@article{ScognamiglioCabezasWallscheidThieretal.2016, author = {Scognamiglio, Roberta and Cabezas-Wallscheid, Nina and Thier, Marc Christian and Altamura, Sandro and Reyes, Alejandro and Prendergast, {\´A}ine M. and Baumg{\"a}rtner, Daniel and Carnevalli, Larissa S. and Atzberger, Ann and Haas, Simon and von Paleske, Lisa and Boroviak, Thorsten and W{\"o}rsd{\"o}rfer, Philipp and Essers, Marieke A. G. and Kloz, Ulrich and Eisenman, Robert N. and Edenhofer, Frank and Bertone, Paul and Huber, Wolfgang and van der Hoeven, Franciscus and Smith, Austin and Trumpp, Andreas}, title = {Myc depletion induces a pluripotent dormant state mimicking diapause}, series = {Cell}, volume = {164}, journal = {Cell}, number = {4}, doi = {10.1016/j.cell.2015.12.033}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190868}, pages = {668-680}, year = {2016}, abstract = {Mouse embryonic stem cells (ESCs) are maintained in a naive ground state of pluripotency in the presence of MEK and GSK3 inhibitors. Here, we show that ground-state ESCs express low Myc levels. Deletion of both c-myc and N-myc (dKO) or pharmacological inhibition of Myc activity strongly decreases transcription, splicing, and protein synthesis, leading to proliferation arrest. This process is reversible and occurs without affecting pluripotency, suggesting that Myc-depleted stem cells enter a state of dormancy similar to embryonic diapause. Indeed, c-Myc is depleted in diapaused blastocysts, and the differential expression signatures of dKO ESCs and diapaused epiblasts are remarkably similar. Following Myc inhibition, pre-implantation blastocysts enter biosynthetic dormancy but can progress through their normal developmental program after transfer into pseudo-pregnant recipients. Our study shows that Myc controls the biosynthetic machinery of stem cells without affecting their potency, thus regulating their entry and exit from the dormant state.}, language = {en} } @article{MrestaniPauliKollmannsbergeretal.2021, author = {Mrestani, Achmed and Pauli, Martin and Kollmannsberger, Philip and Repp, Felix and Kittel, Robert J. and Eilers, Jens and Doose, S{\"o}ren and Sauer, Markus and Sir{\´e}n, Anna-Leena and Heckmann, Manfred and Paul, Mila M.}, title = {Active zone compaction correlates with presynaptic homeostatic potentiation}, series = {Cell Reports}, volume = {37}, journal = {Cell Reports}, number = {1}, doi = {10.1016/j.celrep.2021.109770}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265497}, pages = {109770}, year = {2021}, abstract = {Neurotransmitter release is stabilized by homeostatic plasticity. Presynaptic homeostatic potentiation (PHP) operates on timescales ranging from minute- to life-long adaptations and likely involves reorganization of presynaptic active zones (AZs). At Drosophila melanogaster neuromuscular junctions, earlier work ascribed AZ enlargement by incorporating more Bruchpilot (Brp) scaffold protein a role in PHP. We use localization microscopy (direct stochastic optical reconstruction microscopy [dSTORM]) and hierarchical density-based spatial clustering of applications with noise (HDBSCAN) to study AZ plasticity during PHP at the synaptic mesoscale. We find compaction of individual AZs in acute philanthotoxin-induced and chronic genetically induced PHP but unchanged copy numbers of AZ proteins. Compaction even occurs at the level of Brp subclusters, which move toward AZ centers, and in Rab3 interacting molecule (RIM)-binding protein (RBP) subclusters. Furthermore, correlative confocal and dSTORM imaging reveals how AZ compaction in PHP translates into apparent increases in AZ area and Brp protein content, as implied earlier.}, language = {en} } @article{HeiligFaerberPauletal.2022, author = {Heilig, Philipp and Faerber, Lars-Christopher and Paul, Mila M. and Kupczyk, Eva and Meffert, Rainer H. and Jordan, Martin C. and Hoelscher-Doht, Stefanie}, title = {Plate osteosynthesis combined with bone cement provides the highest stability for tibial head depression fractures under high loading conditions}, series = {Scientific Reports}, volume = {12}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-022-19107-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-299782}, year = {2022}, abstract = {Older patients sustaining tibial head depression fractures often cannot follow the post-operative rehabilitation protocols with partial weight-bearing of the affected limb, leading to osteosynthesis failure, cartilage step-off and arthritis development. Therefore, the aim of this study was to analyse the biomechanical performance of different types of osteosyntheses alone and in combination with bone cement simulating cyclically high loading conditions of tibial head depression fractures. Lateral tibial head depression fractures (AO: 41-B2.2; Schatzker type III) were created in synthetic bones and stabilized using three different osteosyntheses alone and in combination with a commonly used bone cement (chronOS™): 2 screws, 4 screws in the jail technique and a lateral angle-stable buttress plate. After fixation, the lateral tibial plateau was axially loaded in two, from each other independent testing series: In the first test protocol, 5000 cycles with 500 N and in the end load-to-failure tests were performed. In the second test protocol, the cyclic loading was increased to 1000 N. Parameters of interest were the displacement of the articular fracture fragment, the stiffness and the maximum load. The osteosyntheses revealed a higher stiffness in combination with bone cement compared to the same type of osteosynthesis alone (e.g., 500 N level: 2 screws 383 ± 43 N/mm vs. 2 screws + chronOs 520 ± 108 N/mm, increase by 36\%, p < 0.01; 4 screws 368 ± 97 N/mm vs. 4 screws + chronOS 516 ± 109 N/mm, increase by 40\%, p < 0.01; plate: 509 ± 73 N/mm vs. plate + chronOs 792 ± 150 N/mm, increase by 56\%, p < 0.01). Bone cement reduced the displacement of the plate significantly (500 N level: plate: 8.9 ± 2.8 mm vs. plate + chronOs: 3.1 ± 1.4 mm, reduction by 65\%, p < 0.01; 1000 N level: 16.9 ± 3.6 mm vs 5.6 ± 1.3 mm, reduction by 67\%, p < 0.01). Thus, the highest stiffness and lowest displacement values were found when using the plate with bone cement in both loading conditions (500 N level: 2 screws + chronOs 3.7 ± 1.3 mm, 4 screws + chronOs 6.2 ± 2.4 mm; 1000 N level: 2 screws + chronOs 6.5 ± 1.2 mm, 4 screws + chronOs 5.7 ± 0.8 mm). From a biomechanical perspective, plate osteosynthesis of tibial head depression fractures should always be combined with bone cement, provides higher stability than 2-screw and 4-screw fixation and is a valid treatment option in cases where extraordinary stability is required.}, language = {en} } @article{JordanHufnagelMcDonoghetal.2022, author = {Jordan, Martin C. and Hufnagel, Lukas and McDonogh, Miriam and Paul, Mila M. and Schmalzl, Jonas and Kupczyk, Eva and Jansen, Hendrik and Heilig, Philipp and Meffert, Rainer H. and Hoelscher-Doht, Stefanie}, title = {Surgical fixation of calcaneal beak fractures — biomechanical analysis of different osteosynthesis techniques}, series = {Frontiers in Bioengineering and Biotechnology}, volume = {10}, journal = {Frontiers in Bioengineering and Biotechnology}, issn = {2296-4185}, doi = {10.3389/fbioe.2022.896790}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-282792}, year = {2022}, abstract = {The calcaneal beak fracture is a rare avulsion fracture of the tuber calcanei characterized by a solid bony fragment at the Achilles tendon insertion. Treatment usually requires osteosynthesis. However, lack of biomechanical understanding of the ideal fixation technique persists. A beak fracture was simulated in synthetic bones and assigned to five different groups of fixation: A) 6.5-mm partial threaded cannulated screws, B) 4.0-mm partial threaded cannulated screws, C) 5.0-mm headless cannulated compression screws, D) 2.3-mm locking plate, and E) 2.8-mm locking plate. Different traction force levels were applied through an Achilles tendon surrogate in a material-testing machine on all stabilized synthetic bones. Outcome measures were peak-to-peak displacement, total displacement, plastic deformation, stiffness, visual-fracture-line displacement, and mode of implant failure. The 2.3- and 2.8-mm plating groups showed a high drop-out rate at 100 N tension force and failed under higher tension levels of 200 N. The fracture fixation using 4.0-mm partial threaded screws showed a significantly higher repair strength and was able to withhold cyclic loading up to 300 N. The lowest peak-to-peak displacement and the highest load-to-failure and stiffness were provided by fracture fixation using 6.5-mm partial threaded cannulated screws or 5.0-mm headless cannulated compression screws. As anticipated, large 6.5-mm screw diameters provide the best biomechanical fixation. Surprisingly, the 5.0-mm headless cannulated compression screws yield reliable stability despite the absent screw head and washer. When such large screws cannot be applied, 4.0-mm screws also allow reasonable fixation strength. Plate fixation should be implemented with precaution and in combination with a restrictive postoperative motion protocol. Finally, clinical cases about the surgical application and recovery are included.}, language = {en} } @article{ZieglerEhlisWeberetal.2021, author = {Ziegler, Georg C. and Ehlis, Ann-Christine and Weber, Heike and Vitale, Maria Rosaria and Z{\"o}ller, Johanna E. M. and Ku, Hsing-Ping and Schiele, Miriam A. and K{\"u}rbitz, Laura I. and Romanos, Marcel and Pauli, Paul and Kalisch, Raffael and Zwanzger, Peter and Domschke, Katharina and Fallgatter, Andreas J. and Reif, Andreas and Lesch, Klaus-Peter}, title = {A Common CDH13 Variant is Associated with Low Agreeableness and Neural Responses to Working Memory Tasks in ADHD}, series = {Genes}, volume = {12}, journal = {Genes}, number = {9}, issn = {2073-4425}, doi = {10.3390/genes12091356}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245220}, year = {2021}, abstract = {The cell—cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.}, language = {en} } @article{ScheerVokuhlBlanketal.2019, author = {Scheer, Monika and Vokuhl, Christian and Blank, Bernd and Hallmen, Erika and von Kalle, Thekla and M{\"u}nter, Marc and Wessalowski, R{\"u}diger and Hartwig, Maite and Sparber-Sauer, Monika and Schlegel, Paul-Gerhardt and Kramm, Christof M. and Kontny, Udo and Spriewald, Bernd and Kegel, Thomas and Bauer, Sebastian and Kazanowska, Bernarda and Niggli, Felix and Ladenstein, Ruth and Ljungman, Gustaf and Jahnukainen, Kirsi and Fuchs, J{\"o}rg and Bielack, Stefan S. and Klingebiel, Thomas and Koscielniak, Ewa}, title = {Desmoplastic small round cell tumors: Multimodality treatment and new risk factors}, series = {Cancer Medicine}, volume = {8}, journal = {Cancer Medicine}, number = {2}, doi = {10.1002/cam4.1940}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228444}, pages = {527-545}, year = {2019}, abstract = {Background To evaluate optimal therapy and potential risk factors. Methods Data of DSRCT patients <40 years treated in prospective CWS trials 1997-2015 were analyzed. Results Median age of 60 patients was 14.5 years. Male:female ratio was 4:1. Tumors were abdominal/retroperitoneal in 56/60 (93\%). 6/60 (10\%) presented with a localized mass, 16/60 (27\%) regionally disseminated nodes, and 38/60 (63\%) with extraperitoneal metastases. At diagnosis, 23/60 (38\%) patients had effusions, 4/60 (7\%) a thrombosis, and 37/54 (69\%) elevated CRP. 40/60 (67\%) patients underwent tumor resection, 21/60 (35\%) macroscopically complete. 37/60 (62\%) received chemotherapy according to CEVAIE (ifosfamide, vincristine, actinomycin D, carboplatin, epirubicin, etoposide), 15/60 (25\%) VAIA (ifosfamide, vincristine, adriamycin, actinomycin D) and, 5/60 (8\%) P6 (cyclophosphamide, doxorubicin, vincristine, ifosfamide, etoposide). Nine received high-dose chemotherapy, 6 received regional hyperthermia, and 20 received radiotherapy. Among 25 patients achieving complete remission, 18 (72\%) received metronomic therapies. Three-year event-free (EFS) and overall survival (OS) were 11\% (±8 confidence interval [CI] 95\%) and 30\% (±12 CI 95\%), respectively, for all patients and 26.7\% (±18.0 CI 95\%) and 56.9\% (±20.4 CI 95\%) for 25 patients achieving remission. Extra-abdominal site, localized disease, no effusion or ascites only, absence of thrombosis, normal CRP, complete tumor resection, and chemotherapy with VAIA correlated with EFS in univariate analysis. In multivariate analysis, significant factors were no thrombosis and chemotherapy with VAIA. In patients achieving complete remission, metronomic therapy with cyclophosphamide/vinblastine correlated with prolonged time to relapse. Conclusion Pleural effusions, venous thrombosis, and CRP elevation were identified as potential risk factors. The VAIA scheme showed best outcome. Maintenance therapy should be investigated further.}, language = {en} } @article{BonigKuciKucietal.2019, author = {Bonig, Halvard and Ku{\c{c}}i, Zyrafete and Ku{\c{c}}i, Selim and Bakhtiar, Shahrzad and Basu, Oliver and Bug, Gesine and Dennis, Mike and Greil, Johann and Barta, Aniko and K{\´a}llay, Kriszti{\´a}n M. and Lang, Peter and Lucchini, Giovanna and Pol, Raj and Schulz, Ansgar and Sykora, Karl-Walter and Teichert von Luettichau, Irene and Herter-Sprie, Grit and Ashab Uddin, Mohammad and Jenkin, Phil and Alsultan, Abdulrahman and Buechner, Jochen and Stein, Jerry and Kelemen, Agnes and Jarisch, Andrea and Soerensen, Jan and Salzmann-Manrique, Emilia and Hutter, Martin and Sch{\"a}fer, Richard and Seifried, Erhard and Paneesha, Shankara and Novitzky-Basso, Igor and Gefen, Aharon and Nevo, Neta and Beutel, Gernot and Schlegel, Paul-Gerhardt and Klingebiel, Thomas and Bader, Peter}, title = {Children and adults with Refractory acute Graft-versus-Host Disease respond to treatment with the Mesenchymal Stromal cell preparation "MSC-FFM"—Outcome report of 92 patients}, series = {Cells}, volume = {8}, journal = {Cells}, number = {12}, issn = {2073-4409}, doi = {10.3390/cells8121577}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193878}, pages = {1577}, year = {2019}, abstract = {(1) Background: Refractory acute graft-versus-host disease (R-aGvHD) remains a leading cause of death after allogeneic stem cell transplantation. Survival rates of 15\% after four years are currently achieved; deaths are only in part due to aGvHD itself, but mostly due to adverse effects of R-aGvHD treatment with immunosuppressive agents as these predispose patients to opportunistic infections and loss of graft-versus-leukemia surveillance resulting in relapse. Mesenchymal stromal cells (MSC) from different tissues and those generated by various protocols have been proposed as a remedy for R-aGvHD but the enthusiasm raised by initial reports has not been ubiquitously reproduced. (2) Methods: We previously reported on a unique MSC product, which was generated from pooled bone marrow mononuclear cells of multiple third-party donors. The products showed dose-to-dose equipotency and greater immunosuppressive capacity than individually expanded MSCs from the same donors. This product, MSC-FFM, has entered clinical routine in Germany where it is licensed with a national hospital exemption authorization. We previously reported satisfying initial clinical outcomes, which we are now updating. The data were collected in our post-approval pharmacovigilance program, i.e., this is not a clinical study and the data is high-level and non-monitored. (3) Results: Follow-up for 92 recipients of MSC-FFM was reported, 88 with GvHD ≥°III, one-third only steroid-refractory and two-thirds therapy resistant (refractory to steroids plus ≥2 additional lines of treatment). A median of three doses of MSC-FFM was administered without apparent toxicity. Overall response rates were 82\% and 81\% at the first and last evaluation, respectively. At six months, the estimated overall survival was 64\%, while the cumulative incidence of death from underlying disease was 3\%. (4) Conclusions: MSC-FFM promises to be a safe and efficient treatment for severe R-aGvHD.}, language = {en} } @article{MieszczanekRobinsonDaltonetal.2021, author = {Mieszczanek, Pawel and Robinson, Thomas M. and Dalton, Paul D. and Hutmacher, Dietmar W.}, title = {Convergence of Machine Vision and Melt Electrowriting}, series = {Advanced Materials}, volume = {33}, journal = {Advanced Materials}, number = {29}, doi = {10.1002/adma.202100519}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-256365}, year = {2021}, abstract = {Melt electrowriting (MEW) is a high-resolution additive manufacturing technology that balances multiple parametric variables to arrive at a stable fabrication process. The better understanding of this balance is underscored here using high-resolution camera vision of jet stability profiles in different electrical fields. Complementing this visual information are fiber-diameter measurements obtained at precise points, allowing the correlation to electrified jet properties. Two process signatures—the jet angle and for the first time, the Taylor cone area—are monitored and analyzed with a machine vision system, while SEM imaging for diameter measurement correlates real-time information. This information, in turn, allows the detection and correction of fiber pulsing for accurate jet placement on the collector, and the in-process assessment of the fiber diameter. Improved process control is used to successfully fabricate collapsible MEW tubes; structures that require exceptional accuracy and printing stability. Using a precise winding angle of 60° and 300 layers, the resulting 12 mm-thick tubular structures have elastic snap-through instabilities associated with mechanical metamaterials. This study provides a detailed analysis of the fiber pulsing occurrence in MEW and highlights the importance of real-time monitoring of the Taylor cone volume to better understand, control, and predict printing instabilities.}, language = {en} } @article{PauliPaulProppertetal.2021, author = {Pauli, Martin and Paul, Mila M. and Proppert, Sven and Mrestani, Achmed and Sharifi, Marzieh and Repp, Felix and K{\"u}rzinger, Lydia and Kollmannsberger, Philip and Sauer, Markus and Heckmann, Manfred and Sir{\´e}n, Anna-Leena}, title = {Targeted volumetric single-molecule localization microscopy of defined presynaptic structures in brain sections}, series = {Communications Biology}, volume = {4}, journal = {Communications Biology}, doi = {10.1038/s42003-021-01939-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259830}, pages = {407}, year = {2021}, abstract = {Revealing the molecular organization of anatomically precisely defined brain regions is necessary for refined understanding of synaptic plasticity. Although three-dimensional (3D) single-molecule localization microscopy can provide the required resolution, imaging more than a few micrometers deep into tissue remains challenging. To quantify presynaptic active zones (AZ) of entire, large, conditional detonator hippocampal mossy fiber (MF) boutons with diameters as large as 10 mu m, we developed a method for targeted volumetric direct stochastic optical reconstruction microscopy (dSTORM). An optimized protocol for fast repeated axial scanning and efficient sequential labeling of the AZ scaffold Bassoon and membrane bound GFP with Alexa Fluor 647 enabled 3D-dSTORM imaging of 25 mu m thick mouse brain sections and assignment of AZs to specific neuronal substructures. Quantitative data analysis revealed large differences in Bassoon cluster size and density for distinct hippocampal regions with largest clusters in MF boutons. Pauli et al. develop targeted volumetric dSTORM in order to image large hippocampal mossy fiber boutons (MFBs) in brain slices. They can identify synaptic targets of individual MFBs and measured size and density of Bassoon clusters within individual untruncated MFBs at nanoscopic resolution.}, language = {en} } @article{RobinsonHutmacherDalton2019, author = {Robinson, Thomas M. and Hutmacher, Dietmar W. and Dalton, Paul D.}, title = {The next frontier in melt electrospinning: taming the jet}, series = {Advanced Functional Materials}, volume = {29}, journal = {Advanced Functional Materials}, doi = {10.1002/adfm.201904664}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204819}, pages = {1904664}, year = {2019}, abstract = {There is a specialized niche for the electrohydrodynamic jetting of melts, from biomedical products to filtration and soft matter applications. The next frontier includes optics, microfluidics, flexible electronic devices, and soft network composites in biomaterial science and soft robotics. The recent emphasis on reproducibly direct-writing continual molten jets has enabled a spectrum of contemporary microscale 3D objects to be fabricated. One strong suit of melt processing is the capacity for the jet to solidify rapidly into a fiber, thus fixing a particular structure into position. The ability to direct-write complex and multiscaled architectures and structures has greatly contributed to a large number of recent studies, explicitly, toward fiber-hydrogel composites and fugitive inks, and has expanded into several biomedical applications such as cartilage, skin, periosteum, and cardiovascular tissue engineering. Following the footsteps of a publication that summarized melt electrowriting literature up to 2015, the most recent literature from then until now is reviewed to provide a continuous and comprehensive timeline that demonstrates the latest advances as well as new perspectives for this emerging technology.}, language = {en} } @article{GoreLocatelliZugmaieretal.2018, author = {Gore, Lia and Locatelli, Franco and Zugmaier, Gerhard and Handgretinger, Rupert and O'Brien, Maureen M. and Bader, Peter and Bhojwani, Deepa and Schlegel, Paul-Gerhardt and Tuglus, Catherine A. and Stackelberg, Arend von}, title = {Survival after blinatumomab treatment in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia}, series = {Blood Cancer Journal}, volume = {8}, journal = {Blood Cancer Journal}, doi = {10.1038/s41408-018-0117-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230726}, year = {2018}, abstract = {no abstract available}, language = {en} } @article{HinesMaricHinesetal.2018, author = {Hines, Rochelle M. and Maric, Hans Michael and Hines, Dustin J. and Modgil, Amit and Panzanelli, Patrizia and Nakamura, Yasuko and Nathanson, Anna J. and Cross, Alan and Deeb, Tarek and Brandon, Nicholas J. and Davies, Paul and Fritschy, Jean-Marc and Schindelin, Hermann and Moss, Stephen J.}, title = {Developmental seizures and mortality result from reducing GABAA receptor α2-subunit interaction with collybistin}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-05481-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320719}, year = {2018}, abstract = {Fast inhibitory synaptic transmission is mediated by γ-aminobutyric acid type A receptors (GABAARs) that are enriched at functionally diverse synapses via mechanisms that remain unclear. Using isothermal titration calorimetry and complementary methods we demonstrate an exclusive low micromolar binding of collybistin to the α2-subunit of GABAARs. To explore the biological relevance of collybistin-α2-subunit selectivity, we generate mice with a mutation in the α2-subunit-collybistin binding region (Gabra2-1). The mutation results in loss of a distinct subset of inhibitory synapses and decreased amplitude of inhibitory synaptic currents. Gabra2-1 mice have a striking phenotype characterized by increased susceptibility to seizures and early mortality. Surviving Gabra2-1 mice show anxiety and elevations in electroencephalogram δ power, which are ameliorated by treatment with the α2/α3-selective positive modulator, AZD7325. Taken together, our results demonstrate an α2-subunit selective binding of collybistin, which plays a key role in patterned brain activity, particularly during development.}, language = {en} } @article{KrahBuentgenSchaeferetal.2019, author = {Krah, Franz-Sebastian and B{\"u}ntgen, Ulf and Schaefer, Hanno and M{\"u}ller, J{\"o}rg and Andrew, Carrie and Boddy, Lynne and Diez, Jeffrey and Egli, Simon and Freckleton, Robert and Gange, Alan C. and Halvorsen, Rune and Heegaard, Einar and Heideroth, Antje and Heibl, Christoph and Heilmann-Clausen, Jacob and H{\o}iland, Klaus and Kar, Ritwika and Kauserud, H{\aa}vard and Kirk, Paul M. and Kuyper, Thomas W. and Krisai-Greilhuber, Irmgard and Norden, Jenni and Papastefanou, Phillip and Senn-Irlet, Beatrice and B{\"a}ssler, Claus}, title = {European mushroom assemblages are darker in cold climates}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-10767-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224815}, year = {2019}, abstract = {Thermal melanism theory states that dark-colored ectotherm organisms are at an advantage at low temperature due to increased warming. This theory is generally supported for ectotherm animals, however, the function of colors in the fungal kingdom is largely unknown. Here, we test whether the color lightness of mushroom assemblages is related to climate using a dataset of 3.2 million observations of 3,054 species across Europe. Consistent with the thermal melanism theory, mushroom assemblages are significantly darker in areas with cold climates. We further show differences in color phenotype between fungal lifestyles and a lifestyle differentiated response to seasonality. These results indicate a more complex ecological role of mushroom colors and suggest functions beyond thermal adaption. Because fungi play a crucial role in terrestrial carbon and nutrient cycles, understanding the links between the thermal environment, functional coloration and species' geographical distributions will be critical in predicting ecosystem responses to global warming.}, language = {en} } @article{LuebckeEbbersVolzkeetal.2019, author = {L{\"u}bcke, Paul M. and Ebbers, Meinolf N. B. and Volzke, Johann and Bull, Jana and Kneitz, Susanne and Engelmann, Robby and Lang, Hermann and Kreikemeyer, Bernd and M{\"u}ller-Hilke, Brigitte}, title = {Periodontal treatment prevents arthritis in mice and methotrexate ameliorates periodontal bone loss}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-44512-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237355}, year = {2019}, abstract = {Recent studies indicate a causal relationship between the periodontal pathogen P. gingivalis and rheumatoid arthritis involving the production of autoantibodies against citrullinated peptides. We therefore postulated that therapeutic eradication P. gingivalis may ameliorate rheumatoid arthritis development and here turned to a mouse model in order to challenge our hypothesis. F1 (DBA/1 x B10.Q) mice were orally inoculated with P. gingivalis before collagen-induced arthritis was provoked. Chlorhexidine or metronidazole were orally administered either before or during the induction phase of arthritis and their effects on arthritis progression and alveolar bone loss were compared to intraperitoneally injected methotrexate. Arthritis incidence and severity were macroscopically scored and alveolar bone loss was evaluated via microcomputed tomography. Serum antibody titres against P. gingivalis were quantified by ELISA and microbial dysbiosis following oral inoculation was monitored in stool samples via microbiome analyses. Both, oral chlorhexidine and metronidazole reduced the incidence and ameliorated the severity of collagen-induced arthritis comparable to methotrexate. Likewise, all three therapies attenuated alveolar bone loss. Relative abundance of Porphyromonadaceae was increased after oral inoculation with P. gingivalis and decreased after treatment. This is the first study to describe beneficial effects of non-surgical periodontal treatment on collagen-induced arthritis in mice and suggests that mouthwash with chlorhexidine or metronidazole may also be beneficial for patients with rheumatoid arthritis and a coexisting periodontitis. Methotrexate ameliorated periodontitis in mice, further raising the possibility that methotrexate may also positively impact on the tooth supporting tissues of patients with rheumatoid arthritis.}, language = {en} } @article{SchmittEckardtSchlegeletal.2015, author = {Schmitt, Jessica and Eckardt, Sigrid and Schlegel, Paul G and Sir{\´e}n, Anna-Leena and Bruttel, Valentin S and McLaughlin, K John and Wischhusen, J{\"o}rg and M{\"u}ller, Albrecht M}, title = {Human parthenogenetic embryonic stem cell-derived neural stem cells express HLA-G and show unique resistance to NK cell-mediated killing}, series = {Molecular Medicine}, volume = {21}, journal = {Molecular Medicine}, number = {2101185}, doi = {10.2119/molmed.2014.00188}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149170}, pages = {185-196}, year = {2015}, abstract = {Parent-of-origin imprints have been implicated in the regulation of neural differentiation and brain development. Previously we have shown that, despite the lack of a paternal genome, human parthenogenetic (PG) embryonic stem cells (hESCs) can form proliferating neural stem cells (NSCs) that are capable of differentiation into physiologically functional neurons while maintaining allele-specific expression of imprinted genes. Since biparental ("normal") hESC-derived NSCs (N NSCs) are targeted by immune cells, we characterized the immunogenicity of PG NSCs. Flow cytometry and immunocytochemistry revealed that both N NSCs and PG NSCs exhibited surface expression of human leukocyte antigen (HLA) class I but not HLA-DR molecules. Functional analyses using an in vitro mixed lymphocyte reaction assay resulted in less proliferation of peripheral blood mononuclear cells (PBMC) with PG compared with N NSCs. In addition, natural killer (NK) cells cytolyzed PG less than N NSCs. At a molecular level, expression analyses of immune regulatory factors revealed higher HLA-G levels in PG compared with N NSCs. In line with this finding, MIR152, which represses HLA-G expression, is less transcribed in PG compared with N cells. Blockage of HLA-G receptors ILT2 and KIR2DL4 on natural killer cell leukemia (NKL) cells increased cytolysis of PG NSCs. Together this indicates that PG NSCs have unique immunological properties due to elevated HLA-G expression.}, language = {en} }