@article{CoelhoAlvesMonteiroetal.2019, author = {Coelho, Luis Pedro and Alves, Renato and Monteiro, Paulo and Huerta-Cepas, Jaime and Freitas, Ana Teresa and Bork, Peer}, title = {NG-meta-profiler: fast processing of metagenomes using NGLess, a domain-specific language}, series = {Microbiome}, volume = {7}, journal = {Microbiome}, number = {84}, doi = {10.1186/s40168-019-0684-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223161}, year = {2019}, abstract = {Background Shotgun metagenomes contain a sample of all the genomic material in an environment, allowing for the characterization of a microbial community. In order to understand these communities, bioinformatics methods are crucial. A common first step in processing metagenomes is to compute abundance estimates of different taxonomic or functional groups from the raw sequencing data. Given the breadth of the field, computational solutions need to be flexible and extensible, enabling the combination of different tools into a larger pipeline. Results We present NGLess and NG-meta-profiler. NGLess is a domain specific language for describing next-generation sequence processing pipelines. It was developed with the goal of enabling user-friendly computational reproducibility. It provides built-in support for many common operations on sequencing data and is extensible with external tools with configuration files. Using this framework, we developed NG-meta-profiler, a fast profiler for metagenomes which performs sequence preprocessing, mapping to bundled databases, filtering of the mapping results, and profiling (taxonomic and functional). It is significantly faster than either MOCAT2 or htseq-count and (as it builds on NGLess) its results are perfectly reproducible. Conclusions NG-meta-profiler is a high-performance solution for metagenomics processing built on NGLess. It can be used as-is to execute standard analyses or serve as the starting point for customization in a perfectly reproducible fashion. NGLess and NG-meta-profiler are open source software (under the liberal MIT license) and can be downloaded from https://ngless.embl.de or installed through bioconda.}, language = {en} } @article{deNijsChoeSteinbuschetal.2019, author = {de Nijs, Laurence and Choe, Kyonghwan and Steinbusch, Hellen and Schijns, Olaf E. M. G. and Dings, Jim and van den Hove, Daniel L. A. and Rutten, Bart P. F. and Hoogland, Govert}, title = {DNA methyltransferase isoforms expression in the temporal lobe of epilepsy patients with a history of febrile seizures}, series = {Clinical Epigenetics}, volume = {11}, journal = {Clinical Epigenetics}, doi = {10.1186/s13148-019-0721-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223636}, year = {2019}, abstract = {Background Temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) is a common pharmaco-resistant epilepsy referred for adult epilepsy surgery. Though associated with prolonged febrile seizures (FS) in childhood, the neurobiological basis for this relationship is not fully understood and currently no preventive or curative therapies are available. DNA methylation, an epigenetic mechanism catalyzed by DNA methyltransferases (DNMTs), potentially plays a pivotal role in epileptogenesis associated with FS. In an attempt to start exploring this notion, the present cross-sectional pilot study investigated whether global DNA methylation levels (5-mC and 5-hmC markers) and DNMT isoforms (DNMT1, DNMT3a1, and DNMT3a2) expression would be different in hippocampal and neocortical tissues between controls and TLE patients with or without a history of FS. Results We found that global DNA methylation levels and DNMT3a2 isoform expression were lower in the hippocampus for all TLE groups when compared to control patients, with a more significant decrease amongst the TLE groups with a history of FS. Interestingly, we showed that DNMT3a1 expression was severely diminished in the hippocampus of TLE patients with a history of FS in comparison with control and other TLE groups. In the neocortex, we found a higher expression of DNMT1 and DNMT3a1 as well as increased levels of global DNA methylation for all TLE patients compared to controls. Conclusion Together, the findings of this descriptive cross-sectional pilot study demonstrated brain region-specific changes in DNMT1 and DNMT3a isoform expression as well as global DNA methylation levels in human TLE with or without a history of FS. They highlighted a specific implication of DNMT3a isoforms in TLE after FS. Therefore, longitudinal studies that aim at targeting DNMT3a isoforms to evaluate the potential causal relationship between FS and TLE or treatment of FS-induced epileptogenesis seem warranted.}, language = {en} } @article{AbimannanSumathiKrishnarajasekharetal.2019, author = {Abimannan, Nagarajan and Sumathi, G. and Krishnarajasekhar, O. R. and Sinha, Bhanu and Krishnan, Padma}, title = {Clonal Clusters and Virulence Factors of Methicillin-Resistant \(Staphylococcus\) \(Aureus\): Evidence for Community-Acquired Methicillin-Resistant \(Staphylococcus\) \(Aureus\) Infiltration into Hospital Settings in Chennai, South India}, series = {Indian Journal of Medical Microbiology}, volume = {37}, journal = {Indian Journal of Medical Microbiology}, number = {3}, doi = {10.4103/ijmm.IJMM_18_271}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226963}, pages = {326-336}, year = {2019}, abstract = {Background and Objective: Staphylococcus aureus is one of the major pathogens of nosocomial infections as wells as community-acquired (CA) infections worldwide. So far, large-scale comprehensive molecular and epidemiological characterisation of S. aureus from very diverse settings has not been carried out in India. The objective of this study is to evaluate the molecular, epidemiological and virulence characteristics of S. aureus in both community and hospital settings in Chennai, southern India. Methods: S. aureus isolates were obtained from four different groups (a) healthy individuals from closed community settings, (b) inpatients from hospitals, (c) outpatients from hospitals, representing isolates of hospital-community interface and (d) HIV-infected patients to define isolates associated with the immunocompromised. Antibiotic susceptibility testing, multiplex polymerase chain reactions for detection of virulence and resistance determinants, molecular typing including Staphylococcal cassette chromosome mec (SCCmec) and agr typing, were carried out. Sequencing-based typing was done using spa and multilocus sequence typing (MLST) methods. Clonal complexes (CC) of hospital and CA methicillin-resistant S. aureus (MRSA) were identified and compared for virulence and resistance. Results and Conclusion: A total of 769 isolates of S. aureus isolates were studied. The prevalence of MRSA was found to be 7.17\%, 81.67\%, 58.33\% and 22.85\% for groups a, b, c and d, respectively. Of the four SCCmec types (I, III, IV and V) detected, SCCmec V was found to be predominant. Panton-Valentine leucocidin toxin genes were detected among MRSA isolates harbouring SCCmec IV and V. A total of 78 spa types were detected, t657 being the most prevalent. 13 MLST types belonging to 9 CC were detected. CC1 (ST-772, ST-1) and CC8 (ST238, ST368 and ST1208) were found to be predominant among MRSA. CA-MRSA isolates with SCCmec IV and V were isolated from all study groups including hospitalised patients and were found to be similar by molecular tools. This shows that CA MRSA has probably infiltrated into the hospital settings.}, language = {en} } @article{OPUS4-22694, title = {FCC-ee: The Lepton Collider: Future Circular Collider Conceptual Design Report Volume 2}, series = {European Physical Journal - Special Topics}, volume = {228}, journal = {European Physical Journal - Special Topics}, number = {2}, organization = {The FCC Collaboration}, doi = {10.1140/epjst/e2019-900045-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226947}, pages = {261-623}, year = {2019}, abstract = {In response to the 2013 Update of the European Strategy for Particle Physics, the Future Circular Collider (FCC) study was launched, as an international collaboration hosted by CERN. This study covers a highest-luminosity high-energy lepton collider (FCC-ee) and an energy-frontier hadron collider (FCC-hh), which could, successively, be installed in the same 100 km tunnel. The scientific capabilities of the integrated FCC programme would serve the worldwide community throughout the 21st century. The FCC study also investigates an LHC energy upgrade, using FCC-hh technology. This document constitutes the second volume of the FCC Conceptual Design Report, devoted to the electron-positron collider FCC-ee. After summarizing the physics discovery opportunities, it presents the accelerator design, performance reach, a staged operation scenario, the underlying technologies, civil engineering, technical infrastructure, and an implementation plan. FCC-ee can be built with today's technology. Most of the FCC-ee infrastructure could be reused for FCC-hh. Combining concepts from past and present lepton colliders and adding a few novel elements, the FCC-ee design promises outstandingly high luminosity. This will make the FCC-ee a unique precision instrument to study the heaviest known particles (Z, W and H bosons and the top quark), offering great direct and indirect sensitivity to new physics.}, language = {en} } @article{HetzerOrthHoellerWuerzneretal.2019, author = {Hetzer, Benjamin and Orth-H{\"o}ller, Dorothea and W{\"u}rzner, Reinhard and Kreidl, Peter and Lackner, Michaela and M{\"u}ller, Thomas and Knabl, Ludwig and Geisler-Moroder, Daniel Rudolf and Mellmann, Alexander and Sesli, {\"O}zcan and Holzknecht, Jeanett and Noce, Damia and Akarathum, Noppadon and Chotinaruemol, Somporn and Prelog, Martina and Oberdorfer, Peninnah}, title = {"Enhanced acquisition of antibiotic-resistant intestinal E. coli during the first year of life assessed in a prospective cohort study"}, series = {Antimicrobial Resistance \& Infection Control}, volume = {8}, journal = {Antimicrobial Resistance \& Infection Control}, doi = {10.1186/s13756-019-0522-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320284}, year = {2019}, abstract = {Background Increasing bacterial resistance to antibiotics is a serious problem worldwide. We sought to record the acquisition of antibiotic-resistant Escherichia coli (E. coli) in healthy infants in Northern Thailand and investigated potential determinants. Methods Stool samples from 142 infants after birth, at ages 2wk, 2mo, 4 to 6mo, and 1y, and parent stool samples were screened for E. coli resistance to tetracycline, ampicillin, co-trimoxazole, and cefazoline by culture, and isolates were further investigated for multiresistance by disc diffusion method. Pulsed-field gel electrophoresis was performed to identify persistent and transmitted strains. Genetic comparison of resistant and transmitted strains was done by multilocus sequence typing (MLST) and strains were further investigated for extra- and intra-intestinal virulence factors by multiplex PCR. Results Forty-seven (33\%) neonatal meconium samples contained resistant E. coli. Prevalence increased continuously: After 1y, resistance proportion (tetracycline 80\%, ampicillin 72\%, co-trimoxazole 66\%, cefazoline 35\%) almost matched those in parents. In 8 infants (6\%), identical E. coli strains were found in at least 3 sampling time points (suggesting persistence). Transmission of resistant E. coli from parents to child was observed in only 8 families. MLST showed high diversity. We could not identify any virulence genes or factors associated with persistence, or transmission of resistant E. coli. Full-term, vaginal birth and birth in rural hospital were identified as risk factors for early childhood colonization with resistant E. coli. Conclusion One third of healthy Thai neonates harboured antibiotic-resistant E. coli in meconium. The proportion of resistant E. coli increased during the first year of life almost reaching the value in adults. We hypothesize that enhancement of infection control measures and cautious use of antibiotics may help to control further increase of resistance.}, language = {en} } @article{MoremiClausVogeletal.2019, author = {Moremi, Nyambura and Claus, Heike and Vogel, Ulrich and Mshana, Stephen E.}, title = {The role of patients and healthcare workers Staphylococcus aureus nasal colonization in occurrence of surgical site infection among patients admitted in two centers in Tanzania}, series = {Antimicrobial Resistance \& Infection Control}, volume = {8}, journal = {Antimicrobial Resistance \& Infection Control}, doi = {10.1186/s13756-019-0554-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224185}, year = {2019}, abstract = {Background Colonization with Staphylococcus aureus has been identified as a risk for subsequent occurrence of infection. This study investigated the relationship between S. aureus colonization of patients and healthcare workers (HCWs), and subsequent surgical site infections (SSI). Methods Between December 2014 and September 2015, a total of 930 patients and 143 HCWs were enrolled from the Bugando Medical Centre and Sekou Toure hospital in Mwanza, Tanzania. On admission and discharge nasal swabs, with an additional of wound swab for those who developed SSI were collected from patients whereas HCWs were swabbed once. Identification and antimicrobial susceptibility testing were done by VITEK-MS and VITEK-2, respectively. Detection of Panton Valentine leukocidin (PVL) and mecA genes was done by PCR. S. aureus isolates were further characterized by spa typing and Multi-Locus Sequence Typing (MLST). Results Among 930 patients screened for S. aureus on admission, 129 (13.9\%) were positive of which 5.4\% (7/129) were methicillin-resistant S. aureus (MRSA). Amongst 363 patients rescreened on discharge, 301 patients had been tested negative on admission of whom 29 (9.6\%) turned positive after their hospital stay. Three (10.3\%) of the 29 acquired S. aureus were MRSA. Inducible Clindamycin resistance occurred more often among acquired S. aureus isolates than among isolates from admission [34.5\% (10/29) vs. 17.1\% (22/129), P = 0.018]. S. aureus contributed to 21.1\% (n = 12) of the 57 cases of investigated SSIs among 536 patients followed. Seven out of eight S. aureus carriage/infection pairs had the same spa and sequence types. The previously reported dominant PVL-positive ST88 MRSA strain with spa type t690 was detected in patients and HCW. Conclusion A significant proportion of patients acquired S. aureus during hospitalization. The finding of more than 90\% of S. aureus SSI to be of endogenous source underscores the need of improving infection prevention and control measures including screening and decolonization of high risk patients.}, language = {en} } @article{BrumbergBlazhenetsSchroeteretal.2019, author = {Brumberg, Joachim and Blazhenets, Ganna and Schr{\"o}ter, Nils and Frings, Lars and Jost, Wolfgang H. and Lapa, Constantin and Meyer, Philipp T.}, title = {Imaging cardiac sympathetic innervation with MIBG: linear conversion of the heart-to-mediastinum ratio between different collimators}, series = {EJNMMI Physics}, volume = {6}, journal = {EJNMMI Physics}, doi = {10.1186/s40658-019-0250-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221675}, year = {2019}, abstract = {Background The heart-to-mediastinum (H/M) ratio is a commonly used parameter to measure cardiac I-123 metaiodobenzylguanidine (MIBG) uptake. Since the H/M ratio is substantially influenced by the collimator type, we investigated whether an empirical linear conversion of H/M ratios between camera systems with low-energy (LE) and medium-energy (ME) collimator is possible. Methods We included 18 patients with parkinsonism who were referred to one of the two participating molecular imaging facilities for the evaluation of cardiac sympathetic innervation by MIBG scintigraphy. Two consecutive planar image datasets were acquired with LE and ME collimators at 4 h after MIBG administration. Linear regression analyses were performed to describe the association between the H/M ratios gained with both collimator settings, and the accuracy of a linear transfer of the H/M ratio between collimators and across centers was assessed using a leave-one-out procedure. Results H/M ratios acquired with LE and ME collimators showed a strong linear relationship both within each imaging facility (R\(^2\) = 0.99, p < 0.001 and R\(^2\) = 0.90, p < 0.001) and across centers (H/M-LE = 0.41 × H/M-ME + 0.63, R\(^2\) = 0.97, p < 0.001). A linear conversion of H/M ratios between collimators and across centers was estimated to be very accurate (mean absolute error 0.05 ± 0.04; mean relative absolute error 3.2 ± 2.6\%). Conclusions The present study demonstrates that a simple linear conversion of H/M ratios acquired with different collimators is possible with high accuracy. This should greatly facilitate the exchange of normative data between settings and pooling of data from different institutions.}, language = {en} } @article{KienerChenKrebsetal.2019, author = {Kiener, Mirjam and Chen, Lanpeng and Krebs, Markus and Grosjean, Joȅl and Klima, Irena and Kalogirou, Charis and Riedmiller, Hubertus and Kneitz, Burkhard and Thalmann, George N. and Snaar-Jagalska, Ewa and Spahn, Martin and Kruithof-de Julio, Marianna and Zoni, Eugenio}, title = {miR-221-5p regulates proliferation and migration in human prostate cancer cells and reduces tumor growth in vivo}, series = {BMC Cancer}, volume = {19}, journal = {BMC Cancer}, doi = {10.1186/s12885-019-5819-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325762}, year = {2019}, abstract = {Background Despite latest advances in prostate cancer (PCa) therapy, PCa remains the third-leading cause of cancer-related death in European men. Dysregulation of microRNAs (miRNAs), small non-coding RNA molecules with gene expression regulatory function, has been reported in all types of epithelial and haematological cancers. In particular, miR-221-5p alterations have been reported in PCa. Methods miRNA expression data was retrieved from a comprehensive publicly available dataset of 218 PCa patients (GSE21036) and miR-221-5p expression levels were analysed. The functional role of miR-221-5p was characterised in androgen- dependent and androgen- independent PCa cell line models (C4-2 and PC-3M-Pro4 cells) by miR-221-5p overexpression and knock-down experiments. The metastatic potential of highly aggressive PC-3M-Pro4 cells overexpressing miR-221-5p was determined by studying extravasation in a zebrafish model. Finally, the effect of miR-221-5p overexpression on the growth of PC-3M-Pro4luc2 cells in vivo was studied by orthotopic implantation in male Balb/cByJ nude mice and assessment of tumor growth. Results Analysis of microRNA expression dataset for human primary and metastatic PCa samples and control normal adjacent benign prostate revealed miR-221-5p to be significantly downregulated in PCa compared to normal prostate tissue and in metastasis compared to primary PCa. Our in vitro data suggest that miR-221-5p overexpression reduced PCa cell proliferation and colony formation. Furthermore, miR-221-5p overexpression dramatically reduced migration of PCa cells, which was associated with differential expression of selected EMT markers. The functional changes of miR-221-5p overexpression were reversible by the loss of miR-221-5p levels, indicating that the tumor suppressive effects were specific to miR-221-5p. Additionally, miR-221-5p overexpression significantly reduced PC-3M-Pro4 cell extravasation and metastasis formation in a zebrafish model and decreased tumor burden in an orthotopic mouse model of PCa. Conclusions Together these data strongly support a tumor suppressive role of miR-221-5p in the context of PCa and its potential as therapeutic target.}, language = {en} } @article{KlementAbbasiSengerAdebahretal.2019, author = {Klement, Rainer J. and Abbasi-Senger, N. and Adebahr, S. and Alheid, H. and Allgaeuer, M. and Becker, G. and Blanck, O. and Boda-Heggemann, J. and Brunner, T. and Duma, M. and Eble, M. J. and Ernst, I. and Gerum, S. and Habermehl, D. and Hass, P. and Henkenberens, C. and Hildebrandt, G. and Imhoff, D. and Kahl, H. and Klass, N. D. and Krempien, R. and Lewitzki, V. and Lohaus, F. and Ostheimer, C. and Papachristofilou, A. and Petersen, C. and Rieber, J. and Schneider, T. and Schrade, E. and Semrau, R. and Wachter, S. and Wittig, A. and Guckenberger, M. and Andratschke, N.}, title = {The impact of local control on overall survival after stereotactic body radiotherapy for liver and lung metastases from colorectal cancer: a combined analysis of 388 patients with 500 metastases}, series = {BMC Cancer}, volume = {19}, journal = {BMC Cancer}, doi = {10.1186/s12885-019-5362-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325877}, year = {2019}, abstract = {Background The aim of this analysis was to model the effect of local control (LC) on overall survival (OS) in patients treated with stereotactic body radiotherapy (SBRT) for liver or lung metastases from colorectal cancer. Methods The analysis is based on pooled data from two retrospective SBRT databases for pulmonary and hepatic metastases from 27 centers from Germany and Switzerland. Only patients with metastases from colorectal cancer were considered to avoid histology as a confounding factor. An illness-death model was employed to model the relationship between LC and OS. Results Three hundred eighty-eight patients with 500 metastatic lesions (lung n = 209, liver n = 291) were included and analyzed. Median follow-up time for local recurrence assessment was 12.1 months. Ninety-nine patients with 112 lesions experienced local failure. Seventy-one of these patients died after local failure. Median survival time was 27.9 months in all patients and 25.4 months versus 30.6 months in patients with and without local failure after SBRT. The baseline risk of death after local failure exceeds the baseline risk of death without local failure at 10 months indicating better survival with LC. Conclusion In CRC patients with lung or liver metastases, our findings suggest improved long-term OS by achieving metastatic disease control using SBRT in patients with a projected OS estimate of > 12 months.}, language = {en} } @article{HoertererBaumbachLemperleetal.2019, author = {H{\"o}rterer, Hubert and Baumbach, Sebastian Felix and Lemperle, Stefan and Altenberger, Sebastian and Gottschalk, Oliver and Mehlhorn, Alexander Tobias and R{\"o}ser, Anke and Walther, Markus}, title = {Clinical outcome and concomitant injuries in operatively treated fractures of the lateral process of the talus}, series = {BMC Musculoskeletal Disorders}, volume = {20}, journal = {BMC Musculoskeletal Disorders}, doi = {10.1186/s12891-019-2603-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321207}, year = {2019}, abstract = {Background The aim of this study was to review the patient rated outcome (PROM) of surgically treated fractures to the lateral process of the talus (LPTF) and identify factors influencing the outcome. Methods Retrospective study with a current follow-up. Eligible were all patients treated surgically for a LPTF (n = 23) with a minimum follow-up of one year. Demographics, medical history, trauma mechanism, fracture characteristics, concomitant injuries, treatment details, complications, return to work and sports were assessed retrospectively. The current follow-up included the VAS FA, Karlsson Score, and SF-12. The primary outcome was the VAS FA. Secondary aim was the identification of parameters influencing the PROMs. Results 22 patients (96\% follow-up) with a mean age of 32 ± 9 (18 to 49) years were included. 73\% suffered a Hawkins Type 1, 23\% a Type 2, and one patient a Type 3 fracture. 82\% suffered concomitant injuries. 9\% suffered minor surgical side infections, 50\% developed symptomatic subtalar osteoarthritis. At final follow-up (44 ± 2 (12 to 97) months), the mean VAS FA Overall was 77 ± 21 (20 to 100), the Karlsson Score 72 ± 21 (34 to 97), and for the SF 12 the PCS 53 ± 8 (36 to 64) and the MCS 53 ± 7 (32 to 63). 50\% of patients returned to their previous level of sports. Hawkins Type 1 fractures resulted in better VAS FA Overall score than Type 2 fractures. Posttraumatic subtalar osteoarthritis was the independent factor associated to a poor patient rated outcome (VAS FA, Karlsson Score). Conclusion After a follow-up of over 3.5 years, surgically treated LPTF resulted in only moderate results. 50\% suffered posttraumatic symptomatic subtalar osteoarthritis, which was the primary independent parameter for a poor outcome following LPTF. Level of evidence Level III.}, language = {en} } @article{RichterKruppaMunzetal.2019, author = {Richter, Gesa M. and Kruppa, Jochen and Munz, Matthias and Wiehe, Ricarda and H{\"a}sler, Robert and Franke, Andre and Martins, Orlando and Jockel-Schneider, Yvonne and Bruckmann, Corinna and Dommisch, Henrik and Schaefer, Arne S.}, title = {A combined epigenome- and transcriptome-wide association study of the oral masticatory mucosa assigns CYP1B1 a central role for epithelial health in smokers}, series = {Clinical Epigenetics}, volume = {11}, journal = {Clinical Epigenetics}, doi = {10.1186/s13148-019-0697-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226175}, pages = {1-18}, year = {2019}, abstract = {Background The oral mucosa has an important role in maintaining barrier integrity at the gateway to the gastrointestinal and respiratory tracts. Smoking is a strong environmental risk factor for the common oral inflammatory disease periodontitis and oral cancer. Cigarette smoke affects gene methylation and expression in various tissues. This is the first epigenome-wide association study (EWAS) that aimed to identify biologically active methylation marks of the oral masticatory mucosa that are associated with smoking. Results Ex vivo biopsies of 18 current smokers and 21 never smokers were analysed with the Infinium Methylation EPICBeadChip and combined with whole transcriptome RNA sequencing (RNA-Seq; 16 mio reads per sample) of the same samples. We analysed the associations of CpG methylation values with cigarette smoking and smoke pack year (SPY) levels in an analysis of covariance (ANCOVA). Nine CpGs were significantly associated with smoking status, with three CpGs mapping to the genetic region of CYP1B1 (cytochrome P450 family 1 subfamily B member 1;best p=5.5x10(-8)) and two mapping to AHRR (aryl-hydrocarbon receptor repressor; best p=5.9x10(-9)). In the SPY analysis, 61 CpG sites at 52 loci showed significant associations of the quantity of smoking with changes in methylation values. Here, the most significant association located to the gene CYP1B1, with p=4.0x10(-10). RNA-Seq data showed significantly increased expression of CYP1B1 in smokers compared to non-smokers (p=2.2x10(-14)), together with 13 significantly upregulated transcripts. Six transcripts were significantly downregulated. No differential expression was observed for AHRR. In vitro studies with gingival fibroblasts showed that cigarette smoke extract directly upregulated the expression of CYP1B1. Conclusion This study validated the established role of CYP1B1 and AHRR in xenobiotic metabolism of tobacco smoke and highlights the importance of epigenetic regulation for these genes. For the first time, we give evidence of this role for the oral masticatory mucosa.}, subject = {AHRR}, language = {en} } @article{WagnerKunzChowdhuryetal.2019, author = {Wagner, Fabienne and Kunz, Tobias C. and Chowdhury, Suvagata R. and Thiede, Bernd and Fraunholz, Martin and Eger, Debora and Kozjak-Pavlovic, Vera}, title = {Armadillo repeat-containing protein 1 is a dual localization protein associated with mitochondrial intermembrane space bridging complex}, series = {PLoS ONE}, volume = {14}, journal = {PLoS ONE}, number = {10}, doi = {10.1371/journal.pone.0218303}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202670}, pages = {e0218303}, year = {2019}, abstract = {Cristae architecture is important for the function of mitochondria, the organelles that play the central role in many cellular processes. The mitochondrial contact site and cristae organizing system (MICOS) together with the sorting and assembly machinery (SAM) forms the mitochondrial intermembrane space bridging complex (MIB), a large protein complex present in mammalian mitochondria that partakes in the formation and maintenance of cristae. We report here a new subunit of the mammalian MICOS/MIB complex, an armadillo repeat-containing protein 1 (ArmC1). ArmC1 localizes both to cytosol and mitochondria, where it associates with the outer mitochondrial membrane through its carboxy-terminus. ArmC1 interacts with other constituents of the MICOS/MIB complex and its amounts are reduced upon MICOS/MIB complex depletion. Mitochondria lacking ArmC1 do not show defects in cristae structure, respiration or protein content, but appear fragmented and with reduced motility. ArmC1 represents therefore a peripheral MICOS/MIB component that appears to play a role in mitochondrial distribution in the cell.}, language = {en} } @article{BelkaNickelKurth2019, author = {Belka, Janina and Nickel, Joachim and Kurth, Dirk G.}, title = {Growth on metallo-supramolecular coordination polyelectrolyte (MEPE) stimulates osteogenic differentiation of human osteosarcoma cells (MG63) and human bone marrow derived mesenchymal stem cells}, series = {Polymers}, volume = {11}, journal = {Polymers}, number = {7}, issn = {2073-4360}, doi = {10.3390/polym11071090}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197264}, pages = {1090}, year = {2019}, abstract = {Background: Culturing of cells is typically performed on standard tissue culture plates generating growth conditions, which in general do not reflect the native three-dimensional cellular environment. Recent investigations provide insights in parameters, which strongly affect the general cellular behavior triggering essential processes such as cell differentiation. The physical properties of the used material, such as stiffness, roughness, or topology, as well as the chemical composition of the cell-surface interface are shown to play a key role in the initiation of particular cellular responses. Methods: We extended our previous research, which identified thin films of metallo-supramolecular coordination polyelectrolytes (MEPEs) as substrate to trigger the differentiation of muscular precursor cells. Results: Here, we show that the same MEPEs similarly stimulate the osteogenic differentiation of pre-osteoblasts. Remarkably, MEPE modified surfaces also trigger the differentiation of primary bone derived mesenchymal stem cells (BMSCs) towards the osteogenic lineage. Conclusion: This result leads to the conclusion that these surfaces individually support the specification of cell differentiation toward lineages that correspond to the natural commitment of the particular cell types. We, therefore, propose that Fe-MEPEs may be used as scaffold for the treatment of defects at least in muscular or bone tissue.}, language = {en} } @article{ReuschHolzmeierGerlachetal.2019, author = {Reusch, Engelbert and Holzmeier, Fabian and Gerlach, Marius and Fischer, Ingo and Hemberger, Patrick}, title = {Decomposition of Picolyl Radicals at High Temperature: A Mass Selective Threshold Photoelectron Spectroscopy Study}, series = {Chemistry - A European Journal}, volume = {25}, journal = {Chemistry - A European Journal}, number = {72}, doi = {10.1002/chem.201903937}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-208132}, pages = {16652-16659}, year = {2019}, abstract = {The reaction products of the picolyl radicals at high temperature were characterized by mass-selective threshold photoelectron spectroscopy in the gas phase. Aminomethylpyridines were pyrolyzed to initially produce picolyl radicals (m /z =92). At higher temperatures further thermal reaction products are generated in the pyrolysis reactor. All compounds were identified by mass-selected threshold photoelectron spectroscopy and several hitherto unexplored reactive molecules were characterized. The mechanism for several dissociation pathways was outlined in computations. The spectrum of m /z =91, resulting from hydrogen loss of picolyl, shows four isomers, two ethynyl pyrroles with adiabatic ionization energies (IE\(_{ad}\)) of 7.99 eV (2-ethynyl-1H -pyrrole) and 8.12 eV (3-ethynyl-1H -pyrrole), and two cyclopentadiene carbonitriles with IE′s of 9.14 eV (cyclopenta-1,3-diene-1-carbonitrile) and 9.25 eV (cyclopenta-1,4-diene-1-carbonitrile). A second consecutive hydrogen loss forms the cyanocyclopentadienyl radical with IE′s of 9.07 eV (T\(_0\)) and 9.21 eV (S\(_1\)). This compound dissociates further to acetylene and the cyanopropynyl radical (IE=9.35 eV). Furthermore, the cyclopentadienyl radical, penta-1,3-diyne, cyclopentadiene and propargyl were identified in the spectra. Computations indicate that dissociation of picolyl proceeds initially via a resonance-stabilized seven-membered ring.}, language = {en} } @article{RuizDiefenbacherNelsonetal.2019, author = {Ruiz, E. Josue and Diefenbacher, Markus E. and Nelson, Jessica K. and Sancho, Rocio and Pucci, Fabio and Chakraborty, Atanu and Moreno, Paula and Annibaldi, Alessandro and Liccardi, Gianmaria and Encheva, Vesela and Mitter, Richard and Rosenfeldt, Mathias and Snijders, Ambrosius P. and Meier, Pascal and Calzado, Marco A. and Behrens, Axel}, title = {LUBAC determines chemotherapy resistance in squamous cell lung cancer}, series = {Journal of Experimental Medicine}, volume = {216}, journal = {Journal of Experimental Medicine}, number = {2}, doi = {10.1084/jem.20180742}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227146}, pages = {450-465}, year = {2019}, abstract = {Lung squamous cell carcinoma (LSCC) and adenocarcinoma (LADC) are the most common lung cancer subtypes. Molecular targeted treatments have improved LADC patient survival but are largely ineffective in LSCC. The tumor suppressor FBW7 is commonly mutated or down-regulated in human LSCC, and oncogenic KRasG12D activation combined with Fbxw7 inactivation in mice (KF model) caused both LSCC and LADC. Lineage-tracing experiments showed that CC10(+), but not basal, cells are the cells of origin of LSCC in KF mice. KF LSCC tumors recapitulated human LSCC resistance to cisplatin-based chemotherapy, and we identified LUBAC-mediated NF-kappa B signaling as a determinant of chemotherapy resistance in human and mouse. Inhibition of NF-kappa B activation using TAK1 or LUBAC inhibitors resensitized LSCC tumors to cisplatin, suggesting a future avenue for LSCC patient treatment.}, language = {en} } @article{WoersdoerferDaldaKernetal.2019, author = {W{\"o}rsd{\"o}rfer, Philipp and Dalda, Nahide and Kern, Anna and Kr{\"u}ger, Sarah and Wagner, Nicole and Kwok, Chee Keong and Henke, Erik and Erg{\"u}n, S{\"u}leyman}, title = {Generation of complex human organoid models including vascular networks by incorporation of mesodermal progenitor cells}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-52204-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202681}, pages = {15663}, year = {2019}, abstract = {Organoids derived from human pluripotent stem cells are interesting models to study mechanisms of morphogenesis and promising platforms for disease modeling and drug screening. However, they mostly remain incomplete as they lack stroma, tissue resident immune cells and in particular vasculature, which create important niches during development and disease. We propose, that the directed incorporation of mesodermal progenitor cells (MPCs) into organoids will overcome the aforementioned limitations. In order to demonstrate the feasibility of the method, we generated complex human tumor as well as neural organoids. We show that the formed blood vessels display a hierarchic organization and mural cells are assembled into the vessel wall. Moreover, we demonstrate a typical blood vessel ultrastructure including endothelial cell-cell junctions, a basement membrane as well as luminal caveolae and microvesicles. We observe a high plasticity in the endothelial network, which expands, while the organoids grow and is responsive to anti-angiogenic compounds and pro-angiogenic conditions such as hypoxia. We show that vessels within tumor organoids connect to host vessels following transplantation. Remarkably, MPCs also deliver Iba1\(^+\) cells that infiltrate the neural tissue in a microglia-like manner.}, language = {en} } @article{DietrichMeisterDietrichetal.2019, author = {Dietrich, Laura and Meister, Julia and Dietrich, Oliver and Notroff, Jens and Kiep, Janika and Heeb, Julia and Beuger, Andr{\´e} and Sch{\"u}tt, Brigitta}, title = {Cereal processing at Early Neolithic G{\"o}bekli Tepe, southeastern Turkey}, series = {PLoS ONE}, volume = {14}, journal = {PLoS ONE}, number = {5}, doi = {10.1371/journal.pone.0215214}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201504}, pages = {e0215214}, year = {2019}, abstract = {We analyze the processing of cereals and its role at Early Neolithic G{\"o}bekli Tepe, southeastern Anatolia (10th / 9th millennium BC), a site that has aroused much debate in archaeological discourse. To date, only zooarchaeological evidence has been discussed in regard to the subsistence of its builders. G{\"o}bekli Tepe consists of monumental round to oval buildings, erected in an earlier phase, and smaller rectangular buildings, built around them in a partially contemporaneous and later phase. The monumental buildings are best known as they were in the focus of research. They are around 20 m in diameter and have stone pillars that are up to 5.5 m high and often richly decorated. The rectangular buildings are smaller and-in some cases-have up to 2 m high, mostly undecorated, pillars. Especially striking is the number of tools related to food processing, including grinding slabs/bowls, handstones, pestles, and mortars, which have not been studied before. We analyzed more than 7000 artifacts for the present contribution. The high frequency of artifacts is unusual for contemporary sites in the region. Using an integrated approach of formal, experimental, and macro- / microscopical use-wear analyses we show that Neolithic people at G{\"o}bekli Tepe have produced standardized and efficient grinding tools, most of which have been used for the processing of cereals. Additional phytolith analysis confirms the massive presence of cereals at the site, filling the gap left by the weakly preserved charred macro-rests. The organization of work and food supply has always been a central question of research into G{\"o}bekli Tepe, as the construction and maintenance of the monumental architecture would have necessitated a considerable work force. Contextual analyses of the distribution of the elements of the grinding kit on site highlight a clear link between plant food preparation and the rectangular buildings and indicate clear delimitations of working areas for food production on the terraces the structures lie on, surrounding the circular buildings. There is evidence for extensive plant food processing and archaeozoological data hint at large-scale hunting of gazelle between midsummer and autumn. As no large storage facilities have been identified, we argue for a production of food for immediate use and interpret these seasonal peaks in activity at the site as evidence for the organization of large work feasts.}, language = {en} } @article{WegenerSauer2019, author = {Wegener, Sonja and Sauer, Otto A.}, title = {The effective point of measurement for depth-dose measurements in small MV photon beams with different detectors}, series = {Medical Physics}, volume = {46}, journal = {Medical Physics}, number = {11}, doi = {10.1002/mp.13788}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206148}, pages = {5209-5215}, year = {2019}, abstract = {Purpose: The effective point of measurement (EPOM) of cylindrical ionization chambers differs from their geometric center. The exact shift depends on chamber construction details, above all the chamber size, and to some degree on the field-size and beam quality. It generally decreases as the chamber dimensions get smaller. In this work, effective points of measurement in small photon fields of a range of cylindrical chambers of different sizes are investigated, including small chambers that have not been studied previously. Methods: In this investigation, effective points of measurement for different ionization chambers (Farmer type, scanning chambers, micro-ionization chambers) and solid state detectors were determined by measuring depth-ionization curves in a 6 MV beam in field sizes between 2 9 2 cm2 and 10 9 10 cm2 and comparing those curves with curves measured with plane-parallel chambers. Results: It was possible to average the results to one shift per detector, as the results were sufficiently independent of the studied field sizes. For cylindrical ion chambers, shifts of the EPOM were determined to be between 0.49 and 0.30 times the inner chamber radius from the reference point. Conclusions: We experimentally confirmed the previously reported decrease of the EPOM shift with decreasing detector size. Highly accurate data for a large range of detectors, including new very small ones, were determined. Thus, small chambers noticeably differ from the 0.5-times to 0.6-times the inner chamber radius recommendations in current dosimetry protocols. The detector-individual EPOMs need to be considered for measurements of depth-dose curves.}, language = {en} } @article{KammererHoppenstedtPryssetal.2019, author = {Kammerer, Klaus and Hoppenstedt, Burkhard and Pryss, R{\"u}diger and St{\"o}kler, Steffen and Allgaier, Johannes and Reichert, Manfred}, title = {Anomaly Detections for Manufacturing Systems Based on Sensor Data—Insights into Two Challenging Real-World Production Settings}, series = {Sensors}, volume = {19}, journal = {Sensors}, number = {24}, issn = {1424-8220}, doi = {10.3390/s19245370}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193885}, pages = {5370}, year = {2019}, abstract = {o build, run, and maintain reliable manufacturing machines, the condition of their components has to be continuously monitored. When following a fine-grained monitoring of these machines, challenges emerge pertaining to the (1) feeding procedure of large amounts of sensor data to downstream processing components and the (2) meaningful analysis of the produced data. Regarding the latter aspect, manifold purposes are addressed by practitioners and researchers. Two analyses of real-world datasets that were generated in production settings are discussed in this paper. More specifically, the analyses had the goals (1) to detect sensor data anomalies for further analyses of a pharma packaging scenario and (2) to predict unfavorable temperature values of a 3D printing machine environment. Based on the results of the analyses, it will be shown that a proper management of machines and their components in industrial manufacturing environments can be efficiently supported by the detection of anomalies. The latter shall help to support the technical evangelists of the production companies more properly.}, language = {en} } @article{KittelSchneiderWolffQueiseretal.2019, author = {Kittel-Schneider, Sarah and Wolff, Sarah and Queiser, Kristin and Wessendorf, Leonie and Meier, Anna Maria and Verdenhalven, Moritz and Brunkhorst-Kanaan, Nathalie and Grimm, Oliver and McNeill, Rhiannon and Grabow, Sascha and Reimertz, Christoph and Nau, Christoph and Klos, Michelle and Reif, Andreas}, title = {Prevalence of ADHD in accident victims: results of the PRADA study}, series = {Journal of Clinical Medicine}, volume = {8}, journal = {Journal of Clinical Medicine}, number = {10}, issn = {2077-0383}, doi = {10.3390/jcm8101643}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193293}, pages = {1643}, year = {2019}, abstract = {Background: Recent research has shown an increased risk of accidents and injuries in ADHD patients, which could potentially be reduced by stimulant treatment. Therefore, the first aim of our study was to evaluate the prevalence of adult ADHD in a trauma surgery population. The second aim was to investigate accident mechanisms and circumstances which could be specific to ADHD patients, in comparison to the general population. Methods: We screened 905 accident victims for ADHD using the ASRS 18-item self-report questionnaire. The basic demographic data and circumstances of the accidents were also assessed. Results: Prevalence of adult ADHD was found to be 6.18\% in our trauma surgery patient sample. ADHD accident victims reported significantly higher rates of distraction, stress and overconfidence in comparison to non-ADHD accident victims. Overconfidence and being in thoughts as causal mechanisms for the accidents remained significantly higher in ADHD patients after correction for multiple comparison. ADHD patients additionally reported a history of multiple accidents. Conclusion: The majority of ADHD patients in our sample had not previously been diagnosed and were therefore not receiving treatment. The results subsequently suggest that general ADHD screening in trauma surgery patients may be useful in preventing further accidents in ADHD patients. Furthermore, psychoeducation regarding specific causal accident mechanisms could be implemented in ADHD therapy to decrease accident incidence rate}, language = {en} } @article{DrayssClausHubertetal.2019, author = {Drayß, Maria and Claus, Heike and Hubert, Kerstin and Thiel, Katrin and Berger, Anja and Sing, Andreas and van der Linden, Mark and Vogel, Ulrich and L{\^a}m, Thi{\^e}n-Tr{\´i}}, title = {Asymptomatic carriage of Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, Group A Streptococcus and Staphylococcus aureus among adults aged 65 years and older}, series = {PLoS ONE}, volume = {14}, journal = {PLoS ONE}, number = {2}, doi = {10.1371/journal.pone.0212052}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201042}, pages = {e0212052}, year = {2019}, abstract = {Objective The aim of this study was to determine the prevalence of Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, group A Streptococcus (GAS), and Staphylococcus aureus in asymptomatic elderly people and to unravel risk factors leading to colonization. Methods A multi-centre cross-sectional study was conducted including 677 asymptomatic adults aged 65 years or more, living at home or in nursing homes. Study areas were Greater Aachen (North-Rhine-Westphalia) and Wuerzburg (Bavaria), both regions with medium to high population density. Nasal and oropharyngeal swabs as well as questionnaires were collected from October 2012 to May 2013. Statistical analysis included multiple logistic regression models. Results The carriage rate was 1.9\% ([95\%CI: 1.0-3.3\%]; 13/677) for H. influenzae, 0.3\% ([95\%CI: 0-1.1\%]; 2/677) for N. meningitidis and 0\% ([95\% CI: 0-0.5\%]; 0/677) for S. pneumoniae and GAS. Staphylococcus aureus was harboured by 28.5\% of the individuals ([95\% CI: 25.1-32.1\%]; 193/677) and 0.7\% ([95\% CI: 0.2-1.7\%]; 5/677) were positive for methicillin-resistant S. aureus. Among elderly community-dwellers colonization with S. aureus was significantly associated with higher educational level (adjusted OR: 1.905 [95\% CI: 1.248-2.908]; p = 0.003). Among nursing home residents colonization was associated with being married (adjusted OR: 3.367 [1.502-7.546]; p = 0.003). Conclusion The prevalence of N. meningitidis, H. influenzae, S. pneumoniae and GAS was low among older people in Germany. The S. aureus rate was expectedly high, while MRSA was found in less than 1\% of the individuals.}, language = {en} } @article{PasosSteigerwaldReichetal.2019, author = {Pasos, Uri E. Ramirez and Steigerwald, Frank and Reich, Martin M. and Matthies, Cordula and Volkmann, Jens and Reese, Ren{\´e}}, title = {Levodopa modulates functional connectivity in the upper beta band between bubthalamic nucleus and muscle activity in tonic and phasic motor activity patterns in Parkinson's disease}, series = {Frontiers in Human Neuroscience}, volume = {13}, journal = {Frontiers in Human Neuroscience}, number = {223}, doi = {10.3389/fnhum.2019.00223}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201540}, year = {2019}, abstract = {Introduction: Striatal dopamine depletion disrupts basal ganglia function and causes Parkinson's disease (PD). The pathophysiology of the dopamine-dependent relationship between basal ganglia signaling and motor control, however, is not fully understood. We obtained simultaneous recordings of local field potentials (LFPs) from the subthalamic nucleus (STN) and electromyograms (EMGs) in patients with PD to investigate the impact of dopaminergic state and movement on long-range beta functional connectivity between basal ganglia and lower motor neurons. Methods: Eight PD patients were investigated 3 months after implantation of a deep brain stimulation (DBS)-system capable of recording LFPs via chronically-implanted leads (Medtronic, ACTIVA PC+S®). We analyzed STN spectral power and its coherence with EMG in the context of two different movement paradigms (tonic wrist extension vs. alternating wrist extension and flexion) and the effect of levodopa (L-Dopa) intake using an unbiased data-driven approach to determine regions of interest (ROI). Results: Two ROIs capturing prominent coherence within a grand average coherogram were identified. A trend of a dopamine effect was observed for the first ROI (50-150 ms after movement start) with higher STN-EMG coherence in medicated patients. Concerning the second ROI (300-500 ms after movement start), an interaction effect of L-Dopa medication and movement task was observed with higher coherence in the isometric contraction task compared to alternating movements in the medication ON state, a pattern which was reversed in L-Dopa OFF. Discussion: L-Dopa medication may normalize functional connectivity between remote structures of the motor system with increased upper beta coherence reflecting a physiological restriction of the amount of information conveyed between remote structures. This may be necessary to maintain simple movements like isometric contraction. Our study adds dynamic properties to the complex interplay between STN spectral beta power and the nucleus' functional connectivity to remote structures of the motor system as a function of movement and dopaminergic state. This may help to identify markers of neuronal activity relevant for more individualized programming of DBS therapy.}, language = {en} } @article{DjuzenovaFiedlerMemmeletal.2019, author = {Djuzenova, Cholpon S. and Fiedler, Vanessa and Memmel, Simon and Katzer, Astrid and Sisario, Dmitri and Brosch, Philippa K. and G{\"o}hrung, Alexander and Frister, Svenja and Zimmermann, Heiko and Flentje, Michael and Sukhorukov, Vladimir L.}, title = {Differential effects of the Akt inhibitor MK-2206 on migration and radiation sensitivity of glioblastoma cells}, series = {BMC Cancer}, volume = {19}, journal = {BMC Cancer}, doi = {10.1186/s12885-019-5517-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200290}, pages = {299}, year = {2019}, abstract = {Background Most tumor cells show aberrantly activated Akt which leads to increased cell survival and resistance to cancer radiotherapy. Therefore, targeting Akt can be a promising strategy for radiosensitization. Here, we explore the impact of the Akt inhibitor MK-2206 alone and in combination with the dual PI3K and mTOR inhibitor PI-103 on the radiation sensitivity of glioblastoma cells. In addition, we examine migration of drug-treated cells. Methods Using single-cell tracking and wound healing migration tests, colony-forming assay, Western blotting, flow cytometry and electrorotation we examined the effects of MK-2206 and PI-103 and/or irradiation on the migration, radiation sensitivity, expression of several marker proteins, DNA damage, cell cycle progression and the plasma membrane properties in two glioblastoma (DK-MG and SNB19) cell lines, previously shown to differ markedly in their migratory behavior and response to PI3K/mTOR inhibition. Results We found that MK-2206 strongly reduces the migration of DK-MG but only moderately reduces the migration of SNB19 cells. Surprisingly, MK-2206 did not cause radiosensitization, but even increased colony-forming ability after irradiation. Moreover, MK-2206 did not enhance the radiosensitizing effect of PI-103. The results appear to contradict the strong depletion of p-Akt in MK-2206-treated cells. Possible reasons for the radioresistance of MK-2206-treated cells could be unaltered or in case of SNB19 cells even increased levels of p-mTOR and p-S6, as compared to the reduced expression of these proteins in PI-103-treated samples. We also found that MK-2206 did not enhance IR-induced DNA damage, neither did it cause cell cycle distortion, nor apoptosis nor excessive autophagy. Conclusions Our study provides proof that MK-2206 can effectively inhibit the expression of Akt in two glioblastoma cell lines. However, due to an aberrant activation of mTOR in response to Akt inhibition in PTEN mutated cells, the therapeutic window needs to be carefully defined, or a combination of Akt and mTOR inhibitors should be considered.}, language = {en} } @article{StrahlGerlichAlpersetal.2019, author = {Strahl, Andr{\´e} and Gerlich, Christian and Alpers, Georg W. and Gehrke, J{\"o}rg and M{\"u}ller-Garnn, Annette and Vogel, Heiner}, title = {An instrument for quality assurance in work capacity evaluation: development, evaluation, and inter-rater reliability}, series = {BMC Health Services Research}, volume = {19}, journal = {BMC Health Services Research}, doi = {10.1186/s12913-019-4387-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200289}, pages = {556}, year = {2019}, abstract = {Background: Employees insured in pension insurance, who are incapable of working due to ill health, are entitled to a disability pension. To assess whether an individual meets the medical requirements to be considered as disabled, a work capacity evaluation is conducted. However, there are no official guidelines on how to perform an external quality assurance for this evaluation process. Furthermore, the quality of medical reports in the field of insurance medicine can vary substantially, and systematic evaluations are scarce. Reliability studies using peer review have repeatedly shown insufficient ability to distinguish between high, moderate and low quality. Considering literature recommendations, we developed an instrument to examine the quality of medical experts'reports. Methods: The peer review manual developed contains six quality domains (formal structure, clarity, transparency, completeness, medical-scientific principles, and efficiency) comprising 22 items. In addition, a superordinate criterion (survey confirmability) rank the overall quality and usefulness of a report. This criterion evaluates problems of innerlogic and reasoning. Development of the manual was assisted by experienced physicians in a pre-test. We examined the observable variance in peer judgements and reliability as the most important outcome criteria. To evaluate inter-rater reliability, 20 anonymous experts' reports detailing the work capacity evaluation were reviewed by 19 trained raters (peers). Percentage agreement and Kendall's W, a reliability measure of concordance between two or more peers, were calculated. A total of 325 reviews were conducted. Results: Agreement of peer judgements with respect to the superordinate criterion ranged from 29.2 to 87.5\%. Kendall's W for the quality domain items varied greatly, ranging from 0.09 to 0.88. With respect to the superordinate criterion, Kendall's W was 0.39, which indicates fair agreement. The results of the percentage agreement revealed systemic peer preferences for certain deficit scale categories. Conclusion: The superordinate criterion was not sufficiently reliable. However, in comparison to other reliability studies, this criterion showed an equivalent reliability value. This report aims to encourage further efforts to improve evaluation instruments. To reduce disagreement between peer judgments, we propose the revision of the peer review instrumentand the development and implementation of a standardized rater training to improve reliability.}, language = {en} } @article{NoHolzmeisterLuetal.2019, author = {No, Young Jung and Holzmeister, Ib and Lu, Zufu and Prajapati, Shubham and Shi, Jeffrey and Gbureck, Uwe and Zreiqat, Hala}, title = {Effect of Baghdadite Substitution on the Physicochemical Properties of Brushite Cements}, series = {Materials}, volume = {12}, journal = {Materials}, number = {10}, issn = {1996-1944}, doi = {10.3390/ma12101719}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196980}, year = {2019}, abstract = {Brushite cements have been clinically used for irregular bone defect filling applications, and various strategies have been previously reported to modify and improve their physicochemical properties such as strength and injectability. However, strategies to address other limitations of brushite cements such as low radiopacity or acidity without negatively impacting mechanical strength have not yet been reported. In this study, we report the effect of substituting the beta-tricalcium phosphate reactant in brushite cement with baghdadite (Ca\(_3\)ZrSi\(_2\)O\(_9\)), a bioactive zirconium-doped calcium silicate ceramic, at various concentrations (0, 5, 10, 20, 30, 50, and 100 wt\%) on the properties of the final brushite cement product. X-ray diffraction profiles indicate the dissolution of baghdadite during the cement reaction, without affecting the crystal structure of the precipitated brushite. EDX analysis shows that calcium is homogeneously distributed within the cement matrix, while zirconium and silicon form cluster-like aggregates with sizes ranging from few microns to more than 50 µm. X-ray images and µ-CT analysis indicate enhanced radiopacity with increased incorporation of baghdadite into brushite cement, with nearly a doubling of the aluminium equivalent thickness at 50 wt\% baghdadite substitution. At the same time, compressive strength of brushite cement increased from 12.9 ± 3.1 MPa to 21.1 ± 4.1 MPa with 10 wt\% baghdadite substitution. Culture medium conditioned with powdered brushite cement approached closer to physiological pH values when the cement is incorporated with increasing amounts of baghdadite (pH = 6.47 for pure brushite, pH = 7.02 for brushite with 20 wt\% baghdadite substitution). Baghdadite substitution also influenced the ionic content in the culture medium, and subsequently affected the proliferative activity of primary human osteoblasts in vitro. This study indicates that baghdadite is a beneficial additive to enhance the radiopacity, mechanical performance and cytocompatibility of brushite cement}, language = {en} } @article{BruecknerMeiningerGrolletal.2019, author = {Br{\"u}ckner, Theresa and Meininger, Markus and Groll, J{\"u}rgen and K{\"u}bler, Alexander C. and Gbureck, Uwe}, title = {Magnesium Phosphate Cement as Mineral Bone Adhesive}, series = {Materials}, volume = {12}, journal = {Materials}, number = {23}, issn = {1996-1944}, doi = {10.3390/ma12233819}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193052}, year = {2019}, abstract = {Mineral bone cements were actually not developed for their application as bone-bonding agents, but as bone void fillers. In particular, calcium phosphate cements (CPC) are considered to be unsuitable for that application, particularly under moist conditions. Here, we showed the ex vivo ability of different magnesium phosphate cements (MPC) to adhere on bovine cortical bone substrates. The cements were obtained from a mixture of farringtonite (Mg\(_3\)(PO\(_4\))\(_2\)) with different amounts of phytic acid (C\(_6\)H\(_{18}\)O\(_{24}\)P\(_6\), inositol hexaphosphate, IP6), whereas cement setting occurred by a chelation reaction between Mg\(^{2+}\) ions and IP6. We were able to show that cements with 25\% IP6 and a powder-to-liquid ratio (PLR) of 2.0 g/mL resulted in shear strengths of 0.81 ± 0.12 MPa on bone even after 7 d storage in aqueous conditions. The samples showed a mixed adhesive-cohesive failure with cement residues on the bone surface as indicated by scanning electron microscopy and energy-dispersive X-ray analysis. The presented material demonstrated appropriate bonding characteristics, which could enable a broadening of the mineral bone cements' application field to bone adhesives}, language = {en} } @article{MottolaMorschhaeuser2019, author = {Mottola, Austin and Morschh{\"a}user, Joachim}, title = {An intragenic recombination event generates a Snf4-independent form of the essential protein kinase SNF1 in Candida albicans}, series = {mSphere}, volume = {4}, journal = {mSphere}, number = {3}, doi = {10.1128/mSphere.00352-19}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202170}, pages = {e00352-19}, year = {2019}, abstract = {The heterotrimeric protein kinase SNF1 plays a key role in the metabolic adaptation of the pathogenic yeast Candida albicans. It consists of the essential catalytic α-subunit Snf1, the γ-subunit Snf4, and one of the two β-subunits Kis1 and Kis2. Snf4 is required to release the N-terminal catalytic domain of Snf1 from autoinhibition by the C-terminal regulatory domain, and snf4Δ mutants cannot grow on carbon sources other than glucose. In a screen for suppressor mutations that restore growth of a snf4Δ mutant on alternative carbon sources, we isolated a mutant in which six amino acids between the N-terminal kinase domain and the C-terminal regulatory domain of Snf1 were deleted. The deletion was caused by an intragenic recombination event between two 8-bp direct repeats flanking six intervening codons. In contrast to truncated forms of Snf1 that contain only the kinase domain, the Snf4-independent Snf1\(^{Δ311 - 316}\) was fully functional and could replace wild-type Snf1 for normal growth, because it retained the ability to interact with the Kis1 and Kis2 β-subunits via its C-terminal domain. Indeed, the Snf4-independent Snf1\(^{Δ311 - 316}\) still required the β-subunits of the SNF1 complex to perform its functions and did not rescue the growth defects of kis1Δ mutants. Our results demonstrate that a preprogrammed in-frame deletion event within the SNF1 coding region can generate a mutated form of this essential kinase which abolishes autoinhibition and thereby overcomes growth deficiencies caused by a defect in the γ-subunit Snf4.}, language = {en} } @article{LuberLutzAbeleHornetal.2019, author = {Luber, Verena and Lutz, Mathias and Abele-Horn, Marianne and Einsele, Hermann and Grigoleit, G{\"o}tz Ulrich and Mielke, Stephan}, title = {Excretion of Ascaris lumbricoides following reduced-intensity allogeneic hematopoietic stem cell transplantation and consecutive treatment with mebendazole}, series = {Transplant Infectious Disease}, volume = {22}, journal = {Transplant Infectious Disease}, number = {1}, issn = {1399-3062}, doi = {10.1111/tid.13224}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219608}, pages = {1-4}, year = {2019}, abstract = {Here, we present the unique case of a 51-year-old German patient with multiple myeloma excreting Ascaris lumbricoides in his stool five weeks after allogeneic hematopoietic stem cell transplantation. Stool analysis remained negative for the presence of eggs, and there was no eosinophilia in the peripheral blood at any time around stem cell transplantation. The patient was commenced on a three-day treatment with mebendazole, which was well tolerated. No serious interactions with the concomitant post-transplant medication or negative effects on the hematopoiesis were observed, and the myeloma still is in complete remission. To our knowledge, this is the first report on excretion of A lumbricoides in the context of allogeneic stem cell transplantation. The case is remarkable with view to the fact that the parasite has supposedly survived all courses of myeloma treatment including autologous and allogeneic conditioning. Parasitosis with A lumbricoides has a worldwide prevalence of about a billion and is extremely rare in northern Europe. Possibly the patient got infected during a trip to Egypt years before multiple myeloma was diagnosed.}, language = {en} } @article{LangePauli2019, author = {Lange, Bastian and Pauli, Paul}, title = {Social anxiety changes the way we move—A social approach-avoidance task in a virtual reality CAVE system}, series = {PLoS ONE}, volume = {14}, journal = {PLoS ONE}, number = {12}, doi = {10.1371/journal.pone.0226805}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200528}, pages = {e0226805}, year = {2019}, abstract = {Investigating approach-avoidance behavior regarding affective stimuli is important in broadening the understanding of one of the most common psychiatric disorders, social anxiety disorder. Many studies in this field rely on approach-avoidance tasks, which mainly assess hand movements, or interpersonal distance measures, which return inconsistent results and lack ecological validity. Therefore, the present study introduces a virtual reality task, looking at avoidance parameters (movement time and speed, distance to social stimulus, gaze behavior) during whole-body movements. These complex movements represent the most ecologically valid form of approach and avoidance behavior. These are at the core of complex and natural social behavior. With this newly developed task, the present study examined whether high socially anxious individuals differ in avoidance behavior when bypassing another person, here virtual humans with neutral and angry facial expressions. Results showed that virtual bystanders displaying angry facial expressions were generally avoided by all participants. In addition, high socially anxious participants generally displayed enhanced avoidance behavior towards virtual people, but no specifically exaggerated avoidance behavior towards virtual people with a negative facial expression. The newly developed virtual reality task proved to be an ecological valid tool for research on complex approach-avoidance behavior in social situations. The first results revealed that whole body approach-avoidance behavior relative to passive bystanders is modulated by their emotional facial expressions and that social anxiety generally amplifies such avoidance.}, language = {en} } @article{ElhfnawyVolkmannSchliesseretal.2019, author = {Elhfnawy, Ahmed Mohamed and Volkmann, Jens and Schliesser, Mira and Fluri, Felix}, title = {Are cerebral white matter lesions related to the presence of bilateral internal carotid artery stenosis or to the length of stenosis among patients with ischemic cerebrovascular events?}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, number = {919}, doi = {10.3389/fneur.2019.00919}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201241}, year = {2019}, abstract = {Background and purpose: Previous studies delivered contradicting results regarding the relation between the presence of an internal carotid artery stenosis (ICAS) and the occurence of white matter lesions (WMLs). We hypothesize that special characteristics related to the ICAS might be related to the WMLs. We examined the relation between the presence of bilateral ICAS, the degree and length of stenosis and ipsi-, contralateral as well as mean white matter lesion load (MWMLL). Methods: In a retrospective cohort, patients with ischemic stroke or transient ischemic attack (TIA) as well as ipsi- and/or contralateral ICAS were identified. The length and degree of ICAS, as well as plaque morphology (hypoechoic, mixed or echogenic), were assessed on ultrasound scans and, if available, the length was also measured on magnetic resonance angiography (MRA) scans, and/or digital subtraction angiography (DSA). The WMLs were assessed in 4 areas separately, (periventricular and deep WMLs on each hemispherer), using the Fazekas scale. The MWMLL was calculated as the mean of these four values. Results: 136 patients with 177 ICAS were identified. A significant correlation between age and MWMLL was observed (Spearman correlation coefficient, ρ = 0.41, p < 0.001). Before adjusting for other risk factors, a significantly positive relation was found between the presence of bilateral ICAS and MWMLL (p = 0.039). The length but not the degree of ICAS showed a very slight trend toward association with ipsilateral WMLs and with MWMLL. In an age-adjusted multivariate logistic regression with MWMLL ≥2 as the outcome measure, atrial fibrillation (OR 3.54, 95\% CI 1.12-11.18, p = 0.03), female sex (OR 3.11, 95\% CI 1.19-8.11, p = 0.02) and diabetes mellitus (OR 2.76, 95\% CI 1.16-6.53, p = 0.02) were significantly related to WMLs, whereas the presence of bilateral stenosis showed a trend toward significance (OR 2.25, 95\% CI 0.93-5.45, p = 0.074). No relation was found between plaque morphology and MWMLL, periventricular, or deep WMLs. Conclusion: We have shown a slight correlation between the length of stenosis and the presence of WMLs which might be due to microembolisation originating from the carotid plaque. However, the presence of bilateral ICAS seems also to be related to WMLs which may point to common underlying vascular risk factors contributing to the occurrence of WML.}, language = {en} } @article{SaraceniLabopinBrechtetal.2019, author = {Saraceni, Francesco and Labopin, Myriam and Brecht, Arne and Kr{\"o}ger, Nicolaus and Eder, Matthias and Tischer, Johanna and Labussiere-Wallet, Helene and Einsele, Hermann and Beelen, Dietrich and Bunjes, Donald and Niederwieser, Dietger and Bochtler, Tilman and Savani, Bipin N. and Mohty, Mohamad and Nagler, Arnon}, title = {Fludarabine-treosulfan compared to thiotepa-busulfan-fludarabine or FLAMSA as conditioning regimen for patients with primary refractory or relapsed acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)}, series = {Journal of Hematology \& Oncology}, volume = {12}, journal = {Journal of Hematology \& Oncology}, number = {44}, doi = {10.1186/s13045-019-0727-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227345}, pages = {1-10}, year = {2019}, abstract = {Background Limited data is available to guide the choice of the conditioning regimen for patients with acute myeloid leukemia (AML) undergoing transplant with persistent disease. Methods We retrospectively compared outcome of fludarabine-treosulfan (FT), thiotepa-busulfan-fludarabine (TBF), and sequential fludarabine, intermediate dose Ara-C, amsacrine, total body irradiation/busulfan, cyclophosphamide (FLAMSA) conditioning in patients with refractory or relapsed AML. Results Complete remission rates at day 100 were 92\%, 80\%, and 88\% for FT, TBF, and FLAMSA, respectively (p=0.13). Non-relapse mortality, incidence of relapse, acute (a) and chronic (c) graft-versus-host disease (GVHD) rates did not differ between the three groups. Overall survival at 2years was 37\% for FT, 24\% for TBF, and 34\% for FLAMSA (p=0.10). Independent prognostic factors for survival were Karnofsky performance score and patient CMV serology (p=0.01; p=0.02), while survival was not affected by age at transplant. The use of anti-thymocyte globulin (ATG) was associated with reduced risk of grade III-IV aGVHD (p=0.02) and cGVHD (p=0.006), with no influence on relapse. Conclusions In conclusion, FT, TBF, and FLAMSA regimens provided similar outcome in patients undergoing transplant with active AML. Survival was determined by patient characteristics as Karnofsky performance score and CMV serology, however was not affected by age at transplant. ATG appears able to reduce the incidence of acute and chronic GVHD without influencing relapse risk.}, language = {en} } @article{PetschkeHelmStaab2019, author = {Petschke, Danny and Helm, Ricardo and Staab, Torsten E.M.}, title = {Data on pure tin by Positron Annihilation Lifetime Spectroscopy (PALS) acquired with a semi-analog/digital setup using DDRS4PALS}, series = {Data in Brief}, volume = {22}, journal = {Data in Brief}, doi = {10.1016/j.dib.2018.11.121}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177698}, pages = {16-29}, year = {2019}, abstract = {Positron annihilation lifetime spectroscopy (PALS) provides a powerful technique for non-destructive microstructure investigations in a broad field of material classes such as metals, semiconductors, polymers or porous glasses. Even though this method is well established for more than five decades, no proper standardization for the used setup configuration and subsequent data processing exists. Eventually, this could lead to an insufficiency of data reproducibility and avoidable deviations. Here we present experimentally obtained and simulated data of positron lifetime spectra at various statistics measured on pure tin (4N-Sn) by using a semi-analog/digital setup, where the digital section consists of the DRS4 evaluation board, "Design and performance of the 6 GHz waveform digitizing chip DRS4" [1]. The analog section consists of nuclear instrument modules (NIM), which externally trigger the DRS4 evaluation board to reduce the digitization and, thus, increase the acquisition efficiency. For the experimentally obtained lifetime spectra, 22Na sealed in Kapton foil served as a positron source, whereas 60Co was used for the acquisition of the prompt spectrum, i.e. the quasi instrument response function. Both types of measurements were carried out under the same conditions. All necessary data and information regarding the data acquisition and data reduction are provided to allow reproducibility by other research groups.}, language = {en} } @article{KehrbergerHolzschuh2019, author = {Kehrberger, Sandra and Holzschuh, Andrea}, title = {Warmer temperatures advance flowering in a spring plant more strongly than emergence of two solitary spring bee species}, series = {PLoS ONE}, volume = {14}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0218824}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201165}, pages = {e0218824}, year = {2019}, abstract = {Climate warming has the potential to disrupt plant-pollinator interactions or to increase competition of co-flowering plants for pollinators, due to species-specific phenological responses to temperature. However, studies focusing on the effect of temperature on solitary bee emergence and the flowering onset of their food plants under natural conditions are still rare. We studied the effect of temperature on the phenology of the two spring bees Osmia cornuta and Osmia bicornis, by placing bee cocoons on eleven grasslands differing in mean site temperature. On seven grasslands, we additionally studied the effect of temperature on the phenology of the red-list plant Pulsatilla vulgaris, which was the first flowering plant, and of co-flowering plants with later flowering. With a warming of 0.1°C, the abundance-weighted mean emergence of O. cornuta males advanced by 0.4 days. Females of both species did not shift their emergence. Warmer temperatures advanced the abundance-weighted mean flowering of P. vulgaris by 1.3 days per 0.1°C increase, but did not shift flowering onset of co-flowering plants. Competition for pollinators between P. vulgaris and co-flowering plants does not increase within the studied temperature range. We demonstrate that temperature advances plant flowering more strongly than bee emergence suggesting an increased risk of pollinator limitation for the first flowers of P. vulgaris.}, language = {en} } @article{LuebtowMarciniakSchmiedeletal.2019, author = {L{\"u}btow, Michael M. and Marciniak, Henning and Schmiedel, Alexander and Roos, Markus and Lambert, Christoph and Luxenhofer, Robert}, title = {Ultra-high to ultra-low drug loaded micelles: Probing host-guest interactions by fluorescence spectroscopy}, series = {Chemistry - A European Journal}, volume = {25}, journal = {Chemistry - A European Journal}, number = {54}, doi = {10.1002/chem.201902619}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206128}, pages = {12601-12610}, year = {2019}, abstract = {Polymer micelles are an attractive means to solubilize water insoluble compounds such as drugs. Drug loading, formulations stability and control over drug release are crucial factors for drug-loaded polymer micelles. The interactions between the polymeric host and the guest molecules are considered critical to control these factors but typically barely understood. Here, we compare two isomeric polymer micelles, one of which enables ultra-high curcumin loading exceeding 50 wt.\%, while the other allows a drug loading of only 25 wt.\%. In the low capacity micelles, steady-state fluorescence revealed a very unusual feature of curcumin fluorescence, a high energy emission at 510 nm. Time-resolved fluorescence upconversion showed that the fluorescence life time of the corresponding species is too short in the high-capacity micelles, preventing an observable emission in steady-state. Therefore, contrary to common perception, stronger interactions between host and guest can be detrimental to the drug loading in polymer micelles.}, subject = {Polymer-drug interaction}, language = {en} } @article{WinterAndelovicKampfetal.2019, author = {Winter, Patrick and Andelovic, Kristina and Kampf, Thomas and Gutjahr, Fabian Tobias and Heidenreich, Julius and Zernecke, Alma and Bauer, Wolfgang Rudolf and Jakob, Peter Michael and Herold, Volker}, title = {Fast self-navigated wall shear stress measurements in the murine aortic archusing radial 4D-phase contrast cardiovascular magnetic resonance at 17.6 T}, series = {Journal of Cardiovascular Magnetic Resonance}, volume = {21}, journal = {Journal of Cardiovascular Magnetic Resonance}, doi = {10.1186/s12968-019-0566-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201120}, pages = {64}, year = {2019}, abstract = {Purpose 4D flow cardiovascular magnetic resonance (CMR) and the assessment of wall shear stress (WSS) are non-invasive tools to study cardiovascular risks in vivo. Major limitations of conventional triggered methods are the long measurement times needed for high-resolution data sets and the necessity of stable electrocardiographic (ECG) triggering. In this work an ECG-free retrospectively synchronized method is presented that enables accelerated high-resolution measurements of 4D flow and WSS in the aortic arch of mice. Methods 4D flow and WSS were measured in the aortic arch of 12-week-old wildtype C57BL/6 J mice (n = 7) with a radial 4D-phase-contrast (PC)-CMR sequence, which was validated in a flow phantom. Cardiac and respiratory motion signals were extracted from the radial CMR signal and were used for the reconstruction of 4D-flow data. Rigid motion correction and a first order B0 correction was used to improve the robustness of magnitude and velocity data. The aortic lumen was segmented semi-automatically. Temporally averaged and time-resolved WSS and oscillatory shear index (OSI) were calculated from the spatial velocity gradients at the lumen surface at 14 locations along the aortic arch. Reproducibility was tested in 3 animals and the influence of subsampling was investigated. Results Volume flow, cross-sectional areas, WSS and the OSI were determined in a measurement time of only 32 min. Longitudinal and circumferential WSS and radial stress were assessed at 14 analysis planes along the aortic arch. The average longitudinal, circumferential and radial stress values were 1.52 ± 0.29 N/m2, 0.28 ± 0.24 N/m2 and - 0.21 ± 0.19 N/m2, respectively. Good reproducibility of WSS values was observed. Conclusion This work presents a robust measurement of 4D flow and WSS in mice without the need of ECG trigger signals. The retrospective approach provides fast flow quantification within 35 min and a flexible reconstruction framework.}, language = {en} } @article{HeroldKampfJakob2019, author = {Herold, Volker and Kampf, Thomas and Jakob, Peter Michael}, title = {Dynamic magnetic resonance scattering}, series = {Communications Physics}, volume = {2}, journal = {Communications Physics}, doi = {10.1038/s42005-019-0136-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201091}, pages = {46}, year = {2019}, abstract = {Dynamic light scattering is a popular technique to determine the size distribution of small particles in the sub micrometer region. It operates in reciprocal space, by analyzing the signal fluctuations with the photon auto correlation function. Equally, pulsed field gradient magnetic resonance is a technique generating data in the reciprocal space of the density distribution of an object. Here we show the feasibility of employing a magnetic resonance imaging system as a dynamic scattering device similar to dynamic light scattering appliances. By acquiring a time series of single data points from reciprocal space, analogue to dynamic light scattering, we demonstrate the examination of motion patterns of microscopic particles. This method allows the examination of particle dynamics significantly below the spatial resolution of magnetic resonance imaging. It is not limited by relaxation times and covers a wide field of applications for particle or cell motion in opaque media.}, language = {en} } @article{DaViaSolimandoGaritanoTrojaolaetal.2019, author = {Da Vi{\`a}, Matteo Claudio and Solimando, Antonio Giovanni and Garitano-Trojaola, Andoni and Barrio, Santiago and Munawar, Umair and Strifler, Susanne and Haertle, Larissa and Rhodes, Nadine and Vogt, Cornelia and Lapa, Constantin and Beilhack, Andreas and Rasche, Leo and Einsele, Hermann and Kort{\"u}m, K. Martin}, title = {CIC Mutation as a Molecular Mechanism of Acquired Resistance to Combined BRAF-MEK Inhibition in Extramedullary Multiple Myeloma with Central Nervous System Involvement}, series = {The Oncologist}, volume = {25}, journal = {The Oncologist}, number = {2}, doi = {10.1634/theoncologist.2019-0356}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219549}, pages = {112-118}, year = {2019}, abstract = {Combined MEK-BRAF inhibition is a well-established treatment strategy in BRAF-mutated cancer, most prominently in malignant melanoma with durable responses being achieved through this targeted therapy. However, a subset of patients face primary unresponsiveness despite presence of the activating mutation at position V600E, and others acquire resistance under treatment. Underlying resistance mechanisms are largely unknown, and diagnostic tests to predict tumor response to BRAF-MEK inhibitor treatment are unavailable. Multiple myeloma represents the second most common hematologic malignancy, and point mutations in BRAF are detectable in about 10\% of patients. Targeted inhibition has been successfully applied, with mixed responses observed in a substantial subset of patients mirroring the widespread spatial heterogeneity in this genomically complex disease. Central nervous system (CNS) involvement is an extremely rare, extramedullary form of multiple myeloma that can be diagnosed in less than 1\% of patients. It is considered an ultimate high-risk feature, associated with unfavorable cytogenetics, and, even with intense treatment applied, survival is short, reaching less than 12 months in most cases. Here we not only describe the first patient with an extramedullary CNS relapse responding to targeted dabrafenib and trametinib treatment, we furthermore provide evidence that a point mutation within the capicua transcriptional repressor (CIC) gene mediated the acquired resistance in this patient.}, language = {en} } @article{SailerWiedemannStraussetal.2019, author = {Sailer, Clara Odilia and Wiedemann, Sophia Julia and Strauss, Konrad and Schnyder, Ingeborg and Fenske, Wiebke Kristin and Christ-Crain, Mirjam}, title = {Markers of systemic inflammation in response to osmotic stimulus in healthy volunteers}, series = {Endocrine Connections}, volume = {8}, journal = {Endocrine Connections}, number = {9}, doi = {10.1530/EC-19-0280}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227204}, pages = {1282-1287}, year = {2019}, abstract = {Osmotic stimulus or stress results in vasopressin release. Animal and human in vitro studies have shown that inflammatory parameters, such as interle ukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha), increase in parallel in the central nervous system and bronchial, corneal or intestinal epithelial cell lines in response to osmotic stimulus. Whether osmotic stimulus directly causes a systemic inflammatory response in humans is unknown. We therefore investigated the influence of osmotic stimulus on circulatory markers of systemic inflammation in healthy volunteers. In this prospective cohort study, 44 healthy volunteers underwent a standardized test protocol with an osmotic stimulus leading into the hyperosmotic/hypernatremic range (serum sodium >= 150 mmol/L) by hypertonic saline infusion. Copeptin - a marker indicating vasopressin activity - serum sodium and osmolality, plasma IL-8 and TNF-alpha were measured at baseline and directly after osmotic stimulus. Median (range) serum sodium increased from 141 mmol/L (136, 147) to 151 mmol/L (145, 154) (P < 0.01), serum osmolality increased from 295 mmol/L (281, 306) to 315 mmol/L (304, 325) (P < 0.01). Median (range) copeptin increased from 4.3 pg/L (1.1, 21.4) to 28.8 pg/L (19.9, 43.4) (P < 0.01). Median (range) IL-8 levels showed a trend to decrease from 0.79 pg/mL (0.37, 1.6) to 0.7 pg/mL (0.4, 1.9) (P < 0.09) and TNF-alpha levels decreased from 0.53 pg/mL (0.11, 1.1) to 0.45 pg/mL (0.1 2, 0.97) (P < 0.036). Contrary to data obtained in vitro, circulating proinflammatory cytokines tend to or decrease in human plasma after osmotic stimulus. In this study, osmotic stimulus does not increase circulating markers of systemic inflammation.}, subject = {Hyperosmotic Stress}, language = {en} } @article{HermSchurigMartineketal.2019, author = {Herm, Juliane and Schurig, Johannes and Martinek, Martin R. and H{\"o}ltgen, Reinhard and Schirdewan, Alexander and Kirchhof, Paulus and Wieczorek, Marcus and P{\"u}rerfellner, Helmut and Heuschmann, Peter U. and Fiebach, Jochen B. and Haeusler, Karl Georg}, title = {MRI-detected brain lesions in AF patients without further stroke risk factors undergoing ablation - a retrospective analysis of prospective studies}, series = {BMC Cardiovascular Disorders}, volume = {19}, journal = {BMC Cardiovascular Disorders}, doi = {10.1186/s12872-019-1035-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201226}, pages = {58}, year = {2019}, abstract = {Background Atrial fibrillation (AF) without other stroke risk factors is assumed to have a low annual stroke risk comparable to patients without AF. Therefore, current clinical guidelines do not recommend oral anticoagulation for stroke prevention of AF in patients without stroke risk factors. We analyzed brain magnetic resonance imaging (MRI) imaging to estimate the rate of clinically inapparent ("silent") ischemic brain lesions in these patients. Methods We pooled individual patient-level data from three prospective studies comprising stroke-free patients with symptomatic AF. All study patients underwent brain MRI within 24-48 h before planned left atrial catheter ablation. MRIs were analyzed by a neuroradiologist blinded to clinical data. Results In total, 175 patients (median age 60 (IQR 54-67) years, 32\% female, median CHA\(_2\)DS\(_2\)-VASc = 1 (IQR 0-2), 33\% persistent AF) were included. In AF patients without or with at least one stroke risk factor, at least one silent ischemic brain lesion was observed in 4 (8\%) out of 48 and 10 (8\%) out of 127 patients, respectively (p > 0.99). Presence of silent ischemic brain lesions was related to age (p = 0.03) but not to AF pattern (p = 0.77). At least one cerebral microbleed was detected in 5 (13\%) out of 30 AF patients without stroke risk factors and 25 (25\%) out of 108 AF patients with stroke risk factors (p = 0.2). Presence of cerebral microbleeds was related to male sex (p = 0.04) or peripheral artery occlusive disease (p = 0.03). Conclusion In patients with symptomatic AF scheduled for ablation, brain MRI detected silent ischemic brain lesions in approximately one in 12 patients, and microbleeds in one in 5 patients. The prevalence of silent ischemic brain lesions did not differ in AF patients with or without further stroke risk factors.}, language = {en} } @article{HagemannNeuhausDahlmannetal.2019, author = {Hagemann, Carsten and Neuhaus, Nikolas and Dahlmann, Mathias and Kessler, Almuth F. and Kobelt, Dennis and Herrmann, Pia and Eyrich, Matthias and Freitag, Benjamin and Linsenmann, Thomas and Monoranu, Camelia M. and Ernestus, Ralf-Ingo and L{\"o}hr, Mario and Stein, Ulrike}, title = {Circulating MACC1 transcripts in glioblastoma patients predict prognosis and treatment response}, series = {Cancers}, volume = {11}, journal = {Cancers}, number = {6}, issn = {2072-6694}, doi = {10.3390/cancers11060825}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197327}, year = {2019}, abstract = {Glioblastoma multiforme is the most aggressive primary brain tumor of adults, but lacksreliable and liquid biomarkers. We evaluated circulating plasma transcripts of metastasis-associatedin colon cancer-1 (MACC1), a prognostic biomarker for solid cancer entities, for prediction of clinicaloutcome and therapy response in glioblastomas. MACC1 transcripts were significantly higher inpatients compared to controls. Low MACC1 levels clustered together with other prognosticallyfavorable markers. It was associated with patients' prognosis in conjunction with the isocitratedehydrogenase (IDH) mutation status: IDH1 R132H mutation and low MACC1 was most favorable(median overall survival (OS) not yet reached), IDH1 wildtype and high MACC1 was worst (medianOS 8.1 months), while IDH1 wildtype and low MACC1 was intermediate (median OS 9.1 months).No patients displayed IDH1 R132H mutation and high MACC1. Patients with low MACC1 levelsreceiving standard therapy survived longer (median OS 22.6 months) than patients with high MACC1levels (median OS 8.1 months). Patients not receiving the standard regimen showed the worstprognosis, independent of MACC1 levels (low: 6.8 months, high: 4.4 months). Addition of circulatingMACC1 transcript levels to the existing prognostic workup may improve the accuracy of outcomeprediction and help define more precise risk categories of glioblastoma patients.}, language = {en} } @article{KreckelAnanySiegmundetal.2019, author = {Kreckel, Jennifer and Anany, Mohammed A. and Siegmund, Daniela and Wajant, Harald}, title = {TRAF2 controls death receptor-induced caspase-8 processing and facilitates proinflammatory signaling}, series = {Frontiers in Immunology}, volume = {10}, journal = {Frontiers in Immunology}, number = {2024}, doi = {10.3389/fimmu.2019.02024}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201822}, year = {2019}, abstract = {Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) knockout (KO) cells were generated to investigate the role of TRAF2 in signaling by TNFR1 and the CD95-type death receptors (DRs) TRAILR1/2 and CD95. To prevent negative selection effects arising from the increased cell death sensitivity of TRAF2-deficient cells, cell lines were used for the generation of the TRAF2 KO variants that were protected from DR-induced apoptosis downstream of caspase-8 activation. As already described in the literature, TRAF2 KO cells displayed enhanced constitutive alternative NFκB signaling and reduced TNFR1-induced activation of the classical NFκB pathway. There was furthermore a significant but only partial reduction in CD95-type DR-induced upregulation of the proinflammatory NFκB-regulated cytokine interleukin-8 (IL8), which could be reversed by reexpression of TRAF2. In contrast, expression of the TRAF2-related TRAF1 protein failed to functionally restore TRAF2 deficiency. TRAF2 deficiency resulted furthermore in enhanced procaspase-8 processing by DRs, but this surprisingly came along with a reduction in net caspase-8 activity. In sum, our data argue for (i) a non-obligate promoting function of TRAF2 in proinflammatory DR signaling and (ii) a yet unrecognized stabilizing effect of TRAF2 on caspase-8 activity.}, language = {en} } @article{StaigerSeufertArandetal.2019, author = {Staiger, Simona and Seufert, Pascal and Arand, Katja and Burghardt, Markus and Popp, Christian and Riederer, Markus}, title = {The permeation barrier of plant cuticles: uptake of active ingredients is limited by very long-chain aliphatic rather than cyclic wax compounds}, series = {Pest Management Science}, volume = {75}, journal = {Pest Management Science}, number = {12}, doi = {10.1002/ps.5589}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204778}, pages = {3405-3412}, year = {2019}, abstract = {BACKGROUND: The barrier to diffusion of organic solutes across the plant cuticle is composed of waxes consisting of very long-chain aliphatic (VLCA) and, to varying degrees, cyclic compounds like pentacyclic triterpenoids. The roles of both fractions in controlling cuticular penetration by organic solutes, e.g. the active ingredients (AI) of pesticides, are unknown to date. We studied thepermeabilityof isolated leaf cuticularmembranes from Garcinia xanthochymus andPrunus laurocerasus for lipophilic azoxystrobin and theobromine as model compounds for hydrophilic AIs. RESULTS: The wax of P. laurocerasus consists of VLCA (12\%) and cyclic compounds (88\%), whereas VLCAs make up 97\% of the wax of G. xanthochymus.We showthat treating isolated cuticles with methanol almost quantitatively releases the cyclic fraction while leaving the VLCA fraction essentially intact. All VLCAs were subsequently removed using chloroform. In both species, the permeance of the two model compounds did not change significantly after methanol treatment, whereas chloroform extraction had a large effect on organic solute permeability. CONCLUSION: The VLCA wax fractionmakes up the permeability barrier for organic solutes, whereas cyclic compounds even in high amounts have a negligible role. This is of significance when optimizing the foliar uptake of pesticides.}, language = {en} } @article{WajantSiegmund2019, author = {Wajant, Harald and Siegmund, Daniela}, title = {TNFR1 and TNFR2 in the control of the life and death balance of macrophages}, series = {Frontiers in Cell and Developmental Biology}, volume = {7}, journal = {Frontiers in Cell and Developmental Biology}, number = {91}, doi = {10.3389/fcell.2019.00091}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201551}, year = {2019}, abstract = {Macrophages stand in the first line of defense against a variety of pathogens but are also involved in the maintenance of tissue homeostasis. To fulfill their functions macrophages sense a broad range of pathogen- and damage-associated molecular patterns (PAMPs/DAMPs) by plasma membrane and intracellular pattern recognition receptors (PRRs). Intriguingly, the overwhelming majority of PPRs trigger the production of the pleiotropic cytokine tumor necrosis factor-alpha (TNF). TNF affects almost any type of cell including macrophages themselves. TNF promotes the inflammatory activity of macrophages but also controls macrophage survival and death. TNF exerts its activities by stimulation of two different types of receptors, TNF receptor-1 (TNFR1) and TNFR2, which are both expressed by macrophages. The two TNF receptor types trigger distinct and common signaling pathways that can work in an interconnected manner. Based on a brief general description of major TNF receptor-associated signaling pathways, we focus in this review on research of recent years that revealed insights into the molecular mechanisms how the TNFR1-TNFR2 signaling network controls the life and death balance of macrophages. In particular, we discuss how the TNFR1-TNFR2 signaling network is integrated into PRR signaling.}, language = {en} } @article{ElHawarySayedMohammedetal.2019, author = {El-Hawary, Seham S. and Sayed, Ahmed M. and Mohammed, Rabab and Hassan, Hossam M. and Rateb, Mostafa E. and Amin, Elham and Mohammed, Tarek A. and El-Mesery, Mohamed and Bin Muhsinah, Abdullatif and Alsayari, Abdulrhman and Wajant, Harald and Anany, Mohamed A. and Abdelmohsen, Usama Ramadan}, title = {Bioactive brominated oxindole alkaloids from the Red Sea sponge Callyspongia siphonella}, series = {Marine Drugs}, volume = {17}, journal = {Marine Drugs}, number = {8}, doi = {10.3390/md17080465}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201485}, pages = {465}, year = {2019}, abstract = {In the present study, LC-HRESIMS-assisted dereplication along with bioactivity-guided isolation led to targeting two brominated oxindole alkaloids (compounds 1 and 2) which probably play a key role in the previously reported antibacterial, antibiofilm, and cytotoxicity of Callyspongia siphonella crude extracts. Both metabolites showed potent antibacterial activity against Gram-positive bacteria, Staphylococcus aureus (minimum inhibitory concentration (MIC) = 8 and 4 µg/mL) and Bacillus subtilis (MIC = 16 and 4 µg/mL), respectively. Furthermore, they displayed moderate biofilm inhibitory activity in Pseudomonas aeruginosa (49.32\% and 41.76\% inhibition, respectively), and moderate in vitro antitrypanosomal activity (13.47 and 10.27 µM, respectively). In addition, they revealed a strong cytotoxic effect toward different human cancer cell lines, supposedly through induction of necrosis. This study sheds light on the possible role of these metabolites (compounds 1 and 2) in keeping fouling organisms away from the sponge outer surface, and the possible applications of these defensive molecules in the development of new anti-infective agents.}, language = {en} } @article{DuWuertzAdolfietal.2019, author = {Du, Kang and Wuertz, Sven and Adolfi, Mateus and Kneitz, Susanne and St{\"o}ck, Matthias and Oliveira, Marcos and N{\´o}brega, Rafael and Ormanns, Jenny and Kloas, Werner and Feron, Romain and Klopp, Christophe and Parrinello, Hugues and Journot, Laurent and He, Shunping and Postlethwait, John and Meyer, Axel and Guiguen, Yann and Schartl, Manfred}, title = {The genome of the arapaima (Arapaima gigas) provides insights into gigantism, fast growth and chromosomal sex determination system}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-41457-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201333}, pages = {5293}, year = {2019}, abstract = {We have sequenced the genome of the largest freshwater fish species of the world, the arapaima. Analysis of gene family dynamics and signatures of positive selection identified genes involved in the specific adaptations and unique features of this iconic species, in particular it's large size and fast growth. Genome sequences from both sexes combined with RAD-tag analyses from other males and females led to the isolation of male-specific scaffolds and supports an XY sex determination system in arapaima. Whole transcriptome sequencing showed that the product of the gland-like secretory organ on the head surface of males and females may not only provide nutritional fluid for sex-unbiased parental care, but that the organ itself has a more specific function in males, which engage more in parental care.}, language = {en} } @article{PaethPollinger2019, author = {Paeth, Heiko and Pollinger, Felix}, title = {Changes in mean flow and atmospheric wave activity in the North Atlantic sector}, series = {Quarterly Journal of the Royal Meteorological Society}, volume = {145}, journal = {Quarterly Journal of the Royal Meteorological Society}, number = {725}, doi = {10.1002/qj.3660}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-208079}, pages = {3801-3818}, year = {2019}, abstract = {In recent years, the midlatitudes are characterized by more intense heatwaves in summer and sometimes severe cold spells in winter that might emanate from changes in atmospheric circulation, including synoptic-scale and planetary wave activity in the midlatitudes. In this study, we investigate the heat and momentum exchange between the mean flow and atmospheric waves in the North Atlantic sector and adjacent continents by means of the physically consistent Eliassen-Palm flux diagnostics applied to reanalysis and forced climate model data. In the long-term mean, momentum is transferred from the mean flow to atmospheric waves in the northwest Atlantic region, where cyclogenesis prevails. Further downstream over Europe, eddy fluxes return momentum to the mean flow, sustaining the jet stream against friction. A global climate model is able to reproduce this pattern with high accuracy. Atmospheric variability related to atmospheric wave activity is much more expressed at the intraseasonal rather than the interannual time-scale. Over the last 40 years, reanalyses reveal a northward shift of the jet stream and a weakening of intraseasonal weather variability related to synoptic-scale and planetary wave activity. This pertains to the winter and summer seasons, especially over central Europe, and correlates with changes in the North Atlantic Oscillation as well as regional temperature and precipitation. A very similar phenomenon is found in a climate model simulation with business-as-usual scenario, suggesting an anthropogenic trigger in the weakening of intraseasonal weather variability in the midlatitudes.}, language = {en} } @article{AkhoonGuptaTiwarietal.2019, author = {Akhoon, Bashir A. and Gupta, Shishir K. and Tiwari, Sudeep and Rathor, Laxmi and Pant, Aakanksha and Singh, Nivedita and Gupta, Shailendra K. and Dandekar, Thomas and Pandey, Rakesh}, title = {C. elegans protein interaction network analysis probes RNAi validated pro-longevity effect of nhr-6, a human homolog of tumor suppressor Nr4a1}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-51649-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202666}, pages = {15711}, year = {2019}, abstract = {Protein-protein interaction (PPI) studies are gaining momentum these days due to the plethora of various high-throughput experimental methods available for detecting PPIs. Proteins create complexes and networks by functioning in harmony with other proteins and here in silico network biology hold the promise to reveal new functionality of genes as it is very difficult and laborious to carry out experimental high-throughput genetic screens in living organisms. We demonstrate this approach by computationally screening C. elegans conserved homologs of already reported human tumor suppressor and aging associated genes. We select by this nhr-6, vab-3 and gst-23 as predicted longevity genes for RNAi screen. The RNAi results demonstrated the pro-longevity effect of these genes. Nuclear hormone receptor nhr-6 RNAi inhibition resulted in a C. elegans phenotype of 23.46\% lifespan reduction. Moreover, we show that nhr-6 regulates oxidative stress resistance in worms and does not affect the feeding behavior of worms. These findings imply the potential of nhr-6 as a common therapeutic target for aging and cancer ailments, stressing the power of in silico PPI network analysis coupled with RNAi screens to describe gene function.}, language = {en} } @article{ZhangZhengZhengetal.2019, author = {Zhang, Yonghong and Zheng, Lanlan and Zheng, Yan and Zhou, Chao and Huang, Ping and Xiao, Xiao and Zhao, Yongheng and Hao, Xincai and Hu, Zhubing and Chen, Qinhua and Li, Hongliang and Wang, Xuanbin and Fukushima, Kenji and Wang, Guodong and Li, Chen}, title = {Assembly and Annotation of a Draft Genome of the Medicinal Plant Polygonum cuspidatum}, series = {Frontiers in Plant Science}, volume = {10}, journal = {Frontiers in Plant Science}, issn = {1664-462X}, doi = {10.3389/fpls.2019.01274}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189279}, pages = {1274}, year = {2019}, abstract = {Polygonum cuspidatum (Japanese knotweed, also known as Huzhang in Chinese), a plant that produces bioactive components such as stilbenes and quinones, has long been recognized as important in traditional Chinese herbal medicine. To better understand the biological features of this plant and to gain genetic insight into the biosynthesis of its natural products, we assembled a draft genome of P. cuspidatum using Illumina sequencing technology. The draft genome is ca. 2.56 Gb long, with 71.54\% of the genome annotated as transposable elements. Integrated gene prediction suggested that the P. cuspidatum genome encodes 55,075 functional genes, including 6,776 gene families that are conserved in the five eudicot species examined and 2,386 that are unique to P. cuspidatum. Among the functional genes identified, 4,753 are predicted to encode transcription factors. We traced the gene duplication history of P. cuspidatum and determined that it has undergone two whole-genome duplication events about 65 and 6.6 million years ago. Roots are considered the primary medicinal tissue, and transcriptome analysis identified 2,173 genes that were expressed at higher levels in roots compared to aboveground tissues. Detailed phylogenetic analysis demonstrated expansion of the gene family encoding stilbene synthase and chalcone synthase enzymes in the phenylpropanoid metabolic pathway, which is associated with the biosynthesis of resveratrol, a pharmacologically important stilbene. Analysis of the draft genome identified 7 abscisic acid and water deficit stress-induced protein-coding genes and 14 cysteine-rich transmembrane module genes predicted to be involved in stress responses. The draft de novo genome assembly produced in this study represents a valuable resource for the molecular characterization of medicinal compounds in P. cuspidatum, the improvement of this important medicinal plant, and the exploration of its abiotic stress resistance.}, language = {en} } @article{BulittaJiaoLandersdorferetal.2019, author = {Bulitta, J{\"u}rgen B. and Jiao, Yuanyuan and Landersdorfer, Cornelia B. and Sutaria, Dhruvitkumar S. and Tao, Xun and Shin, Eunjeong and H{\"o}hl, Rainer and Holzgrabe, Ulrike and Stephan, Ulrich and S{\"o}rgel, Fritz}, title = {Comparable Bioavailability and Disposition of Pefloxacin in Patients with Cystic Fibrosis and Healthy Volunteers Assessed via Population Pharmacokinetics}, series = {Pharmaceutics}, volume = {11}, journal = {Pharmaceutics}, number = {7}, issn = {1999-4923}, doi = {10.3390/pharmaceutics11070323}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197221}, pages = {323}, year = {2019}, abstract = {Quinolone antibiotics present an attractive oral treatment option in patients with cystic fibrosis (CF). Prior studies have reported comparable clearances and volumes of distribution in patients with CF and healthy volunteers for primarily renally cleared quinolones. We aimed to provide the first pharmacokinetic comparison for pefloxacin as a predominantly nonrenally cleared quinolone and its two metabolites between both subject groups. Eight patients with CF (fat-free mass [FFM]: 36.3 ± 6.9 kg, average ± SD) and ten healthy volunteers (FFM: 51.7 ± 9.9 kg) received 400 mg pefloxacin as a 30 min intravenous infusion and orally in a randomized, two-way crossover study. All plasma and urine data were simultaneously modelled. Bioavailability was complete in both subject groups. Pefloxacin excretion into urine was approximately 74\% higher in patients with CF compared to that in healthy volunteers, whereas the urinary excretion of metabolites was only slightly higher in patients with CF. After accounting for body size and composition via allometric scaling by FFM, pharmacokinetic parameter estimates in patients with CF divided by those in healthy volunteers were 0.912 for total clearance, 0.861 for nonrenal clearance, 1.53 for renal clearance, and 0.916 for volume of distribution. Nonrenal clearance accounted for approximately 90\% of total pefloxacin clearance. Overall, bioavailability and disposition were comparable between both subject groups.}, language = {en} } @article{FathyFawzyHintzscheetal.2019, author = {Fathy, Moustafa and Fawzy, Michael Atef and Hintzsche, Henning and Nikaido, Toshio and Dandekar, Thomas and Othman, Eman M.}, title = {Eugenol exerts apoptotic effect and modulates the sensitivity of HeLa cells to cisplatin and radiation}, series = {Molecules}, volume = {24}, journal = {Molecules}, number = {21}, issn = {1420-3049}, doi = {10.3390/molecules24213979}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193227}, pages = {3979}, year = {2019}, abstract = {Eugenol is a phytochemical present in different plant products, e.g., clove oil. Traditionally, it is used against a number of different disorders and it was suggested to have anticancer activity. In this study, the activity of eugenol was evaluated in a human cervical cancer (HeLa) cell line and cell proliferation was examined after treatment with various concentrations of eugenol and different treatment durations. Cytotoxicity was tested using lactate dehydrogenase (LDH) enzyme leakage. In order to assess eugenol's potential to act synergistically with chemotherapy and radiotherapy, cell survival was calculated after eugenol treatment in combination with cisplatin and X-rays. To elucidate its mechanism of action, caspase-3 activity was analyzed and the expression of various genes and proteins was checked by RT-PCR and western blot analyses. Eugenol clearly decreased the proliferation rate and increased LDH release in a concentration- and time-dependent manner. It showed synergistic effects with cisplatin and X-rays. Eugenol increased caspase-3 activity and the expression of Bax, cytochrome c (Cyt-c), caspase-3, and caspase-9 and decreased the expression of B-cell lymphoma (Bcl)-2, cyclooxygenase-2 (Cox-2), and interleukin-1 beta (IL-1β) indicating that eugenol mainly induced cell death by apoptosis. In conclusion, eugenol showed antiproliferative and cytotoxic effects via apoptosis and also synergism with cisplatin and ionizing radiation in the human cervical cancer cell line.}, language = {en} } @article{ReuterJaeckelsKneitzetal.2019, author = {Reuter, Isabel and J{\"a}ckels, Jana and Kneitz, Susanne and Kuper, Jochen and Lesch, Klaus-Peter and Lillesaar, Christina}, title = {Fgf3 is crucial for the generation of monoaminergic cerebrospinal fluid contacting cells in zebrafish}, series = {Biology Open}, volume = {8}, journal = {Biology Open}, doi = {10.1242/bio.040683}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200749}, pages = {bio040683}, year = {2019}, abstract = {In most vertebrates, including zebrafish, the hypothalamic serotonergic cerebrospinal fluid-contacting (CSF-c) cells constitute a prominent population. In contrast to the hindbrain serotonergic neurons, little is known about the development and function of these cells. Here, we identify fibroblast growth factor (Fgf)3 as the main Fgf ligand controlling the ontogeny of serotonergic CSF-c cells. We show that fgf3 positively regulates the number of serotonergic CSF-c cells, as well as a subset of dopaminergic and neuroendocrine cells in the posterior hypothalamus via control of proliferation and cell survival. Further, expression of the ETS-domain transcription factor etv5b is downregulated after fgf3 impairment. Previous findings identified etv5b as critical for the proliferation of serotonergic progenitors in the hypothalamus, and therefore we now suggest that Fgf3 acts via etv5b during early development to ultimately control the number of mature serotonergic CSF-c cells. Moreover, our analysis of the developing hypothalamic transcriptome shows that the expression of fgf3 is upregulated upon fgf3 loss-of-function, suggesting activation of a self-compensatory mechanism. Together, these results highlight Fgf3 in a novel context as part of a signalling pathway of critical importance for hypothalamic development.}, language = {en} } @article{EderDignath2019, author = {Eder, Andreas B. and Dignath, David}, title = {Expected value of control and the motivational control of habitual action}, series = {Frontiers in Psychology}, volume = {10}, journal = {Frontiers in Psychology}, number = {1812}, issn = {1664-1078}, doi = {10.3389/fpsyg.2019.01812}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195703}, year = {2019}, abstract = {A hallmark of habitual actions is that, once they are established, they become insensitive to changes in the values of action outcomes. In this article, we review empirical research that examined effects of posttraining changes in outcome values in outcome-selective Pavlovian-to-instrumental transfer (PIT) tasks. This review suggests that cue-instigated action tendencies in these tasks are not affected by weak and/or incomplete revaluation procedures (e.g., selective satiety) and substantially disrupted by a strong and complete devaluation of reinforcers. In a second part, we discuss two alternative models of a motivational control of habitual action: a default-interventionist framework and expected value of control theory. It is argued that the default-interventionist framework cannot solve the problem of an infinite regress (i.e., what controls the controller?). In contrast, expected value of control can explain control of habitual actions with local computations and feedback loops without (implicit) references to control homunculi. It is argued that insensitivity to changes in action outcomes is not an intrinsic design feature of habits but, rather, a function of the cognitive system that controls habitual action tendencies.}, language = {en} } @article{vonCollenbergSchmittRuelickeetal.2019, author = {von Collenberg, Cora R. and Schmitt, Dominique and R{\"u}licke, Thomas and Sendtner, Michael and Blum, Robert and Buchner, Erich}, title = {An essential role of the mouse synapse-associated protein Syap1 in circuits for spontaneous motor activity and rotarod balance}, series = {Biology Open}, volume = {8}, journal = {Biology Open}, doi = {10.1242/bio.042366}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201986}, pages = {bio042366}, year = {2019}, abstract = {Synapse-associated protein 1 (Syap1) is the mammalian homologue of synapse-associated protein of 47 kDa (Sap47) in Drosophila. Genetic deletion of Sap47 leads to deficiencies in short-term plasticity and associative memory processing in flies. In mice, Syap1 is prominently expressed in the nervous system, but its function is still unclear. We have generated Syap1 knockout mice and tested motor behaviour and memory. These mice are viable and fertile but display distinct deficiencies in motor behaviour. Locomotor activity specifically appears to be reduced in early phases when voluntary movement is initiated. On the rotarod, a more demanding motor test involving control by sensory feedback, Syap1-deficient mice dramatically fail to adapt to accelerated speed or to a change in rotation direction. Syap1 is highly expressed in cerebellar Purkinje cells and cerebellar nuclei. Thus, this distinct motor phenotype could be due to a so-far unknown function of Syap1 in cerebellar sensorimotor control. The observed motor defects are highly specific since other tests in the modified SHIRPA exam, as well as cognitive tasks like novel object recognition, Pavlovian fear conditioning, anxiety-like behaviour in open field dark-light transition and elevated plus maze do not appear to be affected in Syap1 knockout mice.}, language = {en} } @article{KunzGoetzSaueretal.2019, author = {Kunz, Tobias C. and G{\"o}tz, Ralph and Sauer, Markus and Rudel, Thomas}, title = {Detection of chlamydia developmental forms and secreted effectors by expansion microscopy}, series = {Frontiers in Cellular and Infection Microbiology}, volume = {9}, journal = {Frontiers in Cellular and Infection Microbiology}, number = {276}, issn = {2235-2988}, doi = {10.3389/fcimb.2019.00276}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195716}, year = {2019}, abstract = {Expansion microscopy (ExM) is a novel tool to improve the resolution of fluorescence-based microscopy that has not yet been used to visualize intracellular pathogens. Here we show the expansion of the intracellular pathogen Chlamydia trachomatis, enabling to differentiate its two distinct forms, catabolic active reticulate bodies (RB) and infectious elementary bodies (EB), on a conventional confocal microscope. We show that ExM enables the possibility to precisely locate chlamydial effector proteins, such as CPAF or Cdu1, within and outside of the chlamydial inclusion. Thus, we claim that ExM offers the possibility to address a broad range of questions and may be useful for further research on various intracellular pathogens.}, language = {en} } @article{GoosDejungWehmanetal.2019, author = {Goos, Carina and Dejung, Mario and Wehman, Ann M. and M-Natus, Elisabeth and Schmidt, Johannes and Sunter, Jack and Engstler, Markus and Butter, Falk and Kramer, Susanne}, title = {Trypanosomes can initiate nuclear export co-transcriptionally}, series = {Nucleic Acids Research}, volume = {47}, journal = {Nucleic Acids Research}, number = {1}, doi = {10.1093/nar/gky1136}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177709}, pages = {266-282}, year = {2019}, abstract = {The nuclear envelope serves as important messenger RNA (mRNA) surveillance system. In yeast and human, several control systems act in parallel to prevent nuclear export of unprocessed mRNAs. Trypanosomes lack homologues to most of the involved proteins and their nuclear mRNA metabolism is non-conventional exemplified by polycistronic transcription and mRNA processing by trans-splicing. We here visualized nuclear export in trypanosomes by intra- and intermolecular multi-colour single molecule FISH. We found that, in striking contrast to other eukaryotes, the initiation of nuclear export requires neither the completion of transcription nor splicing. Nevertheless, we show that unspliced mRNAs are mostly prevented from reaching the nucleus-distant cytoplasm and instead accumulate at the nuclear periphery in cytoplasmic nuclear periphery granules (NPGs). Further characterization of NPGs by electron microscopy and proteomics revealed that the granules are located at the cytoplasmic site of the nuclear pores and contain most cytoplasmic RNA-binding proteins but none of the major translation initiation factors, consistent with a function in preventing faulty mRNAs from reaching translation. Our data indicate that trypanosomes regulate the completion of nuclear export, rather than the initiation. Nuclear export control remains poorly understood, in any organism, and the described way of control may not be restricted to trypanosomes.}, language = {en} } @article{RydzekNerreterPengetal.2019, author = {Rydzek, Julian and Nerreter, Thomas and Peng, Haiyong and Jutz, Sabrina and Leitner, Judith and Steinberger, Peter and Einsele, Hermann and Rader, Christoph and Hudecek, Michael}, title = {Chimeric Antigen Receptor Library Screening Using a Novel NF-kappa B/NFAT Reporter Cell Platform}, series = {Molecular Therapy}, volume = {27}, journal = {Molecular Therapy}, number = {2}, doi = {10.1016/j.ymthe.2018.11.015}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227193}, pages = {287-299}, year = {2019}, abstract = {Chimeric antigen receptor (CAR)-T cell immunotherapy is under intense preclinical and clinical investigation, and it involves a rapidly increasing portfolio of novel target antigens and CAR designs. We established a platform that enables rapid and high-throughput CAR-screening campaigns with reporter cells derived from the T cell lymphoma line Jurkat. Reporter cells were equipped with nuclear factor kappa B (NF kappa B) and nuclear factor of activated T cells (NFAT) reporter genes that generate a duplex output of enhanced CFP (ECFP) and EGFP, respectively. As a proof of concept, we modified reporter cells with CD19-specific and ROR1-specific CARs, and we detected high-level reporter signals that allowed distinguishing functional from non-functional CAR constructs. The reporter data were highly reproducible, and the time required for completing each testing campaign was substantially shorter with reporter cells (6 days) compared to primary CAR-T cells (21 days). We challenged the reporter platform to a large-scale screening campaign on a ROR1-CAR library, and we showed that reporter cells retrieved a functional CAR variant that was present with a frequency of only 6 in 1.05 x 10(6). The data illustrate the potential to implement this reporter platform into the preclinical development path of novel CAR-T cell products and to inform and accelerate the selection of lead CAR candidates for clinical translation.}, language = {en} } @article{LinsenmannMonoranuAlkonyietal.2019, author = {Linsenmann, Thomas and Monoranu, Camelia M. and Alkonyi, Balint and Westermaier, Thomas and Hagemann, Carsten and Kessler, Almuth F. and Ernestus, Ralf-Ingo and L{\"o}hr, Mario}, title = {Cerebellar liponeurocytoma - molecular signature of a rare entity and the importance of an accurate diagnosis}, series = {Interdisciplinary Neurosurgery}, volume = {16}, journal = {Interdisciplinary Neurosurgery}, doi = {10.1016/j.inat.2018.10.017}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177652}, pages = {7-11}, year = {2019}, abstract = {Background: Cerebellar liponeurocytoma is an extremely rare tumour entity of the central nervous system. It is histologically characterised by prominent neuronal/neurocytic differentiation with focal lipidisation and corresponding histologically to WHO grade II. It typically develops in adults, and usually shows a low proliferative potential. Recurrences have been reported in almost 50\% of cases, and in some cases the recurrent tumour may display increased mitotic activity and proliferation index, vascular proliferations and necrosis. Thus pathological diagnosis of liponeurocytoma is challenging. This case presentation highlights the main clinical, radiographic and pathological features of a cerebellar liponeurocytoma. Case presentation: A 59-year-old, right-handed woman presented at our department with a short history of persistent headache, vertigo and gait disturbances. Examination at presentation revealed that the patient was awake, alert and fully oriented. The cranial nerve status was normal. Uncertainties were noted in the bilateral finger-to-nose testing with bradydiadochokinesis on both sides. Strength was full and no pronator drift was observed. Sensation was intact. No signs of pyramidal tract dysfunction were detected. Her gait appeared insecure. The patient underwent surgical resection. Afterward no further disturbances could be detected. Conclusions: To date >40 cases of liponeurocytoma have been reported, including cases with supratentorial location. A review of the 5 published cases of recurrent cerebellar. Liponeurocytoma revealed that the median interval between the first and second relapse was rather short, indicating uncertain malignant potential. The most recent WHO classification of brain tumours (2016) classifies the cerebellar liponeurocytoma as a separate entity and assigns the tumour to WHO grade II. Medulloblastoma is the most important differential diagnosis commonly seen in children and young adults. In contrast, cerebellar liponeurocytoma is typically diagnosed in adults. The importance of accurate diagnosis should not be underestimated especially in the view of possible further therapeutic interventions and for the determination of the patient's prognosis.}, language = {en} } @article{HaarmannSchuhmannSilwedeletal.2019, author = {Haarmann, Axel and Schuhmann, Michael K. and Silwedel, Christine and Monoranu, Camelia-Maria and Stoll, Guido and Buttmann, Mathias}, title = {Human brain endothelial CXCR2 is inflammation-inducible and mediates CXCL5- and CXCL8-triggered paraendothelial barrier breakdown}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {3}, issn = {1422-0067}, doi = {10.3390/ijms20030602}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201297}, year = {2019}, abstract = {Chemokines (C-X-C) motif ligand (CXCL) 5 and 8 are overexpressed in patients with multiple sclerosis, where CXCL5 serum levels were shown to correlate with blood-brain barrier dysfunction as evidenced by gadolinium-enhanced magnetic resonance imaging. Here, we studied the potential role of CXCL5/CXCL8 receptor 2 (CXCR2) as a regulator of paraendothelial brain barrier function, using the well-characterized human cerebral microvascular endothelial cell line hCMEC/D3. Low basal CXCR2 mRNA and protein expression levels in hCMEC/D3 were found to strongly increase under inflammatory conditions. Correspondingly, immunohistochemistry of brain biopsies from two patients with active multiple sclerosis revealed upregulation of endothelial CXCR2 compared to healthy control tissue. Recombinant CXCL5 or CXCL8 rapidly and transiently activated Akt/protein kinase B in hCMEC/D3. This was followed by a redistribution of tight junction-associated protein zonula occludens-1 (ZO-1) and by the formation of actin stress fibers. Functionally, these morphological changes corresponded to a decrease of paracellular barrier function, as measured by a real-time electrical impedance-sensing system. Importantly, preincubation with the selective CXCR2 antagonist SB332235 partially prevented chemokine-induced disturbance of both tight junction morphology and function. We conclude that human brain endothelial CXCR2 may contribute to blood-brain barrier disturbance under inflammatory conditions with increased CXCL5 and CXCL8 expression, where CXCR2 may also represent a novel pharmacological target for blood-brain barrier stabilization.}, language = {en} } @article{RudeliusRosenfeldtLeichetal.2019, author = {Rudelius, Martina and Rosenfeldt, Mathias Tillmann and Leich, Ellen and Rauert-Wunderlich, Hilka and Solimando, Antonio Giovanni and Ott, German and Rosenwald, Andreas and Beilhack, Andreas}, title = {Inhibition of focal adhesion kinase overcomes resistance of mantle cell lymphoma to ibrutinib in the bone marrow microenvironment}, series = {Haematologica}, volume = {103}, journal = {Haematologica}, number = {1}, doi = {10.3324/haematol.2017.177162}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227117}, pages = {116-125}, year = {2019}, abstract = {Mantle cell lymphoma and other lymphoma subtypes often spread to the bone marrow, and stromal interactions mediated by focal adhesion kinase frequently enhance survival and drug resistance of the lymphoma cells. To study the role of focal adhesion kinase in mantle cell lymphoma, immunohistochemistry of primary cases and functional analysis of mantle cell lymphoma cell lines and primary mantle cell lymphoma cells co-cultured with bone marrow stromal cells (BMSC) using small molecule inhibitors and RNAi-based focal adhesion kinase silencing was performed. We showed that focal adhesion kinase is highly expressed in bone marrow infiltrates of mantle cell lymphoma and in mantle cell lymphoma cell lines. Stroma-mediated activation of focal adhesion kinase led to activation of multiple kinases (AKT, p42/44 and NF-kappa B), that are important for prosurvival and proliferation signaling. Interestingly, RNAi-based focal adhesion kinase silencing or inhibition with small molecule inhibitors (FAKi) resulted in blockage of targeted cell invasion and induced apoptosis by inactivation of multiple signaling cascades, including the classic and alternative NF-kappa B pathway. In addition, the combined treatment of ibrutinib and FAKi was highly synergistic, and ibrutinib resistance of mantle cell lymphoma could be overcome. These data demonstrate that focal adhesion kinase is important for stroma-mediated survival and drug resistance in mantle cell lymphoma, providing indications for a targeted therapeutic strategy.}, subject = {Multiple}, language = {en} } @article{ReichertsPauliMoesleretal.2019, author = {Reicherts, Philipp and Pauli, Paul and M{\"o}sler, Camilla and Wieser, Matthias J.}, title = {Placebo manipulations reverse pain potentiation by unpleasant affective stimuli}, series = {Frontiers in Psychiatry}, volume = {10}, journal = {Frontiers in Psychiatry}, number = {663}, doi = {10.3389/fpsyt.2019.00663}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201200}, year = {2019}, abstract = {According to the motivational priming hypothesis, unpleasant stimuli activate the motivational defense system, which in turn promotes congruent affective states such as negative emotions and pain. The question arises to what degree this bottom-up impact of emotions on pain is susceptible to a manipulation of top-down-driven expectations. To this end, we investigated whether verbal instructions implying pain potentiation vs. reduction (placebo or nocebo expectations)—later on confirmed by corresponding experiences (placebo or nocebo conditioning)—might alter behavioral and neurophysiological correlates of pain modulation by unpleasant pictures. We compared two groups, which underwent three experimental phases: first, participants were either instructed that watching unpleasant affective pictures would increase pain (nocebo group) or that watching unpleasant pictures would decrease pain (placebo group) relative to neutral pictures. During the following placebo/nocebo-conditioning phase, pictures were presented together with electrical pain stimuli of different intensities, reinforcing the instructions. In the subsequent test phase, all pictures were presented again combined with identical pain stimuli. Electroencephalogram was recorded in order to analyze neurophysiological responses of pain (somatosensory evoked potential) and picture processing [visually evoked late positive potential (LPP)], in addition to pain ratings. In the test phase, ratings of pain stimuli administered while watching unpleasant relative to neutral pictures were significantly higher in the nocebo group, thus confirming the motivational priming effect for pain perception. In the placebo group, this effect was reversed such that unpleasant compared with neutral pictures led to significantly lower pain ratings. Similarly, somatosensory evoked potentials were decreased during unpleasant compared with neutral pictures, in the placebo group only. LPPs of the placebo group failed to discriminate between unpleasant and neutral pictures, while the LPPs of the nocebo group showed a clear differentiation. We conclude that the placebo manipulation already affected the processing of the emotional stimuli and, in consequence, the processing of the pain stimuli. In summary, the study revealed that the modulation of pain by emotions, albeit a reliable and well-established finding, is further tuned by reinforced expectations—known to induce placebo/nocebo effects—which should be addressed in future research and considered in clinical applications.}, language = {en} } @article{SchererEllgringDieckmannetal.2019, author = {Scherer, Klaus R. and Ellgring, Heiner and Dieckmann, Anja and Unfried, Matthias and Mortillaro, Marcello}, title = {Dynamic Facial Expression of Emotion and Observer Inference}, series = {Frontiers in Psychology}, volume = {10}, journal = {Frontiers in Psychology}, number = {508}, issn = {1664-1078}, doi = {10.3389/fpsyg.2019.00508}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195853}, year = {2019}, abstract = {Research on facial emotion expression has mostly focused on emotion recognition, assuming that a small number of discrete emotions is elicited and expressed via prototypical facial muscle configurations as captured in still photographs. These are expected to be recognized by observers, presumably via template matching. In contrast, appraisal theories of emotion propose a more dynamic approach, suggesting that specific elements of facial expressions are directly produced by the result of certain appraisals and predicting the facial patterns to be expected for certain appraisal configurations. This approach has recently been extended to emotion perception, claiming that observers first infer individual appraisals and only then make categorical emotion judgments based on the estimated appraisal patterns, using inference rules. Here, we report two related studies to empirically investigate the facial action unit configurations that are used by actors to convey specific emotions in short affect bursts and to examine to what extent observers can infer a person's emotions from the predicted facial expression configurations. The results show that (1) professional actors use many of the predicted facial action unit patterns to enact systematically specified appraisal outcomes in a realistic scenario setting, and (2) na{\"i}ve observers infer the respective emotions based on highly similar facial movement configurations with a degree of accuracy comparable to earlier research findings. Based on estimates of underlying appraisal criteria for the different emotions we conclude that the patterns of facial action units identified in this research correspond largely to prior predictions and encourage further research on appraisal-driven expression and inference.}, language = {en} } @article{GebertSteffanDewenterMorettoetal.2019, author = {Gebert, Friederike and Steffan-Dewenter, Ingolf and Moretto, Philippe and Peters, Marcell K.}, title = {Climate rather than dung resources predict dung beetle abundance and diversity along elevational and land use gradients on Mt. Kilimanjaro}, series = {Journal of Biogeography}, volume = {47}, journal = {Journal of Biogeography}, number = {2}, doi = {10.1111/jbi.13710}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204701}, pages = {371 -- 381}, year = {2019}, abstract = {Aim: While elevational gradients in species richness constitute some of the best depicted patterns in ecology, there is a large uncertainty concerning the role of food resource availability for the establishment of diversity gradients in insects. Here, we analysed the importance of climate, area, land use and food resources for determining diversity gradients of dung beetles along extensive elevation and land use gradients on Mt. Kilimanjaro, Tanzania. Location: Mt. Kilimanjaro, Tanzania. Taxon: Scarabaeidae (Coleoptera). Methods: Dung beetles were recorded with baited pitfall traps at 66 study plots along a 3.6 km elevational gradient. In order to quantify food resources for the dung beetle community in form of mammal defecation rates, we assessed mammalian diversity and biomass with camera traps. Using a multi-model inference framework and path analysis, we tested the direct and indirect links between climate, area, land use and mammal defecation rates on the species richness and abundance of dung beetles. Results: We found that the species richness of dung beetles declined exponentially with increasing elevation. Human land use diminished the species richness of functional groups exhibiting complex behaviour but did not have a significant influence on total species richness. Path analysis suggested that climate, in particular temperature and to a lesser degree precipitation, were the most important predictors of dung beetle species richness while mammal defecation rate was not supported as a predictor variable. Main conclusions: Along broad climatic gradients, dung beetle diversity is mainly limited by climatic factors rather than by food resources. Our study points to a predominant role of temperature-driven processes for the maintenance and origination of species diversity of ectothermic organisms, which will consequently be subject to ongoing climatic changes.}, language = {en} } @article{RequierPailletLarocheetal.2019, author = {Requier, Fabrice and Paillet, Yoan and Laroche, Fabienne and Rutschmann, Benjamin and Zhang, Jie and Lombardi, Fabio and Svoboda, Miroslav and Steffan-Dewenter, Ingolf}, title = {Contribution of European forests to safeguard wild honeybee populations}, series = {Conservation Letters}, volume = {13}, journal = {Conservation Letters}, number = {2}, doi = {10.1111/conl.12693}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204407}, pages = {e12693}, year = {2019}, abstract = {Abstract Recent studies reveal the use of tree cavities by wild honeybee colonies in European forests. This highlights the conservation potential of forests for a highly threatened component of the native entomofauna in Europe, but currently no estimate of potential wild honeybee population sizes exists. Here, we analyzed the tree cavity densities of 106 forest areas across Europe and inferred an expected population size of wild honeybees. Both forest and management types affected the density of tree cavities. Accordingly, we estimated that more than 80,000 wild honeybee colonies could be sustained in European forests. As expected, potential conservation hotspots were identified in unmanaged forests, and, surprisingly, also in other large forest areas across Europe. Our results contribute to the EU policy strategy to halt pollinator declines and reveal the potential of forest areas for the conservation of so far neglected wild honeybee populations in Europe.}, language = {en} } @article{HettichSchierjottEppleetal.2019, author = {Hettich, Georg and Schierjott, Ronja A. and Epple, Matthias and Gbureck, Uwe and Heinemann, Sascha and Mozaffari-Jovein, Hadi and Grupp, Thomas M.}, title = {Calcium phosphate bone graft substitutes with high mechanical load capacity and high degree of interconnecting porosity}, series = {Materials}, volume = {12}, journal = {Materials}, number = {21}, issn = {1996-1944}, doi = {10.3390/ma12213471}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193233}, pages = {3471}, year = {2019}, abstract = {Bone graft substitutes in orthopedic applications have to fulfill various demanding requirements. Most calcium phosphate (CaP) bone graft substitutes are highly porous to achieve bone regeneration, but typically lack mechanical stability. This study presents a novel approach, in which a scaffold structure with appropriate properties for bone regeneration emerges from the space between specifically shaped granules. The granule types were tetrapods (TEPO) and pyramids (PYRA), which were compared to porous CaP granules (CALC) and morselized bone chips (BC). Bulk materials of the granules were mechanically loaded with a peak pressure of 4 MP; i.e., comparable to the load occurring behind an acetabular cup. Mechanical loading reduced the volume of CALC and BC considerably (89\% and 85\%, respectively), indicating a collapse of the macroporous structure. Volumes of TEPO and PYRA remained almost constant (94\% and 98\%, respectively). After loading, the porosity was highest for BC (46\%), lowest for CALC (25\%) and comparable for TEPO and PYRA (37\%). The pore spaces of TEPO and PYRA were highly interconnected in a way that a virtual object with a diameter of 150 µm could access 34\% of the TEPO volume and 36\% of the PYRA volume. This study shows that a bulk of dense CaP granules in form of tetrapods and pyramids can create a scaffold structure with load capacities suitable for the regeneration of an acetabular bone defect}, language = {en} } @article{KunzKozjakPavlovic2019, author = {Kunz, Tobias C. and Kozjak-Pavlovic, Vera}, title = {Diverse facets of sphingolipid involvement in bacterial infections}, series = {Frontiers in Cell and Developmental Biology}, volume = {7}, journal = {Frontiers in Cell and Developmental Biology}, number = {203}, doi = {10.3389/fcell.2019.00203}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201757}, year = {2019}, abstract = {Sphingolipids are constituents of the cell membrane that perform various tasks as structural elements and signaling molecules, in addition to regulating many important cellular processes, such as apoptosis and autophagy. In recent years, it has become increasingly clear that sphingolipids and sphingolipid signaling play a vital role in infection processes. In many cases the attachment and uptake of pathogenic bacteria, as well as bacterial development and survival within the host cell depend on sphingolipids. In addition, sphingolipids can serve as antimicrobials, inhibiting bacterial growth and formation of biofilms. This review will give an overview of our current information about these various aspects of sphingolipid involvement in bacterial infections.}, language = {en} } @article{GromerReinkeChristneretal.2019, author = {Gromer, Daniel and Reinke, Max and Christner, Isabel and Pauli, Paul}, title = {Causal interactive links between presence and fear in virtual reality height exposure}, series = {Frontiers in Psychology}, volume = {10}, journal = {Frontiers in Psychology}, number = {141}, doi = {10.3389/fpsyg.2019.00141}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201855}, year = {2019}, abstract = {Virtual reality plays an increasingly important role in research and therapy of pathological fear. However, the mechanisms how virtual environments elicit and modify fear responses are not yet fully understood. Presence, a psychological construct referring to the 'sense of being there' in a virtual environment, is widely assumed to crucially influence the strength of the elicited fear responses, however, causality is still under debate. The present study is the first that experimentally manipulated both variables to unravel the causal link between presence and fear responses. Height-fearful participants (N = 49) were immersed into a virtual height situation and a neutral control situation (fear manipulation) with either high versus low sensory realism (presence manipulation). Ratings of presence and verbal and physiological (skin conductance, heart rate) fear responses were recorded. Results revealed an effect of the fear manipulation on presence, i.e., higher presence ratings in the height situation compared to the neutral control situation, but no effect of the presence manipulation on fear responses. However, the presence ratings during the first exposure to the high quality neutral environment were predictive of later fear responses in the height situation. Our findings support the hypothesis that experiencing emotional responses in a virtual environment leads to a stronger feeling of being there, i.e., increase presence. In contrast, the effects of presence on fear seem to be more complex: on the one hand, increased presence due to the quality of the virtual environment did not influence fear; on the other hand, presence variability that likely stemmed from differences in user characteristics did predict later fear responses. These findings underscore the importance of user characteristics in the emergence of presence.}, language = {en} } @article{PattschullWalzGruendletal.2019, author = {Pattschull, Grit and Walz, Susanne and Gr{\"u}ndl, Marco and Schwab, Melissa and R{\"u}hl, Eva and Baluapuri, Apoorva and Cindric-Vranesic, Anita and Kneitz, Susanne and Wolf, Elmar and Ade, Carsten P. and Rosenwald, Andreas and von Eyss, Bj{\"o}rn and Gaubatz, Stefan}, title = {The Myb-MuvB complex is required for YAP-dependent transcription of mitotic genes}, series = {Cell Reports}, volume = {27}, journal = {Cell Reports}, number = {12}, doi = {10.1016/j.celrep.2019.05.071}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202039}, pages = {3533-3546}, year = {2019}, abstract = {YAP and TAZ, downstream effectors of the Hippo pathway, are important regulators of proliferation. Here, we show that the ability of YAP to activate mitotic gene expression is dependent on the Myb-MuvB (MMB) complex, a master regulator of genes expressed in the G2/M phase of the cell cycle. By carrying out genome-wide expression and binding analyses, we found that YAP promotes binding of the MMB subunit B-MYB to the promoters of mitotic target genes. YAP binds to B-MYB and stimulates B-MYB chromatin association through distal enhancer elements that interact with MMB-regulated promoters through chromatin looping. The cooperation between YAP and B-MYB is critical for YAP-mediated entry into mitosis. Furthermore, the expression of genes coactivated by YAP and B-MYB is associated with poor survival of cancer patients. Our findings provide a molecular mechanism by which YAP and MMB regulate mitotic gene expression and suggest a link between two cancer-relevant signaling pathways.}, language = {en} } @article{KhayenkoMaric2019, author = {Khayenko, Vladimir and Maric, Hans Michael}, title = {Targeting GABA\(_A\)R-associated proteins: new modulators, labels and concepts}, series = {Frontiers in Molecular Neuroscience}, volume = {12}, journal = {Frontiers in Molecular Neuroscience}, number = {162}, doi = {10.3389/fnmol.2019.00162}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201876}, year = {2019}, abstract = {γ-aminobutyric acid type A receptors (GABA\(_A\)Rs) are the major mediators of synaptic inhibition in the brain. Aberrant GABA\(_A\)R activity or regulation is observed in various neurodevelopmental disorders, neurodegenerative diseases and mental illnesses, including epilepsy, Alzheimer's and schizophrenia. Benzodiazepines, anesthetics and other pharmaceutics targeting these receptors find broad clinical use, but their inherent lack of receptor subtype specificity causes unavoidable side effects, raising a need for new or adjuvant medications. In this review article, we introduce a new strategy to modulate GABAeric signaling: targeting the intracellular protein interactors of GABA\(_A\)Rs. Of special interest are scaffolding, anchoring and supporting proteins that display high GABA\(_A\)R subtype specificity. Recent efforts to target gephyrin, the major intracellular integrator of GABAergic signaling, confirm that GABA\(_A\)R-associated proteins can be successfully targeted through diverse molecules, including recombinant proteins, intrabodies, peptide-based probes and small molecules. Small-molecule artemisinins and peptides derived from endogenous interactors, that specifically target the universal receptor binding site of gephyrin, acutely affect synaptic GABA\(_A\)R numbers and clustering, modifying neuronal transmission. Interference with GABA\(_A\)R trafficking provides another way to modulate inhibitory signaling. Peptides blocking the binding site of GABA\(_A\)R to AP2 increase the surface concentration of GABA\(_A\)R clusters and enhance GABAergic signaling. Engineering of gephyrin binding peptides delivered superior means to interrogate neuronal structure and function. Fluorescent peptides, designed from gephyrin binders, enable live neuronal staining and visualization of gephyrin in the post synaptic sites with submicron resolution. We anticipate that in the future, novel fluorescent probes, with improved size and binding efficiency, may find wide application in super resolution microscopy studies, enlightening the nanoscale architecture of the inhibitory synapse. Broader studies on GABA\(_A\)R accessory proteins and the identification of the exact molecular binding interfaces and affinities will advance the development of novel GABA\(_A\)R modulators and following in vivo studies will reveal their clinical potential as adjuvant or stand-alone drugs.}, language = {en} } @article{MateosKangKloppetal.2019, author = {Mateos, Mariana and Kang, Du and Klopp, Christophe and Parrinello, Hugues and Garc{\´i}a-Olaz{\´a}bal, Mateo and Schumer, Molly and Jue, Nathaniel K. and Guiguen, Yann and Schartl, Manfred}, title = {Draft genome assembly and annotation of the Gila Topminnow Poeciliopsis occidentalis}, series = {Frontiers in Ecology and Evolution}, volume = {7}, journal = {Frontiers in Ecology and Evolution}, number = {404}, issn = {2296-701X}, doi = {10.3389/fevo.2019.00404}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190339}, year = {2019}, abstract = {No abstract available.}, language = {en} } @article{LangeAndrianWerburgAdleretal.2019, author = {Lange, Benjamin P. and Andrian-Werburg, Maximilian T. P. von and Adler, Dorothea C. and Zaretsky, Eugen}, title = {The name is the game: nicknames as predictors of personality and mating strategy in online dating}, series = {Frontiers in Communication}, volume = {4}, journal = {Frontiers in Communication}, number = {3}, doi = {10.3389/fcomm.2019.00003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201659}, year = {2019}, abstract = {Objective: We investigated the communicative function of online dating nicknames. Our aim was to assess if it is possible to correctly guess personality traits of a user simply by reading his/her nickname. Method: We had 69 nickname users (average age: 33.59 years, 36 female) complete questionnaires assessing their personality (Big 5 + narcissism) and mating strategy (short- vs. long-term). We then checked (using a total of 638 participants, average age: 26.83 years, 355 female), whether personality and mating strategy of the nickname users could be assessed correctly based only on the nickname. We also captured the motivation to contact the user behind a nickname and looked at linguistic features of the nicknames. Results: We found that personality and mating strategy could be inferred from a nickname. Furthermore, going by trends, women were better at intersexual personality judgments, whereas men were better in intrasexual judgements. We also found several correlates of the motivation to contact the person behind the nickname. Among other factors, long nicknames seemed to deter people from contacting the nickname user. Conclusions: Findings display that humans are capable of making accurate personality judgements in computer-mediated communication by means of even small cues like nicknames.}, language = {en} } @article{ReichelRuecklFenwicketal.2019, author = {Reichel, Thomas and Rueckl, Kilian and Fenwick, Annabel and Vogt, Niklas and Rudert, Maximilian and Plumhoff, Piet}, title = {Hibernoma of the upper extremity: complete case of a rare but benign soft tissue tumor}, series = {Case Reports in Orthopedics}, volume = {2019}, journal = {Case Reports in Orthopedics}, doi = {10.1155/2019/6840693}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201669}, pages = {6840693}, year = {2019}, abstract = {Hibernoma is a rare benign lipomatous tumor showing differentiation of brown fatty tissue. To the author's best knowledge, there is no known case of malignant transformation or metastasis. Due to their slow, noninfiltrating growth hibernomas are often an incidental finding in the third or fourth decade of life. The vast majority are located in the thigh, neck, and periscapular region. A diagnostic workup includes ultrasound and contrast-enhanced MRI. Differential diagnosis is benign lipoma, well-differentiated liposarcoma, and rhabdomyoma. An incisional biopsy followed by marginal resection of the tumor is the standard of care, and recurrence after complete resection is not reported. The current paper presents diagnostic and intraoperative findings of a hibernoma of the upper arm and reviews similar reports in the current literature.}, language = {en} } @article{Menke2019, author = {Menke, Andreas}, title = {Is the HPA axis as target for depression outdated, or is there a new hope?}, series = {Frontiers in Psychiatry}, volume = {10}, journal = {Frontiers in Psychiatry}, number = {101}, issn = {1664-0640}, doi = {10.3389/fpsyt.2019.00101}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195780}, year = {2019}, abstract = {Major depressive disorder (MDD) is a very common stress-related mental disorder that carries a huge burden for affected patients and the society. It is associated with a high mortality that derives from suicidality and the development of serious medical conditions such as heart diseases, diabetes, and stroke. Although a range of effective antidepressants are available, more than 50\% of the patients do not respond to the first treatment they are prescribed and around 30\% fail to respond even after several treatment attempts. The heterogeneous condition of MDD, the lack of biomarkers matching patients with the right treatments and the situation that almost all available drugs are only targeting the serotonin, norepinephrine, or dopamine signaling, without regulating other potentially dysregulated systems may explain the insufficient treatment status. The hypothalamic-pituitary-adrenal (HPA) axis is one of these other systems, there is numerous and robust evidence that it is implicated in MDD and other stress-related conditions, but up to date there is no specific drug targeting HPA axis components that is approved and no test that is routinely used in the clinical setting identifying patients for such a specific treatment. Is there still hope after these many years for a breakthrough of agents targeting the HPA axis? This review will cover tests detecting altered HPA axis function and the specific treatment options such as glucocorticoid receptor (GR) antagonists, corticotropin-releasing hormone 1 (CRH1) receptor antagonists, tryptophan 2,3-dioxygenase (TDO) inhibitors and FK506 binding protein 5 (FKBP5) receptor antagonists.}, language = {en} } @article{LuleKueblerLudolph2019, author = {Lul{\´e}, Doroth{\´e}e and K{\"u}bler, Andrea and Ludolph, Albert C.}, title = {Ethical principles in patient-centered medical care to support quality of life in amyotrophic lateral sclerosis}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, issn = {1664-2295}, doi = {10.3389/fneur.2019.00259}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196239}, year = {2019}, abstract = {It is one of the primary goals of medical care to secure good quality of life (QoL) while prolonging survival. This is a major challenge in severe medical conditions with a prognosis such as amyotrophic lateral sclerosis (ALS). Further, the definition of QoL and the question whether survival in this severe condition is compatible with a good QoL is a matter of subjective and culture-specific debate. Some people without neurodegenerative conditions believe that physical decline is incompatible with satisfactory QoL. Current data provide extensive evidence that psychosocial adaptation in ALS is possible, indicated by a satisfactory QoL. Thus, there is no fatalistic link of loss of QoL when physical health declines. There are intrinsic and extrinsic factors that have been shown to successfully facilitate and secure QoL in ALS which will be reviewed in the following article following the four ethical principles (1) Beneficence, (2) Non-maleficence, (3) Autonomy and (4) Justice, which are regarded as key elements of patient centered medical care according to Beauchamp and Childress. This is a JPND-funded work to summarize findings of the project NEEDSinALS (www.NEEDSinALS.com) which highlights subjective perspectives and preferences in medical decision making in ALS.}, language = {en} } @article{RaheemTawfikeAbdelmohsenetal.2019, author = {Raheem, Dotsha J. and Tawfike, Ahmed F. and Abdelmohsen, Usama R. and Edrada-Ebel, RuAngelie and Fitzsimmons-Thoss, Vera}, title = {Application of metabolomics and molecular networking in investigating the chemical profile and antitrypanosomal activity of British bluebells (\(Hyacinthoides\) \(non-scripta\))}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-38940-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224935}, pages = {2547, 1-13}, year = {2019}, abstract = {Bulb, leaf, scape and flower samples of British bluebells (Hyacinthoides non-scripta) were collected regularly for one growth period. Methanolic extracts of freeze-dried and ground samples showed antitrypanosomal activity, giving more than 50\% inhibition, for 20 out of 41 samples. High-resolution mass spectrometry was used in the dereplication of the methanolic extracts of the different plant parts. The results revealed differences in the chemical profile with bulb samples being distinctly different from all aerial parts. High molecular weight metabolites were more abundant in the flowers, shoots and leaves compared to smaller molecular weight ones in the bulbs. The anti-trypanosomal activity of the extracts was linked to the accumulation of high molecular weight compounds, which were matched with saponin glycosides, while triterpenoids and steroids occurred in the inactive extracts. Dereplication studies were employed to identify the significant metabolites via chemotaxonomic filtration and considering their previously reported bioactivities. Molecular networking was implemented to look for similarities in fragmentation patterns between the isolated saponin glycoside at m/z 1445.64 [M + formic-H](-) equivalent to C64H104O33 and the putatively found active metabolite at m/z 1283.58 [M + formic-H](-) corresponding to scillanoside L-1. A combination of metabolomics and bioactivity-guided approaches resulted in the isolation of a norlanostane-type saponin glycoside with antitrypanosoma I activity of 98.9\% inhibition at 20 mu M.}, language = {en} } @article{AlacevichCarloniCalameChiesaetal.2019, author = {Alacevich, Massimo and Carloni Calame, Carlo M. and Chiesa, Mauro and Montagna, Guido and Nicrosini, Oreste and Piccinini, Fulvio}, title = {Muon-electron scattering at NLO}, series = {Journal of High Energy Physics}, volume = {155}, journal = {Journal of High Energy Physics}, number = {2}, doi = {10.1007/JHEP02(2019)155}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227777}, pages = {1-25}, year = {2019}, abstract = {We consider the process of muon-electron elastic scattering, which has been proposed as an ideal framework to measure the running of the electromagnetic coupling constant at space-like momenta and determine the leading-order hadronic contribution to the muon g-2 (MUonE experiment). We compute the next-to-leading (NLO) contributions due to QED and purely weak corrections and implement them into a fully differential Monte Carlo event generator, which is available for first experimental studies. We show representative phenomenological results of interest for the MUonE experiment and examine in detail the impact of the various sources of radiative corrections under different selection criteria, in order to study the dependence of the NLO contributions on the applied cuts. The study represents the first step towards the realisation of a high-precision Monte Carlo code necessary for data analysis.}, language = {en} } @article{AktasUpcinHenkeetal.2019, author = {Aktas, Bertal H. and Upcin, Berin and Henke, Erik and Padmasekar, Manju and Qin, Xuebin and Erg{\"u}n, S{\"u}leyman}, title = {The Best for the Most Important: Maintaining a Pristine Proteome in Stem and Progenitor Cells}, series = {Stem Cells International}, journal = {Stem Cells International}, doi = {10.1155/2019/1608787}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227769}, pages = {1-20}, year = {2019}, abstract = {Pluripotent stem cells give rise to reproductively enabled offsprings by generating progressively lineage-restricted multipotent stem cells that would differentiate into lineage-committed stem and progenitor cells. These lineage-committed stem and progenitor cells give rise to all adult tissues and organs. Adult stem and progenitor cells are generated as part of the developmental program and play critical roles in tissue and organ maintenance and/or regeneration. The ability of pluripotent stem cells to self-renew, maintain pluripotency, and differentiate into a multicellular organism is highly dependent on sensing and integrating extracellular and extraorganismal cues. Proteins perform and integrate almost all cellular functions including signal transduction, regulation of gene expression, metabolism, and cell division and death. Therefore, maintenance of an appropriate mix of correctly folded proteins, a pristine proteome, is essential for proper stem cell function. The stem cells' proteome must be pristine because unfolded, misfolded, or otherwise damaged proteins would interfere with unlimited self-renewal, maintenance of pluripotency, differentiation into downstream lineages, and consequently with the development of properly functioning tissue and organs. Understanding how various stem cells generate and maintain a pristine proteome is therefore essential for exploiting their potential in regenerative medicine and possibly for the discovery of novel approaches for maintaining, propagating, and differentiating pluripotent, multipotent, and adult stem cells as well as induced pluripotent stem cells. In this review, we will summarize cellular networks used by various stem cells for generation and maintenance of a pristine proteome. We will also explore the coordination of these networks with one another and their integration with the gene regulatory and signaling networks.}, language = {en} } @article{OPUS4-22779, title = {Measuring the atmospheric neutrino oscillation parameters and constraining the 3+1 neutrino model with ten years of ANTARES data}, series = {Journal of High Energy Physics}, volume = {113}, journal = {Journal of High Energy Physics}, number = {6}, organization = {The ANTARES collaboration}, doi = {10.1007/JHEP06(2019)113}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227791}, pages = {1-20}, year = {2019}, abstract = {The ANTARES neutrino telescope has an energy threshold of a few tens of GeV. This allows to study the phenomenon of atmospheric muon neutrino disappearance due to neutrino oscillations. In a similar way, constraints on the 3+1 neutrino model, which foresees the existence of one sterile neutrino, can be inferred. Using data collected by the ANTARES neutrino telescope from 2007 to 2016, a new measurement of m 2 and (23) has been performed which is consistent with world best-fit values and constraints on the 3+1 neutrino model have been derived.}, language = {en} } @article{AbtErdmengerGerbershagenetal.2019, author = {Abt, Raimond and Erdmenger, Johanna and Gerbershagen, Marius and Melby-Thompson, Charles M. and Northe, Christian}, title = {Holographic subregion complexity from kinematic space}, series = {Journal of High Energy Physics}, volume = {1}, journal = {Journal of High Energy Physics}, number = {12}, doi = {10.1007/JHEP01(2019)012}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227711}, pages = {1-35}, year = {2019}, abstract = {We consider the computation of volumes contained in a spatial slice of AdS(3) in terms of observables in a dual CFT. Our main tool is kinematic space, defined either from the bulk perspective as the space of oriented bulk geodesics, or from the CFT perspective as the space of entangling intervals. We give an explicit formula for the volume of a general region in a spatial slice of AdS(3) as an integral over kinematic space. For the region lying below a geodesic, we show how to write this volume purely in terms of entangling entropies in the dual CFT. This expression is perhaps most interesting in light of the complexity = volume proposal, which posits that complexity of holographic quantum states is computed by bulk volumes. An extension of this idea proposes that the holographic subregion complexity of an interval, defined as the volume under its Ryu-Takayanagi surface, is a measure of the complexity of the corresponding reduced density matrix. If this is true, our results give an explicit relationship between entanglement and subregion complexity in CFT, at least in the vacuum. We further extend many of our results to conical defect and BTZ black hole geometries.}, language = {en} } @article{OPUS4-22775, title = {Sensitivity of the KM3NeT/ARCA neutrino telescope to point-like neutrino sources}, series = {Astroparticle Physics}, volume = {111}, journal = {Astroparticle Physics}, organization = {The KM3NeT Collaboration}, doi = {10.1016/j.astropartphys.2019.04.002}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227759}, pages = {100-110}, year = {2019}, abstract = {KM3NeT will be a network of deep-sea neutrino telescopes in the Mediterranean Sea. The KM3NeT/ARCA detector, to be installed at the Capo Passero site (Italy), is optimised for the detection of high-energy neutrinos of cosmic origin. Thanks to its geographical location on the Northern hemisphere, KM3NeT/ARCA can observe upgoing neutrinos from most of the Galactic Plane, including the Galactic Centre. Given its effective area and excellent pointing resolution, KM3NeT/ARCA will measure or significantly constrain the neutrino flux from potential astrophysical neutrino sources. At the same time, it will test flux predictions based on gamma-ray measurements and the assumption that the gamma-ray flux is of hadronic origin. Assuming this scenario, discovery potentials and sensitivities for a selected list of Galactic sources and to generic point sources with an E-2 spectrum are presented. These spectra are assumed to be time independent. The results indicate that an observation with 3 sigma significance is possible in about six years of operation for the most intense sources, such as Supernovae Remnants RX J1713.7-3946 and Vela Jr. If no signal will be found during this time, the fraction of the gamma-ray flux coming from hadronic processes can be constrained to be below 50\% for these two objects. (C) 2019 The Authors. Published by Elsevier B.V.}, language = {en} } @article{OPUS4-36018, title = {Search for Multimessenger Sources of Gravitational Waves and High-energy Neutrinos with Advanced LIGO during Its First Observing Run, ANTARES, and IceCube}, series = {The Astrophysical Journal}, volume = {870}, journal = {The Astrophysical Journal}, number = {2}, publisher = {The American Astronomical Society}, organization = {The LIGO Scientific Collaboration and the Virgo Collaboration}, doi = {10.3847/1538-4357/aaf21d}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360189}, pages = {1-16}, year = {2019}, abstract = {Astrophysical sources of gravitational waves, such as binary neutron star and black hole mergers or core-collapse supernovae, can drive relativistic outflows, giving rise to non-thermal high-energy emission. High-energy neutrinos are signatures of such outflows. The detection of gravitational waves and high-energy neutrinos from common sources could help establish the connection between the dynamics of the progenitor and the properties of the outflow. We searched for associated emission of gravitational waves and high-energy neutrinos from astrophysical transients with minimal assumptions using data from Advanced LIGO from its first observing run O1, and data from the Antares and IceCube neutrino observatories from the same time period. We focused on candidate events whose astrophysical origins could not be determined from a single messenger. We found no significant coincident candidate, which we used to constrain the rate density of astrophysical sources dependent on their gravitational-wave and neutrino emission processes.}, language = {en} } @article{AlbrechtMuellerBallarinietal.2019, author = {Albrecht, Franziska and Mueller, Karsten and Ballarini, Tommaso and Lampe, Leonie and Diehl-Schmid, Janine and Fassbender, Klaus and Fliessbach, Klaus and Jahn, Holger and Jech, Robert and Kassubek, Jan and Kornhuber, Johannes and Landwehrmeyer, Bernhard and Lauer, Martin and Ludolph, Albert C. and Lyros, Epameinondas and Prudlo, Johannes and Schneider, Anja and Synofzik, Matthis and Wiltfang, Jens and Danek, Adrian and Otto, Markus and Schroeter, Matthias L.}, title = {Unraveling corticobasal syndrome and alien limb syndrome with structural brain imaging}, series = {Cortex}, volume = {117}, journal = {Cortex}, doi = {10.1016/j.cortex.2019.02.015}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221040}, pages = {33-40}, year = {2019}, abstract = {Alien limb phenomenon is a rare syndrome associated with a feeling of non-belonging and disowning toward one's limb. In contrast, anarchic limb phenomenon leads to involuntary but goal-directed movements. Alien/anarchic limb phenomena are frequent in corticobasal syndrome (CBS), an atypical parkinsonian syndrome characterized by rigidity, akinesia, dystonia, cortical sensory deficit, and apraxia. The structure function relationship of alien/anarchic limb was investigated in multi centric structural magnetic resonance imaging (MRI) data. Whole-group and single subject comparisons were made in 25 CBS and eight CBS-alien/anarchic limb patients versus controls. Support vector machine was used to see if CBS with and without alien/anarchic limb could be distinguished by structural MRI patterns. Whole-group comparison of CBS versus controls revealed asymmetric frontotemporal atrophy. CBS with alien/anarchic limb syndrome versus controls showed frontoparietal atrophy including the supplementary motor area contralateral to the side of the affected limb. Exploratory analysis identified frontotemporal regions encompassing the pre-/and postcentral gyrus as compromised in CBS with alien limb syndrome. Classification of CBS patients yielded accuracies of 79\%. CBS-alien/anarchic limb syndrome was differentiated from CBS patients with an accuracy of 81\%. Predictive differences were found in the cingulate gyrus spreading to frontomedian cortex, postcentral gyrus, and temporoparietoocipital regions. We present the first MRI-based group analysis on CBS-alien/anarchic limb. Results pave the way for individual clinical syndrome prediction and allow understanding the underlying neurocognitive architecture. (C) 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).}, language = {en} } @article{RiesSanderDeoletal.2019, author = {Ries, Lena K. and Sander, Bodo and Deol, Kirandeep K. and Letzelter, Marie-Annick and Strieter, Eric Robert and Lorenz, Sonja}, title = {Analysis of ubiquitin recognition by the HECT ligase E6AP provides insight into its linkage specificity}, series = {Journal of Biological Chemistry}, volume = {294}, journal = {Journal of Biological Chemistry}, number = {15}, doi = {10.1074/jbc.RA118.007014}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226207}, pages = {6113-6129}, year = {2019}, abstract = {Deregulation of the HECT-type ubiquitin ligase E6AP (UBE3A) is implicated in human papilloma virus-induced cervical tumorigenesis and several neurodevelopmental disorders. Yet the structural underpinnings of activity and specificity in this crucial ligase are incompletely understood. Here, we unravel the determinants of ubiquitin recognition by the catalytic domain of E6AP and assign them to particular steps in the catalytic cycle. We identify a functionally critical interface that is specifically required during the initial formation of a thioester-linked intermediate between the C terminus of ubiquitin and the ligase-active site. This interface resembles the one utilized by NEDD4-type enzymes, indicating that it is widely conserved across HECT ligases, independent of their linkage specificities. Moreover, we uncover surface regions in ubiquitin and E6AP, both in the N- and C-terminal portions of the catalytic domain, that are important for the subsequent reaction step of isopeptide bond formation between two ubiquitin molecules. We decipher key elements of linkage specificity, including the C-terminal tail of E6AP and a hydrophilic surface region of ubiquitin in proximity to the acceptor site Lys-48. Intriguingly, mutation of Glu-51, a single residue within this region, permits formation of alternative chain types, thus pointing to a key role of ubiquitin in conferring linkage specificity to E6AP. We speculate that substrate-assisted catalysis, as described previously for certain RING-associated ubiquitin-conjugating enzymes, constitutes a common principle during linkage-specific ubiquitin chain assembly by diverse classes of ubiquitination enzymes, including HECT ligases.}, language = {en} } @article{AlbertAndreAnghinolfietal.2019, author = {Albert, A. and Andr{\´e}, M. and Anghinolfi, M. and Anton, G. and Ardid, M. and Aubert, J.-J. and Aublin, J. and Avgitas, T. and Baret, B. and Barrios-Mart{\´i}t, J. and Basa, S. and Belhorma, B. and Bertin, V. and Biagi, S. and Bormuth, R. and Boumaaza, J and Bourret, S. and Bouwhuis, M. C. and Br{\^a}nzas, H. and Bruijn, R. and Brunner, J. and Busto, J. and Capone, A. and Caramete, L. and Carr, J. and Celli, S. and Chabab, M. and Cherkaoui El Moursli, R. and Chiarusi, T. and Circella, M. and Coelho, J. A. B. and Coleiro, A. and Colomer, M and Coniglione, R. and Costantini, H. and Coyle, P. and Creusot, A. and D{\´i}az, A. F. and Deschamps, A. and Distefano, C. and Di Palma, I. and Domi, A. and Donzaud, C. and Dornic, D. and Drouhin, D. and Eberl, T. and El Bojaddaini, I. and El Khayati, N. and Els{\"a}sser, D. and Enzenh{\"o}fer, A. and Ettahiri, A. and Fassi, F. and Felis, I. and Fermani, P. and Ferrara, G. and Fusco, L. A. and Gay, P. and Glotin, H. and Gr{\´e}goire, T. and Gracia Ruiz, R. and Graf, K. and Hallmann, S. and van Haren, H. and Heijboer, A. J. and Hello, Y. and Hern{\´a}ndez-Rey, J. J. and H{\"o}ßl, J. and Hofest{\"a}dt, J. and Illuminati, G. and de Jong, M. and Jongen, M. and Kadler, M. and Kalekin, O. and Katz, U. and Khan-Chowdhury, N. R. and Kouchner, A. and Kreter, M. and Kreykenbohm, I. and Kulikovskiy, V. and Lachaud, C. and Lahmann, R. and Lef{\`e}vre, D. and Leonora, E. and Levi, G. and Lotze, M. and Loucatos, S. and Marcelin, M. and Margiotta, A. and Marinelli, A. and Mart{\´i}nez-Mora, J. A. and Mele, R. and Melis, K. and Migliozzi, P. and Moussa, A. and Navas, S. and Nezri, E. and Nu{\~n}ez, A. and Organokov, M. and Pavalas, G. E. and Pellegrino, C. and Piattelli, P. and Popa, V. and Pradier, T. and Quinn, L. and Racca, C. and Randazzo, N. and Riccobene, G. and S{\´a}nchez-Losa, A. and Salda{\~n}a, M. and Salvadori, I. and Samtleben, D. F. E. and Sanguineti, M. and Sapienza, P. and Sch{\"u}ssler, F. and Spurio, M. and Stolarczyk, Th. and Taiuti, M. and Tayalati, Y. and Trovato, A. and Vallage, B. and Van Elewyck, V. and Versari, F. and Vivolo, D. and Wilms, J. and Zaborov, D. and Zornoza, J. D. and Z{\´u}{\~n}iga, J.}, title = {The cosmic ray shadow of the Moon observed with the ANTARES neutrino telescope}, series = {European Physical Journal C}, volume = {78}, journal = {European Physical Journal C}, doi = {10.1140/epjc/s10052-018-6451-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227802}, pages = {1-9}, year = {2019}, abstract = {One of the main objectives of the ANTARES telescope is the search for point- like neutrino sources. Both the pointing accuracy and the angular resolution of the detector are important in this context and a reliableway to evaluate this performance is needed. In order to measure the pointing accuracy of the detector, one possibility is to study the shadow of the Moon, i. e. the deficit of the atmospheric muon flux from the direction of the Moon induced by the absorption of cosmic rays. Analysing the data taken between 2007 and 2016, theMoon shadow is observed with 3.5s statistical significance. The detector angular resolution for downwardgoing muons is 0.73. +/- 0.14.. The resulting pointing performance is consistent with the expectations. An independent check of the telescope pointing accuracy is realised with the data collected by a shower array detector onboard of a ship temporarily moving around the ANTARES location.}, language = {en} } @article{EisenreichRudelHeesemannetal.2019, author = {Eisenreich, Wolfgang and Rudel, Thomas and Heesemann, J{\"u}rgen and Goebel, Werner}, title = {How viral and intracellular bacterial pathogens reprogram the metabolism of host cells to allow their intracellular replication}, series = {Frontiers in Cellular and Infection Microbiology}, volume = {9}, journal = {Frontiers in Cellular and Infection Microbiology}, issn = {2235-2988}, doi = {10.3389/fcimb.2019.00042}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197188}, year = {2019}, abstract = {Viruses and intracellular bacterial pathogens (IBPs) have in common the need of suitable host cells for efficient replication and proliferation during infection. In human infections, the cell types which both groups of pathogens are using as hosts are indeed quite similar and include phagocytic immune cells, especially monocytes/macrophages (MOs/MPs) and dendritic cells (DCs), as well as nonprofessional phagocytes, like epithelial cells, fibroblasts and endothelial cells. These terminally differentiated cells are normally in a metabolically quiescent state when they are encountered by these pathogens during infection. This metabolic state of the host cells does not meet the extensive need for nutrients required for efficient intracellular replication of viruses and especially IBPs which, in contrast to the viral pathogens, have to perform their own specific intracellular metabolism to survive and efficiently replicate in their host cell niches. For this goal, viruses and IBPs have to reprogram the host cell metabolism in a pathogen-specific manner to increase the supply of nutrients, energy, and metabolites which have to be provided to the pathogen to allow its replication. In viral infections, this appears to be often achieved by the interaction of specific viral factors with central metabolic regulators, including oncogenes and tumor suppressors, or by the introduction of virus-specific oncogenes. Less is so far known on the mechanisms leading to metabolic reprogramming of the host cell by IBPs. However, the still scant data suggest that similar mechanisms may also determine the reprogramming of the host cell metabolism in IBP infections. In this review, we summarize and compare the present knowledge on this important, yet still poorly understood aspect of pathogenesis of human viral and especially IBP infections.}, language = {en} } @article{RapaDiIorioCampigliaetal.2019, author = {Rapa, Shara Francesca and Di Iorio, Biagio Raffaele and Campiglia, Pietro and Heidland, August and Marzocco, Stefania}, title = {Inflammation and oxidative stress in chronic kidney disease — Potential therapeutic role of minerals, vitamins and plant-derived metabolites}, series = {International Journal of Molecular Sciences}, volume = {21}, journal = {International Journal of Molecular Sciences}, number = {1}, issn = {1422-0067}, doi = {10.3390/ijms21010263}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284998}, year = {2019}, abstract = {Chronic kidney disease (CKD) is a debilitating pathology with various causal factors, culminating in end stage renal disease (ESRD) requiring dialysis or kidney transplantation. The progression of CKD is closely associated with systemic inflammation and oxidative stress, which are responsible for the manifestation of numerous complications such as malnutrition, atherosclerosis, coronary artery calcification, heart failure, anemia and mineral and bone disorders, as well as enhanced cardiovascular mortality. In addition to conventional therapy with anti-inflammatory and antioxidative agents, growing evidence has indicated that certain minerals, vitamins and plant-derived metabolites exhibit beneficial effects in these disturbances. In the current work, we review the anti-inflammatory and antioxidant properties of various agents which could be of potential benefit in CKD/ESRD. However, the related studies were limited due to small sample sizes and short-term follow-up in many trials. Therefore, studies of several anti-inflammatory and antioxidant agents with long-term follow-ups are necessary.}, language = {en} } @article{WobserWeberGlunzetal.2019, author = {Wobser, Marion and Weber, Alexandra and Glunz, Amelie and Tauch, Saskia and Seitz, Kristina and Butelmann, Tobias and Hesbacher, Sonja and Goebeler, Matthias and Bartz, Ren{\´e} and Kohlhof, Hella and Schrama, David and Houben, Roland}, title = {Elucidating the mechanism of action of domatinostat (4SC-202) in cutaneous T cell lymphoma cells}, series = {Journal of Hematology \& Oncology}, volume = {12}, journal = {Journal of Hematology \& Oncology}, doi = {10.1186/s13045-019-0719-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200703}, pages = {30}, year = {2019}, abstract = {Background Targeting epigenetic modifiers is effective in cutaneous T cell lymphoma (CTCL). However, there is a need for further improvement of this therapeutic approach. Here, we compared the mode of action of romidepsin (FK228), an established class I histone deacetylase inhibitor, and domatinostat (4SC-202), a novel inhibitor of class I HDACs, which has been reported to also target the lysine-specific histone demethylase 1A (LSD1). Methods We performed MTS assays and flow cytometric analyses of propidium iodide or annexin V-stained cells to assess drug impact on cellular proliferation, cell cycle distribution, and survival. Histone acetylation and methylation as well as caspase activation was analyzed by immunoblot. Gene expression analysis was performed using NanosString technology. Knockdown and knockout of LSD1 was achieved with shRNA and CRISPR/Cas9, respectively, while the CRISPR/Cas9 synergistic activation mediator system was used to induce expression of endogenous HDACs and LSD1. Furthermore, time-lapse fluorescence microscopy and an in vitro tubulin polymerization assay were applied. Results While FK228 as well as 4SC-202 potently induced cell death in six different CTCL cell lines, only in the case of 4SC-202 death was preceded by an accumulation of cells in the G2/M phase of the cell cycle. Surprisingly, apoptosis and accumulation of cells with double DNA content occurred already at 4SC-202 concentrations hardly affecting histone acetylation and methylation, and provoking significantly less changes in gene expression compared to biologically equivalent doses of FK228. Indeed, we provide evidence that the 4SC-202-induced G2/M arrest in CTCL cells is independent of de novo transcription. Furthermore, neither enforced expression of HDAC1 nor knockdown or knockout of LSD1 affected the 4SC-202-induced effects. Since time-lapse microscopy revealed that 4SC-202 could affect mitotic spindle formation, we performed an in vitro tubulin polymerization assay revealing that 4SC-202 can directly inhibit microtubule formation. Conclusions We demonstrate that 4SC-202, a drug currently tested in clinical trials, effectively inhibits growth of CTCL cells. The anti-cancer cell activity of 4SC-202 is however not limited to LSD1-inhibition, modulation of histone modifications, and consecutive alteration of gene expression. Indeed, the compound is also a potent microtubule-destabilizing agent.}, language = {en} } @article{WeidnerLardenoijeEijssenetal.2019, author = {Weidner, Magdalena T. and Lardenoije, Roy and Eijssen, Lars and Mogavero, Floriana and De Groodt, Lilian P. M. T. and Popp, Sandy and Palme, Rupert and F{\"o}rstner, Konrad U. and Strekalova, Tatyana and Steinbusch, Harry W. M. and Schmitt-B{\"o}hrer, Angelika G. and Glennon, Jeffrey C. and Waider, Jonas and van den Hove, Daniel L. A. and Lesch, Klaus-Peter}, title = {Identification of cholecystokinin by genome-wide profiling as potential mediator of serotonin-dependent behavioral effects of maternal separation in the amygdala}, series = {Frontiers in Neuroscience}, volume = {13}, journal = {Frontiers in Neuroscience}, doi = {10.3389/fnins.2019.00460}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201340}, pages = {460}, year = {2019}, abstract = {Converging evidence suggests a role of serotonin (5-hydroxytryptamine, 5-HT) and tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of 5-HT synthesis in the brain, in modulating long-term, neurobiological effects of early-life adversity. Here, we aimed at further elucidating the molecular mechanisms underlying this interaction, and its consequences for socio-emotional behaviors, with a focus on anxiety and social interaction. In this study, adult, male Tph2 null mutant (Tph2\(^{-/-}\)) and heterozygous (Tph2\(^{+/-}\)) mice, and their wildtype littermates (Tph2\(^{+/+}\)) were exposed to neonatal, maternal separation (MS) and screened for behavioral changes, followed by genome-wide RNA expression and DNA methylation profiling. In Tph2\(^{-/-}\) mice, brain 5-HT deficiency profoundly affected socio-emotional behaviors, i.e., decreased avoidance of the aversive open arms in the elevated plus-maze (EPM) as well as decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Tph2\(^{+/-}\) mice showed an ambiguous profile with context-dependent, behavioral responses. In the EPM they showed similar avoidance of the open arm but decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Notably, MS effects on behavior were subtle and depended on the Tph2 genotype, in particular increasing the observed avoidance of EPM open arms in wildtype and Tph2\(^{+/-}\) mice when compared to their Tph2\(^{-/-}\) littermates. On the genomic level, the interaction of Tph2 genotype with MS differentially affected the expression of numerous genes, of which a subset showed an overlap with DNA methylation profiles at corresponding loci. Remarkably, changes in methylation nearby and expression of the gene encoding cholecystokinin, which were inversely correlated to each other, were associated with variations in anxiety-related phenotypes. In conclusion, next to various behavioral alterations, we identified gene expression and DNA methylation profiles to be associated with TPH2 inactivation and its interaction with MS, suggesting a gene-by-environment interaction-dependent, modulatory function of brain 5-HT availability.}, language = {en} } @article{KasaragodSchindelin2019, author = {Kasaragod, Vikram Babu and Schindelin, Hermann}, title = {Structure of Heteropentameric GABAA Receptors and Receptor-Anchoring Properties of Gephyrin}, series = {Frontiers in Molecular Neuroscience}, volume = {12}, journal = {Frontiers in Molecular Neuroscience}, issn = {1662-5099}, doi = {10.3389/fnmol.2019.00191}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189308}, pages = {191}, year = {2019}, abstract = {γ-Aminobutyric acid type A receptors (GABAARs) mediate the majority of fast synaptic inhibition in the central nervous system (CNS). GABAARs belong to the Cys-loop superfamily of pentameric ligand-gated ion channels (pLGIC) and are assembled from 19 different subunits. As dysfunctional GABAergic neurotransmission manifests itself in neurodevelopmental disorders including epilepsy and anxiety, GABAARs are key drug targets. The majority of synaptic GABAARs are anchored at the inhibitory postsynaptic membrane by the principal scaffolding protein gephyrin, which acts as the central organizer in maintaining the architecture of the inhibitory postsynaptic density (iPSD). This interaction is mediated by the long intracellular loop located in between transmembrane helices 3 and 4 (M3-M4 loop) of the receptors and a universal receptor-binding pocket residing in the C-terminal domain of gephyrin. In 2014, the crystal structure of the β3-homopentameric GABAAR provided crucial information regarding the architecture of the receptor; however, an understanding of the structure and assembly of heteropentameric receptors at the atomic level was lacking. This review article will highlight recent advances in understanding the structure of heteropentameric synaptic GABAARs and how these structures have provided fundamental insights into the assembly of these multi-subunit receptors as well as their modulation by diverse ligands including the physiological agonist GABA. We will further discuss the role of gephyrin in the anchoring of synaptic GABAARs and glycine receptors (GlyRs), which are crucial for maintaining the architecture of the iPSD. Finally, we will also summarize how anti-malarial artemisinin drugs modulate gephyrin-mediated inhibitory neurotransmission.}, language = {en} } @article{KasaragodSchindelin2019, author = {Kasaragod, Vikram Babu and Schindelin, Hermann}, title = {Structure of heteropentameric GABA\(_A\) receptors and receptor-anchoring properties of gephyrin}, series = {Frontiers in Molecular Neuroscience}, volume = {12}, journal = {Frontiers in Molecular Neuroscience}, number = {191}, doi = {10.3389/fnmol.2019.00191}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201886}, year = {2019}, abstract = {γ-Aminobutyric acid type A receptors (GABA\(_A\)Rs) mediate the majority of fast synaptic inhibition in the central nervous system (CNS). GABA\(_A\)Rs belong to the Cys-loop superfamily of pentameric ligand-gated ion channels (pLGIC) and are assembled from 19 different subunits. As dysfunctional GABAergic neurotransmission manifests itself in neurodevelopmental disorders including epilepsy and anxiety, GABA\(_A\)Rs are key drug targets. The majority of synaptic GABA\(_A\)Rs are anchored at the inhibitory postsynaptic membrane by the principal scaffolding protein gephyrin, which acts as the central organizer in maintaining the architecture of the inhibitory postsynaptic density (iPSD). This interaction is mediated by the long intracellular loop located in between transmembrane helices 3 and 4 (M3-M4 loop) of the receptors and a universal receptor-binding pocket residing in the C-terminal domain of gephyrin. In 2014, the crystal structure of the β3-homopentameric GABA\(_A\)R provided crucial information regarding the architecture of the receptor; however, an understanding of the structure and assembly of heteropentameric receptors at the atomic level was lacking. This review article will highlight recent advances in understanding the structure of heteropentameric synaptic GABA\(_A\)Rs and how these structures have provided fundamental insights into the assembly of these multi-subunit receptors as well as their modulation by diverse ligands including the physiological agonist GABA. We will further discuss the role of gephyrin in the anchoring of synaptic GABA\(_A\)Rs and glycine receptors (GlyRs), which are crucial for maintaining the architecture of the iPSD. Finally, we will also summarize how anti-malarial artemisinin drugs modulate gephyrin-mediated inhibitory neurotransmission.}, language = {en} } @article{PanzerBrychBatschaueretal.2019, author = {Panzer, Sabine and Brych, Annika and Batschauer, Alfred and Terpitz, Ulrich}, title = {Opsin 1 and Opsin 2 of the corn smut fungus ustilago maydis are green light-driven proton pumps}, series = {Frontiers in Microbiology}, volume = {10}, journal = {Frontiers in Microbiology}, doi = {10.3389/fmicb.2019.00735}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201453}, pages = {735}, year = {2019}, abstract = {In fungi, green light is absorbed by rhodopsins, opsin proteins carrying a retinal molecule as chromophore. The basidiomycete Ustilago maydis, a fungal pathogen that infects corn plants, encodes three putative photoactive opsins, called ops1 (UMAG_02629), ops2 (UMAG_00371), and ops3 (UMAG_04125). UmOps1 and UmOps2 are expressed during the whole life cycle, in axenic cultures as well as in planta, whereas UmOps3 was recently shown to be absent in axenic cultures but highly expressed during plant infection. Here we show that expression of UmOps1 and UmOps2 is induced by blue light under control of white collar 1 (Wco1). UmOps1 is mainly localized in the plasma membrane, both when expressed in HEK cells and U. maydis sporidia. In contrast, UmOps2 was mostly found intracellularly in the membranes of vacuoles. Patch-clamp studies demonstrated that both rhodopsins are green light-driven outward rectifying proton pumps. UmOps1 revealed an extraordinary pH dependency with increased activity in more acidic environment. Also, UmOps1 showed a pronounced, concentration-dependent enhancement of pump current caused by weak organic acids (WOAs), especially by acetic acid and indole-3-acetic acid (IAA). In contrast, UmOps2 showed the typical behavior of light-driven, outwardly directed proton pumps, whereas UmOps3 did not exhibit any electrogenity. With this work, insights were gained into the localization and molecular function of two U. maydis rhodopsins, paving the way for further studies on the biological role of these rhodopsins in the life cycle of U. maydis.}, language = {en} } @article{DirimanovHoegger2019, author = {Dirimanov, Stoyan and H{\"o}gger, Petra}, title = {Screening of inhibitory effects of polyphenols on Akt-phosphorylation in endothelial cells and determination of structure-activity features}, series = {Biomolecules}, volume = {9}, journal = {Biomolecules}, number = {6}, issn = {2218-273X}, doi = {10.3390/biom9060219}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197333}, pages = {219}, year = {2019}, abstract = {Polyphenols exert beneficial effects in type 2 diabetes mellitus (T2DM). However, their mechanism of action remains largely unknown. Endothelial Akt-kinase plays a key role in the pathogenesis of cardiovascular complications in T2DM and therefore the modulation of its activity is of interest. This work aimed to characterize effects of structurally different polyphenols on Akt-phosphorylation (pAkt) in endothelial cells (Ea.hy926) and to describe structure-activity features. A comprehensive screening via ELISA quantified the effects of 44 polyphenols (10 µM) on pAkt Ser473. The most pronounced inhibitors were luteolin (44 ± 18\%), quercetin (36 ± 8\%), urolithin A (35 ± 12\%), apigenin, fisetin, and resveratrol; (p < 0.01). The results were confirmed by Western blotting and complemented with corresponding experiments in HUVEC cells. A strong positive and statistically significant correlation between the mean inhibitory effects of the tested polyphenols on both Akt-residues Ser473 and Thr308 (r = 0.9478, p = 0.0003) was determined by immunoblotting. Interestingly, the structural characteristics favoring pAkt inhibition partially differed from structural features enhancing the compounds' antioxidant activity. The present study is the first to quantitatively compare the influence of polyphenols from nine different structural subclasses on pAkt in endothelial cells. These effects might be advantageous in certain T2DM-complications involving over-activation of the Akt-pathway. The suggested molecular mode of action of polyphenols involving Akt-inhibition contributes to understanding their effects on the cellular level.}, language = {en} } @article{ScheurerBrandsElMeseryetal.2019, author = {Scheurer, Mario Joachim Johannes and Brands, Roman Camillus and El-Mesery, Mohamed and Hartmann, Stefan and M{\"u}ller-Richter, Urs Dietmar Achim and K{\"u}bler, Alexander Christian and Seher, Axel}, title = {The selection of NFκB inhibitors to block inflammation and induce sensitisation to FasL-induced apoptosis in HNSCC cell lines is critical for their use as a prospective cancer therapy}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {6}, issn = {1422-0067}, doi = {10.3390/ijms20061306}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201524}, year = {2019}, abstract = {Inflammation is a central aspect of tumour biology and can contribute significantly to both the origination and progression of tumours. The NFκB pathway is one of the most important signal transduction pathways in inflammation and is, therefore, an excellent target for cancer therapy. In this work, we examined the influence of four NFκB inhibitors — Cortisol, MLN4924, QNZ and TPCA1 — on proliferation, inflammation and sensitisation to apoptosis mediated by the death ligand FasL in the HNSCC cell lines PCI1, PCI9, PCI13, PCI52 and SCC25 and in the human dermal keratinocyte cell line HaCaT. We found that the selection of the inhibitor is critical to ensure that cells do not respond by inducing counteracting activities in the context of cancer therapy, e.g., the extreme IL-8 induction mediated by MLN4924 or FasL resistance mediated by Cortisol. However, TPCA1 was qualified by this in vitro study as an excellent therapeutic mediator in HNSCC by four positive qualities: (1) proliferation was inhibited at low μM-range concentrations; (2) TNFα-induced IL-8 secretion was blocked; (3) HNSCC cells were sensitized to TNFα-induced cell death; and (4) FasL-mediated apoptosis was not disrupted.}, language = {en} } @article{KrakowCrescimoneBartelsetal.2019, author = {Krakow, S{\"o}ren and Crescimone, Marie L. and Bartels, Charlotte and Wiegering, Verena and Eyrich, Matthias and Schlegel, Paul G. and W{\"o}lfl, Matthias}, title = {Re-expression of CD14 in response to a combined IL-10/TLR stimulus defines monocyte-derived cells with an immunoregulatory phenotype}, series = {Frontiers in Immunology}, volume = {10}, journal = {Frontiers in Immunology}, number = {1484}, doi = {10.3389/fimmu.2019.01484}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201537}, year = {2019}, abstract = {Interleukin 10 is a central regulator of the antigen-presenting function of myeloid cells. It exerts immunomodulatory effects in vivo and induces a regulatory phenotype in monocyte-derived cells in vitro. We analyzed phenotype and function of monocytic cells in vitro in relation to the cytokine milieu and the timing of TLR-based activation. In GM-CSF/IL-4 cultured human monocytic cells, we identified two, mutually exclusive cell populations arising from undifferentiated cells: CD83\(^+\) fully activated dendritic cells and CD14\(^+\) macrophage like cells. Re-expression of CD14 occurs primarily after a sequential trigger with a TLR signal following IL-10 preincubation. This cell population with re-expressed CD14 greatly differs in phenotype and function from the CD83+ cells. Detailed analysis of individual subpopulations reveals that exogenous IL-10 is critical for inducing the shift toward the CD14\(^+\) population, but does not affect individual changes in marker expression or cell function in most cases. Thus, plasticity of CD14 expression, defining a subset of immunoregulatory cells, is highly relevant for the composition of cellular products (such as DC vaccines) as it affects the function of the total product.}, language = {en} } @article{KuehnischHerbstAl‐Wakeel‐Marquardetal.2019, author = {K{\"u}hnisch, Jirko and Herbst, Christopher and Al-Wakeel-Marquard, Nadya and Dartsch, Josephine and Holtgrewe, Manuel and Baban, Anwar and Mearini, Giulia and Hardt, Juliane and Kolokotronis, Konstantinos and Gerull, Brenda and Carrier, Lucie and Beule, Dieter and Schubert, Stephan and Messroghli, Daniel and Degener, Franziska and Berger, Felix and Klaassen, Sabine}, title = {Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3}, series = {Clinical Genetics}, volume = {96}, journal = {Clinical Genetics}, number = {6}, doi = {10.1111/cge.13645}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213958}, pages = {549 -- 559}, year = {2019}, abstract = {The underlying genetic mechanisms and early pathological events of children with primary cardiomyopathy (CMP) are insufficiently characterized. In this study, we aimed to characterize the mutational spectrum of primary CMP in a large cohort of patients ≤18 years referred to a tertiary center. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel-based next-generation sequencing approach of 89 genes. At least one pathogenic or probably pathogenic variant was identified in 30/80 (38\%) index patients. In all CMP subgroups, patients carried most frequently variants of interest in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. In MYH7, MYBPC3, and TNNI3, we identified 18 pathogenic/probably pathogenic variants (MYH7 n = 7, MYBPC3 n = 6, TNNI3 n = 5, including one homozygous (TNNI3 c.24+2T>A) truncating variant. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of TNNI3 revealed that the TNNI3 protein is absent and associated with upregulation of the fetal isoform TNNI1. The present study further supports the clinical importance of sarcomeric mutation—not only in adult—but also in pediatric primary CMP. TNNI3 is the third most important disease gene in this cohort and complete loss of TNNI3 leads to severe pediatric CMP.}, language = {en} } @article{SchartlKneitzVolkoffetal.2019, author = {Schartl, Manfred and Kneitz, Susanne and Volkoff, Helene and Adolfi, Mateus and Schmidt, Cornelia and Fischer, Petra and Minx, Patrick and Tomlinson, Chad and Meyer, Axel and Warren, Wesley C.}, title = {The piranha genome provides molecular insight associated to its unique feeding behavior}, series = {Genome Biology and Evolution}, volume = {11}, journal = {Genome Biology and Evolution}, number = {8}, doi = {10.1093/gbe/evz139}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202218}, pages = {2099-2106}, year = {2019}, abstract = {The piranha enjoys notoriety due to its infamous predatory behavior but much is still not understood about its evolutionary origins and the underlying molecular mechanisms for its unusual feeding biology. We sequenced and assembled the red-bellied piranha (Pygocentrus nattereri) genome to aid future phenotypic and genetic investigations. The assembled draft genome is similar to other related fishes in repeat composition and gene count. Our evaluation of genes under positive selection suggests candidates for adaptations of piranhas' feeding behavior in neural functions, behavior, and regulation of energy metabolism. In the fasted brain, we find genes differentially expressed that are involved in lipid metabolism and appetite regulation as well as genes that may control the aggression/boldness behavior of hungry piranhas. Our first analysis of the piranha genome offers new insight and resources for the study of piranha biology and for feeding motivation and starvation in other organisms.}, language = {en} } @article{KaethnerBaderPauli2019, author = {K{\"a}thner, Ivo and Bader, Thomas and Pauli, Paul}, title = {Heat pain modulation with virtual water during a virtual hand illusion}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-55407-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202221}, pages = {19137}, year = {2019}, abstract = {Immersive virtual reality is a powerful method to modify the environment and thereby influence experience. The present study used a virtual hand illusion and context manipulation in immersive virtual reality to examine top-down modulation of pain. Participants received painful heat stimuli on their forearm and placed an embodied virtual hand (co-located with their real one) under a virtual water tap, which dispensed virtual water under different experimental conditions. We aimed to induce a temperature illusion by a red, blue or white light suggesting warm, cold or no virtual water. In addition, the sense of agency was manipulated by allowing participants to have high or low control over the virtual hand's movements. Most participants experienced a thermal sensation in response to the virtual water and associated the blue and red light with cool/cold or warm/hot temperatures, respectively. Importantly, the blue light condition reduced and the red light condition increased pain intensity and unpleasantness, both compared to the control condition. The control manipulation influenced the sense of agency, but did not influence pain ratings. The large effects revealed in our study suggest that context effects within an embodied setting in an immersive virtual environment should be considered within VR based pain therapy.}, language = {en} } @article{PoppRamirezZavalaSchwanfelderetal.2019, author = {Popp, Christina and Ram{\´i}rez-Zavala, Bernardo and Schwanfelder, Sonja and Kr{\"u}ger, Ines and Morschh{\"a}user, Joachim}, title = {Evolution of fluconazole-resistant Candida albicans strains by drug-induced mating competence and parasexual recombination}, series = {mBio}, volume = {10}, journal = {mBio}, number = {1}, doi = {10.1128/mBio.02740-18}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200901}, pages = {e02740-18}, year = {2019}, abstract = {The clonal population structure of Candida albicans suggests that (para)sexual recombination does not play an important role in the lifestyle of this opportunistic fungal pathogen, an assumption that is strengthened by the fact that most C. albicans strains are heterozygous at the mating type locus (MTL) and therefore mating-incompetent. On the other hand, mating might occur within clonal populations and allow the combination of advantageous traits that were acquired by individual cells to adapt to adverse conditions. We have investigated if parasexual recombination may be involved in the evolution of highly drug-resistant strains exhibiting multiple resistance mechanisms against fluconazole, an antifungal drug that is commonly used to treat infections by C. albicans. Growth of strains that were heterozygous for MTL and different fluconazole resistance mutations in the presence of the drug resulted in the emergence of derivatives that had become homozygous for the mutated allele and the mating type locus and exhibited increased drug resistance. When MTLa/a and MTLα/α cells of these strains were mixed in all possible combinations, we could isolate mating products containing the genetic material from both parents. The initial mating products did not exhibit higher drug resistance than their parental strains, but further propagation under selective pressure resulted in the loss of the wild-type alleles and increased fluconazole resistance. Therefore, fluconazole treatment not only selects for resistance mutations but also promotes genomic alterations that confer mating competence, which allows cells in an originally clonal population to exchange individually acquired resistance mechanisms and generate highly drug-resistant progeny.}, language = {en} } @article{JurowichLichthardtKastneretal.2019, author = {Jurowich, Christian and Lichthardt, Sven and Kastner, Caroline and Haubitz, Imme and Prock, Andre and Filser, J{\"o}rg and Germer, Christoph-Thomas and Wiegering, Armin}, title = {Laparoscopic versus open right hemicolectomy in colon carcinoma: A propensity score analysis of the DGAV StuDoQ|ColonCancer registry}, series = {PLoS ONE}, volume = {14}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0218829}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202184}, pages = {e0218829}, year = {2019}, abstract = {Objective To assess whether laparoscopy has any advantages over open resection for right-sided colon cancer. Summary background data Right hemicolectomy can be performed using either a conventional open or a minimally invasive laparoscopic technique. It is not clear whether these different access routes differ with regard to short-term postoperative outcomes. Methods Patients documented in the German Society for General and Visceral Surgery StuDoQ|ColonCancer registry who underwent right hemicolectomy were analyzed regarding early postoperative complications according to Clavien-Dindo (primary endpoint), operation (OP) time, length of postoperative hospital stay (LOS), MTL30 and number of lymph nodes retrieved (secondary endpoints). Results A total of 4.997 patients were identified as undergoing oncological right hemicolectomy without additional interventions. Of these, 4.062 (81.3\%) underwent open, 935 (18.7\%) laparoscopic surgery. Propensity score analysis showed a significantly shorter LOS (OR: 0.55 CI 95\%0.47-.64) and a significantly longer OP time (OR2.32 CI 1.98-2.71) for the laparoscopic route. Risk factors for postoperative complications, anastomotic insufficiency, ileus, reoperation and positive MTL30 were higher ASA status, higher age and increasing BMI. The surgical access route (open / lap) had no influence on these factors, but the laparoscopic group did have markedly fewer lymph nodes retrieved. Conclusion The present registry-based analysis could detect no relevant advantages for the minimally invasive laparoscopic access route. Further oncological analyses are needed to clarify the extent to which the smaller lymph node harvest in the laparoscopic group is accompanied by a poorer oncological outcome.}, language = {en} } @article{SilwedelSpeerHaarmannetal.2019, author = {Silwedel, Christine and Speer, Christian P. and Haarmann, Axel and Fehrholz, Markus and Claus, Heike and Schlegel, Nicolas and Glaser, Kirsten}, title = {Ureaplasma species modulate cytokine and chemokine responses in human brain microvascular endothelial cells}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {14}, issn = {1422-0067}, doi = {10.3390/ijms20143583}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201848}, year = {2019}, abstract = {Ureaplasma species are common colonizers of the adult genitourinary tract and often considered as low-virulence commensals. Intraamniotic Ureaplasma infections, however, facilitate chorioamnionitis and preterm birth, and cases of Ureaplasma-induced neonatal sepsis, pneumonia, and meningitis raise a growing awareness of their clinical relevance. In vitro studies are scarce but demonstrate distinct Ureaplasma-driven impacts on immune mechanisms. The current study addressed cytokine and chemokine responses upon exposure of native or lipopolysaccharide (LPS) co-stimulated human brain microvascular endothelial cells (HBMEC) to Ureaplasma urealyticum or U. parvum, using qRT-PCR, RNA sequencing, multi-analyte immunoassay, and flow cytometry. Ureaplasma exposure in native HBMEC reduced monocyte chemoattractant protein (MCP)-3 mRNA expression (p < 0.01, vs. broth). In co-stimulated HBMEC, Ureaplasma spp. attenuated LPS-evoked mRNA responses for C-X-C chemokine ligand 5, MCP-1, and MCP-3 (p < 0.05, vs. LPS) and mitigated LPS-driven interleukin (IL)-1α protein secretion, as well as IL-8 mRNA and protein responses (p < 0.05). Furthermore, Ureaplasma isolates increased C-X-C chemokine receptor 4 mRNA levels in native and LPS co-stimulated HBMEC (p < 0.05). The presented results may imply immunomodulatory capacities of Ureaplasma spp. which may ultimately promote chronic colonization and long-term neuroinflammation.}, language = {en} } @article{PenagosCalveteDuqueMarimonetal.2019, author = {Penagos-Calvete, Diana and Duque, Valeria and Marimon, Claudia and Parra, Diana M. and Restrepo-Arango, Sandra K. and Scherf-Clavel, Oliver and Holzgrabe, Ulrike and Montoya, Guillermo and Salamanca, Constain H.}, title = {Glycerolipid composition and advanced physicochemical considerations of sacha inchi oil toward cosmetic products formulation}, series = {Cosmetics}, volume = {6}, journal = {Cosmetics}, number = {4}, issn = {2079-9284}, doi = {10.3390/cosmetics6040070}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193857}, year = {2019}, abstract = {Sacha inchi oil is a premier raw material with highly nutritional and functional features for the foodstuff, pharmaceutical, beauty, and personal care industries. One of the most important facts about this oil is the huge chemical content of unsaturated and polyunsaturated fatty acids. However, the current available information on the characterization of the triglyceride composition and the advance physicochemical parameters relevant to emulsion development is limited. Therefore, this research focused on providing a detailed description of the lipid composition using high-resolution tandem mass spectrometry and thorough physicochemical characterization to find the value of the required hydrophilic-lipophilic balance (HLB). For this, a study in the interfacial tension was evaluated, followed by the assessment of different parameters such as creaming index, droplet size, viscosity, zeta potential, pH, and electrical conductivity for a series emulsified at thermal stress condition. The results show that fatty acids are arranged into glycerolipids and the required HLB to achieve the maximum physical stability is around 8.}, language = {en} }