risk for future injury. Leveraging these opportunities can transform athletic development and the practice of sports science in general. Threats include over-dependence on technology, less involvement of human expertise, risks with respect to data privacy, breaching of the integrity and manipulation of data, and resistance to adopting such new technology. Understanding and addressing these SWOT factors is essential for maximizing the benefits of AI while mitigating its risks, thereby paving the way for its successful integration into sport science research, coaching, and optimization of athletic performance.}, language = {en} } @article{BuergerSchoenfeldScheineretal.2023, author = {B{\"u}rger, Arne and Schoenfeld, Cornelia von and Scheiner, Christin and Seidel, Alexandra and Wasserscheid, Antonia and Gad, Doreya and Kittel-Schneider, Sarah and Romanos, Marcel and Reiter, Andrea M. F.}, title = {Universal prevention for non-suicidal self-injury in adolescents is scarce - A systematic review}, series = {Frontiers in Psychiatry}, volume = {14}, journal = {Frontiers in Psychiatry}, doi = {10.3389/fpsyt.2023.1130610}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357490}, year = {2023}, abstract = {Non-suicidal self-injury (NSSI) during adolescence is a high-risk marker for the development and persistence of mental health problems and has been recognized as a significant public health problem. Whereas targeted prevention has indeed shown to be effective in reducing NSSI and improve mental health problems, access to such programs is limited. By face validity, universal prevention of NSSI seems an ideal starting point for a stepped-care model to circumvent a lack of resources in the medical care system. However, it is yet unclear how effective such approaches are. Here, we provide a summary of existing work on universal prevention of NSSI in adolescents younger than 21 years based on a systematic literature search. We found that only seven studies are available. None of the programs evaluated was found to be effective in reducing the incidence or frequency of NSSI. After providing a comprehensive summary of the existing work, we evaluate the fact that existing work primarily focusses on selected/targeted prevention and on psychoeducational methods. We derive implications for future directions in the field of universal prevention of NSSI.}, language = {en} } @article{MurtiFenderGlatzleetal.2023, author = {Murti, Krisna and Fender, Hendrik and Glatzle, Carolin and Wismer, Rhoda and Sampere-Birlanga, Salvador and Wild, Vanessa and Muhammad, Khalid and Rosenwald, Andreas and Serfling, Edgar and Avots, Andris}, title = {Calcineurin-independent NFATc1 signaling is essential for survival of Burkitt lymphoma cells}, series = {Frontiers in Oncology}, volume = {13}, journal = {Frontiers in Oncology}, doi = {10.3389/fonc.2023.1205788}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323103}, year = {2023}, abstract = {In Burkitt lymphoma (BL), a tumor of germinal center B cells, the pro-apoptotic properties of MYC are controlled by tonic B cell receptor (BCR) signals. Since BL cells do not exhibit constitutive NF-κB activity, we hypothesized that anti-apoptotic NFATc1 proteins provide a major transcriptional survival signal in BL. Here we show that post-transcriptional mechanisms are responsible for the calcineurin (CN) independent constitutive nuclear over-expression of NFATc1 in BL and Eµ-MYC - induced B cell lymphomas (BCL). Conditional inactivation of the Nfatc1 gene in B cells of Eµ-MYC mice leads to apoptosis of BCL cells in vivo and ex vivo. Inhibition of BCR/SYK/BTK/PI3K signals in BL cells results in cytosolic re-location of NFATc1 and apoptosis. Therefore, NFATc1 activity is an integrated part of tonic BCR signaling and an alternative target for therapeutic intervention in BL.}, language = {en} } @article{daSilvaSeiffertTovote2023, author = {da Silva, Gabriela Neubert and Seiffert, Nina and Tovote, Philip}, title = {Cerebellar contribution to the regulation of defensive states}, series = {Frontiers in Systems Neuroscience}, volume = {17}, journal = {Frontiers in Systems Neuroscience}, doi = {10.3389/fnsys.2023.1160083}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-311620}, year = {2023}, abstract = {Despite fine tuning voluntary movement as the most prominently studied function of the cerebellum, early human studies suggested cerebellar involvement emotion regulation. Since, the cerebellum has been associated with various mood and anxiety-related conditions. Research in animals provided evidence for cerebellar contributions to fear memory formation and extinction. Fear and anxiety can broadly be referred to as defensive states triggered by threat and characterized by multimodal adaptations such as behavioral and cardiac responses integrated into an intricately orchestrated defense reaction. This is mediated by an evolutionary conserved, highly interconnected network of defense-related structures with functional connections to the cerebellum. Projections from the deep cerebellar nucleus interpositus to the central amygdala interfere with retention of fear memory. Several studies uncovered tight functional connections between cerebellar deep nuclei and pyramis and the midbrain periaqueductal grey. Specifically, the fastigial nucleus sends direct projections to the ventrolateral PAG to mediate fear-evoked innate and learned freezing behavior. The cerebellum also regulates cardiovascular responses such as blood pressure and heart rate-effects dependent on connections with medullary cardiac regulatory structures. Because of the integrated, multimodal nature of defensive states, their adaptive regulation has to be highly dynamic to enable responding to a moving threatening stimulus. In this, predicting threat occurrence are crucial functions of calculating adequate responses. Based on its role in prediction error generation, its connectivity to limbic regions, and previous results on a role in fear learning, this review presents the cerebellum as a regulator of integrated cardio-behavioral defensive states.}, language = {en} } @article{RauschenbergerPiroKasaragodetal.2023, author = {Rauschenberger, Vera and Piro, Inken and Kasaragod, Vikram Babu and H{\"o}rlin, Verena and Eckes, Anna-Lena and Kluck, Christoph J. and Schindelin, Hermann and Meinck, Hans-Michael and Wickel, Jonathan and Geis, Christian and T{\"u}z{\"u}n, Erdem and Doppler, Kathrin and Sommer, Claudia and Villmann, Carmen}, title = {Glycine receptor autoantibody binding to the extracellular domain is independent from receptor glycosylation}, series = {Frontiers in Molecular Neuroscience}, volume = {16}, journal = {Frontiers in Molecular Neuroscience}, doi = {10.3389/fnmol.2023.1089101}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304206}, year = {2023}, abstract = {Glycine receptor (GlyR) autoantibodies are associated with stiff-person syndrome and the life-threatening progressive encephalomyelitis with rigidity and myoclonus in children and adults. Patient histories show variability in symptoms and responses to therapeutic treatments. A better understanding of the autoantibody pathology is required to develop improved therapeutic strategies. So far, the underlying molecular pathomechanisms include enhanced receptor internalization and direct receptor blocking altering GlyR function. A common epitope of autoantibodies against the GlyRα1 has been previously defined to residues 1A-33G at the N-terminus of the mature GlyR extracellular domain. However, if other autoantibody binding sites exist or additional GlyR residues are involved in autoantibody binding is yet unknown. The present study investigates the importance of receptor glycosylation for binding of anti-GlyR autoantibodies. The glycine receptor α1 harbors only one glycosylation site at the amino acid residue asparagine 38 localized in close vicinity to the identified common autoantibody epitope. First, non-glycosylated GlyRs were characterized using protein biochemical approaches as well as electrophysiological recordings and molecular modeling. Molecular modeling of non-glycosylated GlyRα1 did not show major structural alterations. Moreover, non-glycosylation of the GlyRα1N38Q did not prevent the receptor from surface expression. At the functional level, the non-glycosylated GlyR demonstrated reduced glycine potency, but patient GlyR autoantibodies still bound to the surface-expressed non-glycosylated receptor protein in living cells. Efficient adsorption of GlyR autoantibodies from patient samples was possible by binding to native glycosylated and non-glycosylated GlyRα1 expressed in living not fixed transfected HEK293 cells. Binding of patient-derived GlyR autoantibodies to the non-glycosylated GlyRα1 offered the possibility to use purified non-glycosylated GlyR extracellular domain constructs coated on ELISA plates and use them as a fast screening readout for the presence of GlyR autoantibodies in patient serum samples. Following successful adsorption of patient autoantibodies by GlyR ECDs, binding to primary motoneurons and transfected cells was absent. Our results indicate that the glycine receptor autoantibody binding is independent of the receptor's glycosylation state. Purified non-glycosylated receptor domains harbouring the autoantibody epitope thus provide, an additional reliable experimental tool besides binding to native receptors in cell-based assays for detection of autoantibody presence in patient sera.}, language = {en} } @article{KirchnerSchrammIvanovaetal.2024, author = {Kirchner, Philipp H. and Schramm, Louis and Ivanova, Svetlana and Shoyama, Kazutaka and W{\"u}rthner, Frank and Beuerle, Florian}, title = {A water-stable boronate ester cage}, series = {Journal of the American Chemical Society}, volume = {146}, journal = {Journal of the American Chemical Society}, number = {8}, issn = {0002-7863}, doi = {10.1021/jacs.3c12002}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-361245}, pages = {5305-5315}, year = {2024}, abstract = {The reversible condensation of catechols and boronic acids to boronate esters is a paradigm reaction in dynamic covalent chemistry. However, facile backward hydrolysis is detrimental for stability and has so far prevented applications for boronate-based materials. Here, we introduce cubic boronate ester cages 6 derived from hexahydroxy tribenzotriquinacenes and phenylene diboronic acids with ortho-t-butyl substituents. Due to steric shielding, dynamic exchange at the Lewis acidic boron sites is feasible only under acid or base catalysis but fully prevented at neutral conditions. For the first time, boronate ester cages 6 tolerate substantial amounts of water or alcohols both in solution and solid state. The unprecedented applicability of these materials under ambient and aqueous conditions is showcased by efficient encapsulation and on-demand release of β-carotene dyes and heterogeneous water oxidation catalysis after the encapsulation of ruthenium catalysts.}, language = {en} } @article{NollWuerthner2024, author = {Noll, Niklas and W{\"u}rthner, Frank}, title = {Bioinspired water preorganization in confined space for efficient water oxidation catalysis in metallosupramolecular ruthenium architectures}, series = {Accounts of Chemical Research}, volume = {57}, journal = {Accounts of Chemical Research}, number = {10}, issn = {0001-4842}, doi = {10.1021/acs.accounts.4c00148}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-361232}, pages = {1538-1549}, year = {2024}, abstract = {Conspectus Nature has established a sustainable way to maintain aerobic life on earth by inventing one of the most sophisticated biological processes, namely, natural photosynthesis, which delivers us with organic matter and molecular oxygen derived from the two abundant resources sunlight and water. The thermodynamically demanding photosynthetic water splitting is catalyzed by the oxygen-evolving complex in photosystem II (OEC-PSII), which comprises a distorted tetramanganese-calcium cluster (CaMn\(_4\)O\(_5\)) as catalytic core. As an ubiquitous concept for fine-tuning and regulating the reactivity of the active site of metalloenzymes, the surrounding protein domain creates a sophisticated environment that promotes substrate preorganization through secondary, noncovalent interactions such as hydrogen bonding or electrostatic interactions. Based on the high-resolution X-ray structure of PSII, several water channels were identified near the active site, which are filled with extensive hydrogen-bonding networks of preorganized water molecules, connecting the OEC with the protein surface. As an integral part of the outer coordination sphere of natural metalloenzymes, these channels control the substrate and product delivery, carefully regulate the proton flow by promoting pivotal proton-coupled electron transfer processes, and simultaneously stabilize short-lived oxidized intermediates, thus highlighting the importance of an ordered water network for the remarkable efficiency of the natural OEC. Transferring this concept from nature to the engineering of artificial metal catalysts for fuel production has fostered the fascinating field of metallosupramolecular chemistry by generating defined cavities that conceptually mimic enzymatic pockets. However, the application of supramolecular approaches to generate artificial water oxidation catalysts remained scarce prior to our initial reports, since such molecular design strategies for efficient activation of substrate water molecules in confined nanoenvironments were lacking. In this Account, we describe our research efforts on combining the state-of-the art Ru(bda) catalytic framework with structurally programmed ditopic ligands to guide the water oxidation process in defined metallosupramolecular assemblies in spatial proximity. We will elucidate the governing factors that control the quality of hydrogen-bonding water networks in multinuclear cavities of varying sizes and geometries to obtain high-performance, state-of-the-art water oxidation catalysts. Pushing the boundaries of artificial catalyst design, embedding a single catalytic Ru center into a well-defined molecular pocket enabled sophisticated water preorganization in front of the active site through an encoded basic recognition site, resulting in high catalytic rates comparable to those of the natural counterpart OEC-PSII. To fully explore their potential for solar fuel devices, the suitability of our metallosupramolecular assemblies was demonstrated under (electro)chemical and photocatalytic water oxidation conditions. In addition, testing the limits of structural diversity allowed the fabrication of self-assembled linear coordination oligomers as novel photocatalytic materials and long-range ordered covalent organic framework (COF) materials as recyclable and long-term stable solid-state materials for future applications.}, language = {en} } @article{KleihDahmsBotrel2023, author = {Kleih-Dahms, Sonja C. and Botrel, Loic}, title = {Neurofeedback therapy to improve cognitive function in patients with chronic post-stroke attention deficits: a within-subjects comparison}, series = {Frontiers in Human Neuroscience}, volume = {17}, journal = {Frontiers in Human Neuroscience}, doi = {10.3389/fnhum.2023.1155584}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322454}, year = {2023}, abstract = {Introduction We investigated a slow-cortical potential (SCP) neurofeedback therapy approach for rehabilitating chronic attention deficits after stroke. This study is the first attempt to train patients who survived stroke with SCP neurofeedback therapy. Methods We included N = 5 participants in a within-subjects follow-up design. We assessed neuropsychological and psychological performance at baseline (4 weeks before study onset), before study onset, after neurofeedback training, and at 3 months follow-up. Participants underwent 20 sessions of SCP neurofeedback training. Results Participants learned to regulate SCPs toward negativity, and we found indications for improved attention after the SCP neurofeedback therapy in some participants. Quality of life improved throughout the study according to engagement in activities of daily living. The self-reported motivation was related to mean SCP activation in two participants. Discussion We would like to bring attention to the potential of SCP neurofeedback therapy as a new rehabilitation method for treating post-stroke cognitive deficits. Studies with larger samples are warranted to corroborate the results.}, language = {en} } @article{GoepfertTraubSelletal.2023, author = {G{\"o}pfert, Dennis and Traub, Jan and Sell, Roxane and Homola, Gy{\"o}rgy A. and Vogt, Marius and Pham, Mirko and Frantz, Stefan and St{\"o}rk, Stefan and Stoll, Guido and Frey, Anna}, title = {Profiles of cognitive impairment in chronic heart failure—A cluster analytic approach}, series = {Frontiers in Human Neuroscience}, volume = {17}, journal = {Frontiers in Human Neuroscience}, doi = {10.3389/fnhum.2023.1126553}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313429}, year = {2023}, abstract = {Background Cognitive impairment is a major comorbidity in patients with chronic heart failure (HF) with a wide range of phenotypes. In this study, we aimed to identify and compare different clusters of cognitive deficits. Methods The prospective cohort study "Cognition.Matters-HF" recruited 147 chronic HF patients (aged 64.5 ± 10.8 years; 16.2\% female) of any etiology. All patients underwent extensive neuropsychological testing. We performed a hierarchical cluster analysis of the cognitive domains, such as intensity of attention, visual/verbal memory, and executive function. Generated clusters were compared exploratively with respect to the results of cardiological, neurological, and neuroradiological examinations without correction for multiple testing. Results Dendrogram and the scree plot suggested three distinct cognitive profiles: In the first cluster, 42 patients (28.6\%) performed without any deficits in all domains. Exclusively, the intensity of attention deficits was seen in the second cluster, including 55 patients (37.4\%). A third cluster with 50 patients (34.0\%) was characterized by deficits in all cognitive domains. Age (p = 0.163) and typical clinical markers of chronic HF, such as ejection fraction (p = 0.222), 6-min walking test distance (p = 0.138), NT-proBNP (p = 0.364), and New York Heart Association class (p = 0.868) did not differ between clusters. However, we observed that women (p = 0.012) and patients with previous cardiac valve surgery (p = 0.005) prevailed in the "global deficits" cluster and the "no deficits" group had a lower prevalence of underlying arterial hypertension (p = 0.029). Total brain volume (p = 0.017) was smaller in the global deficit cluster, and serum levels of glial fibrillary acidic protein were increased (p = 0.048). Conclusion Apart from cognitively healthy and globally impaired HF patients, we identified a group with deficits only in the intensity of attention. Women and patients with previous cardiac valve surgery are at risk for global cognitive impairment when suffering HF and could benefit from special multimodal treatment addressing the psychosocial condition.}, language = {en} } @article{LehriederZapantisPhametal.2023, author = {Lehrieder, Dominik and Zapantis, Nikolaos and Pham, Mirko and Schuhmann, Michael Klaus and Haarmann, Axel}, title = {Treating seronegative neuromyelitis optica spectrum disorder with inebilizumab: a case report}, series = {Frontiers in Neurology}, volume = {14}, journal = {Frontiers in Neurology}, doi = {10.3389/fneur.2023.1297341}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-354031}, year = {2023}, abstract = {Background Neuromyelitis optica spectrum disorder (NMOSD) is a devastating inflammatory disease of the central nervous system that is often severely disabling from the outset. The lack of pathognomonic aquaporin 4 (AQP4) antibodies in seronegative NMOSD not only hinders early diagnosis, but also limits therapeutic options, in contrast to AQP4 antibody-positive NMOSD, where the therapeutic landscape has recently evolved massively. Case presentation We report a 56-year-old woman with bilateral optic neuritis and longitudinally extensive myelitis as the index events of a seronegative NMOSD, who was successfully treated with inebilizumab. Conclusion Treatment with inebilizumab may be considered in aggressive seronegative NMOSD. Whether broader CD19-directed B cell depletion is more effective than treatment with rituximab remains elusive.}, language = {en} } @article{RebsStreckfussBoemeke2023, author = {Rebs, Sabine and Streckfuss-B{\"o}meke, Katrin}, title = {How can we use stem cell-derived cardiomyocytes to understand the involvement of energetic metabolism in alterations of cardiac function?}, series = {Frontiers in Molecular Medicine}, volume = {3}, journal = {Frontiers in Molecular Medicine}, doi = {10.3389/fmmed.2023.1222986}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-327344}, year = {2023}, abstract = {Mutations in the mitochondrial-DNA or mitochondria related nuclear-encoded-DNA lead to various multisystemic disorders collectively termed mitochondrial diseases. One in three cases of mitochondrial disease affects the heart muscle, which is called mitochondrial cardiomyopathy (MCM) and is associated with hypertrophic, dilated, and noncompact cardiomyopathy. The heart is an organ with high energy demand, and mitochondria occupy 30\%-40\% of its cardiomyocyte-cell volume. Mitochondrial dysfunction leads to energy depletion and has detrimental effects on cardiac performance. However, disease development and progression in the context of mitochondrial and nuclear DNA mutations, remains incompletely understood. The system of induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CM) is an excellent platform to study MCM since the unique genetic identity to their donors enables a robust recapitulation of the predicted phenotypes in a dish on a patient-specific level. Here, we focus on recent insights into MCM studied by patient-specific iPSC-CM and further discuss research gaps and advances in metabolic maturation of iPSC-CM, which is crucial for the study of mitochondrial dysfunction and to develop novel therapeutic strategies.}, language = {en} } @article{FroehlichZahnerSchmalzingetal.2023, author = {Froehlich, Matthias and Zahner, Antonia and Schmalzing, Marc and Gernert, Michael and Strunz, Patrick-Pascal and Hueper, Sebastian and Portegys, Jan and Schwaneck, Eva Christina and Gadeholt, Ottar and K{\"u}bler, Andrea and Hewig, Johannes and Ziebell, Philipp}, title = {Patient-reported outcomes provide evidence for increased depressive symptoms and increased mental impairment in giant cell arteritis}, series = {Frontiers in Medicine}, volume = {10}, journal = {Frontiers in Medicine}, doi = {10.3389/fmed.2023.1146815}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319761}, year = {2023}, abstract = {Objectives The spectrum of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) represents highly inflammatory rheumatic diseases. Patients mostly report severe physical impairment. Possible consequences for mental health have been scarcely studied. The aim of this study was to investigate psychological well-being in the context of GCA and PMR. Methods Cross-sectional study with N = 100 patients with GCA and/or PMR (GCA-PMR). Patient-reported outcomes (PROs) were measured using the Short Form 36 Version 2 (SF-36v2) and visual analog scale (VAS) assessment. Moreover, the Patient Health Questionnaire 9 (PHQ-9) was used in 35 of 100 patients to detect depression. To compare PROs with physician assessment, VAS was also rated from physician perspective. To assess a possible association with inflammation itself, serological parameters of inflammation (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR]) were included. Results In all scales of the SF-36v2 except General Health (GH) and in the physical and mental sum score (PCS, MCS), a significant impairment compared to the German reference collective was evident (MCS: d = 0.533, p < 0.001). In the PHQ-9 categorization, 14 of the 35 (40\%) showed evidence of major depression disorder. VAS Patient correlated significantly with PHQ-9 and SF-36 in all categories, while VAS Physician showed only correlations to physical categories and not in the mental dimensions. Regarding inflammatory parameters, linear regression showed CRP to be a complementary significant positive predictor of mental health subscale score, independent of pain. Conclusion PRO show a relevant impairment of mental health up to symptoms of major depression disorder. The degree of depressive symptoms is also distinctly associated with the serological inflammatory marker CRP.}, language = {en} } @article{OsmanogluGuptaAlmasietal.2023, author = {Osmanoglu, {\"O}zge and Gupta, Shishir K. and Almasi, Anna and Yagci, Seray and Srivastava, Mugdha and Araujo, Gabriel H. M. and Nagy, Zoltan and Balkenhol, Johannes and Dandekar, Thomas}, title = {Signaling network analysis reveals fostamatinib as a potential drug to control platelet hyperactivation during SARS-CoV-2 infection}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1285345}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-354158}, year = {2023}, abstract = {Introduction Pro-thrombotic events are one of the prevalent causes of intensive care unit (ICU) admissions among COVID-19 patients, although the signaling events in the stimulated platelets are still unclear. Methods We conducted a comparative analysis of platelet transcriptome data from healthy donors, ICU, and non-ICU COVID-19 patients to elucidate these mechanisms. To surpass previous analyses, we constructed models of involved networks and control cascades by integrating a global human signaling network with transcriptome data. We investigated the control of platelet hyperactivation and the specific proteins involved. Results Our study revealed that control of the platelet network in ICU patients is significantly higher than in non-ICU patients. Non-ICU patients require control over fewer proteins for managing platelet hyperactivity compared to ICU patients. Identification of indispensable proteins highlighted key subnetworks, that are targetable for system control in COVID-19-related platelet hyperactivity. We scrutinized FDA-approved drugs targeting indispensable proteins and identified fostamatinib as a potent candidate for preventing thrombosis in COVID-19 patients. Discussion Our findings shed light on how SARS-CoV-2 efficiently affects host platelets by targeting indispensable and critical proteins involved in the control of platelet activity. We evaluated several drugs for specific control of platelet hyperactivity in ICU patients suffering from platelet hyperactivation. The focus of our approach is repurposing existing drugs for optimal control over the signaling network responsible for platelet hyperactivity in COVID-19 patients. Our study offers specific pharmacological recommendations, with drug prioritization tailored to the distinct network states observed in each patient condition. Interactive networks and detailed results can be accessed at https://fostamatinib.bioinfo-wuerz.eu/.}, language = {en} } @article{ElgheznawyOefteringEnglertetal.2023, author = {Elgheznawy, Amro and {\"O}ftering, Patricia and Englert, Maximilian and Mott, Kristina and Kaiser, Friederike and Kusch, Charly and Gbureck, Uwe and B{\"o}sl, Michael R. and Schulze, Harald and Nieswandt, Bernhard and V{\"o}gtle, Timo and Hermanns, Heike M.}, title = {Loss of zinc transporters ZIP1 and ZIP3 augments platelet reactivity in response to thrombin and accelerates thrombus formation in vivo}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1197894}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320154}, year = {2023}, abstract = {Zinc (Zn2+) is considered as important mediator of immune cell function, thrombosis and haemostasis. However, our understanding of the transport mechanisms that regulate Zn2+ homeostasis in platelets is limited. Zn2+ transporters, ZIPs and ZnTs, are widely expressed in eukaryotic cells. Using mice globally lacking ZIP1 and ZIP3 (ZIP1/3 DKO), our aim was to explore the potential role of these Zn2+ transporters in maintaining platelet Zn2+ homeostasis and in the regulation of platelet function. While ICP-MS measurements indicated unaltered overall Zn2+ concentrations in platelets of ZIP1/3 DKO mice, we observed a significantly increased content of FluoZin3-stainable free Zn2+, which, however, appears to be released less efficiently upon thrombin-stimulated platelet activation. On the functional level, ZIP1/3 DKO platelets exhibited a hyperactive response towards threshold concentrations of G protein-coupled receptor (GPCR) agonists, while immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptor agonist signalling was unaffected. This resulted in enhanced platelet aggregation towards thrombin, bigger thrombus volume under flow ex vivo and faster in vivo thrombus formation in ZIP1/3 DKO mice. Molecularly, augmented GPCR responses were accompanied by enhanced Ca2+ and PKC, CamKII and ERK1/2 signalling. The current study thereby identifies ZIP1 and ZIP3 as important regulators for the maintenance of platelet Zn2+ homeostasis and function.}, language = {en} } @article{ZaitsevaHoffmannLoestetal.2023, author = {Zaitseva, Olena and Hoffmann, Annett and L{\"o}st, Margaretha and Anany, Mohamed A. and Zhang, Tengyu and Kucka, Kirstin and Wiegering, Armin and Otto, Christoph and Wajant, Harald}, title = {Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1194610}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323116}, year = {2023}, abstract = {Fibroblast growth factor (FGF)-inducible 14 (Fn14) activates the classical and alternative NFκB (nuclear factor 'kappa-light-chain-enhancer' of activated B-cells) signaling pathway but also enhances tumor necrosis factor (TNF)-induced cell death. Fn14 expression is upregulated in non-hematopoietic cells during tissue injury and is also often highly expressed in solid cancers. In view of the latter, there were and are considerable preclinical efforts to target Fn14 for tumor therapy, either by exploiting Fn14 as a target for antibodies with cytotoxic activity (e.g. antibody-dependent cellular cytotoxicity (ADCC)-inducing IgG variants, antibody drug conjugates) or by blocking antibodies with the aim to interfere with protumoral Fn14 activities. Noteworthy, there are yet no attempts to target Fn14 with agonistic Fc effector function silenced antibodies to unleash the proinflammatory and cell death-enhancing activities of this receptor for tumor therapy. This is certainly not at least due to the fact that anti-Fn14 antibodies only act as effective agonists when they are presented bound to Fcγ receptors (FcγR). Thus, there are so far no antibodies that robustly and selectively engage Fn14 signaling without triggering unwanted FcγR-mediated activities. In this study, we investigated a panel of variants of the anti-Fn14 antibody 18D1 of different valencies and domain architectures with respect to their inherent FcγR-independent ability to trigger Fn14-associated signaling pathways. In contrast to conventional 18D1, the majority of 18D1 antibody variants with four or more Fn14 binding sites displayed a strong ability to trigger the alternative NFκB pathway and to enhance TNF-induced cell death and therefore resemble in their activity soluble (TNF)-like weak inducer of apoptosis (TWEAK), one form of the natural occurring ligand of Fn14. Noteworthy, activation of the classical NFκB pathway, which naturally is predominately triggered by membrane-bound TWEAK but not soluble TWEAK, was preferentially observed with a subset of constructs containing Fn14 binding sites at opposing sites of the IgG scaffold, e.g. IgG1-scFv fusion proteins. A superior ability of IgG1-scFv fusion proteins to trigger classical NFκB signaling was also observed with the anti-Fn14 antibody PDL192 suggesting that we identified generic structures for Fn14 antibody variants mimicking soluble and membrane-bound TWEAK.}, language = {en} } @article{HeckerGruenerHartmannsbergeretal.2023, author = {Hecker, Katharina and Gr{\"u}ner, Julia and Hartmannsberger, Beate and Appeltshauser, Luise and Villmann, Carmen and Sommer, Claudia and Doppler, Kathrin}, title = {Different binding and pathogenic effect of neurofascin and contactin-1 autoantibodies in autoimmune nodopathies}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1189734}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320395}, year = {2023}, abstract = {Introduction IgG4 autoantibodies against paranodal proteins are known to induce acute-onset and often severe sensorimotor autoimmune neuropathies. How autoantibodies reach their antigens at the paranode in spite of the myelin barrier is still unclear. Methods We performed in vitro incubation experiments with patient sera on unfixed and unpermeabilized nerve fibers and in vivo intraneural and intrathecal passive transfer of patient IgG to rats, to explore the access of IgG autoantibodies directed against neurofascin-155 and contactin-1 to the paranodes and their pathogenic effect. Results We found that in vitro incubation resulted in weak paranodal binding of anti-contactin-1 autoantibodies whereas anti-neurofascin-155 autoantibodies bound to the nodes more than to the paranodes. After short-term intraneural injection, no nodal or paranodal binding was detectable when using anti-neurofascin-155 antibodies. After repeated intrathecal injections, nodal more than paranodal binding could be detected in animals treated with anti-neurofascin-155, accompanied by sensorimotor neuropathy. In contrast, no paranodal binding was visible in rats intrathecally injected with anti-contactin-1 antibodies, and animals remained unaffected. Conclusion These data support the notion of different pathogenic mechanisms of anti-neurofascin-155 and anti-contactin-1 autoantibodies and different accessibility of paranodal and nodal structures.}, language = {en} } @article{SealSchwabChiarollaetal.2023, author = {Seal, Rishav and Schwab, Lara S. U. and Chiarolla, Cristina M. and Hundhausen, Nadine and Klose, Georg Heinrich and Reu-Hofer, Simone and Rosenwald, Andreas and Wiest, Johannes and Berberich-Siebelt, Friederike}, title = {Delayed and limited administration of the JAKinib tofacitinib mitigates chronic DSS-induced colitis}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1179311}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-317815}, year = {2023}, abstract = {In inflammatory bowel disease, dysregulated T cells express pro-inflammatory cytokines. Using a chronic azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis model resembling ulcerative colitis, we evaluated whether and when treatment with the Janus kinase (JAK) inhibitor tofacitinib could be curative. Comparing the treatment with two and three cycles of tofacitinib medication in drinking water - intermittently with DSS induction - revealed that two cycles were not only sufficient but also superior over the 3-x regimen. The two cycles of the 2-x protocol paralleled the second and third cycles of the longer protocol. T cells were less able to express interferon gamma (IFN-γ) and the serum levels of IFN-γ, interleukin (IL)-2, IL-6, IL-17, and tumor necrosis factor (TNF) were significantly reduced in sera, while those of IL-10 and IL-22 increased under the 2-x protocol. Likewise, the frequency and effector phenotype of regulatory T cells (Tregs) increased. This was accompanied by normal weight gain, controlled clinical scores, and restored stool consistency. The general and histologic appearance of the colons revealed healing and tissue intactness. Importantly, two phases of tofacitinib medication completely prevented AOM-incited pseudopolyps and the hyper-proliferation of epithelia, which was in contrast to the 3-x regimen. This implies that the initial IBD-induced cytokine expression is not necessarily harmful as long as inflammatory signaling can later be suppressed and that time-restricted treatment allows for anti-inflammatory and tissue-healing cytokine activities.}, language = {en} } @article{LauruschkatMuchsinReinetal.2023, author = {Lauruschkat, Chris David and Muchsin, Ihsan and Rein, Alice and Erhard, Florian and Grathwohl, Denise and D{\"o}lken, Lars and K{\"o}chel, Carolin and Falk, Christine Susanne and Einsele, Hermann and Wurster, Sebastian and Grigoleit, G{\"o}tz Ulrich and Kraus, Sabrina}, title = {CD4+ T cells are the major predictor of HCMV control in allogeneic stem cell transplant recipients on letermovir prophylaxis}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1148841}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-316982}, year = {2023}, abstract = {Introduction Human cytomegalovirus (HCMV) causes significant morbidity and mortality in allogeneic stem cell transplant (alloSCT) recipients. Recently, antiviral letermovir prophylaxis during the first 100 days after alloSCT replaced PCR-guided preemptive therapy as the primary standard of care for HCMV reactivations. Here, we compared NK-cell and T-cell reconstitution in alloSCT recipients receiving preemptive therapy or letermovir prophylaxis in order to identify potential biomarkers predicting prolonged and symptomatic HCMV reactivation. Methods To that end, the NK-cell and T-cell repertoire of alloSCT recipients managed with preemptive therapy (n=32) or letermovir prophylaxis (n=24) was characterized by flow cytometry on days +30, +60, +90 and +120 after alloSCT. Additionally, background-corrected HCMV-specific T-helper (CD4+IFNγ+) and cytotoxic (CD8+IFNγ+CD107a+) T cells were quantified after pp65 stimulation. Results Compared to preemptive therapy, letermovir prophylaxis prevented HCMV reactivation and decreased HCMV peak viral loads until days +120 and +365. Letermovir prophylaxis resulted in decreased T-cell numbers but increased NK-cell numbers. Interestingly, despite the inhibition of HCMV, we found high numbers of "memory-like" (CD56dimFcεRIγ- and/or CD159c+) NK cells and an expansion of HCMV-specific CD4+ and CD8+ T cells in letermovir recipients. We further compared immunological readouts in patients on letermovir prophylaxis with non/short-term HCMV reactivation (NSTR) and prolonged/symptomatic HCMV reactivation (long-term HCMV reactivation, LTR). Median HCMV-specific CD4+ T-cell frequencies were significantly higher in NSTR patients (day +60, 0.35 \% vs. 0.00 \% CD4+IFNγ+/CD4+ cells, p=0.018) than in patients with LTR, whereas patients with LTR had significantly higher median regulatory T-cell (Treg) frequencies (day +90, 2.2 \% vs. 6.2 \% CD4+CD25+CD127dim/CD4+ cells, p=0.019). ROC analysis confirmed low HCMV specific CD4+ (AUC on day +60: 0.813, p=0.019) and high Treg frequencies (AUC on day +90: 0.847, p=0.021) as significant predictors of prolonged and symptomatic HCMV reactivation. Discussion Taken together, letermovir prophylaxis delays HCMV reactivation and alters NK- and T-cell reconstitution. High numbers of HCMV-specific CD4+ T cells and low numbers of Tregs seem to be pivotal to suppress post-alloSCT HCMV reactivation during letermovir prophylaxis. Administration of more advanced immunoassays that include Treg signature cytokines might contribute to the identification of patients at high-risk for long-term and symptomatic HCMV reactivation who might benefit from prolonged administration of letermovir.}, language = {en} } @article{AintablianStrozniakHeueretal.2023, author = {Aintablian, Arpa and Strozniak, Sandra and Heuer, Marion and Lutz, Manfred B.}, title = {M-MDSC in vitro generation from mouse bone marrow with IL-3 reveals high expression and functional activity of arginase 1}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1130600}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-317769}, year = {2023}, abstract = {Myeloid-derived suppressor cells (MDSC) represent major regulators of immune responses, which can control T cells via their inducible nitric oxide synthase (iNOS)- and arginase 1 (Arg1)-mediated effector functions. While GM-CSF is well documented to promote MDSC development, little is known about this potential of IL-3, an established growth factor for mast cells. Here, we show that IL-3, similar to GM-CSF, generates monocytic MDSC (M-MDSC) from murine bone marrow (BM) cells after 3 days of in vitro culture. At this time point, predominantly CD11b+ CD49a+ monocytic and CD11b+ CD49a- FcεR I- neutrophilic cells were detectable, while CD11blow/neg FcεR I+ mast cells accumulated only after extended culture periods. Both growth factors were equivalent in generating M-MDSC with respect to phenotype, cell yield and typical surface markers. However, IL-3 generated M-MDSC produced less TNF, IL-1β and IL-10 after activation with LPS + IFN-γ but showed higher Arg1 expression compared to GM-CSF generated M-MDSC. Arg1 was further induced together with iNOS after MDSC activation. Accordingly, an increased Arg1-dependent suppressor activity by the IL-3 generated M-MDSC was observed using respective iNOS and Arg1 inhibitors. Together, these data indicate that M-MDSC can be generated in vitro by IL-3, similar to GM-CSF, but with increased Arg1 expression and Arg1-mediated suppression capacity. This protocol now allows further in vitro studies on the role of IL-3 for MDSC biology.}, language = {en} } @article{HungKasperkowitzKurzetal.2023, author = {Hung, Sophia and Kasperkowitz, Amelie and Kurz, Florian and Dreher, Liane and Diessner, Joachim and Ibrahim, Eslam S. and Schwarz, Stefan and Ohlsen, Knut and Hertlein, Tobias}, title = {Next-generation humanized NSG-SGM3 mice are highly susceptible to Staphylococcus aureus infection}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1127709}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-306966}, year = {2023}, abstract = {Humanized hemato-lymphoid system mice, or humanized mice, emerged in recent years as a promising model to study the course of infection of human-adapted or human-specific pathogens. Though Staphylococcus aureus infects and colonizes a variety of species, it has nonetheless become one of the most successful human pathogens of our time with a wide armory of human-adapted virulence factors. Humanized mice showed increased vulnerability to S. aureus compared to wild type mice in a variety of clinically relevant disease models. Most of these studies employed humanized NSG (NOD-scid IL2Rgnull) mice which are widely used in the scientific community, but show poor human myeloid cell reconstitution. Since this immune cell compartment plays a decisive role in the defense of the human immune system against S. aureus, we asked whether next-generation humanized mice, like NSG-SGM3 (NOD-scid IL2Rgnull-3/GM/SF) with improved myeloid reconstitution, would prove to be more resistant to infection. To our surprise, we found the contrary when we infected humanized NSG-SGM3 (huSGM3) mice with S. aureus: although they had stronger human immune cell engraftment than humanized NSG mice, particularly in the myeloid compartment, they displayed even more pronounced vulnerability to S. aureus infection. HuSGM3 mice had overall higher numbers of human T cells, B cells, neutrophils and monocytes in the blood and the spleen. This was accompanied by elevated levels of pro-inflammatory human cytokines in the blood of huSGM3 mice. We further identified that the impaired survival of huSGM3 mice was not linked to higher bacterial burden nor to differences in the murine immune cell repertoire. Conversely, we could demonstrate a correlation of the rate of humanization and the severity of infection. Collectively, this study suggests a detrimental effect of the human immune system in humanized mice upon encounter with S. aureus which might help to guide future therapy approaches and analysis of virulence mechanisms.}, language = {en} } @article{ZaitsevaAnanyWajantetal.2023, author = {Zaitseva, Olena and Anany, Mohamed and Wajant, Harald and Lang, Isabell}, title = {Basic characterization of antibodies targeting receptors of the tumor necrosis factor receptor superfamily}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1115667}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-311407}, year = {2023}, abstract = {Many new immunotherapeutic approaches aim on the stimulatory targeting of receptors of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF) using antibodies with intrinsic or conditional agonism. There is an initial need to characterize corresponding TNFRSF receptor (TNFR)-targeting antibodies with respect to affinity, ligand binding, receptor activation and the epitope recognized. Here, we report a collection of simple and matched protocols enabling the detailed investigation of these aspects by help of Gaussia princeps luciferase (GpL) fusion proteins and analysis of interleukin-8 (IL8) production as an easily measurable readout of TNFR activation. In a first step, the antibodies and antibody variants of interest are transiently expressed in human embryonal kidney 293 cells, either in non-modified form or as fusion proteins with GpL as a reporter domain. The supernatants containing the antibody-GpL fusion proteins can then be used without further purification in cell-free and/or cellular binding studies to determine affinity. Similarly, binding studies with mutated TNFR variants enable the characterization of the antibody binding site within the TNFR ectodomain. Furthermore, in cellular binding studies with GpL fusion proteins of soluble TNFL molecules, the ability of the non-modified antibody variants to interfere with TNFL-TNFR interaction can be analyzed. Last but not least, we describe a protocol to determine the intrinsic and the Fc gamma receptor (FcγR)-dependent agonism of anti-TNFR antibodies which exploits i) the capability of TNFRs to trigger IL8 production in tumor cell lines lacking expression of FcγRs and ii) vector- and FcγR-transfected cells, which produce no or only very low amounts of human IL8. The presented protocols only require standard molecular biological equipment, eukaryotic cell culture and plate readers for the quantification of luminescent and colorimetric signals.}, language = {en} } @article{DirksAndresPauletal.2023, author = {Dirks, Johannes and Andres, Oliver and Paul, Luisa and Manukjan, Georgi and Schulze, Harald and Morbach, Henner}, title = {IgD shapes the pre-immune na{\"i}ve B cell compartment in humans}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1096019}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304758}, year = {2023}, abstract = {B cell maturation and immunoglobulin (Ig) repertoire selection are governed by expression of a functional B cell receptor (BCR). Na{\"i}ve B cells co-express their BCR as IgM and IgD isotype. However, the role of the additionally expressed IgD on na{\"i}ve B cells is not known. Here we assessed the impact of IgD on na{\"i}ve B cell maturation and Ig repertoire selection in 8 individuals from 3 different families with heterozygous loss-of-function or loss-of expression mutations in IGHD. Although na{\"i}ve B cells from these individuals expressed IgM on their surface, the IGHD variant in heterozygous state entailed a chimeric situation by allelic exclusion with almost half of the na{\"i}ve B cell population lacking surface IgD expression. Flow cytometric analyses revealed a distinct phenotype of IgD-negative na{\"i}ve B cells with decreased expression of CD19, CD20 and CD21 as well as lower BAFF-R and integrin-β7 expression. IgD-negative B cells were less responsive in vitro after engaging the IgM-BCR, TLR7/9 or CD40 pathway. Additionally, a selective disadvantage of IgD-negative B cells within the T2 transitional and mature na{\"i}ve B cell compartment as well as reduced frequencies of IgMlo/- B cells within the mature na{\"i}ve B cell compartment lacking IgD were evident. RNA-Ig-seq of bulk sorted B cell populations showed an altered selection of distinct VH segments in the IgD-negative mature na{\"i}ve B cell population. We conclude that IgD expression on human na{\"i}ve B cells is redundant for generation of na{\"i}ve B cells in general, but further shapes the naive B cell compartment starting from T2 transitional B cells. Our observations suggest an unexpected role of IgD expression to be critical for selection of distinct Ig VH segments into the pre-immune Ig repertoire and for the survival of IgMlo/- na{\"i}ve B cells known to be enriched in poly-/autoreactive B cell clones.}, language = {en} } @article{HeinemannStalpBonifacioetal.2023, author = {Heinemann, Anna Sophie and Stalp, Jan Lennart and Bonifacio, Jo{\~a}o Pedro Pereira and Silva, Filo and Willers, Maike and Heckmann, Julia and Fehlhaber, Beate and V{\"o}llger, Lena and Raafat, Dina and Normann, Nicole and Klos, Andreas and Hansen, Gesine and Schmolke, Mirco and Viemann, Dorothee}, title = {Silent neonatal influenza A virus infection primes systemic antimicrobial immunity}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1072142}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304782}, year = {2023}, abstract = {Infections with influenza A viruses (IAV) cause seasonal epidemics and global pandemics. The majority of these infections remain asymptomatic, especially among children below five years of age. Importantly, this is a time, when immunological imprinting takes place. Whether early-life infections with IAV affect the development of antimicrobial immunity is unknown. Using a preclinical mouse model, we demonstrate here that silent neonatal influenza infections have a remote beneficial impact on the later control of systemic juvenile-onset and adult-onset infections with an unrelated pathogen, Staphylococcus aureus, due to improved pathogen clearance and clinical resolution. Strategic vaccination with a live attenuated IAV vaccine elicited a similar protection phenotype. Mechanistically, the IAV priming effect primarily targets antimicrobial functions of the developing innate immune system including increased antimicrobial plasma activity and enhanced phagocyte functions and antigen-presenting properties at mucosal sites. Our results suggest a long-term benefit from an exposure to IAV during the neonatal phase, which might be exploited by strategic vaccination against influenza early in life to enforce the host's resistance to later bacterial infections.}, language = {en} } @article{GarciaFernandezHoefflinRauschetal.2023, author = {Garc{\´i}a-Fern{\´a}ndez, Patricia and H{\"o}fflin, Klemens and Rausch, Antonia and Strommer, Katharina and Neumann, Astrid and Cebulla, Nadine and Reinhold, Ann-Kristin and Rittner, Heike and {\"U}{\c{c}}eyler, Nurcan and Sommer, Claudia}, title = {Systemic inflammatory markers in patients with polyneuropathies}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1067714}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304217}, year = {2023}, abstract = {Introduction In patients with peripheral neuropathies (PNP), neuropathic pain is present in 50\% of the cases, independent of the etiology. The pathophysiology of pain is poorly understood, and inflammatory processes have been found to be involved in neuro-degeneration, -regeneration and pain. While previous studies have found a local upregulation of inflammatory mediators in patients with PNP, there is a high variability described in the cytokines present systemically in sera and cerebrospinal fluid (CSF). We hypothesized that the development of PNP and neuropathic pain is associated with enhanced systemic inflammation. Methods To test our hypothesis, we performed a comprehensive analysis of the protein, lipid and gene expression of different pro- and anti-inflammatory markers in blood and CSF from patients with PNP and controls. Results While we found differences between PNP and controls in specific cytokines or lipids, such as CCL2 or oleoylcarnitine, PNP patients and controls did not present major differences in systemic inflammatory markers in general. IL-10 and CCL2 levels were related to measures of axonal damage and neuropathic pain. Lastly, we describe a strong interaction between inflammation and neurodegeneration at the nerve roots in a specific subgroup of PNP patients with blood-CSF barrier dysfunction. Conclusion In patients with PNP systemic inflammatory, markers in blood or CSF do not differ from controls in general, but specific cytokines or lipids do. Our findings further highlight the importance of CSF analysis in patients with peripheral neuropathies.}, language = {en} } @article{GoetzRueckschlossBalketal.2023, author = {G{\"o}tz, Lisa and Rueckschloss, Uwe and Balk, G{\"o}zde and Pfeiffer, Verena and Erg{\"u}n, S{\"u}leyman and Kleefeldt, Florian}, title = {The role of carcinoembryonic antigen-related cell adhesion molecule 1 in cancer}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1295232}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357250}, year = {2023}, abstract = {The Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), also known as CD66a, is a member of the immunoglobulin superfamily. CEACAM1 was shown to be a prognostic marker in patients suffering from cancer. In this review, we summarize pre-clinical and clinical evidence linking CEACAM1 to tumorigenicity and cancer progression. Furthermore, we discuss potential CEACAM1-based mechanisms that may affect cancer biology.}, language = {en} } @article{StaudtZieglerMartinVisekrunaetal.2023, author = {Staudt, Sarah and Ziegler-Martin, Kai and Visekruna, Alexander and Slingerland, John and Shouval, Roni and Hudecek, Michael and Van den Brink, Marcel and Luu, Maik}, title = {Learning from the microbes: exploiting the microbiome to enforce T cell immunotherapy}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1269015}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-328019}, year = {2023}, abstract = {The opportunities genetic engineering has created in the field of adoptive cellular therapy for cancer are accelerating the development of novel treatment strategies using chimeric antigen receptor (CAR) and T cell receptor (TCR) T cells. The great success in the context of hematologic malignancies has made especially CAR T cell therapy a promising approach capable of achieving long-lasting remission. However, the causalities involved in mediating resistance to treatment or relapse are still barely investigated. Research on T cell exhaustion and dysfunction has drawn attention to host-derived factors that define both the immune and tumor microenvironment (TME) crucially influencing efficacy and toxicity of cellular immunotherapy. The microbiome, as one of the most complex host factors, has become a central topic of investigations due to its ability to impact on health and disease. Recent findings support the hypothesis that commensal bacteria and particularly microbiota-derived metabolites educate and modulate host immunity and TME, thereby contributing to the response to cancer immunotherapy. Hence, the composition of microbial strains as well as their soluble messengers are considered to have predictive value regarding CAR T cell efficacy and toxicity. The diversity of mechanisms underlying both beneficial and detrimental effects of microbiota comprise various epigenetic, metabolic and signaling-related pathways that have the potential to be exploited for the improvement of CAR T cell function. In this review, we will discuss the recent findings in the field of microbiome-cancer interaction, especially with respect to new trajectories that commensal factors can offer to advance cellular immunotherapy.}, language = {en} } @article{HuttelmaierBenoitGoebeler2023, author = {Huttelmaier, Johanna and Benoit, Sandra and Goebeler, Matthias}, title = {Comorbidity in bullous pemphigoid: up-date and clinical implications}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1196999}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321671}, year = {2023}, abstract = {Bullous pemphigoid is the most common autoimmune blistering disease in industrialized countries and particularly affects the elderly. In this patient population, comorbid diseases are frequent and may complicate management and treatment of bullous pemphigoid. A better understanding why distinct diseases are more frequent in bullous pemphigoid patients may lead to new pathophysiological insights and - as a consequence - result in better patient care. The association of bullous pemphigoid with neurological and psychiatric diseases is well known and confirmed by several case-control studies. Association with further diseases such as malignancy and metabolic diseases are still discussed controversially. In recent years new relationships between bullous pemphigoid and autoimmune as well as inflammatory skin diseases have been reported. This review provides a systematic overview on studies addressing comorbidity in bullous pemphigoid patients. Increasing the awareness of both, common and rare comorbid diseases, may enable clinicians to optimize patient support and individualized treatment of bullous pemphigoid.}, language = {en} } @article{SchaeferFaethKneiseletal.2023, author = {Sch{\"a}fer, Christian and F{\"a}th, Julian and Kneisel, Christof and Baumhauer, Roland and Ullmann, Tobias}, title = {Multidimensional hydrological modeling of a forested catchment in a German low mountain range using a modular runoff and water balance model}, series = {Frontiers in Forests and Global Change}, volume = {6}, journal = {Frontiers in Forests and Global Change}, doi = {10.3389/ffgc.2023.1186304}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357358}, year = {2023}, abstract = {Sufficient plant-available water is one of the most important requirements for vital, stable, and well-growing forest stands. In the face of climate change, there are various approaches to derive recommendations considering tree species selection based on plant-available water provided by measurements or simulations. Owing to the small-parcel management of Central European forests as well as small-spatial variation of soil and stand properties, in situ data collection for individual forest stands of large areas is not feasible, considering time and cost effort. This problem can be addressed using physically based modeling, aiming to numerically simulate the water balance. In this study, we parameterized, calibrated, and verified the hydrological multidimensional WaSiM-ETH model to assess the water balance at a spatial resolution of 30 m in a German forested catchment area (136.4 km2) for the period 2000-2021 using selected in situ data, remote sensing products, and total runoff. Based on the model output, drought-sensitive parameters, such as the difference between potential and effective stand transpiration (Tdiff) and the water balance, were deduced from the model, analyzed, and evaluated. Results show that the modeled evapotranspiration (ET) correlated significantly (R2 = 0.80) with the estimated ET using MODIS data (MOD16A2GFv006). Compared with observed daily, monthly, and annual runoff data, the model shows a good performance (R2: 0.70|0.77|0.73; Kling-Gupta efficiency: 0.59|0.62|0.83; volumetric efficiency: 0.52|0.60|0.83). The comparison with in situ data from a forest monitoring plot, established at the end of 2020, indicated good agreement between observed and simulated interception and soil water content. According to our results, WaSiM-ETH is a potential supplement for forest management, owing to its multidimensionality and the ability to model soil water balance for large areas at comparable high spatial resolution. The outputs offer, compared to non-distributed models (like LWF-Brook90), spatial differentiability, which is important for small-scale parceled forests, regarding stand structure and soil properties. Due to the spatial component offered, additional verification possibilities are feasible allowing a reliable and profound verification of the model and its parameterization.}, 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{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{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{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{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{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{BaumbachHoertererOppeltetal.2022, author = {Baumbach, Sebastian Felix and H{\"o}rterer, Hubert and Oppelt, Sonja and Szeimies, Ulrike and Polzer, Hans and Walther, Markus}, title = {Do pre-operative radiologic assessment predict postoperative outcomes in patients with insertional Achilles tendinopathy?: a retrospective database study}, series = {Archives of Orthopaedic and Trauma Surgery}, volume = {142}, journal = {Archives of Orthopaedic and Trauma Surgery}, number = {11}, issn = {1434-3916}, doi = {10.1007/s00402-021-03897-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307963}, pages = {3045-3052}, year = {2022}, abstract = {Introduction Diagnosis and treatment of insertional tendinopathy of the Achilles tendon (IAT) remains a challenge. The aim of this study was to assess the influence of pre-operative radiological pathologies on the patient-reported outcomes following open debridement of all pathologies for IAT. Materials and methods In this IRB-approved retrospective correlation and comparative study, patients with pre-operative imaging were identified from the authors' retrospective IAT database comprising of 118 patients. All were treated by a standardized surgical treatment strategy utilizing a midline, transachillary approach and debridement of all pathologies. A total of fifteen radiologic parameters were measured on radiographs (RX) and MRI. The patient-reported outcomes were assessed using the Victorian Institute of Sport Assessment-Achilles questionnaire (VISA-A-G) and the general health questionnaire SF-12 at a minimum follow-up of 12 months. The data are presented as mean ± SD (95\% CI). Results 88 patients (74.6\%) with an average age of 50 ± 12 (47-52) years were included. Radiographs were available in 68 patients and MRI in 53. The mean follow-up was 3.8 ± 1.9 (3.4-4.3) years. The overall VISA-A-G was 81 ± 22 (77-86), the SF-12 PCS 54 ± 7 (52-55), and the SF-12 MCS 52 ± 9 (50-54) points. None of the assessed radiological parameters had a significant influence on the patient-reported outcome following surgical treatment for IAT. Conclusion In this retrospective correlation study, no significant association was found between preoperative radiographic and MRI radiologic parameters for IAT and postoperative patient-reported outcomes (VISA-A-G and SF-12).}, language = {en} } @article{HornKristLiebetal.2021, author = {Horn, A. and Krist, L. and Lieb, W. and Montellano, F. A. and Kohls, M. and Haas, K. and Gelbrich, G. and Bolay-Gehrig, S. J. and Morbach, C. and Reese, J. P. and St{\"o}rk, S. and Fricke, J. and Zoller, T. and Schmidt, S. and Triller, P. and Kretzler, L. and R{\"o}nnefarth, M. and Von Kalle, C. and Willich, S. N. and Kurth, F. and Steinbeis, F. and Witzenrath, M. and Bahmer, T. and Hermes, A. and Krawczak, M. and Reinke, L. and Maetzler, C. and Franzenburg, J. and Enderle, J. and Flinspach, A. and Vehreschild, J. and Schons, M. and Illig, T. and Anton, G. and Ungeth{\"u}m, K. and Finkenberg, B. C. and Gehrig, M. T. and Savaskan, N. and Heuschmann, P. U. and Keil, T. and Schreiber, S.}, title = {Long-term health sequelae and quality of life at least 6 months after infection with SARS-CoV-2: design and rationale of the COVIDOM-study as part of the NAPKON population-based cohort platform (POP)}, series = {Infection}, volume = {49}, journal = {Infection}, number = {6}, issn = {0300-8126}, doi = {10.1007/s15010-021-01707-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308960}, pages = {1277-1287}, year = {2021}, abstract = {Purpose Over the course of COVID-19 pandemic, evidence has accumulated that SARS-CoV-2 infections may affect multiple organs and have serious clinical sequelae, but on-site clinical examinations with non-hospitalized samples are rare. We, therefore, aimed to systematically assess the long-term health status of samples of hospitalized and non-hospitalized SARS-CoV-2 infected individuals from three regions in Germany. Methods The present paper describes the COVIDOM-study within the population-based cohort platform (POP) which has been established under the auspices of the NAPKON infrastructure (German National Pandemic Cohort Network) of the national Network University Medicine (NUM). Comprehensive health assessments among SARS-CoV-2 infected individuals are conducted at least 6 months after the acute infection at the study sites Kiel, W{\"u}rzburg and Berlin. Potential participants were identified and contacted via the local public health authorities, irrespective of the severity of the initial infection. A harmonized examination protocol has been implemented, consisting of detailed assessments of medical history, physical examinations, and the collection of multiple biosamples (e.g., serum, plasma, saliva, urine) for future analyses. In addition, patient-reported perception of the impact of local pandemic-related measures and infection on quality-of-life are obtained. Results As of July 2021, in total 6813 individuals infected in 2020 have been invited into the COVIDOM-study. Of these, about 36\% wished to participate and 1295 have already been examined at least once. Conclusion NAPKON-POP COVIDOM-study complements other Long COVID studies assessing the long-term consequences of an infection with SARS-CoV-2 by providing detailed health data of population-based samples, including individuals with various degrees of disease severity. Trial registration Registered at the German registry for clinical studies (DRKS00023742).}, language = {en} } @article{DichtlKocForsteretal.2021, author = {Dichtl, Karl and Koc, {\"O}zlem and Forster, Johannes and Scharf, Christina and Suerbaum, Sebastian and Andrassy, Joachim and Wagener, Johannes and Schroeder, Ines}, title = {An invasive infection caused by the thermophilic mold Talaromyces thermophilus}, series = {Infection}, volume = {49}, journal = {Infection}, number = {6}, issn = {0300-8126}, doi = {10.1007/s15010-021-01648-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308970}, pages = {1347-1353}, year = {2021}, abstract = {Background Increasing incidence of invasive infections caused by rare fungi was observed over the recent years. Case Here, we describe the first reported case of an infection caused by the thermophilic mold Talaromyces thermophilus. Cultivation and, hence, identification of this fastidious organism is challenging since standard incubation conditions are not sufficient. Retrospective analysis of patient samples and in vitro experiments demonstrated that testing for fungal antigens, i.e., the cell wall components galactomannan and β-1,3-D-glucan, is a promising tool.}, language = {en} } @article{PilgramEberweinWilleetal.2021, author = {Pilgram, Lisa and Eberwein, Lukas and Wille, Kai and Koehler, Felix C. and Stecher, Melanie and Rieg, Siegbert and Kielstein, Jan T. and Jakob, Carolin E. M. and R{\"u}thrich, Maria and Burst, Volker and Prasser, Fabian and Borgmann, Stefan and M{\"u}ller, Roman-Ulrich and Lanznaster, Julia and Isberner, Nora and Tometten, Lukas and Dolff, Sebastian}, title = {Clinical course and predictive risk factors for fatal outcome of SARS-CoV-2 infection in patients with chronic kidney disease}, series = {Infection}, volume = {49}, journal = {Infection}, number = {4}, organization = {LEOSS Study group}, issn = {0300-8126}, doi = {10.1007/s15010-021-01597-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308957}, pages = {725-737}, year = {2021}, abstract = {Purpose The ongoing pandemic caused by the novel severe acute respiratory coronavirus 2 (SARS-CoV-2) has stressed health systems worldwide. Patients with chronic kidney disease (CKD) seem to be more prone to a severe course of coronavirus disease (COVID-19) due to comorbidities and an altered immune system. The study's aim was to identify factors predicting mortality among SARS-CoV-2-infected patients with CKD. Methods We analyzed 2817 SARS-CoV-2-infected patients enrolled in the Lean European Open Survey on SARS-CoV-2-infected patients and identified 426 patients with pre-existing CKD. Group comparisons were performed via Chi-squared test. Using univariate and multivariable logistic regression, predictive factors for mortality were identified. Results Comparative analyses to patients without CKD revealed a higher mortality (140/426, 32.9\% versus 354/2391, 14.8\%). Higher age could be confirmed as a demographic predictor for mortality in CKD patients (> 85 years compared to 15-65 years, adjusted odds ratio (aOR) 6.49, 95\% CI 1.27-33.20, p = 0.025). We further identified markedly elevated lactate dehydrogenase (> 2 × upper limit of normal, aOR 23.21, 95\% CI 3.66-147.11, p < 0.001), thrombocytopenia (< 120,000/µl, aOR 11.66, 95\% CI 2.49-54.70, p = 0.002), anemia (Hb < 10 g/dl, aOR 3.21, 95\% CI 1.17-8.82, p = 0.024), and C-reactive protein (≥ 30 mg/l, aOR 3.44, 95\% CI 1.13-10.45, p = 0.029) as predictors, while renal replacement therapy was not related to mortality (aOR 1.15, 95\% CI 0.68-1.93, p = 0.611). Conclusion The identified predictors include routinely measured and universally available parameters. Their assessment might facilitate risk stratification in this highly vulnerable cohort as early as at initial medical evaluation for SARS-CoV-2.}, language = {en} } @article{ElhfnawyElsalamawyAbdelraoufetal.2020, author = {Elhfnawy, Ahmed Mohamed and Elsalamawy, Doaa and Abdelraouf, Mervat and Schliesser, Mira and Volkmann, Jens and Fluri, Felix}, title = {Red flags for a concomitant giant cell arteritis in patients with vertebrobasilar stroke: a cross-sectional study and systematic review}, series = {Acta Neurologica Belgica}, volume = {120}, journal = {Acta Neurologica Belgica}, number = {6}, issn = {0300-9009}, doi = {10.1007/s13760-020-01344-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-315610}, pages = {1389-1398}, year = {2020}, abstract = {Giant cell arteritis (GCA) may affect the brain-supplying arteries, resulting in ischemic stroke, whereby the vertebrobasilar territory is most often involved. Since etiology is unknown in 25\% of stroke patients and GCA is hardly considered as a cause, we examined in a pilot study, whether screening for GCA after vertebrobasilar stroke might unmask an otherwise missed disease. Consecutive patients with vertebrobasilar stroke were prospectively screened for GCA using erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hemoglobin, and halo sign of the temporal and vertebral artery on ultrasound. Furthermore, we conducted a systematic literature review for relevant studies. Sixty-five patients were included, and two patients (3.1\%) were diagnosed with GCA. Patients with GCA were older in age (median 85 versus 69 years, p = 0.02). ESR and CRP were significantly increased and hemoglobin was significantly lower in GCA patients compared to non-GCA patients (median, 75 versus 11 mm in 1 h, p = 0.001; 3.84 versus 0.25 mg/dl, p = 0.01, 10.4 versus 14.6 mg/dl, p = 0.003, respectively). Multiple stenoses/occlusions in the vertebrobasilar territory affected our two GCA patients (100\%), but only five (7.9\%) non-GCA patients (p = 0.01). Our literature review identified 13 articles with 136 stroke patients with concomitant GCA. Those were old in age. Headache, increased inflammatory markers, and anemia were frequently reported. Multiple stenoses/occlusions in the vertebrobasilar territory affected around 70\% of stroke patients with GCA. Increased inflammatory markers, older age, anemia, and multiple stenoses/occlusions in the vertebrobasilar territory may be regarded as red flags for GCA among patients with vertebrobasilar stroke.}, language = {en} } @article{AlbrechtClassenVollstaedtetal.2018, author = {Albrecht, J{\"o}rg and Classen, Alice and Vollst{\"a}dt, Maximilian G.R. and Mayr, Antonia and Mollel, Neduvoto P. and Schellenberger Costa, David and Dulle, Hamadi I. and Fischer, Markus and Hemp, Andreas and Howell, Kim M. and Kleyer, Michael and Nauss, Thomas and Peters, Marcell K. and Tschapka, Marco and Steffan-Dewenter, Ingolf and B{\"o}hning-Gaese, Katrin and Schleuning, Matthias}, title = {Plant and animal functional diversity drive mutualistic network assembly across an elevational gradient}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-05610-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221056}, pages = {1-10}, year = {2018}, abstract = {Species' functional traits set the blueprint for pair-wise interactions in ecological networks. Yet, it is unknown to what extent the functional diversity of plant and animal communities controls network assembly along environmental gradients in real-world ecosystems. Here we address this question with a unique dataset of mutualistic bird-fruit, bird-flower and insect-flower interaction networks and associated functional traits of 200 plant and 282 animal species sampled along broad climate and land-use gradients on Mt. Kilimanjaro. We show that plant functional diversity is mainly limited by precipitation, while animal functional diversity is primarily limited by temperature. Furthermore, shifts in plant and animal functional diversity along the elevational gradient control the niche breadth and partitioning of the respective other trophic level. These findings reveal that climatic constraints on the functional diversity of either plants or animals determine the relative importance of bottom-up and top-down control in plant-animal interaction networks.}, language = {en} } @article{DongKuzmanoskiWehneretal.2017, author = {Dong, Hailong and Kuzmanoski, Ana and Wehner, Tobias and Mueller-Buschbaum, Klaus and Feldmann, Claus}, title = {Microwave-assisted polyol synthesis of water dispersible red-emitting Eu\(^{3+}\)-modified carbon dots}, series = {Materials}, volume = {10}, journal = {Materials}, doi = {10.3390/ma10010025}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181674}, year = {2017}, abstract = {Eu\(^{3+}\)-modified carbon dots (C-dots), 3-5 nm in diameter, were prepared, functionalized, and stabilized via a one-pot polyol synthesis. The role of Eu\(^{2+}\)/Eu\(^{3+}\), the influence of O\(_2\) (oxidation) and H\(_2\)O (hydrolysis), as well as the impact of the heating procedure (conventional resistance heating and microwave (MW) heating) were explored. With the reducing conditions of the polyol at the elevated temperature of synthesis (200-230 °C), first of all, Eu\(^{2+}\) was obtained resulting in the blue emission of the C-dots. Subsequent to O\(_2\)-driven oxidation, Eu\(^{3+}\)-modified, red-emitting C-dots were realized. However, the Eu\(^{3+}\) emission is rapidly quenched by water for C-dots prepared via conventional resistance heating. In contrast to the hydroxyl functionalization of conventionally-heated C-dots, MW-heating results in a carboxylate functionalization of the C-dots. Carboxylate-coordinated Eu\(^{3+}\), however, turned out as highly stable even in water. Based on this fundamental understanding of synthesis and material, in sum, a one-pot polyol approach is established that results in H\(_2\)O-dispersable C-dots with intense red Eu\(^{3+}\)-line-type emission.}, language = {en} } @article{AlbrechtMuellerBallarinietal.2019, author = {Albrecht, Franziska and Mueller, Karsten and Ballarini, Tommaso and Lampe, Leonie and Diehl-Schmid, Janine and Fassbender, Klaus and Fliessbach, Klaus and Jahn, Holger and Jech, Robert and Kassubek, Jan and Kornhuber, Johannes and Landwehrmeyer, Bernhard and Lauer, Martin and Ludolph, Albert C. and Lyros, Epameinondas and Prudlo, Johannes and Schneider, Anja and Synofzik, Matthis and Wiltfang, Jens and Danek, Adrian and Otto, Markus and Schroeter, Matthias L.}, title = {Unraveling corticobasal syndrome and alien limb syndrome with structural brain imaging}, series = {Cortex}, volume = {117}, journal = {Cortex}, doi = {10.1016/j.cortex.2019.02.015}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221040}, pages = {33-40}, year = {2019}, abstract = {Alien limb phenomenon is a rare syndrome associated with a feeling of non-belonging and disowning toward one's limb. In contrast, anarchic limb phenomenon leads to involuntary but goal-directed movements. Alien/anarchic limb phenomena are frequent in corticobasal syndrome (CBS), an atypical parkinsonian syndrome characterized by rigidity, akinesia, dystonia, cortical sensory deficit, and apraxia. The structure function relationship of alien/anarchic limb was investigated in multi centric structural magnetic resonance imaging (MRI) data. Whole-group and single subject comparisons were made in 25 CBS and eight CBS-alien/anarchic limb patients versus controls. Support vector machine was used to see if CBS with and without alien/anarchic limb could be distinguished by structural MRI patterns. Whole-group comparison of CBS versus controls revealed asymmetric frontotemporal atrophy. CBS with alien/anarchic limb syndrome versus controls showed frontoparietal atrophy including the supplementary motor area contralateral to the side of the affected limb. Exploratory analysis identified frontotemporal regions encompassing the pre-/and postcentral gyrus as compromised in CBS with alien limb syndrome. Classification of CBS patients yielded accuracies of 79\%. CBS-alien/anarchic limb syndrome was differentiated from CBS patients with an accuracy of 81\%. Predictive differences were found in the cingulate gyrus spreading to frontomedian cortex, postcentral gyrus, and temporoparietoocipital regions. We present the first MRI-based group analysis on CBS-alien/anarchic limb. Results pave the way for individual clinical syndrome prediction and allow understanding the underlying neurocognitive architecture. (C) 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).}, language = {en} } @misc{Werner2024, type = {Master Thesis}, author = {Werner, Lennart}, title = {Terrain Mapping for Autonomous Navigation of Lunar Rovers}, doi = {10.25972/OPUS-35826}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-358268}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Autonomous mobile robots operating in unknown terrain have to guide their drive decisions through local perception. Local mapping and traversability analysis is essential for safe rover operation and low level locomotion. This thesis deals with the challenge of building a local, robot centric map from ultra short baseline stereo imagery for height and traversability estimation. Several grid-based, incremental mapping algorithms are compared and evaluated in a multi size, multi resolution framework. A new, covariance based mapping update is introduced, which is capable of detecting sub- cellsize obstacles and abstracts the terrain of one cell as a first order surface. The presented mapping setup is capable of producing reliable ter- rain and traversability estimates under the conditions expected for the Cooperative Autonomous Distributed Robotic Exploreration (CADRE) mission. Algorithmic- and software architecture design targets high reliability and efficiency for meeting the tight constraints implied by CADRE's small on-board embedded CPU. Extensive evaluations are conducted to find possible edge-case scenar- ios in the operating envelope of the map and to confirm performance parameters. The research in this thesis targets the CADRE mission, but is applicable to any form of mobile robotics which require height- and traversability mapping.}, subject = {Mondfahrzeug}, language = {en} }