@article{LeopoldZeilbeckWeberetal.2017, author = {Leopold, Stephanie A. and Zeilbeck, Ludwig F. and Weber, Gregor and Seitz, Roswitha and B{\"o}sl, Michael R. and J{\"a}gle, Herbert and Fuchshofer, Rudolf and Tamm, Ernst R. and Ohlmann, Andreas}, title = {Norrin protects optic nerve axons from degeneration in a mouse model of glaucoma}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, doi = {10.1038/s41598-017-14423-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173494}, year = {2017}, abstract = {Norrin is a secreted signaling molecule activating the Wnt/β-catenin pathway. Since Norrin protects retinal neurons from experimental acute injury, we were interested to learn if Norrin attenuates chronic damage of retinal ganglion cells (RGC) and their axons in a mouse model of glaucoma. Transgenic mice overexpressing Norrin in the retina (Pax6-Norrin) were generated and crossed with DBA/2J mice with hereditary glaucoma and optic nerve axonal degeneration. One-year old DBA/2J/Pax6-Norrin animals had significantly more surviving optic nerve axons than their DBA/2J littermates. The protective effect correlated with an increase in insulin-like growth factor (IGF)-1 mRNA and an enhanced Akt phosphorylation in DBA/2J/Pax6-Norrin mice. Both mouse strains developed an increase in intraocular pressure during the second half of the first year and marked degenerative changes in chamber angle, ciliary body and iris structure. The degenerations were slightly attenuated in the chamber angle of DBA/2J/Pax6-Norrin mice, which showed a β-catenin increase in the trabecular meshwork. We conclude that high levels of Norrin and the subsequent constitutive activation of Wnt/β-catenin signaling in RGC protect from glaucomatous axonal damage via IGF-1 causing increased activity of PI3K-Akt signaling. Our results identify components of a protective signaling network preventing degeneration of optic nerve axons in glaucoma.}, language = {en} } @article{LavyshSokolovaSlashchevaetal.2017, author = {Lavysh, Daria and Sokolova, Maria and Slashcheva, Marina and F{\"o}rstner, Konrad U. and Severinov, Konstantin}, title = {Transcription profiling of "bacillus subtilis" cells infected with AR9, a giant phage encoding two multisubunit RNA polymerases}, series = {mBio}, volume = {8}, journal = {mBio}, number = {1}, doi = {10.1128/mBio.02041-16}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181810}, year = {2017}, abstract = {Bacteriophage AR9 is a recently sequenced jumbo phage that encodes two multisubunit RNA polymerases. Here we investigated the AR9 transcription strategy and the effect of AR9 infection on the transcription of its host, Bacillus subtilis. Analysis of whole-genome transcription revealed early, late, and continuously expressed AR9 genes. Alignment of sequences upstream of the 5′ ends of AR9 transcripts revealed consensus sequences that define early and late phage promoters. Continuously expressed AR9 genes have both early and late promoters in front of them. Early AR9 transcription is independent of protein synthesis and must be determined by virion RNA polymerase injected together with viral DNA. During infection, the overall amount of host mRNAs is significantly decreased. Analysis of relative amounts of host transcripts revealed notable differences in the levels of some mRNAs. The physiological significance of up- or downregulation of host genes for AR9 phage infection remains to be established. AR9 infection is significantly affected by rifampin, an inhibitor of host RNA polymerase transcription. The effect is likely caused by the antibiotic-induced killing of host cells, while phage genome transcription is solely performed by viral RNA polymerases.}, language = {en} } @article{LapaSchrederSchirbeletal.2017, author = {Lapa, Constantin and Schreder, Martin and Schirbel, Andreas and Samnick, Samuel and Kort{\"u}m, Klaus Martin and Herrmann, Ken and Kropf, Saskia and Einsele, Herrmann and Buck, Andreas K. and Wester, Hans-J{\"u}rgen and Knop, Stefan and L{\"u}ckerath, Katharina}, title = {[\(^{68}\)Ga]Pentixafor-PET/CT for imaging of chemokine receptor CXCR4 expression in multiple myeloma - comparison to [\(^{18}\)F]FDG and laboratory values}, series = {Theranostics}, volume = {7}, journal = {Theranostics}, number = {1}, doi = {10.7150/thno.16576}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172106}, pages = {205-212}, year = {2017}, abstract = {Chemokine (C-X-C motif) receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer including multiple myeloma (MM). Proof-of-concept of CXCR4-directed radionuclide therapy in MM has recently been reported. This study assessed the diagnostic performance of the CXCR4-directed radiotracer [\(^{68}\)Ga]Pentixafor in MM and a potential role for stratifying patients to CXCR4-directed therapies. Thirty-five patients with MM underwent [\(^{68}\)Ga]Pentixafor-PET/CT for evaluation of eligibility for endoradiotherapy. In 19/35 cases, [\(^{18}\)F]FDG-PET/CT for correlation was available. Scans were compared on a patient and on a lesion basis. Tracer uptake was correlated with standard clinical parameters of disease activity. [\(^{68}\)Ga]Pentixafor-PET detected CXCR4-positive disease in 23/35 subjects (66\%). CXCR4-positivity at PET was independent from myeloma subtypes, cytogenetics or any serological parameters and turned out as a negative prognostic factor. In the 19 patients in whom a comparison to [\(^{18}\)F]FDG was available, [\(^{68}\)Ga]Pentixafor-PET detected more lesions in 4/19 (21\%) subjects, [\(^{18}\)F]FDG proved superior in 7/19 (37\%). In the remaining 8/19 (42\%) patients, both tracers detected an equal number of lesions. [\(^{18}\)F]FDG-PET positivity correlated with [\(^{68}\)Ga]Pentixafor-PET positivity (p=0.018). [\(^{68}\)Ga]Pentixafor-PET provides further evidence that CXCR4 expression frequently occurs in advanced multiple myeloma, representing a negative prognostic factor and a potential target for myeloma specific treatment. However, selecting patients for CXCR4 directed therapies and prognostic stratification seem to be more relevant clinical applications for this novel imaging modality, rather than diagnostic imaging of myeloma.}, language = {en} } @article{LapaKircherSchirbeletal.2017, author = {Lapa, Constantin and Kircher, Stefan and Schirbel, Andreas and Rosenwald, Andreas and Kropf, Saskia and Pelzer, Theo and Walles, Thorsten and Buck, Andreas K. and Weber, Wolfgang A. and Wester, Hans-Juergen and Herrmann, Ken and L{\"u}ckerath, Katharina}, title = {Targeting CXCR4 with [\(^{68}\)Ga]Pentixafor: a suitable theranostic approach in pleural mesothelioma?}, series = {Oncotarget}, volume = {8}, journal = {Oncotarget}, number = {57}, doi = {10.18632/oncotarget.18235}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-169989}, pages = {96732-96737}, year = {2017}, abstract = {C-X-C motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. This study investigated the feasibility of CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using [\(^{68}\)Ga]Pentixafor in malignant pleural mesothelioma. Six patients with pleural mesothelioma underwent [\(^{68}\)Ga]Pentixafor-PET/CT. 2′-[\(^{18}\)F]fluoro-2′-deoxy-D-glucose ([\(^{18}\)F]FDG)-PET/CT (4/6 patients) and immunohistochemistry obtained from biopsy or surgery (all) served as standards of reference. Additionally, 9 surgical mesothelioma samples were available for histological work-up. Whereas [\(^{18}\)F]FDG-PET depicted active lesions in all patients, [\(^{68}\)Ga]Pentixafor-PET/CT recorded physiologic tracer distribution and none of the 6 patients presented [\(^{68}\)Ga]Pentixafor-positive lesions. This finding paralleled results of immunohistochemistry which also could not identify relevant CXCR4 surface expression in the samples analyzed. In contrast to past reports, our data suggest widely absence of CXCR4 expression in pleural mesothelioma. Hence, robust cell surface expression should be confirmed prior to targeting this chemokine receptor for diagnosis and/or therapy.}, language = {en} } @article{LapaHerrmannSchirbeletal.2017, author = {Lapa, Constantin and Herrmann, Ken and Schirbel, Andreas and H{\"a}nscheid, Heribert and L{\"u}ckerath, Katharina and Schottelius, Margret and Kircher, Malte and Werner, Rudolf A. and Schreder, Martin and Samnick, Samuel and Kropf, Saskia and Knop, Stefan and Buck, Andreas K. and Einsele, Hermann and Wester, Hans-Juergen and Kort{\"u}m, K. Martin}, title = {CXCR4-directed endoradiotherapy induces high response rates in extramedullary relapsed multiple myeloma}, series = {Theranostics}, volume = {7}, journal = {Theranostics}, number = {6}, doi = {10.7150/thno.19050}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172095}, pages = {1589-1597}, year = {2017}, abstract = {C-X-C-motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. We have recently reported promising first-in-man experience with CXCR4-directed endoradiotherapy (ERT) in multiple myeloma (MM). Eight heavily pretreated MM patients underwent a total of 10 ERT cycles (7 patients with 1 cycle and a single patient with 3 cycles). ERT was administered in combination with chemotherapy and autologous stem cell support. End points were occurrence and timing of adverse events, progression-free and overall survival. ERT was overall well tolerated without any unexpected acute adverse events or changes in vital signs. With absorbed tumor doses >30-70 Gy in intra- or extramedullary lesions, significant anti-myeloma activity was observed with 1 patient achieving complete remission and 5/8 partial remission. Directly after ERT major infectious complications were seen in one patient who died from sepsis 22 days after ERT, another patient with high tumor burden experienced lethal tumor lysis syndrome. Median progression-free survival was 54 days (range, 13-175), median overall survival was 223 days (range, 13-313). During follow-up (6 patients available), one patient died from infectious complications, 2/8 from disease progression, the remaining 3/8 patients are still alive. CXCR4-directed ERT was well-tolerated and exerted anti-myeloma activity even at very advanced stage MM with presence of extramedullary disease. Further assessment of this novel treatment option is highly warranted.}, language = {en} } @article{LapaGarciaVellosoLueckerathetal.2017, author = {Lapa, Constantin and Garcia-Velloso, Maria J. and L{\"u}ckerath, Katharina and Samnick, Samuel and Schreder, Martin and Otero, Paula Rodriguez and Schmid, Jan-Stefan and Herrmann, Ken and Knop, Stefan and Buck, Andreas K. and Einsele, Hermann and San-Miguel, Jesus and Kort{\"u}m, Klaus Martin}, title = {\(^{11}\)C-methionine-PET in multiple myeloma: a combined study from two different institutions}, series = {Theranostics}, volume = {7}, journal = {Theranostics}, number = {11}, doi = {10.7150/thno.20491}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172038}, pages = {2956-2964}, year = {2017}, abstract = {\(^{11}\)C-methionine (MET) has recently emerged as an accurate marker of tumor burden and disease activity in patients with multiple myeloma (MM). This dual-center study aimed at further corroboration of the superiority of MET as positron emission tomography (PET) tracer for staging and re-staging MM, as compared to \(^{18}\)F-2`-deoxy-2`-fluoro-D-glucose (FDG). 78 patients with a history of solitary plasmacytoma (n=4), smoldering MM (SMM, n=5), and symptomatic MM (n=69) underwent both MET- and FDG-PET/computed tomography (CT) at the University Centers of W{\"u}rzburg, Germany and Navarra, Spain. Scans were compared on a patient and on a lesion basis. Inter-reader agreement was also evaluated. In 2 patients, tumor biopsies for verification of discordant imaging results were available. MET-PET detected focal lesions (FL) in 59/78 subjects (75.6\%), whereas FDG-PET/CT showed lesions in only 47 patients (60.3\%; p<0.01), accordingly disease activity would have been missed in 12 patients. Directed biopsies of discordant results confirmed MET-PET/CT results in both cases. MET depicted more FL in 44 patients (56.4\%; p<0.01), whereas in two patients (2/78), FDG proved superior. In the remainder (41.0\%, 32/78), both tracers yielded comparable results. Inter-reader agreement for MET was higher than for FDG (κ = 0.82 vs κ = 0.72). This study demonstrates higher sensitivity of MET in comparison to standard FDG to detect intra- and extramedullary MM including histologic evidence of FDG-negative, viable disease exclusively detectable by MET-PET/CT. MET holds the potential to replace FDG as functional imaging standard for staging and re-staging of MM.}, language = {en} } @article{LapaAriasLozaHayakawaetal.2017, author = {Lapa, Constantin and Arias-Loza, Paula and Hayakawa, Nobuyuki and Wakabayashi, Hiroshi and Werner, Rudolf A. and Chen, Xinyu and Shinaji, Tetsuya and Herrmann, Ken and Pelzer, Theo and Higuchi, Takahiro}, title = {Whitening and impaired glucose utilization of brown adipose tissue in a rat model of type 2 diabetes mellitus}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, doi = {10.1038/s41598-017-17148-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159066}, pages = {16795}, year = {2017}, abstract = {Brown adipose tissue (BAT) is an attractive therapeutic target to combat diabetes and obesity due to its ability to increase glucose expenditure. In a genetic rat model (ZDF fa/fa) of type-2 diabetes and obesity, we aimed to investigate glucose utilization of BAT by \(^{18}\)F-FDG PET imaging. Male Zucker diabetic fatty (ZDF) and Male Zucker lean (ZL) control rats were studied at 13 weeks. Three weeks prior to imaging, ZDF rats were randomized into a no-restriction (ZDF-ND) and a mild calorie restriction (ZDF-CR) group. Dynamic \(^{18}\)F-FDG PET using a dedicated small animal PET system was performed under hyperinsulinemic-euglycemic clamp. \(^{18}\)F-FDG PET identified intense inter-scapular BAT glucose uptake in all ZL control rats, while no focally increased \(^{18}\)F-FDG uptake was detected in all ZDF-ND rats. Mild but significant improved BAT tracer uptake was identified after calorie restriction in diabetic rats (ZDF-CR). The weight of BAT tissue and fat deposits were significantly increased in ZDF-CR and ZDF-ND rats as compared to ZL controls, while UCP-1 and mitochondrial concentrations were significantly decreased. Whitening and severely impaired insulin-stimulated glucose uptake in BAT was confirmed in a rat model of type-2 diabetes. Additionally, calorie restriction partially restored the impaired BAT glucose uptake.}, language = {en} } @article{LandmannHennigIgnat'evetal.2017, author = {Landmann, Johannes and Hennig, Philipp T. and Ignat'ev, Nikolai V. and Finze, Maik}, title = {Borylation of fluorinated arenes using the boron centred nucleophile B(CN)\(_{3}\)\(^{2-}\) - a unique entry to aryltricyanoborates}, series = {Chemical Science}, volume = {8}, journal = {Chemical Science}, number = {9}, doi = {10.1039/c7sc02249b}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170417}, pages = {5962-5968}, year = {2017}, abstract = {The potassium salt of the boron-centred nucleophile B(CN)\(_{3}\)\(^{2-}\)(1) readily reacts with perfluorinated arenes, such as hexafluorobenzene, decafluorobiphenyl, octafluoronaphthalene and pentafluoropyridine, which results in KF and the K\(^{+}\) salts of the respective borate anions with one {B(CN)\(_{3}\)} unit bonded to the (hetero)arene. An excess of K\(_{2}\)1 leads to the successive reaction of two or, in the case of perfluoropyridine, even three C-F moieties and the formation of di- and trianions, respectively. Moreover, all of the 11 partially fluorinated benzene derivatives, C\(_{6}\)F\(_{6-n}\)H\(_{n}\) (n = 1-5), generally react with K\(_{2}\)1 to give new tricyano(phenyl)borate anions with high chemo- and regioselectivity. A decreasing number of fluorine substituents on benzene results in a decrease in the reaction rate. In the cases of partially fluorinated benzenes, the addition of LiCl is advantageous or even necessary to facilitate the reaction. Also, pentafluorobenzenes R-C\(_{6}\)F\(_{5}\) (R = -CN, -OMe, -Me, or -CF\(_{3}\)) react via C-F/C-B exchange that mostly occurs in the para position and to a lesser extent in the meta or ortho positions. Most of the reactions proceed via an S\(_{N}\)Ar mechanism. The reaction of 1,4-F\(_{2}\)C\(_{6}\)H\(_{4}\) with K\(_{2}\)1 shows that an aryne mechanism has to be considered in some cases as well. In summary, a wealth of new stable tricyano(aryl)borates have been synthesised and fully characterized using multi-NMR spectroscopy and most of them were characterised using single-crystal X-ray diffraction.}, language = {en} } @article{LamazeOeztuerkColakFischeretal.2017, author = {Lamaze, Angelique and {\"O}zt{\"u}rk-{\c{C}}olak, Arzu and Fischer, Robin and Peschel, Nicolai and Koh, Kyunghee and Jepson, James E. C.}, title = {Regulation of sleep plasticity by a thermo-sensitive circuit in Drosophila}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, doi = {10.1038/srep40304}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181146}, pages = {12}, year = {2017}, abstract = {Sleep is a highly conserved and essential behaviour in many species, including the fruit fly Drosophila melanogaster. In the wild, sensory signalling encoding environmental information must be integrated with sleep drive to ensure that sleep is not initiated during detrimental conditions. However, the molecular and circuit mechanisms by which sleep timing is modulated by the environment are unclear. Here we introduce a novel behavioural paradigm to study this issue. We show that in male fruit flies, onset of the daytime siesta is delayed by ambient temperatures above 29°C. We term this effect Prolonged Morning Wakefulness (PMW). We show that signalling through the TrpA1 thermo-sensor is required for PMW, and that TrpA1 specifically impacts siesta onset, but not night sleep onset, in response to elevated temperatures. We identify two critical TrpA1-expressing circuits and show that both contact DN1p clock neurons, the output of which is also required for PMW. Finally, we identify the circadian blue-light photoreceptor CRYPTOCHROME as a molecular regulator of PMW, and propose a model in which the Drosophila nervous system integrates information encoding temperature, light, and time to dynamically control when sleep is initiated. Our results provide a platform to investigate how environmental inputs co-ordinately regulate sleep plasticity.}, language = {en} } @article{LaglerElMeseryKuebleretal.2017, author = {Lagler, Charlotte and El-Mesery, Mohamed and K{\"u}bler, Alexander Christian and M{\"u}ller-Richter, Urs Dietmar Achim and St{\"u}hmer, Thorsten and Nickel, Joachim and M{\"u}ller, Thomas Dieter and Wajant, Harald and Seher, Axel}, title = {The anti-myeloma activity of bone morphogenetic protein 2 predominantly relies on the induction of growth arrest and is apoptosis-independent}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {10}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158993}, pages = {e0185720}, year = {2017}, abstract = {Multiple myeloma (MM), a malignancy of the bone marrow, is characterized by a pathological increase in antibody-producing plasma cells and an increase in immunoglobulins (plasmacytosis). In recent years, bone morphogenetic proteins (BMPs) have been reported to be activators of apoptotic cell death in neoplastic B cells in MM. Here, we use bone morphogenetic protein 2 (BMP2) to show that the "apoptotic" effect of BMPs on human neoplastic B cells is dominated by anti-proliferative activities and cell cycle arrest and is apoptosis-independent. The anti-proliferative effect of BMP2 was analysed in the human cell lines KMS12-BM and L363 using WST-1 and a Coulter counter and was confirmed using CytoTox assays with established inhibitors of programmed cell death (zVAD-fmk and necrostatin-1). Furthermore, apoptotic activity was compared in both cell lines employing western blot analysis for caspase 3 and 8 in cells treated with BMP2 and FasL. Additionally, expression profiles of marker genes of different cell death pathways were analysed in both cell lines after stimulation with BMP2 for 48h using an RT-PCR-based array. In our experiments we observed that there was rather no reduction in absolute cell number, but cells stopped proliferating following treatment with BMP2 instead. The time frame (48-72 h) after BMP2 treatment at which a reduction in cell number is detectable is too long to indicate a directly BMP2-triggered apoptosis. Moreover, in comparison to robust apoptosis induced by the approved apoptotic factor FasL, BMP2 only marginally induced cell death. Consistently, neither the known inhibitor of apoptotic cell death zVAD-fmk nor the necroptosis inhibitor necrostatin-1 was able to rescue myeloma cell growth in the presence of BMP2.}, language = {en} } @article{KoepingShehataDielerCebullaetal.2017, author = {K{\"o}ping, Maria and Shehata-Dieler, Wafaa and Cebulla, Mario and Rak, Kristen and Oder, Daniel and M{\"u}ntze, Jonas and Nordbeck, Peter and Wanner, Christoph and Hagen, Rudolf and Schraven, Sebastian}, title = {Cardiac and renal dysfunction is associated with progressive hearing loss in patients with Fabry disease}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {11}, doi = {10.1371/journal.pone.0188103}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-169961}, pages = {e0188103}, year = {2017}, abstract = {Background Fabry disease (FD) is an X-linked recessive hereditary lysosomal storage disorder which results in the accumulation of globotriaosylceramid (Gb3) in tissues of kidney and heart as well as central and peripheral nervous system. Besides prominent renal and cardiac organ involvement, cochlear symptoms like high-frequency hearing loss and tinnitus are frequently found with yet no comprehensive data available in the literature. Objective To examine hearing loss in patients with FD depending on cardiac and renal function. Material and methods Single-center study with 68 FD patients enrolled between 2012 and 2016 at the Department of Oto-Rhino-Laryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery of the University of W{\"u}rzburg. Every subject underwent an oto-rhino-laryngological examination as well as behavioral, electrophysiological and electroacoustical audiological testing. High-frequency thresholds were evaluated by using a modified PTA\(_{6}\) (0.5, 1, 2, 4, 6, 8) and HF-PTA (6, 8 kHz). Renal function was measured by eGFR, cardiac impairment was graduated by NYHA class. Results Sensorineural hearing loss was detected in 58.8\% of the cohort, which occurred typically in sudden episodes and affected especially high frequencies. Hearing loss is asymmetric, beginning unilaterally and affecting the contralateral ear later. Tinnitus was reported by 41.2\%. Renal and cardiac impairment influenced the severity of hearing loss (p < 0.05). Conclusions High frequency hearing loss is a common problem in patients with FD. Although not life-threatening, it can seriously reduce quality of life and should be taken into account in diagnosis and therapy. Optimized extensive hearing assessment including higher frequency thresholds should be used.}, language = {en} } @article{KaethnerHalderHintermuelleretal.2017, author = {K{\"a}thner, Ivo and Halder, Sebastian and Hinterm{\"u}ller, Christoph and Espinosa, Arnau and Guger, Christoph and Miralles, Felip and Vargiu, Eloisa and Dauwalder, Stefan and Rafael-Palou, Xavier and Sol{\`a}, Marc and Daly, Jean M. and Armstrong, Elaine and Martin, Suzanne and K{\"u}bler, Andrea}, title = {A Multifunctional Brain-Computer Interface Intended for Home Use: An Evaluation with Healthy Participants and Potential End Users with Dry and Gel-Based Electrodes}, series = {Frontiers in Neuroscience}, volume = {11}, journal = {Frontiers in Neuroscience}, number = {286}, doi = {10.3389/fnins.2017.00286}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157925}, year = {2017}, abstract = {Current brain-computer interface (BCIs) software is often tailored to the needs of scientists and technicians and therefore complex to allow for versatile use. To facilitate home use of BCIs a multifunctional P300 BCI with a graphical user interface intended for non-expert set-up and control was designed and implemented. The system includes applications for spelling, web access, entertainment, artistic expression and environmental control. In addition to new software, it also includes new hardware for the recording of electroencephalogram (EEG) signals. The EEG system consists of a small and wireless amplifier attached to a cap that can be equipped with gel-based or dry contact electrodes. The system was systematically evaluated with a healthy sample, and targeted end users of BCI technology, i.e., people with a varying degree of motor impairment tested the BCI in a series of individual case studies. Usability was assessed in terms of effectiveness, efficiency and satisfaction. Feedback of users was gathered with structured questionnaires. Two groups of healthy participants completed an experimental protocol with the gel-based and the dry contact electrodes (N = 10 each). The results demonstrated that all healthy participants gained control over the system and achieved satisfactory to high accuracies with both gel-based and dry electrodes (average error rates of 6 and 13\%). Average satisfaction ratings were high, but certain aspects of the system such as the wearing comfort of the dry electrodes and design of the cap, and speed (in both groups) were criticized by some participants. Six potential end users tested the system during supervised sessions. The achieved accuracies varied greatly from no control to high control with accuracies comparable to that of healthy volunteers. Satisfaction ratings of the two end-users that gained control of the system were lower as compared to healthy participants. The advantages and disadvantages of the BCI and its applications are discussed and suggestions are presented for improvements to pave the way for user friendly BCIs intended to be used as assistive technology by persons with severe paralysis.}, language = {en} } @article{KuznetsovAlmuzzainiKritikouetal.2017, author = {Kuznetsov, Nikolai V. and Almuzzaini, Bader and Kritikou, Joanna S. and Baptista, Marisa A. P. and Oliveira, Mariana M. S. and Keszei, Marton and Snapper, Scott B. and Percipalle, Piergiorgio and Westerberg, Lisa S.}, title = {Nuclear Wiskott-Aldrich syndrome protein co-regulates T cell factor 1-mediated transcription in T cells}, series = {Genome Medicine}, volume = {9}, journal = {Genome Medicine}, doi = {10.1186/s13073-017-0481-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173486}, year = {2017}, abstract = {Background The Wiskott-Aldrich syndrome protein (WASp) family of actin-nucleating factors are present in the cytoplasm and in the nucleus. The role of nuclear WASp for T cell development remains incompletely defined. Methods We performed WASp chromatin immunoprecipitation and deep sequencing (ChIP-seq) in thymocytes and spleen CD4\(^+\) T cells. Results WASp was enriched at genic and intergenic regions and associated with the transcription start sites of protein-coding genes. Thymocytes and spleen CD4\(^+\) T cells showed 15 common WASp-interacting genes, including the gene encoding T cell factor (TCF)12. WASp KO thymocytes had reduced nuclear TCF12 whereas thymocytes expressing constitutively active WASp\(^{L272P}\) and WASp\(^{I296T}\) had increased nuclear TCF12, suggesting that regulated WASp activity controlled nuclear TCF12. We identify a putative DNA element enriched in WASp ChIP-seq samples identical to a TCF1-binding site and we show that WASp directly interacted with TCF1 in the nucleus. Conclusions These data place nuclear WASp in proximity with TCF1 and TCF12, essential factors for T cell development.}, language = {en} } @article{KunzGoettlichWallesetal.2017, author = {Kunz, Meik and G{\"o}ttlich, Claudia and Walles, Thorsten and Nietzer, Sarah and Dandekar, Gudrun and Dandekar, Thomas}, title = {MicroRNA-21 versus microRNA-34: Lung cancer promoting and inhibitory microRNAs analysed in silico and in vitro and their clinical impact}, series = {Tumor Biology}, volume = {39}, journal = {Tumor Biology}, number = {7}, doi = {10.1177/1010428317706430}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158399}, year = {2017}, abstract = {MicroRNAs are well-known strong RNA regulators modulating whole functional units in complex signaling networks. Regarding clinical application, they have potential as biomarkers for prognosis, diagnosis, and therapy. In this review, we focus on two microRNAs centrally involved in lung cancer progression. MicroRNA-21 promotes and microRNA-34 inhibits cancer progression. We elucidate here involved pathways and imbed these antagonistic microRNAs in a network of interactions, stressing their cancer microRNA biology, followed by experimental and bioinformatics analysis of such microRNAs and their targets. This background is then illuminated from a clinical perspective on microRNA-21 and microRNA-34 as general examples for the complex microRNA biology in lung cancer and its diagnostic value. Moreover, we discuss the immense potential that microRNAs such as microRNA-21 and microRNA-34 imply by their broad regulatory effects. These should be explored for novel therapeutic strategies in the clinic.}, language = {en} } @article{KrsticHerrmannGadjanskietal.2017, author = {Krstic, Jelena and Herrmann, Marietta and Gadjanski, Ivana and Mojsilovic, Slavko}, title = {Editorial: Microenvironment-derived stem cell plasticity}, series = {Frontiers in Cell and Developmental Biology}, volume = {5}, journal = {Frontiers in Cell and Developmental Biology}, issn = {2296-634X}, doi = {10.3389/fcell.2017.00082}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197424}, year = {2017}, abstract = {No abstract available.}, language = {en} } @article{KrohnMoltAlawiFoerstneretal.2017, author = {Krohn-Molt, Ines and Alawi, Malik and F{\"o}rstner, Konrad U. and Wiegandt, Alena and Burkhardt, Lia and Indenbirken, Daniela and Thieß, Melanie and Grundhoff, Adam and Kehr, Julia and Tholey, Andreas and Streit, Wolfgang R.}, title = {Insights into microalga and bacteria interactions of selected phycosphere biofilms using metagenomic, transcriptomic, and proteomic approaches}, series = {Frontiers in Microbiology}, volume = {2017}, journal = {Frontiers in Microbiology}, number = {8}, doi = {10.3389/fmicb.2017.01941}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173701}, year = {2017}, abstract = {Microalga are of high relevance for the global carbon cycling and it is well-known that they are associated with a microbiota. However, it remains unclear, if the associated microbiota, often found in phycosphere biofilms, is specific for the microalga strains and which role individual bacterial taxa play. Here we provide experimental evidence that \(Chlorella\) \(saccharophila\), \(Scenedesmus\) \(quadricauda\), and \(Micrasterias\) \(crux-melitensis\), maintained in strain collections, are associated with unique and specific microbial populations. Deep metagenome sequencing, binning approaches, secretome analyses in combination with RNA-Seq data implied fundamental differences in the gene expression profiles of the microbiota associated with the different microalga. Our metatranscriptome analyses indicates that the transcriptionally most active bacteria with respect to key genes commonly involved in plant-microbe interactions in the Chlorella (Trebouxiophyceae) and Scenedesmus (Chlorophyceae) strains belong to the phylum of the α-Proteobacteria. In contrast, in the Micrasterias (Zygnematophyceae) phycosphere biofilm bacteria affiliated with the phylum of the Bacteroidetes showed the highest gene expression rates. We furthermore show that effector molecules known from plant-microbe interactions as inducers for the innate immunity are already of relevance at this evolutionary early plant-microbiome level.}, language = {en} } @article{KredelKunzmannSchlegeletal.2017, author = {Kredel, Markus and Kunzmann, Steffen and Schlegel, Paul-Gerhardt and W{\"o}lfl, Matthias and Nordbeck, Peter and B{\"u}hler, Christoph and Lotz, Christopher and Lepper, Philipp M. and Wirbelauer, Johannes and Roewer, Norbert and Muellenbach, Ralf M.}, title = {Double Peripheral Venous and Arterial Cannulation for Extracorporeal Membrane Oxygenation in Combined Septic and Cardiogenic Shock}, series = {American Journal of Case Reports}, volume = {18}, journal = {American Journal of Case Reports}, doi = {10.12659/AJCR.902485}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158193}, pages = {723-727}, year = {2017}, abstract = {Background: The use of venoarterial extracorporeal membrane oxygenation (va-ECMO) via peripheral cannulation for septic shock is limited by blood flow and increased afterload for the left ventricle. Case Report: A 15-year-old girl with acute myelogenous leukemia, suffering from severe septic and cardiogenic shock, was treated by venoarterial extracorporeal membrane oxygenation (va-ECMO). Sufficient extracorporeal blood flow matching the required oxygen demand could only be achieved by peripheral cannulation of both femoral arteries. Venous drainage was performed with a bicaval cannula inserted via the left V. femoralis. To accomplish left ventricular unloading, an additional drainage cannula was placed in the left atrium via percutaneous atrioseptostomy (va-va-ECMO). Cardiac function recovered and the girl was weaned from the ECMO on day 6. Successful allogenic stem cell transplantation took place 2 months later. Conclusions: In patients with vasoplegic septic shock and impaired cardiac contractility, double peripheral venoarterial extracorporeal membrane oxygenation (va-va-ECMO) with transseptal left atrial venting can by a lifesaving option.}, language = {en} } @article{Kramer2017, author = {Kramer, Susanne}, title = {The ApaH-like phosphatase TbALPH1 is the major mRNA decapping enzyme of trypanosomes}, series = {PLoS Pathogens}, volume = {13}, journal = {PLoS Pathogens}, number = {6}, doi = {10.1371/journal.ppat.1006456}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158482}, pages = {e1006456}, year = {2017}, abstract = {5'-3' decay is the major mRNA decay pathway in many eukaryotes, including trypanosomes. After deadenylation, mRNAs are decapped by the nudix hydrolase DCP2 of the decapping complex and finally degraded by the 5'-3' exoribonuclease. Uniquely, trypanosomes lack homologues to all subunits of the decapping complex, while deadenylation and 5'-3' degradation are conserved. Here, I show that the parasites use an ApaH-like phosphatase (ALPH1) as their major mRNA decapping enzyme. The protein was recently identified as a novel trypanosome stress granule protein and as involved in mRNA binding. A fraction of ALPH1 co-localises exclusively with the trypanosome 5'-3' exoribonuclease XRNA to a special granule at the posterior pole of the cell, indicating a connection between the two enzymes. RNAi depletion of ALPH1 is lethal and causes a massive increase in total mRNAs that are deadenylated, but have not yet started 5'-3' decay. These data suggest that ALPH1 acts downstream of deadenylation and upstream of mRNA degradation, consistent with a function in mRNA decapping. In vitro experiments show that recombinant, N-terminally truncated ALHP1 protein, but not a catalytically inactive mutant, sensitises the capped trypanosome spliced leader RNA to yeast Xrn1, but only if an RNA 5' polyphosphatase is included. This indicates that the decapping mechanism of ALPH1 differs from the decapping mechanism of Dcp2 by leaving more than one phosphate group at the mRNA's 5' end. This is the first reported function of a eukaryotic ApaH-like phosphatase, a bacterial-derived class of enzymes present in all phylogenetic super-groups of the eukaryotic kingdom. The substrates of eukaryotic ApaH-like phosphatases are unknown. However, the substrate of the related bacterial enzyme ApaH, diadenosine tetraphosphate, is highly reminiscent of a eukaryotic mRNA cap.}, language = {en} } @article{Kraft2017, author = {Kraft, Stephan}, title = {Wider den „Hauffen junger Schnautzhahnen" : Grimmelshausens Versuch, die Erinnerung an den Dreißigj{\"a}hrigen Krieg in der Gegenwart festzuhalten}, series = {Internationales Archiv f{\"u}r Sozialgeschichte der deutschen Literatur}, volume = {42}, journal = {Internationales Archiv f{\"u}r Sozialgeschichte der deutschen Literatur}, number = {1}, issn = {1865-9128}, doi = {10.1515/iasl-2017-0005}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193938}, pages = {122-134}, year = {2017}, abstract = {This paper retraces the specific conception of the 'present' as manifested in Satyrischer Pilgram, Grimmelshausen's first published work. In the face of progressively vanishing consciousness of the past terrors of the Thirty Years' War, the Pilgram devises a program for bringing the experience of a whole generation to the present, thereby saving it for the future. Instead of delivering a general reflection on the nature of war, it suggests to narrate individually experienced "particularities." It is crucial that all of these experiences are negative, not meant to prompt imitation, but instead rather to build and keep up a stronghold against attitudes and actions of the past.}, language = {de} } @article{Kraft2017, author = {Kraft, Stephan}, title = {Vom Kopf auf die F{\"u}ße gestellt, auf dass die Welt kopfsteht. B{\"u}rgerliches Trauerspiel und Kom{\"o}die in Karl von Holteis Trauerspiel in Berlin und Johann Nestroys Die verh{\"a}ngnißvolle Faschings-Nacht}, series = {Nestroyana}, volume = {37}, journal = {Nestroyana}, publisher = {Lehner}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-257900}, pages = {39-50}, year = {2017}, abstract = {Kein Abstract verf{\"u}gbar.}, language = {de} } @article{KraftSchuhmannGarzetal.2017, author = {Kraft, Peter and Schuhmann, Michael K. and Garz, Cornelia and Jandke, Solveig and Urlaub, Daniela and Mencl, Stine and Zernecke, Alma and Heinze, Hans-Jochen and Carare, Roxana O. and Kleinschnitz, Christoph and Schreiber, Stefanie}, title = {Hypercholesterolemia induced cerebral small vessel disease}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {8}, doi = {10.1371/journal.pone.0182822}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170493}, pages = {e0182822}, year = {2017}, abstract = {Background While hypercholesterolemia plays a causative role for the development of ischemic stroke in large vessels, its significance for cerebral small vessel disease (CSVD) remains unclear. We thus aimed to understand the detailed relationship between hypercholesterolemia and CSVD using the well described Ldlr\(^{-/-}\) mouse model. Methods We used Ldlr\(^{-/-}\) mice (n = 16) and wild-type (WT) mice (n = 15) at the age of 6 and 12 months. Ldlr\(^{-/-}\) mice develop high plasma cholesterol levels following a high fat diet. We analyzed cerebral capillaries and arterioles for intravascular erythrocyte accumulations, thrombotic vessel occlusions, blood-brain barrier (BBB) dysfunction and microbleeds. Results We found a significant increase in the number of erythrocyte stases in 6 months old Ldlr\(^{-/-}\) mice compared to all other groups (P < 0.05). Ldlr\(^{-/-}\) animals aged 12 months showed the highest number of thrombotic occlusions while in WT animals hardly any occlusions could be observed (P < 0.001). Compared to WT mice, Ldlr\(^{-/-}\) mice did not display significant gray matter BBB breakdown. Microhemorrhages were observed in one Ldlr\(^{-/-}\) mouse that was 6 months old. Results did not differ when considering subcortical and cortical regions. Conclusions In Ldlr\(^{-/-}\) mice, hypercholesterolemia is related to a thrombotic CSVD phenotype, which is different from hypertension-related CSVD that associates with a hemorrhagic CSVD phenotype. Our data demonstrate a relationship between hypercholesterolemia and the development of CSVD. Ldlr\(^{-/-}\) mice appear to be an adequate animal model for research into CSVD.}, language = {en} } @article{KraftFleischerWiedmannetal.2017, author = {Kraft, Peter and Fleischer, Anna and Wiedmann, Silke and R{\"u}cker, Viktoria and Mackenrodt, Daniel and Morbach, Caroline and Malzahn, Uwe and Kleinschnitz, Christoph and St{\"o}rk, Stefan and Heuschmann, Peter U.}, title = {Feasibility and diagnostic accuracy of point-of-care handheld echocardiography in acute ischemic stroke patients - a pilot study}, series = {BMC Neurology}, volume = {17}, journal = {BMC Neurology}, number = {159}, doi = {10.1186/s12883-017-0937-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158081}, year = {2017}, abstract = {Background: Standard echocardiography (SE) is an essential part of the routine diagnostic work-up after ischemic stroke (IS) and also serves for research purposes. However, access to SE is often limited. We aimed to assess feasibility and accuracy of point-of-care (POC) echocardiography in a stroke unit (SU) setting. Methods: IS patients were recruited on the SU of the University Hospital W{\"u}rzburg, Germany. Two SU team members were trained in POC echocardiography for a three-month period to assess a set of predefined cardiac parameters including left ventricular ejection fraction (LVEF). Diagnostic agreement was assessed by comparing POC with SE executed by an expert sonographer, and intraclass correlation coefficient (ICC) or kappa (κ) with 95\% confidence intervals (95\% CI) were calculated. Results: In the 78 patients receiving both POC and SE agreement for cardiac parameters was good, with ICC varying from 0.82 (95\% CI 0.71-0.89) to 0.93 (95\% CI 0.87-0.96), and κ from 0.39 (-95\% CI 0.14-0.92) to 0.79 (95\% CI 0.67-0.91). Detection of systolic dysfunction with POC echocardiography compared to SE was very good, with an area under the curve of 0.99 (0.96-1.00). Interrater agreement for LVEF measured by POC echocardiography was good with κ 0.63 (95\% CI 0.40-0.85). Conclusions: POC echocardiography in a SU setting is feasible enabling reliable quantification of LVEF and preliminary assessment of selected cardiac parameters that might be used for research purposes. Its potential clinical utility in triaging stroke patients who should undergo or do not necessarily require SE needs to be investigated in larger prospective diagnostic studies.}, language = {en} } @article{KraftStanglKrauseetal.2017, author = {Kraft, Andreas and Stangl, Johannes and Krause, Ana-Maria and M{\"u}ller-Buschbaum, Klaus and Beuerle, Florian}, title = {Supramolecular frameworks based on [60]fullerene hexakisadducts}, series = {Beilstein Journal of Organic Chemistry}, volume = {13}, journal = {Beilstein Journal of Organic Chemistry}, doi = {10.3762/bjoc.13.1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171996}, pages = {1-9}, year = {2017}, abstract = {[60]Fullerene hexakisadducts possessing 12 carboxylic acid side chains form crystalline hydrogen-bonding frameworks in the solid state. Depending on the length of the linker between the reactive sites and the malonate units, the distance of the [60]fullerene nodes and thereby the spacing of the frameworks can be controlled and for the most elongated derivative, continuous channels are obtained within the structure. Stability, structural integrity and porosity of the material were investigated by powder X-ray diffraction, thermogravimetry and sorption measurements.}, language = {en} } @article{KollmannsbergerKerschnitzkiReppetal.2017, author = {Kollmannsberger, Philip and Kerschnitzki, Michael and Repp, Felix and Wagermaier, Wolfgang and Weinkamer, Richard and Fratzl, Peter}, title = {The small world of osteocytes: connectomics of the lacuno-canalicular network in bone}, series = {New Journal of Physics}, volume = {19}, journal = {New Journal of Physics}, number = {073019}, doi = {10.1088/1367-2630/aa764b}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170662}, year = {2017}, abstract = {Osteocytes and their cell processes reside in a large, interconnected network of voids pervading the mineralized bone matrix of most vertebrates. This osteocyte lacuno-canalicular network (OLCN) is believed to play important roles in mechanosensing, mineral homeostasis, and for the mechanical properties of bone. While the extracellular matrix structure of bone is extensively studied on ultrastructural and macroscopic scales, there is a lack of quantitative knowledge on how the cellular network is organized. Using a recently introduced imaging and quantification approach, we analyze the OLCN in different bone types from mouse and sheep that exhibit different degrees of structural organization not only of the cell network but also of the fibrous matrix deposited by the cells. We define a number of robust, quantitative measures that are derived from the theory of complex networks. These measures enable us to gain insights into how efficient the network is organized with regard to intercellular transport and communication. Our analysis shows that the cell network in regularly organized, slow-growing bone tissue from sheep is less connected, but more efficiently organized compared to irregular and fast-growing bone tissue from mice. On the level of statistical topological properties (edges per node, edge length and degree distribution), both network types are indistinguishable, highlighting that despite pronounced differences at the tissue level, the topological architecture of the osteocyte canalicular network at the subcellular level may be independent of species and bone type. Our results suggest a universal mechanism underlying the self-organization of individual cells into a large, interconnected network during bone formation and mineralization.}, language = {en} } @article{KohlmorgenEliasSchoen2017, author = {Kohlmorgen, Britta and Elias, Johannes and Schoen, Christoph}, title = {Improved performance of the artus Mycobacterium tuberculosis RG PCR kit in a low incidence setting: a retrospective monocentric study}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, number = {14127}, doi = {10.1038/s41598-017-14367-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159248}, year = {2017}, abstract = {Tuberculosis (TB) and the spread of Mycobacterium tuberculosis complex (MTBC) strains resistant against rifampin (RIF) and isoniazid (INH) pose a serious threat to global health. However, rapid and reliable MTBC detection along with RIF/INH susceptibility testing are challenging in low prevalence countries due to the higher rate of false positives. Here, we provide the first performance data for the artus MTBC PCR assay in a low prevalence setting. We analyze 1323 respiratory and 311 non-respiratory samples with the artus MTBC PCR assay as well as by mycobacterial culture and microscopy. We propose retesting of specimens in duplicate and consideration of a determined cycle-threshold value cut-off greater than 34, as this significantly increases accuracy, specificity, and negative predictive value without affecting sensitivity. Furthermore, we tested fourteen MTBC positive samples with the GenoType MTBDRplus test and demonstrate that using an identical DNA extraction protocol for both assays does not impair downstream genotypic testing for RIF and INH susceptibility. In conclusion, our procedure optimizes the use of the artus MTB assay with workload efficient methods in a low incidence setting. Combining the modified artus MTB with the GenoType MTBDRplus assays allows rapid and accurate detection of MTBC and RIF/INH resistance.}, language = {en} } @article{KoesslerSchwarzWeberetal.2017, author = {Koessler, Juergen and Schwarz, Michaela and Weber, Katja and Etzel, Julia and Koessler, Angela and Boeck, Markus and Kobsar, Anna}, title = {The role of adenosine diphosphate mediated platelet responsiveness for the stability of platelet integrity in citrated whole blood under ex vivo conditions}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {11}, doi = {10.1371/journal.pone.0188193}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159879}, pages = {e0188193}, year = {2017}, abstract = {Background: Platelets are important for effective hemostasis and considered to be involved in pathophysiological processes, e.g. in cardiovascular diseases. Platelets provided for research or for therapeutic use are frequently separated from citrated whole blood (WB) stored for different periods of time. Although functionally intact platelets are required, the stability of platelet integrity, e.g. adenosine diphosphate (ADP) mediated responsiveness, has never been thoroughly investigated in citrated WB under ex vivo conditions. Objectives: Platelet integrity was evaluated at different time points in citrated WB units, collected from healthy donors and stored for 5 days at ambient temperature. The analysis included the measurement of activation markers, of induced light transmission aggregometry and of purinergic receptor expression or function. Inhibitory pathways were explored by determination of basal vasodilator-stimulated phosphoprotein (VASP)-phosphorylation, intracellular cyclic nucleotide levels and the content of phosphodiesterase 5A. Fresh peripheral blood (PB) samples served as controls. Results: On day 5 of storage, thrombin receptor activating peptide-6 (TRAP-6) stimulated CD62P expression and fibrinogen binding were comparable to PB samples. ADP induced aggregation continuously decreased during storage. Purinergic receptor expression remained unchanged, whereas the P2Y1 activity progressively declined in contrast to preserved P2Y12 and P2X1 function. Inhibitory pathways were unaffected except for a slight elevation of VASP phosphorylation at Ser\(^{239}\) on day 5. Conclusion: After 5 days of storage in citrated WB, platelet responsiveness to TRAP-6 is sufficiently maintained. However, ADP-mediated platelet integrity is more sensitive to deterioration, especially after storage for more than 2 days. Decreasing ADP-induced aggregation is particularly caused by the impairment of the purinergic receptor P2Y1 activity. These characteristics should be considered in the use of platelets from stored citrated WB for experimental or therapeutic issues.}, language = {en} } @article{KoenigerKuerten2017, author = {Koeniger, Tobias and Kuerten, Stefanie}, title = {Splitting the "unsplittable": Dissecting resident and infiltrating macrophages in experimental autoimmune encephalomyelitis}, series = {International Journal of Molecular Sciences}, volume = {18}, journal = {International Journal of Molecular Sciences}, number = {10}, issn = {1422-0067}, doi = {10.3390/ijms18102072}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285067}, year = {2017}, abstract = {Macrophages predominate the inflammatory landscape within multiple sclerosis (MS) lesions, not only regarding cellularity but also with respect to the diverse functions this cell fraction provides during disease progression and remission. Researchers have been well aware of the fact that the macrophage pool during central nervous system (CNS) autoimmunity consists of a mixture of myeloid cells. Yet, separating these populations to define their unique contribution to disease pathology has long been challenging due to their similar marker expression. Sophisticated lineage tracing approaches as well as comprehensive transcriptome analysis have elevated our insight into macrophage biology to a new level enabling scientists to dissect the roles of resident (microglia and non-parenchymal macrophages) and infiltrating macrophages with unprecedented precision. To do so in an accurate way, researchers have to know their toolbox, which has been filled with diverse, discriminating approaches from decades of studying neuroinflammation in animal models. Every method has its own strengths and weaknesses, which will be addressed in this review. The focus will be on tools to manipulate and/or identify different macrophage subgroups within the injured murine CNS.}, language = {en} } @article{KnauerGessnerFensholtetal.2017, author = {Knauer, Kim and Gessner, Ursula and Fensholt, Rasmus and Forkuor, Gerald and Kuenzer, Claudia}, title = {Monitoring agricultural expansion in Burkina Faso over 14 years with 30 m resolution time series: the role of population growth and implications for the environment}, series = {Remote Sensing}, volume = {9}, journal = {Remote Sensing}, number = {2}, doi = {10.3390/rs9020132}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171905}, year = {2017}, abstract = {Burkina Faso ranges amongst the fastest growing countries in the world with an annual population growth rate of more than three percent. This trend has consequences for food security since agricultural productivity is still on a comparatively low level in Burkina Faso. In order to compensate for the low productivity, the agricultural areas are expanding quickly. The mapping and monitoring of this expansion is difficult, even on the basis of remote sensing imagery, since the extensive farming practices and frequent cloud coverage in the area make the delineation of cultivated land from other land cover and land use types a challenging task. However, as the rapidly increasing population could have considerable effects on the natural resources and on the regional development of the country, methods for improved mapping of LULCC (land use and land cover change) are needed. For this study, we applied the newly developed ESTARFM (Enhanced Spatial and Temporal Adaptive Reflectance Fusion Model) framework to generate high temporal (8-day) and high spatial (30 m) resolution NDVI time series for all of Burkina Faso for the years 2001, 2007, and 2014. For this purpose, more than 500 Landsat scenes and 3000 MODIS scenes were processed with this automated framework. The generated ESTARFM NDVI time series enabled extraction of per-pixel phenological features that all together served as input for the delineation of agricultural areas via random forest classification at 30 m spatial resolution for entire Burkina Faso and the three years. For training and validation, a randomly sampled reference dataset was generated from Google Earth images and based on expert knowledge. The overall accuracies of 92\% (2001), 91\% (2007), and 91\% (2014) indicate the well-functioning of the applied methodology. The results show an expansion of agricultural area of 91\% between 2001 and 2014 to a total of 116,900 km\(^2\). While rainfed agricultural areas account for the major part of this trend, irrigated areas and plantations also increased considerably, primarily promoted by specific development projects. This expansion goes in line with the rapid population growth in most provinces of Burkina Faso where land was still available for an expansion of agricultural area. The analysis of agricultural encroachment into protected areas and their surroundings highlights the increased human pressure on these areas and the challenges of environmental protection for the future.}, language = {en} } @article{KlughammerDittrichBlometal.2017, author = {Klughammer, Johanna and Dittrich, Marcus and Blom, Jochen and Mitesser, Vera and Vogel, Ulrich and Frosch, Matthias and Goesmann, Alexander and M{\"u}ller, Tobias and Schoen, Christoph}, title = {Comparative genome sequencing reveals within-host genetic changes in Neisseria meningitidis during invasive disease}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0169892}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159547}, pages = {e0169892}, year = {2017}, abstract = {Some members of the physiological human microbiome occasionally cause life-threatening disease even in immunocompetent individuals. A prime example of such a commensal pathogen is Neisseria meningitidis, which normally resides in the human nasopharynx but is also a leading cause of sepsis and epidemic meningitis. Using N. meningitidis as model organism, we tested the hypothesis that virulence of commensal pathogens is a consequence of within host evolution and selection of invasive variants due to mutations at contingency genes, a mechanism called phase variation. In line with the hypothesis that phase variation evolved as an adaptation to colonize diverse hosts, computational comparisons of all 27 to date completely sequenced and annotated meningococcal genomes retrieved from public databases showed that contingency genes are indeed enriched for genes involved in host interactions. To assess within-host genetic changes in meningococci, we further used ultra-deep whole-genome sequencing of throat-blood strain pairs isolated from four patients suffering from invasive meningococcal disease. We detected up to three mutations per strain pair, affecting predominantly contingency genes involved in type IV pilus biogenesis. However, there was not a single (set) of mutation(s) that could invariably be found in all four pairs of strains. Phenotypic assays further showed that these genetic changes were generally not associated with increased serum resistance, higher fitness in human blood ex vivo or differences in the interaction with human epithelial and endothelial cells in vitro. In conclusion, we hypothesize that virulence of meningococci results from accidental emergence of invasive variants during carriage and without within host evolution of invasive phenotypes during disease progression in vivo.}, language = {en} } @article{KleinHesslingMuhammadKleinetal.2017, author = {Klein-Hessling, Stefan and Muhammad, Khalid and Klein, Matthias and Pusch, Tobias and Rudolf, Ronald and Fl{\"o}ter, Jessica and Qureischi, Musga and Beilhack, Andreas and Vaeth, Martin and Kummerow, Carsten and Backes, Christian and Schoppmeyer, Rouven and Hahn, Ulrike and Hoth, Markus and Bopp, Tobias and Berberich-Siebelt, Friederike and Patra, Amiya and Avots, Andris and M{\"u}ller, Nora and Schulze, Almut and Serfling, Edgar}, title = {NFATc1 controls the cytotoxicity of CD8\(^{+}\) T cells}, series = {Nature Communications}, volume = {8}, journal = {Nature Communications}, number = {511}, doi = {10.1038/s41467-017-00612-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170353}, year = {2017}, abstract = {Cytotoxic T lymphocytes are effector CD8\(^{+}\) T cells that eradicate infected and malignant cells. Here we show that the transcription factor NFATc1 controls the cytotoxicity of mouse cytotoxic T lymphocytes. Activation of Nfatc1\(^{-/-}\) cytotoxic T lymphocytes showed a defective cytoskeleton organization and recruitment of cytosolic organelles to immunological synapses. These cells have reduced cytotoxicity against tumor cells, and mice with NFATc1-deficient T cells are defective in controlling Listeria infection. Transcriptome analysis shows diminished RNA levels of numerous genes in Nfatc1\(^{-/-}\) CD8\(^{+}\) T cells, including Tbx21, Gzmb and genes encoding cytokines and chemokines, and genes controlling glycolysis. Nfatc1\(^{-/-}\), but not Nfatc2\(^{-/-}\) CD8\(^{+}\) T cells have an impaired metabolic switch to glycolysis, which can be restored by IL-2. Genome-wide ChIP-seq shows that NFATc1 binds many genes that control cytotoxic T lymphocyte activity. Together these data indicate that NFATc1 is an important regulator of cytotoxic T lymphocyte effector functions.}, language = {en} } @article{KingslakeDiasDawsonetal.2017, author = {Kingslake, Jonathan and Dias, Rebecca and Dawson, Gerard R. and Simon, Judit and Goodwin, Guy M. and Harmer, Catherine J. and Morriss, Richard and Brown, Susan and Guo, Boliang and Dourish, Colin T. and Ruh{\´e}, Henricus G. and Lever, Anne G. and Veltman, Dick J. and van Schaik, Anneke and Deckert, J{\"u}rgen and Reif, Andreas and St{\"a}blein, Michael and Menke, Andreas and Gorwood, Philip and Voegeli, G{\´e}raldine and Perez, Victor and Browning, Michael}, title = {The effects of using the PReDicT Test to guide the antidepressant treatment of depressed patients: study protocol for a randomised controlled trial}, series = {Trials}, volume = {18}, journal = {Trials}, doi = {10.1186/s13063-017-2247-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173012}, year = {2017}, abstract = {Background Antidepressant medication is commonly used to treat depression. However, many patients do not respond to the first medication prescribed and improvements in symptoms are generally only detectable by clinicians 4-6 weeks after the medication has been initiated. As a result, there is often a long delay between the decision to initiate an antidepressant medication and the identification of an effective treatment regimen. Previous work has demonstrated that antidepressant medications alter subtle measures of affective cognition in depressed patients, such as the appraisal of facial expression. Furthermore, these cognitive effects of antidepressants are apparent early in the course of treatment and can also predict later clinical response. This trial will assess whether an electronic test of affective cognition and symptoms (the Predicting Response to Depression Treatment Test; PReDicT Test) can be used to guide antidepressant treatment in depressed patients and, therefore, hasten treatment response compared to a control group of patients treated as usual. Methods/design The study is a randomised, two-arm, multi-centre, open-label, clinical investigation of a medical device, the PReDicT Test. It will be conducted in five European countries (UK, France, Spain, Germany and the Netherlands) in depressed patients who are commencing antidepressant medication. Patients will be randomised to treatment guided by the PReDicT Test (PReDicT arm) or to Treatment as Usual (TaU arm). Patients in the TaU arm will be treated as per current standard guidelines in their particular country. Patients in the PReDicT arm will complete the PReDicT Test after 1 (and if necessary, 2) weeks of treatment. If the test indicates non-response to the treatment, physicians will be advised to immediately alter the patient's antidepressant therapy by dose escalation or switching to another compound. The primary outcome of the study is the proportion of patients showing a clinical response (defined as 50\% or greater decrease in baseline scores of depressionmeasured using the Quick Inventory of Depressive Symptoms - Self-Rated questionnaire) at week 8. Health economic and acceptability data will also be collected and analysed. Discussion This trial will test the clinical efficacy, cost-effectiveness and acceptability of using the novel PReDicT Test to guide antidepressant treatment selection in depressed patients. Trial registration ClinicalTrials.gov, ID: NCT02790970. Registered on 30 March 2016.}, language = {en} } @article{KelmSeyfriedReimeretal.2017, author = {Kelm, M. and Seyfried, F. and Reimer, S. and Krajinovic, K. and Miras, A. D. and Jurowich, C. and Germer, C. T. and Brand, M.}, title = {Proximal jejunal stoma as ultima ratio in case of traumatic distal duodenal perforation facilitating successful EndoVAC\(^{®}\) treatment: a case report}, series = {International Journal of Surgery Case Reports}, volume = {41}, journal = {International Journal of Surgery Case Reports}, doi = {10.1016/j.ijscr.2017.11.022}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159292}, pages = {401-403}, year = {2017}, abstract = {Introduction: During damage control surgery for blunt abdominal traumata simultaneous duodenal perforations can be missed making secondary sufficient surgical treatment challenging. Endoluminal vacuum (EndoVAC™) therapy has been shown to be a revolutionary option but has anatomical and technical limits. Presentation of the case: A 59-year old man with hemorrhagic shock due to rupture of the mesenteric root after blunt abdominal trauma received damage control treatment. Within a scheduled second-look, perforation of the posterior duodenal wall was identified. Due to local and systemic conditions, further surgical treatment was limited. Decision for endoscopic treatment was made but proved to be difficult due to the distal location. Finally, double-barreled jejunal stoma was created for transstomal EndoVAC™ treatment. Complete leakage healing was achieved and jejunostomy reversal followed subsequently. Discussion: During damage control surgery simultaneous bowel injuries can be missed leading to life-threatening complications with limited surgical options. EndoVAC™ treatment is an option for gastrointestinal perforations but has anatomical limitations that can be sufficiently shifted by a transstomal approach for intestinal leakage. Conclusion: In trauma related laparotomy complete mobilization of the duodenum is crucial. As ultima ratio, transstomal EndoVAC™ is a safe and feasible option and can be considered for similar cases.}, language = {en} } @article{KatzorkeZellerMuelleretal.2017, author = {Katzorke, Andrea and Zeller, Julia B. M. and M{\"u}ller, Laura D. and Lauer, Martin and Polak, Thomas and Reif, Andreas and Deckert, J{\"u}rgen and Herrmann, Martin J.}, title = {Reduced activity in the right inferior frontal gyrus in elderly APOE-E4 carriers during a verbal fluency task}, series = {Frontiers in Human Neuroscience}, volume = {11}, journal = {Frontiers in Human Neuroscience}, doi = {10.3389/fnhum.2017.00046}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171892}, year = {2017}, abstract = {Apolipoprotein-E4 (APOE-E4) is a major genetic risk factor for developing Alzheimer's disease (AD). The verbal fluency task (VFT), especially the subtask category fluency, has shown to provide a good discrimination between cognitively normal controls and subjects with AD. Interestingly, APOE-E4 seems to have no effect on the behavioral performance during a VFT in healthy elderly. Thus, the purpose of the present study was to reveal possible compensation mechanisms by investigating the effect of APOE-E4 on the hemodynamic response in non-demented elderly during a VFT by using functional near-infrared spectroscopy (fNIRS). We compared performance and hemodynamic response of high risk APOE-E4/E4, -E3/E4 carriers with neutral APOE-E3/E3 non-demented subjects (N = 288; 70-77 years). No difference in performance was found. APOE-E4/E4, -E3/E4 carriers had a decreased hemodynamic response in the right inferior frontal junction (IFJ) with a corresponding higher response in the left middle frontal gyrus (MFG) during category fluency. Performance was correlated with the hemodynamic response in the MFG. We assume a compensation of decreased IFJ brain activation by utilizing the MFG during category fluency and thus resulting in no behavioral differences between APOE-groups during the performance of a VFT.}, language = {en} } @article{KasaragodMidekessaSridharetal.2017, author = {Kasaragod, Prasad and Midekessa, Getnet B. and Sridhar, Shruthi and Schmitz, Werner and Kiema, Tiila-Riikka and Hiltunen, Jukka K. and Wierenga, Rik K.}, title = {Structural enzymology comparisons of multifunctional enzyme, type-1 (MFE1): the flexibility of its dehydrogenase part}, series = {FEBS Open Bio}, volume = {7}, journal = {FEBS Open Bio}, number = {12}, doi = {10.1002/2211-5463.12337}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172732}, pages = {1830-1842}, year = {2017}, abstract = {Multifunctional enzyme, type-1 (MFE1) is a monomeric enzyme with a 2E-enoyl-CoA hydratase and a 3S-hydroxyacyl-CoA dehydrogenase (HAD) active site. Enzyme kinetic data of rat peroxisomal MFE1 show that the catalytic efficiencies for converting the short-chain substrate 2E-butenoyl-CoA into acetoacetyl-CoA are much lower when compared with those of the homologous monofunctional enzymes. The mode of binding of acetoacetyl-CoA (to the hydratase active site) and the very similar mode of binding of NAD\(^+\) and NADH (to the HAD part) are described and compared with those of their monofunctional counterparts. Structural comparisons suggest that the conformational flexibility of the HAD and hydratase parts of MFE1 are correlated. The possible importance of the conformational flexibility of MFE1 for its biocatalytic properties is discussed.}, language = {en} } @article{KarlGriesshammerUeceyleretal.2017, author = {Karl, Franziska and Grießhammer, Anne and {\"U}{\c{c}}eyler, Nurcan and Sommer, Claudia}, title = {Differential Impact of miR-21 on Pain and Associated Affective and Cognitive Behavior after Spared Nerve Injury in B7-H1 ko Mouse}, series = {Frontiers in Molecular Neuroscience}, volume = {10}, journal = {Frontiers in Molecular Neuroscience}, number = {219}, doi = {10.3389/fnmol.2017.00219}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170722}, year = {2017}, abstract = {MicroRNAs (miRNAs) are increasingly recognized as regulators of immune and neuronal gene expression and are potential master switches in neuropathic pain pathophysiology. miR-21 is a promising candidate that may link the immune and the pain system. To investigate the pathophysiological role of miR-21 in neuropathic pain, we assessed mice deficient of B7 homolog 1 (B7-H1), a major inhibitor of inflammatory responses. In previous studies, an upregulation of miR-21 had been shown in mouse lymphocytes. Young (8 weeks), middle-aged (6 months), and old (12 months) B7-H1 ko mice and wildtype littermates (WT) received a spared nerve injury (SNI). We assessed thermal withdrawal latencies and mechanical withdrawal thresholds. Further, we performed tests for anxiety-like and cognitive behavior. Quantitative real time PCR was used to determine miR-21 relative expression in peripheral nerves, and dorsal root ganglia (DRG) at distinct time points after SNI. We found mechanical hyposensitivity with increasing age of na{\"i}ve B7-H1 ko mice. Young and middle-aged B7-H1 ko mice were more sensitive to mechanical stimuli compared to WT mice (young: p < 0.01, middle-aged: p < 0.05). Both genotypes developed mechanical and heat hypersensitivity (p < 0.05) after SNI, without intergroup differences. No relevant differences were found after SNI in three tests for anxiety like behavior in B7-H1 ko and WT mice. Also, SNI had no effect on cognition. B7-H1 ko and WT mice showed a higher miR-21 expression (p < 0.05) and invasion of macrophages and T cells in the injured nerve 7 days after SNI without intergroup differences. Our study reveals that increased miR-21 expression in peripheral nerves after SNI is associated with reduced mechanical and heat withdrawal thresholds. These results point to a role of miR-21 in the pathophysiology of neuropathic pain, while affective behavior and cognition seem to be spared. Contrary to expectations, B7-H1 ko mice did not show higher miR-21 expression than WT mice, thus, a B7-H1 knockout may be of limited relevance for the study of miR-21 related pain.}, language = {en} } @article{KaluzaWallaceKelleretal.2017, author = {Kaluza, Benjamin F. and Wallace, Helen and Keller, Alexander and Heard, Tim A. and Jeffers, Bradley and Drescher, Nora and Bl{\"u}thgen, Nico and Leonhardt, Sara D.}, title = {Generalist social bees maximize diversity intake in plant species-rich and resource-abundant environments}, series = {Ecosphere}, volume = {8}, journal = {Ecosphere}, number = {3}, doi = {10.1002/ecs2.1758}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171155}, pages = {e01758}, year = {2017}, abstract = {Numerous studies revealed a positive relationship between biodiversity and ecosystem functioning, suggesting that biodiverse environments may not only enhance ecosystem processes, but also benefit individual ecosystem members by, for example, providing a higher diversity of resources. Whether and how the number of available resources affects resource collection and subsequently consumers (e.g., through impacting functions associated with resources) have, however, been little investigated, although a better understanding of this relationship may help explain why the abundance and richness of many animal species typically decline with decreasing plant (resource) diversity. Using a social bee species as model (Tetragonula carbonaria), we investigated how plant species richness—recorded for study sites located in different habitats—and associated resource abundance affected the diversity and functionality (here defined as nutritional content and antimicrobial activity) of resources (i.e., pollen, nectar, and resin) collected by a generalist herbivorous consumer. The diversity of both pollen and resin collected strongly increased with increasing plant/tree species richness, while resource abundance was only positively correlated with resin diversity. These findings suggest that bees maximize resource diversity intake in (resource) diverse habitats. Collecting more diverse resources did, however, not increase their functionality, which appeared to be primarily driven by the surrounding (plant) source community in our study. In generalist herbivores, maximizing resource diversity intake may therefore primarily secure collection of sufficient amounts of resources across the entire foraging season, but it also ensures that the allocated resources meet all functional needs. Decreasing available resource diversity may thus impact consumers primarily by reduced resource abundance, but also by reduced resource functionality, particularly when resources of high functionality (e.g., from specific plant species) become scarce.}, language = {en} } @article{KaltdorfSchulzeHelmprobstetal.2017, author = {Kaltdorf, Kristin Verena and Schulze, Katja and Helmprobst, Frederik and Kollmannsberger, Philip and Dandekar, Thomas and Stigloher, Christian}, title = {Fiji macro 3D ART VeSElecT: 3D automated reconstruction tool for vesicle structures of electron tomograms}, series = {PLoS Computational Biology}, volume = {13}, journal = {PLoS Computational Biology}, number = {1}, doi = {10.1371/journal.pcbi.1005317}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172112}, year = {2017}, abstract = {Automatic image reconstruction is critical to cope with steadily increasing data from advanced microscopy. We describe here the Fiji macro 3D ART VeSElecT which we developed to study synaptic vesicles in electron tomograms. We apply this tool to quantify vesicle properties (i) in embryonic Danio rerio 4 and 8 days past fertilization (dpf) and (ii) to compare Caenorhabditis elegans N2 neuromuscular junctions (NMJ) wild-type and its septin mutant (unc-59(e261)). We demonstrate development-specific and mutant-specific changes in synaptic vesicle pools in both models. We confirm the functionality of our macro by applying our 3D ART VeSElecT on zebrafish NMJ showing smaller vesicles in 8 dpf embryos then 4 dpf, which was validated by manual reconstruction of the vesicle pool. Furthermore, we analyze the impact of C. elegans septin mutant unc-59(e261) on vesicle pool formation and vesicle size. Automated vesicle registration and characterization was implemented in Fiji as two macros (registration and measurement). This flexible arrangement allows in particular reducing false positives by an optional manual revision step. Preprocessing and contrast enhancement work on image-stacks of 1nm/pixel in x and y direction. Semi-automated cell selection was integrated. 3D ART VeSElecT removes interfering components, detects vesicles by 3D segmentation and calculates vesicle volume and diameter (spherical approximation, inner/outer diameter). Results are collected in color using the RoiManager plugin including the possibility of manual removal of non-matching confounder vesicles. Detailed evaluation considered performance (detected vesicles) and specificity (true vesicles) as well as precision and recall. We furthermore show gain in segmentation and morphological filtering compared to learning based methods and a large time gain compared to manual segmentation. 3D ART VeSElecT shows small error rates and its speed gain can be up to 68 times faster in comparison to manual annotation. Both automatic and semi-automatic modes are explained including a tutorial.}, language = {en} } @article{KalbheimZiebertz2017, author = {Kalbheim, Boris and Ziebertz, Hans-Georg}, title = {S{\"a}kular - mehr als „nichtreligi{\"o}s"?}, series = {International Journal of Practical Theology}, volume = {21}, journal = {International Journal of Practical Theology}, number = {1}, issn = {1612-9768}, doi = {10.1515/ijpt-2015-0005}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-194408}, pages = {58-88}, year = {2017}, abstract = {There is hardly an autonomous description of those who do not belong to a religious denomination and who don't regard themselves as religious in a traditional way. The terms "non-denominational" and "non-religious" implicate a dissociation from the historically traditional concept of religion, but they do not offer any alternative ideological communalities. This article discusses the option of a "secular worldview" and investigates whether religious and non-religious respondents differ in their attitudes on selected human rights - and if so, to what extent. The empirical study (N=2244) shows that human rights are supported by all young people, athough in some cases with differing emphases. In basic terms, we can discern a common worldview or 'Weltanschauung' of secular respondents. This is recognizable as an approval of the intrinsic value of the Other as well as a recognition of norms set by public society.}, language = {de} } @article{KaiserSauerKisker2017, author = {Kaiser, Sebastian and Sauer, Florian and Kisker, Caroline}, title = {The structural and functional characterization of human RecQ4 reveals insights into its helicase mechanism}, series = {Nature Communications}, volume = {8}, journal = {Nature Communications}, number = {15907}, doi = {10.1038/ncomms15907}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170769}, year = {2017}, abstract = {RecQ4 is a member of the RecQ helicase family, an evolutionarily conserved class of enzymes, dedicated to preserving genomic integrity by operating in telomere maintenance, DNA repair and replication. While reduced RecQ4 activity is associated with cancer predisposition and premature aging, RecQ4 upregulation is related to carcinogenesis and metastasis. Within the RecQ family, RecQ4 assumes an exceptional position, lacking several characteristic RecQ domains. Here we present the crystal structure of human RecQ4, encompassing the conserved ATPase core and a novel C-terminal domain that lacks resemblance to the RQC domain observed in other RecQ helicases. The new domain features a zinc-binding site and two distinct types of winged-helix domains, which are not involved in canonical DNA binding or helicase activity. Based on our structural and functional analysis, we propose that RecQ4 exerts a helicase mechanism, which may be more closely related to bacterial RecQ helicases than to its human family members.}, language = {en} } @article{KaireitSorrentinoRenneetal.2017, author = {Kaireit, Till F. and Sorrentino, Sajoscha A. and Renne, Julius and Schoenfeld, Christian and Voskrebenzev, Andreas and Gutberlet, Marcel and Schulz, Angela and Jakob, Peter M. and Hansen, Gesine and Wacker, Frank and Welte, Tobias and T{\"u}mmler, Burkhard and Vogel-Claussen, Jens}, title = {Functional lung MRI for regional monitoring of patients with cystic fibrosis}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {12}, doi = {10.1371/journal.pone.0187483}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172457}, year = {2017}, abstract = {Purpose To test quantitative functional lung MRI techniques in young adults with cystic fibrosis (CF) compared to healthy volunteers and to monitor immediate treatment effects of a single inhalation of hypertonic saline in comparison to clinical routine pulmonary function tests. Materials and methods Sixteen clinically stable CF patients and 12 healthy volunteers prospectively underwent two functional lung MRI scans and pulmonary function tests before and 2h after a single treatment of inhaled hypertonic saline or without any treatment. MRI-derived oxygen enhanced T1 relaxation measurements, fractional ventilation, first-pass perfusion parameters and a morpho-functional CF-MRI score were acquired. Results Compared to healthy controls functional lung MRI detected and quantified significantly increased ventilation heterogeneity in CF patients. Regional functional lung MRI measures of ventilation and perfusion as well as the CF-MRI score and pulmonary function tests could not detect a significant treatment effect two hours after a single treatment with hypertonic saline in young adults with CF (p>0.05). Conclusion This study shows the feasibility of functional lung MRI as a non-invasive, radiation-free tool for monitoring patients with CF.}, language = {en} } @article{KadochovaFrouzRoces2017, author = {Kadochov{\´a}, Štěp{\´a}nka and Frouz, Jan and Roces, Flavio}, title = {Sun basking in red wood ants Formica polyctena (Hymenoptera, Formicidae): Individual behaviour and temperature-dependent respiration rates}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0170570}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171936}, year = {2017}, abstract = {In early spring, red wood ants Formica polyctena are often observed clustering on the nest surface in large numbers basking in the sun. It has been hypothesized that sun-basking behaviour may contribute to nest heating because of both heat carriage into the nest by sunbasking workers, and catabolic heat production from the mobilization of the workers' lipid reserves. We investigated sun-basking behaviour in laboratory colonies of F. polyctena exposed to an artificial heat source. Observations on identified individuals revealed that not all ants bask in the sun. Sun-basking and non-sun-basking workers did not differ in body size nor in respiration rates. The number of sun-basking ants and the number of their visits to the hot spot depended on the temperature of both the air and the hot spot. To investigate whether sun basking leads to a physiological activation linked with increased lipolysis, we measured respiration rates of individual workers as a function of temperature, and compared respiration rates of sun-basking workers before and two days after they were allowed to expose themselves to a heat source over 10 days, at self-determined intervals. As expected for ectothermic animals, respiration rates increased with increasing temperatures in the range 5 to 35˚C. However, the respiration rates of sun-basking workers measured two days after a long-term exposure to the heat source were similar to those before sun basking, providing no evidence for a sustained increase of the basal metabolic rates after prolonged sun basking. Based on our measurements, we argue that self-heating of the nest mound in early spring has therefore to rely on alternative heat sources, and speculate that physical transport of heat in the ant bodies may have a significant effect.}, language = {en} } @article{JordanBittrichFehskeetal.2017, author = {Jordan, Martin C. and Bittrich, Leonie A. and Fehske, Kai and Meffert, Rainer H. and Jansen, Hendrik}, title = {A rare case of Hoffa fracture combined with lateral patellar dislocation}, series = {Trauma Case Reports}, volume = {9}, journal = {Trauma Case Reports}, doi = {10.1016/j.tcr.2017.05.001}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158315}, pages = {13-16}, year = {2017}, abstract = {The coronal unicondylar fracture of the distal femur (AO 33-B3) is a rare intraarticular injury within the weight bearing area of the knee, initially described by Albert Hoffa in 1904. We report an unusual combination of a Hoffa fracture with lateral patellar dislocation in a young adult. Our patient sustained the injury by a sudden twist of his leg during sports. He presented clinically with knee swelling, dislocation of the patella, and localized tenderness; unable to bare weight. After plane radiograph confirmed the injury, manual reduction of the patella was done by hyperextension of the knee and medialward pressure. Afterwards, a CT scan and MRI were conducted. The injury was surgically treated with lag-screws, locking-plate and MPFL-reconstruction.}, language = {en} } @article{JodeleitPalamidesBeigeletal.2017, author = {Jodeleit, Henrika and Palamides, Pia and Beigel, Florian and Mueller, Thomas and Wolf, Eckhard and Siebeck, Matthias and Gropp, Roswitha}, title = {Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model}, series = {Journal of Translational Medicine}, volume = {15}, journal = {Journal of Translational Medicine}, doi = {10.1186/s12967-017-1368-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225516}, year = {2017}, abstract = {Background: Ulcerative colitis (UC) is a highly progressive inflammatory disease that requires the interaction of epithelial, immune, endothelial and muscle cells and fibroblasts. Previous studies suggested two inflammatory conditions in UC-patients: 'acute' and 'remodeling' and that the design of a disease network might improve the understanding of the inflammatory processes. The objective of the study was to design and validate a disease network in the NOD-SCID IL2rγ\(^{null}\) (NSG)-UC mouse model to get a better understanding of the inflammatory processes. Methods: Leukocytes were isolated from the spleen of NSG-UC mice and subjected to flow cytometric analysis. RT-PCR and RNAseq analysis were performed from distal parts of the colon. Based on these analyses and the effects of interleukins, chemokines and growth factors described in the literature, a disease network was designed. To validate the disease network the effect of infliximab and pitrakinra was tested in the NSG-UC model. A clinical- and histological score, frequencies of human leukocytes isolated from spleen and mRNA expression levels from distal parts of the colon were determined. Results: Analysis of leukocytes isolated from the spleen of challenged NSG-UC mice corroborated CD64, CD163 and CD1a expressing CD14+ monocytes, CD1a expressing CD11b+ macrophages and HGF, TARC, IFNγ and TGFß1 mRNA as inflammatory markers. The disease network suggested that a proinflammatory condition elicited by IL-17c and lipids and relayed by cytotoxic T-cells, Th17 cells and CD1a expressing macrophages and monocytes. Conversely, the remodeling condition was evoked by IL-34 and TARC and promoted by Th2 cells and M2 monocytes. Mice benefitted from treatment with infliximab as indicated by the histological- and clinical score. As predicted by the disease network infliximab reduced the proinflammatory response by suppressing M1 monocytes and CD1a expressing monocytes and macrophages and decreased levels of IFNγ, TARC and HGF mRNA. As predicted by the disease network inflammation aggravated in the presence of pitrakinra as indicated by the clinical and histological score, elevated frequencies of CD1a expressing macrophages and TNFα and IFNγ mRNA levels. Conclusions: The combination of the disease network and the NSG-UC animal model might be developed into a powerful tool to predict efficacy or in-efficacy and potential mechanistic side effects.}, language = {en} } @article{JiGriesbeckMarder2017, author = {Ji, Lei and Griesbeck, Stefanie and Marder, Todd B.}, title = {Recent developments in and perspectives on three-coordinate boron materials: a bright future}, series = {Chemical Science}, volume = {8}, journal = {Chemical Science}, number = {2}, doi = {10.1039/c6sc04245g}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171912}, pages = {846-863}, year = {2017}, abstract = {The empty p\(_z\)-orbital of a three-coordinate organoboron compound leads to its electron-deficient properties, which make it an excellent π-acceptor in conjugated organic chromophores. The empty p-orbital in such Lewis acids can be attacked by nucleophiles, so bulky groups are often employed to provide air-stable materials. However, many of these can still bind fluoride and cyanide anions leading to applications as anion-selective sensors. One electron reduction generates radical anions. The π-acceptor strength can be easily tuned by varying the organic substituents. Many of these compounds show strong two-photon absorption (TPA) and two-photon excited fluorescence (TPEF) behaviour, which can be applied for e.g. biological imaging. Furthermore, these chromophores can be used as emitters and electron transporters in OLEDs, and examples have recently been found to exhibit efficient thermally activated delayed fluorescence (TADF). The three-coordinate organoboron unit can also be incorporated into polycyclic aromatic hydrocarbons. Such boron-doped compounds exhibit very interesting properties, distinct from their all-carbon analogues. Significant developments have been made in all of these areas in recent years and new applications are rapidly emerging for this class of boron compounds.}, language = {en} } @article{JessbergerHoeggerGenestetal.2017, author = {Jessberger, Steffen and H{\"o}gger, Petra and Genest, Franca and Salter, Donald M. and Seefried, Lothar}, title = {Cellular pharmacodynamic effects of Pycnogenol\(^{®}\) in patients with severe osteoarthritis: a randomized controlled pilot study}, series = {BMC Complementary and Alternative Medicine}, volume = {17}, journal = {BMC Complementary and Alternative Medicine}, number = {537}, doi = {10.1186/s12906-017-2044-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159532}, year = {2017}, abstract = {Background: The standardized maritime pine bark extract (Pycnogenol\(^{®}\)) has previously shown symptom alleviating effects in patients suffering from moderate forms of knee osteoarthritis (OA). The cellular mechanisms for this positive impact are so far unknown. The purpose of the present randomized pilot controlled study was to span the knowledge gap between the reported clinical effects of Pycnogenol\(^{®}\) and its in vivo mechanism of action in OA patients. Methods: Thirty three patients with severe OA scheduled for a knee arthroplasty either received 100 mg of Pycnogenol\(^{®}\) twice daily or no treatment (control group) three weeks before surgery. Cartilage, synovial fluid and serum samples were collected during surgical intervention. Relative gene expression of cartilage homeostasis markers were analyzed in the patients' chondrocytes. Inflammatory and cartilage metabolism mediators were investigated in serum and synovial fluid samples. Results: The oral intake of Pycnogenol\(^{®}\) downregulated the gene expression of various cartilage degradation markers in the patients' chondrocytes, the decrease of MMP3, MMP13 and the pro-inflammatory cytokine IL1B were statistically significant (p ≤ 0.05). Additionally, protein concentrations of ADAMTS-5 in serum were reduced significantly (p ≤ 0.05) after three weeks intake of the pine bark extract. Conclusions: This is the first report about positive cellular effects of a dietary supplement on key catabolic and inflammatory markers in patients with severe OA. The results provide a rational basis for understanding previously reported clinical effects of Pycnogenol\(^{®}\) on symptom scores of patients suffering from OA.}, language = {en} } @article{JannaschWeigelEngelhardtetal.2017, author = {Jannasch, Maren and Weigel, Tobias and Engelhardt, Lisa and Wiezoreck, Judith and Gaetzner, Sabine and Walles, Heike and Schmitz, Tobias and Hansmann, Jan}, title = {\({In}\) \({vitro}\) chemotaxis and tissue remodeling assays quantitatively characterize foreign body reaction}, series = {ALTEX - Alternatives to Animal Experimentation}, volume = {34}, journal = {ALTEX - Alternatives to Animal Experimentation}, number = {2}, doi = {10.14573/altex.1610071}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172080}, pages = {253-266}, year = {2017}, abstract = {Surgical implantation of a biomaterial triggers foreign-body-induced fibrous encapsulation. Two major mechanisms of this complex physiological process are (I) chemotaxis of fibroblasts from surrounding tissue to the implant region, followed by (II) tissue remodeling. As an alternative to animal studies, we here propose a process-aligned \({in}\) \({vitro}\) test platform to investigate the material dependency of fibroblast chemotaxis and tissue remodeling mediated by material-resident macrophages. Embedded in a biomimetic three-dimensional collagen hydrogel, chemotaxis of fibroblasts in the direction of macrophage-material-conditioned cell culture supernatant was analyzed by live cell imaging. A combination of statistical analysis with a complementary parameterized random walk model allowed quantitative and qualitative characterization of the cellular walk process. We thereby identified an increasing macrophage-mediated chemotactic potential ranking of biomaterials from glass over polytetrafluorethylene to titanium. To address long-term effects of biomaterial-resident macrophages on fibroblasts in a three-dimensional microenvironment, we further studied tissue remodeling by applying macrophage-material-conditioned medium on fibrous \({in}\) \({vitro}\) tissue models. A high correlation of the \({in}\) \({vitro}\) tissue model to state of the art \({in}\) \({vivo}\) study data was found. Titanium exhibited a significantly lower tissue remodeling capacity compared to polytetrafluorethylene. With this approach, we identified a material dependency of both chemotaxis and tissue remodeling processes, strengthening knowledge on their specific contribution to the foreign body reaction.}, language = {en} } @article{JannaschGaetznerWeigeletal.2017, author = {Jannasch, Maren and Gaetzner, Sabine and Weigel, Tobias and Walles, Heike and Schmitz, Tobias and Hansmann, Jan}, title = {A comparative multi-parametric in vitro model identifies the power of test conditions to predict the fibrotic tendency of a biomaterial}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, number = {1689}, doi = {10.1038/s41598-017-01584-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170908}, year = {2017}, abstract = {Despite growing effort to advance materials towards a low fibrotic progression, all implants elicit adverse tissue responses. Pre-clinical biomaterial assessment relies on animals testing, which can be complemented by in vitro tests to address the Russell and Burch's 3R aspect of reducing animal burden. However, a poor correlation between in vitro and in vivo biomaterial assessments confirms a need for suitable in vitro biomaterial tests. The aim of the study was to identify a test setting, which is predictive and might be time- and cost-efficient. We demonstrated how sensitive in vitro biomaterial assessment based on human primary macrophages depends on test conditions. Moreover, possible clinical scenarios such as lipopolysaccharide contamination, contact to autologous blood plasma, and presence of IL-4 in an immune niche influence the outcome of a biomaterial ranking. Nevertheless, by using glass, titanium, polytetrafluorethylene, silicone, and polyethylene representing a specific material-induced fibrotic response and by comparison to literature data, we were able to identify a test condition that provides a high correlation to state-of-the-art in vivo studies. Most important, biomaterial ranking obtained under native plasma test conditions showed a high predictive accuracy compared to in vivo assessments, strengthening a biomimetic three-dimensional in vitro test platform.}, language = {en} } @article{JakubietzNickelNeshkovaetal.2017, author = {Jakubietz, Rafael G. and Nickel, Aljoscha and Neshkova, Iva and Schmidt, Karsten and Gilbert, Fabian and Meffert, Rainer H. and Jakubietz, Michael G.}, title = {Long-term patency of twisted vascular pedicles in perforator-based propeller flaps}, series = {Plastic and Reconstructive Surgery Global Open}, volume = {5}, journal = {Plastic and Reconstructive Surgery Global Open}, number = {10}, doi = {10.1097/GOX.0000000000001544}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158870}, pages = {e1544}, year = {2017}, abstract = {Background: Propeller flaps require torsion of the vascular pedicle of up to 180 degrees. Contrary to free flaps, where the relevance of an intact vascular pedicle has been documented, little is known regarding twisted pedicles of propeller flaps. As secondary surgeries requiring undermining of the flap are common in the extremities, knowledge regarding the necessity to protect the pedicle is relevant. The aim of this study was a long-term evaluation of the patency of vascular pedicle of propeller flaps. Methods: In a retrospective clinical study, 22 patients who underwent soft-tissue reconstruction with a propeller flap were evaluated after 43 months. A Doppler probe was used to locate and evaluate the patency of the vascular pedicle of the flap. Results: The flaps were used in the lower extremity in 19 cases, on the trunk in 3 cases. All flaps had healed. In all patients, an intact vascular pedicle could be found. Flap size, source vessel, or infection could therefore not be linked to an increased risk of pedicle loss. Conclusions: The vascular pedicle of propeller flaps remains patent in the long term. This allows reelevation and undermining of the flap. We therefore recommend protecting the pedicle in all secondary cases to prevent later flap loss.}, language = {en} } @article{JakubietzJakubietzMeffertetal.2017, author = {Jakubietz, Rafael G. and Jakubietz, Michael G. and Meffert, Rainer H. and Schmidt, Karsten}, title = {Multiple-level replantation in elderly patients: risk versus benefit}, series = {Plastic and Reconstructive Surgery Global Open}, volume = {5}, journal = {Plastic and Reconstructive Surgery Global Open}, number = {4}, doi = {10.1097/GOX.0000000000001313}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158443}, pages = {e1313}, year = {2017}, abstract = {Multiple-level amputations of the upper extremity represent a surgical challenge generally only attempted in young patients. This case demonstrates a successful replantation in an elderly woman. The postoperative course was complicated by disseminated intravascular coagulopathy most likely due to inadequate resuscitation. Hand trauma is often underestimated in its general severity. Upper extremity amputations need to be handled similar to polytraumatized patients.}, language = {en} } @article{JakubietzMeffertSchmidtetal.2017, author = {Jakubietz, Michael G. and Meffert, Rainer H. and Schmidt, Karsten and Gruenert, Joerg G. and Jakubietz, Rafael G.}, title = {Acute A4 Pulley Reconstruction with a First Extensor Compartment Onlay Graft}, series = {Plastic and Reconstructive Surgery Global Open}, volume = {5}, journal = {Plastic and Reconstructive Surgery Global Open}, number = {6}, doi = {10.1097/GOX.0000000000001361}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158057}, pages = {e1361}, year = {2017}, abstract = {Background: The integrity of the flexor tendon pulley apparatus is crucial for unimpaired function of the digits. Although secondary reconstruction is an established procedure in multi-pulley injuries, acute reconstruction of isolated, closed pulley ruptures is a rare occurrence. There are 3 factors influencing the functional outcome of a reconstruction: gapping distance between tendon and bone (E-space), bulkiness of the reconstruction, and stability. As direct repair is rarely done, grafts are used to reinforce the pulley. An advantage of the first extensor retinaculum graft is the synovial coating providing the possibility to be used both as a direct graft with synovial coating or as an onlay graft after removal of the synovia when the native synovial layer is present. Methods: A graft from the first dorsal extensor compartment is used as an onlay graft to reinforce the sutured A4 pulley. This technique allows reconstruction of the original dimensions of the pulley system while stability is ensured by anchoring the onlay graft to the bony insertions of the pulley. Results: Anatomical reconstruction can be achieved with this method. The measured E-space remained 0 mm throughout the recovery, while the graft incorporated as a slim reinforcement of the pulley, displaying no bulkiness. Conclusions: The ideal reconstruction should provide synovial coating and sufficient strength with minimal bulk. Early reconstruction using an onlay graft offers these options. The native synovial lining is preserved and the graft is used to reinforce the pulley.}, language = {en} }