@article{NotzLotzHerrmannetal.2021, author = {Notz, Quirin and Lotz, Christopher and Herrmann, Johannes and Vogt, Marius and Schlesinger, Tobias and Kredel, Markus and Muellges, Wolfgang and Weismann, Dirk and Westermaier, Thomas and Meybohm, Patrick and Kranke, Peter}, title = {Severe neurological complications in critically ill COVID‑19 patients}, series = {Journal of Neurology}, journal = {Journal of Neurology}, issn = {0340-5354}, doi = {10.1007/s00415-020-10152-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232429}, pages = {1576-1579}, year = {2021}, abstract = {No abstract available.}, language = {en} } @article{HerbertWoeckelKreienbergetal.2021, author = {Herbert, S. L. and W{\"o}ckel, A. and Kreienberg, R. and K{\"u}hn, T. and Flock, F. and Felberbaum, R. and Janni, W. and Curtaz, C. and Kiesel, M. and St{\"u}ber, T. and Diessner, J. and Salmen, J. and Schwentner, L. and Fink, V. and Bekes, I. and Leinert, E. and Lato, K. and Polasik, A. and Schochter, F. and Singer, S.}, title = {To which extent do breast cancer survivors feel well informed about disease and treatment 5 years after diagnosis?}, series = {Breast Cancer Research and Treatment}, volume = {185}, journal = {Breast Cancer Research and Treatment}, organization = {BRENDA study group}, issn = {0167-6806}, doi = {10.1007/s10549-020-05974-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232356}, pages = {677-684}, year = {2021}, abstract = {Objective In this study, we investigated to which extent patients feel well informed about their disease and treatment, which areas they wish more or less information and which variables are associated with a need for information about the disease, medical tests and treatment. Methods In a German multi-centre prospective study, we enrolled 759 female breast cancer patients at the time of cancer diagnosis (baseline). Data on information were captured at 5 years after diagnosis with the European Organisation for Research and Treatment of Cancer (EORTC) Information Module (EORTC QLQ-INFO24). Good information predictors were analysed using linear regression models. Results There were 456 patients who participated at the 5-year follow-up. They reported to feel well informed about medical tests (mean score 78.5) and the disease itself (69.3) but relatively poorly about other services (44.3) and about different places of care (31.3). The survivors expressed a need for more information concerning: side effects and long-term consequences of therapy, more information in general, information about aftercare, prognosis, complementary medicine, disease and therapy. Patients with higher incomes were better informed about medical tests (β 0.26, p 0.04) and worse informed with increasing levels of fear of treatment (β - 0.11, p 0.02). Information about treatment was reported to be worse by survivors > 70 years old (β -0.34, p 0.03) and by immigrants (β -0.11, p 0.02). Survivors who had received additional written information felt better informed about disease, medical tests, treatment and other services (β 0.19/0.19/0.20/0.25; each p < 0.01). Conclusion Health care providers have to reconsider how and what kind of information they provide. Providing written information, in addition to oral information, may improve meeting those information needs.}, language = {en} } @article{AghaiZimmermannKurlbaumetal.2021, author = {Aghai, Fatemeh and Zimmermann, Sebastian and Kurlbaum, Max and Jung, Pius and Pelzer, Theo and Klinker, Hartwig and Isberner, Nora and Scherf-Clavel, Oliver}, title = {Development and validation of a sensitive liquid chromatography tandem mass spectrometry assay for the simultaneous determination of ten kinase inhibitors in human serum and plasma}, series = {Analytical and Bioanalytical Chemistry}, volume = {413}, journal = {Analytical and Bioanalytical Chemistry}, issn = {1618-2642}, doi = {10.1007/s00216-020-03031-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231925}, pages = {599-612}, year = {2021}, abstract = {A liquid chromatography tandem mass spectrometry method for the analysis of ten kinase inhibitors (afatinib, axitinib, bosutinib,cabozantinib, dabrafenib, lenvatinib, nilotinib, osimertinib, ruxolitinib, and trametinib) in human serum and plasma for theapplication in daily clinical routine has been developed and validated according to the US Food and Drug Administration andEuropean Medicines Agency validation guidelines for bioanalytical methods. After protein precipitation of plasma samples withacetonitrile, chromatographic separation was performed at ambient temperature using a Waters XBridge® Phenyl 3.5μm(2.1×50 mm) column. The mobile phases consisted of water-methanol (9:1, v/v) with 10 mM ammonium bicarbonate as phase A andmethanol-water (9:1, v/v) with 10 mM ammonium bicarbonate as phase B. Gradient elution was applied at a flow rate of 400μL/min. Analytes were detected and quantified using multiple reaction monitoring in electrospray ionization positive mode. Stableisotopically labeled compounds of each kinase inhibitor were used as internal standards. The acquisition time was 7.0 min perrun. All analytes and internal standards eluted within 3.0 min. The calibration curves were linear over the range of 2-500 ng/mLfor afatinib, axitinib, bosutinib, lenvatinib, ruxolitinib, and trametinib, and 6-1500 ng/mL for cabozantinib, dabrafenib, nilotinib,and osimertinib (coefficients of correlation≥0.99). Validation assays for accuracy and precision, matrix effect, recovery,carryover, and stability were appropriate according to regulatory agencies. The rapid and sensitive assay ensures high throughputand was successfully applied to monitor concentrations of kinase inhibitors in patients.}, language = {en} } @article{KurzZanzingerHagenetal.2021, author = {Kurz, Anja and Zanzinger, Maren and Hagen, Rudolf and Rak, Kirsten}, title = {The impact of cochlear implant microphone settings on the binaural hearing of experienced cochlear implant users with single sided deafness}, series = {European Archives of Oto-Rhino-Laryngology}, journal = {European Archives of Oto-Rhino-Laryngology}, edition = {corrected version}, issn = {0937-4477}, doi = {10.1007/s00405-020-06450-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231750}, year = {2021}, abstract = {Objective Cochlear implantation has become a well-accepted treatment option for people with single-sided deafness (SSD) and has become a clinical standard in many countries. A cochlear implant (CI) is the only device which restores binaural hearing. The effect of microphone directionality (MD) settings has been investigated in other CI indication groups, but its impact on speech perception in noise has not been established in CI users with SSD. The focus of this investigation was, therefore, to assess binaural hearing effects using different MD settings in CI users with SSD. Methods Twenty-nine experienced CI users with SSD were recruited to determine speech reception thresholds with varying target and noise sources to define binaural effects (head shadow, squelch, summation, and spatial release from masking), sound localization, and sound quality using the SSQ12 and HISQUI19 questionnaires. Outcome measures included the MD settings "natural", "adaptive", and "omnidirectional". Results The 29 participants involved in the study were divided into two groups: 11 SONNET users and 18 OPUS 2/RONDO users. In both groups, a significant head shadow effect of 7.4-9.2 dB was achieved with the CI. The MD setting "adaptive" provided a significant head shadow effect of 9.2 dB, a squelch effect of 0.9 dB, and spatial release from masking of 7.6 dB in the SONNET group. No significant summation effect could be determined in either group with CI. Outcomes with the omnidirectional setting were not significantly different between groups. For both groups, localization improved significantly when the CI was activated and was best when the omnidirectional setting was used. The groups' sound quality scores did not significantly differ. Conclusions Adaptive directional microphone settings improve speech perception and binaural hearing abilities in CI users with SSD. Binaural effect measures are valuable to quantify the benefit of CI use, especially in this indication group.}, language = {en} } @article{HaringReinerLiuetal.2021, author = {Haring, Bernhard and Reiner, Alexander P. and Liu, Jungmin and Tobias, Deirdre K. and Whitsel, Eric and Berger, Jeffrey S. and Desai, Pinkal and Wassertheil-Smoller, Sylvia and LaMonte, Michael J. and Hayden, Kathleen and Bick, Alexander G. and Natarajan, Pradeep and Weinstock, Joshua S. and Nguyen, Patricia K. and Stefanick, Marcia and Simon, Michael S. and Eaton, Charles and Kooperberg, Charles and Manson, JoAnn E.}, title = {Healthy Lifestyle and Clonal Hematopoiesis of Indeterminate Potential. Results from the Women's Health Initiative}, series = {Journal of the American Heart Association}, volume = {10}, journal = {Journal of the American Heart Association}, number = {5}, doi = {10.1161/JAHA.120.018789}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236146}, year = {2021}, abstract = {Background Presence of clonal hematopoiesis of indeterminate potential (CHIP) is associated with a higher risk of atherosclerotic cardiovascular disease, cancer, and mortality. The relationship between a healthy lifestyle and CHIP is unknown. Methods and Results This analysis included 8709 postmenopausal women (mean age, 66.5 years) enrolled in the WHI (Women's Health Initiative), free of cancer or cardiovascular disease, with deep-coverage whole genome sequencing data available. Information on lifestyle factors (body mass index, smoking, physical activity, and diet quality) was obtained, and a healthy lifestyle score was created on the basis of healthy criteria met (0 point [least healthy] to 4 points [most healthy]). CHIP was derived on the basis of a prespecified list of leukemogenic driver mutations. The prevalence of CHIP was 8.6\%. A higher healthy lifestyle score was not associated with CHIP (multivariable-adjusted odds ratio [OR] [95\% CI], 0.99 [0.80-1.23] and 1.13 [0.93-1.37]) for the upper (3 or 4 points) and middle category (2 points), respectively, versus referent (0 or 1 point). Across score components, a normal and overweight body mass index compared with obese was significantly associated with a lower odds for CHIP (OR, 0.71 [95\% CI, 0.57-0.88] and 0.83 [95\% CI, 0.68-1.01], respectively; P-trend 0.0015). Having never smoked compared with being a current smoker tended to be associated with lower odds for CHIP. Conclusions A healthy lifestyle, based on a composite score, was not related to CHIP among postmenopausal women. However, across individual lifestyle factors, having a normal body mass index was strongly associated with a lower prevalence of CHIP. These findings support the idea that certain healthy lifestyle factors are associated with a lower frequency of CHIP.}, language = {en} } @article{OberdorfHanftRamleretal.2021, author = {Oberdorf, Kai and Hanft, Anna and Ramler, Jacqueline and Krummenacher, Ivo and Bickelhaupt, Matthias and Poater, Jordi and Lichtenberg, Crispin}, title = {Bismuth Amides Mediate Facile and Highly Selective Pn-Pn Radical-Coupling Reactions (Pn=N, P, As)}, series = {Angewandte Chemie, International Edition}, volume = {60}, journal = {Angewandte Chemie, International Edition}, number = {12}, doi = {10.1002/anie.202015514}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236582}, pages = {6441-6445}, year = {2021}, abstract = {The controlled release of well-defined radical species under mild conditions for subsequent use in selective reactions is an important and challenging task in synthetic chemistry. We show here that simple bismuth amide species [Bi(NAr\(_2\))\(_3\)] readily release aminyl radicals [NAr\(_2\)]. at ambient temperature in solution. These reactions yield the corresponding hydrazines, Ar\(_2\)N-NAr\(_2\), as a result of highly selective N-N coupling. The exploitation of facile homolytic Bi-Pn bond cleavage for Pn-Pn bond formation was extended to higher homologues of the pnictogens (Pn=N-As): homoleptic bismuth amides mediate the highly selective dehydrocoupling of HPnR\(_2\) to give R\(_2\)Pn-PnR\(_2\). Analyses by NMR and EPR spectroscopy, single-crystal X-ray diffraction, and DFT calculations reveal low Bi-N homolytic bond-dissociation energies, suggest radical coupling in the coordination sphere of bismuth, and reveal electronic and steric parameters as effective tools to control these reactions.}, language = {en} } @article{HeuschmannMontellanoUngethuemetal.2021, author = {Heuschmann, Peter U. and Montellano, Felipe A. and Ungeth{\"u}m, Kathrin and R{\"u}cker, Viktoria and Wiedmann, Silke and Mackenrodt, Daniel and Quilitzsch, Anika and Ludwig, Timo and Kraft, Peter and Albert, Judith and Morbach, Caroline and Frantz, Stefan and St{\"o}rk, Stefan and Haeusler, Karl Georg and Kleinschnitz, Christoph}, title = {Prevalence and determinants of systolic and diastolic cardiac dysfunction and heart failure in acute ischemic stroke patients: The SICFAIL study}, series = {ESC Heart Failure}, volume = {8}, journal = {ESC Heart Failure}, number = {2}, doi = {10.1002/ehf2.13145}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225656}, pages = {1117-1129}, year = {2021}, abstract = {Aims Ischaemic stroke (IS) might induce alterations of cardiac function. Prospective data on frequency of cardiac dysfunction and heart failure (HF) after IS are lacking. We assessed prevalence and determinants of diastolic dysfunction (DD), systolic dysfunction (SD), and HF in patients with acute IS. Methods and results The Stroke-Induced Cardiac FAILure in mice and men (SICFAIL) study is a prospective, hospital-based cohort study. Patients with IS underwent a comprehensive assessment of cardiac function in the acute phase (median 4 days after IS) including clinical examination, standardized transthoracic echocardiography by expert sonographers, and determination of blood-based biomarkers. Information on demographics, lifestyle, risk factors, symptoms suggestive of HF, and medical history was collected by a standardized personal interview. Applying current guidelines, cardiac dysfunction was classified based on echocardiographic criteria into SD (left ventricular ejection fraction < 52\% in men or <54\% in women) and DD (≥3 signs of DD in patients without SD). Clinically overt HF was classified into HF with reduced, mid-range, or preserved ejection fraction. Between January 2014 and February 2017, 696 IS patients were enrolled. Of them, patients with sufficient echocardiographic data on SD were included in the analyses {n = 644 patients [median age 71 years (interquartile range 60-78), 61.5\% male]}. In these patients, full assessment of DD was feasible in 549 patients without SD (94\%). Prevalence of cardiac dysfunction and HF was as follows: SD 9.6\% [95\% confidence interval (CI) 7.6-12.2\%]; DD in patients without SD 23.3\% (95\% CI 20.0-27.0\%); and clinically overt HF 5.4\% (95\% CI 3.9-7.5\%) with subcategories of HF with preserved ejection fraction 4.35\%, HF with mid-range ejection fraction 0.31\%, and HF with reduced ejection fraction 0.78\%. In multivariable analysis, SD and fulfilment of HF criteria were associated with history of coronary heart disease [SD: odds ratio (OR) 3.87, 95\% CI 1.93-7.75, P = 0.0001; HF: OR 2.29, 95\% CI 1.04-5.05, P = 0.0406] and high-sensitive troponin T at baseline (SD: OR 1.78, 95\% CI 1.31-2.42, P = 0.0003; HF: OR 1.66, 95\% CI 1.17-2.33, P = 0.004); DD was associated with older age (OR 1.08, 95\% CI 1.05-1.11, P < 0.0001) and treated hypertension vs. no hypertension (OR 2.84, 95\% CI 1.23-6.54, P = 0.0405). Conclusions A substantial proportion of the study population exhibited subclinical and clinical cardiac dysfunction. SICFAIL provides reliable data on prevalence and determinants of SD, DD, and clinically overt HF in patients with acute IS according to current guidelines, enabling further clarification of its aetiological and prognostic role.}, language = {en} } @article{LauererTiedemannPolaketal.2021, author = {Lauerer, Elias and Tiedemann, Elena and Polak, Thomas and Simmenroth, Anne}, title = {Can smoking cessation be taught online? A prospective study comparing e-learning and role-playing in medical education}, series = {International Journal of Medical Education}, volume = {12}, journal = {International Journal of Medical Education}, doi = {10.5116/ijme.5ff9.bccc}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230056}, pages = {12-21}, year = {2021}, abstract = {Objectives: We compared the effect of different didactic formats - e - learning and role-playing - on medical students' knowledge and counselling skills in smoking cessation training. Methods: At a German medical school, 145 third-year students were randomly allocated to attend an online course with video examples or an attendance course with role-playing. Students were trained in smoking cessation counselling according to the 5A's (ask, advise, assess, assist, arrange) for approximately 90 minutes. Practical skills were measured in an objective structured clinical examination (OSCE) and represent the primary endpoint of this prospective comparative study. Additionally, changes in theoretic knowledge were assessed by pre - and post - interventional questionnaires and a final written exam. Results: In the OSCE, overall scores were higher in the attendance group (Mdn=70.8 \% vs. 62.8 \%; U=119; p=.087, n=36), but a statistical advantage was only found in one single counselling sequence ("Assist": Mdn=66.7 \% vs. 51.4 \%; p = .049) and the rating of the standardised patients (M=4.7 vs. 4.2 out of 5 points, t(27.836)=2.0, p=.028). Students' results (n=130) from self-assessment and written exams suggest that both approaches are equally well suited to increase theoretical knowledge. The online course was more time efficient (90 vs. 73 minutes). Conclusions: Seminar and web-based training seem equally well suited for transferring knowledge and skills on tobacco cessation counselling. Considering their particular strengths, these two teaching approaches could be combined.}, language = {en} } @article{VogelChungaSunetal.2021, author = {Vogel, Cassandra and Chunga, Timothy L. and Sun, Xiaoxuan and Poveda, Katja and Steffan-Dewenter, Ingolf}, title = {Higher bee abundance, but not pest abundance, in landscapes with more agriculture on a late-flowering legume crop in tropical smallholder farms}, series = {PeerJ}, volume = {9}, journal = {PeerJ}, doi = {10.7717/peerj.10732}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231491}, year = {2021}, abstract = {Background Landscape composition is known to affect both beneficial insect and pest communities on crop fields. Landscape composition therefore can impact ecosystem (dis)services provided by insects to crops. Though landscape effects on ecosystem service providers have been studied in large-scale agriculture in temperate regions, there is a lack of representation of tropical smallholder agriculture within this field of study, especially in sub-Sahara Africa. Legume crops can provide important food security and soil improvement benefits to vulnerable agriculturalists. However, legumes are dependent on pollinating insects, particularly bees (Hymenoptera: Apiformes) for production and are vulnerable to pests. We selected 10 pigeon pea (Fabaceae: Cajunus cajan (L.)) fields in Malawi with varying proportions of semi-natural habitat and agricultural area within a 1 km radius to study: (1) how the proportion of semi-natural habitat and agricultural area affects the abundance and richness of bees and abundance of florivorous blister beetles (Coleoptera: Melloidae), (2) if the proportion of flowers damaged and fruit set difference between open and bagged flowers are correlated with the proportion of semi-natural habitat or agricultural area and (3) if pigeon pea fruit set difference between open and bagged flowers in these landscapes was constrained by pest damage or improved by bee visitation. Methods We performed three, ten-minute, 15 m, transects per field to assess blister beetle abundance and bee abundance and richness. Bees were captured and identified to (morpho)species. We assessed the proportion of flowers damaged by beetles during the flowering period. We performed a pollinator and pest exclusion experiment on 15 plants per field to assess whether fruit set was pollinator limited or constrained by pests. Results In our study, bee abundance was higher in areas with proportionally more agricultural area surrounding the fields. This effect was mostly driven by an increase in honeybees. Bee richness and beetle abundances were not affected by landscape characteristics, nor was flower damage or fruit set difference between bagged and open flowers. We did not observe a positive effect of bee density or richness, nor a negative effect of florivory, on fruit set difference. Discussion In our study area, pigeon pea flowers relatively late—well into the dry season. This could explain why we observe higher densities of bees in areas dominated by agriculture rather than in areas with more semi-natural habitat where resources for bees during this time of the year are scarce. Therefore, late flowering legumes may be an important food resource for bees during a period of scarcity in the seasonal tropics. The differences in patterns between our study and those conducted in temperate regions highlight the need for landscape-scale studies in areas outside the temperate region.}, language = {en} } @article{SanchezNayaStepanenkoMandeletal.2021, author = {Sanchez-Naya, Roberto and Stepanenko, Vladimir and Mandel, Karl and Beuerle, Florian}, title = {Modulation of Crystallinity and Optical Properties in Composite Materials Combining Iron Oxide Nanoparticles and Dye-Containing Covalent Organic Frameworks}, series = {Organic Materials}, volume = {3}, journal = {Organic Materials}, doi = {10.1055/s-0040-1722655}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231480}, pages = {17-24}, year = {2021}, abstract = {Two series of organic-inorganic composite materials were synthesized through solvothermal imine condensation between diketopyrrolopyrrole dialdehyde DPP-1 and 5,10,15,20-tetrakis(4-aminophenyl)porphyrin (TAPP) in the presence of varying amounts of either amino- or carboxy-functionalized superparamagnetic iron oxide nanoparticles (FeO). Whereas high FeO loading induced cross-linking of the inorganic nanoparticles by amorphous imine polymers, a lower FeO content resulted in the formation of crystalline covalent organic framework domains. All hybrid materials were analyzed by magnetization measurements, powder X-ray diffraction, electron microscopy, IR, and UV/Vis absorption spectroscopy. Crystallinity, chromophore stacking, and visible absorption features are directly correlated to the mass fraction of the components, thus allowing for a fine-tuning of materials properties.}, language = {en} } @article{HelfrichFoersterMoneckeSpiousasetal.2021, author = {Helfrich-F{\"o}rster, C. and Monecke, S. and Spiousas, I. and Hovestadt, T. and Mitesser, O. and Wehr, T. A.}, title = {Women temporarily synchronize their menstrual cycles with the luminance and gravimetric cycles of the Moon}, series = {Science Advances}, volume = {7}, journal = {Science Advances}, number = {5}, doi = {10.1126/sciadv.abe1358}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231479}, year = {2021}, abstract = {Many species synchronize reproductive behavior with a particular phase of the lunar cycle to increase reproductive success. In humans, a lunar influence on reproductive behavior remains controversial, although the human menstrual cycle has a period close to that of the lunar cycle. Here, we analyzed long-term menstrual recordings of individual women with distinct methods for biological rhythm analysis. We show that women's menstrual cycles with a period longer than 27 days were intermittently synchronous with the Moon's luminance and/or gravimetric cycles. With age and upon exposure to artificial nocturnal light, menstrual cycles shortened and lost this synchrony. We hypothesize that in ancient times, human reproductive behavior was synchronous with the Moon but that our modern lifestyles have changed reproductive physiology and behavior.}, language = {en} } @article{KuehnemundtLeifeldSchergetal.2021, author = {K{\"u}hnemundt, Johanna and Leifeld, Heidi and Scherg, Florian and Schmitt, Matthias and Nelke, Lena C. and Schmitt, Tina and Bauer, Florentin and G{\"o}ttlich, Claudia and Fuchs, Maximilian and Kunz, Meik and Peindl, Matthias and Br{\"a}hler, Caroline and Kronenthaler, Corinna and Wischhusen, J{\"o}rg and Prelog, Martina and Walles, Heike and Dandekar, Thomas and Dandekar, Gudrun and Nietzer, Sarah L.}, title = {Modular micro-physiological human tumor/tissue models based on decellularized tissue for improved preclinical testing}, series = {ALTEX}, volume = {38}, journal = {ALTEX}, doi = {10.14573/altex.2008141}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231465}, pages = {289-306}, year = {2021}, abstract = {High attrition-rates entailed by drug testing in 2D cell culture and animal models stress the need for improved modeling of human tumor tissues. In previous studies our 3D models on a decellularized tissue matrix have shown better predictivity and higher chemoresistance. A single porcine intestine yields material for 150 3D models of breast, lung, colorectal cancer (CRC) or leukemia. The uniquely preserved structure of the basement membrane enables physiological anchorage of endothelial cells and epithelial-derived carcinoma cells. The matrix provides different niches for cell growth: on top as monolayer, in crypts as aggregates and within deeper layers. Dynamic culture in bioreactors enhances cell growth. Comparing gene expression between 2D and 3D cultures, we observed changes related to proliferation, apoptosis and stemness. For drug target predictions, we utilize tumor-specific sequencing data in our in silico model finding an additive effect of metformin and gefitinib treatment for lung cancer in silico, validated in vitro. To analyze mode-of-action, immune therapies such as trispecific T-cell engagers in leukemia, as well as toxicity on non-cancer cells, the model can be modularly enriched with human endothelial cells (hECs), immune cells and fibroblasts. Upon addition of hECs, transmigration of immune cells through the endothelial barrier can be investigated. In an allogenic CRC model we observe a lower basic apoptosis rate after applying PBMCs in 3D compared to 2D, which offers new options to mirror antigen-specific immunotherapies in vitro. In conclusion, we present modular human 3D tumor models with tissue-like features for preclinical testing to reduce animal experiments.}, language = {en} } @article{PetritschPannbeckerWengetal.2021, author = {Petritsch, Bernhard and Pannbecker, Pauline and Weng, Andreas M. and Grunz, Jan-Peter and Veldhoen, Simon and Bley, Thorsten A. and Kosmala, Aleksander}, title = {Split-filter dual-energy CT pulmonary angiography for the diagnosis of acute pulmonary embolism: a study on image quality and radiation dose}, series = {Quantitative Imaging in Medicine and Surgery}, volume = {11}, journal = {Quantitative Imaging in Medicine and Surgery}, number = {5}, doi = {10.21037/qims-20-740}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231456}, pages = {1817-1827}, year = {2021}, abstract = {Background: Computed tomography (CT) pulmonary angiography is the diagnostic reference standard in suspected pulmonary embolism (PE). Favorable results for dual-energy CT (DECT) images have been reported for this condition. Nowadays, dual-energy data acquisition is feasible with different technical options, including a single-source split-filter approach. Therefore, the aim of this retrospective study was to investigate image quality and radiation dose of thoracic split-filter DECT in comparison to conventional single-energy CT in patients with suspected PE. Methods: A total of 110 CT pulmonary angiographies were accomplished either as standard single-energy CT with automatic tube voltage selection (ATVS) (n=58), or as split-filter DECT (n=52). Objective [pulmonary artery CT attenuation, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR)] and subjective image quality [four-point Likert scale; three readers (R)] were compared among the two study groups. Size-specific dose estimates (SSDE), dose-length-product (DLP) and volume CT dose index (CTDIvol) were assessed for radiation dose analysis. Results: Split-filter DECT images yielded 67.7\% higher SNR (27.0 vs. 16.1; P<0.001) and 61.9\% higher CNR (22.5 vs. 13.9; P<0.001) over conventional single-energy images, whereas CT attenuation was significantly lower (344.5 vs. 428.2 HU; P=0.013). Subjective image quality was rated good or excellent in 93.0\%/98.3\%/77.6\% (R1/R2/R3) of the single-energy CT scans, and 84.6\%/82.7\%/80.8\% (R1/R2/R3) of the split-filter DECT scans. SSDE, DLP and CTDIvol were significantly lower for conventional single-energy CT compared to split-filter DECT (all P<0.05), which was associated with 26.7\% higher SSDE. Conclusions: In the diagnostic workup of acute PE, the split-filter allows for dual-energy data acquisition from single-source single-layer CT scanners. The existing opportunity to assess pulmonary "perfusion" based on analysis of iodine distribution maps is associated with higher radiation dose in terms of increased SSDE than conventional single-energy CT with ATVS. Moreover, a proportion of up to 3.8\% non-diagnostic examinations in the current reference standard test for PE is not negligible.}, language = {en} } @article{KramerMeyerNatusStigloheretal.2021, author = {Kramer, Susanne and Meyer-Natus, Elisabeth and Stigloher, Christian and Thoma, Hanna and Schnaufer, Achim and Engstler, Markus}, title = {Parallel monitoring of RNA abundance, localization and compactness with correlative single molecule FISH on LR White embedded samples}, series = {Nucleic Acids Research}, volume = {49}, journal = {Nucleic Acids Research}, number = {3}, doi = {10.1093/nar/gkaa1142}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230647}, year = {2021}, abstract = {Single mRNA molecules are frequently detected by single molecule fluorescence in situ hybridization (smFISH) using branched DNA technology. While providing strong and background-reduced signals, the method is inefficient in detecting mRNAs within dense structures, in monitoring mRNA compactness and in quantifying abundant mRNAs. To overcome these limitations, we have hybridized slices of high pressure frozen, freeze-substituted and LR White embedded cells (LR White smFISH). mRNA detection is physically restricted to the surface of the resin. This enables single molecule detection of RNAs with accuracy comparable to RNA sequencing, irrespective of their abundance, while at the same time providing spatial information on RNA localization that can be complemented with immunofluorescence and electron microscopy, as well as array tomography. Moreover, LR White embedding restricts the number of available probe pair recognition sites for each mRNA to a small subset. As a consequence, differences in signal intensities between RNA populations reflect differences in RNA structures, and we show that the method can be employed to determine mRNA compactness. We apply the method to answer some outstanding questions related to trans-splicing, RNA granules and mitochondrial RNA editing in single-cellular trypanosomes and we show an example of differential gene expression in the metazoan Caenorhabditis elegans.}, language = {en} } @article{Khaled2021, author = {Khaled, Mohamed Ismail}, title = {Nomes of Lower Egypt in the early Fifth Dynasty}, series = {E\&G Quaternary Science Journal}, volume = {70}, journal = {E\&G Quaternary Science Journal}, number = {1}, doi = {10.5194/egqsj-70-19-2021}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230350}, pages = {19-27}, year = {2021}, abstract = {Having control over the landscape played an important role in the geography and economy of Egypt from the predynastic period onwards. Especially from the beginning of the Old Kingdom, we have evidence that kings created new places (funerary domains) called (centers) and (Ezbah) for the equipment of the building projects of the royal tomb and the funerary cult of the king, as well as to ensure the eternal life of both kings and individuals. Kings used these localities in order to do so, and they oftentimes expanded the border of an existing nome and created new establishments. Consequently, these establishments were united or divided into new nomes. The paper discusses the geography of Lower Egypt and the associated royal domains in the early Fifth Dynasty based on the new discoveries from the causeway of Sahura at Abusir.}, language = {en} } @article{AlbertLeziusStoerketal.2021, author = {Albert, Judith and Lezius, Susanne and St{\"o}rk, Stefan and Morbach, Caroline and G{\"u}der, G{\"u}lmisal and Frantz, Stefan and Wegscheider, Karl and Ertl, Georg and Angermann, Christiane E.}, title = {Trajectories of Left Ventricular Ejection Fraction After Acute Decompensation for Systolic Heart Failure: Concomitant Echocardiographic and Systemic Changes, Predictors, and Impact on Clinical Outcomes}, series = {Journal of the American Heart Association}, volume = {10}, journal = {Journal of the American Heart Association}, doi = {10.1161/JAHA.120.017822}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230210}, year = {2021}, abstract = {Prospective longitudinal follow-up of left ventricular ejection fraction (LVEF) trajectories after acute cardiac decompensation of heart failure is lacking. We investigated changes in LVEF and covariates at 6-months' follow-up in patients with a predischarge LVEF ≤40\%, and determined predictors and prognostic implications of LVEF changes through 18-months' follow-up. Methods and Results Interdisciplinary Network Heart Failure program participants (n=633) were categorized into subgroups based on LVEF at 6-months' follow-up: normalized LVEF (>50\%; heart failure with normalized ejection fraction, n=147); midrange LVEF (41\%-50\%; heart failure with midrange ejection fraction, n=195), or persistently reduced LVEF (≤40\%; heart failure with persistently reduced LVEF , n=291). All received guideline-directed medical therapies. At 6-months' follow-up, compared with patients with heart failure with persistently reduced LVEF, heart failure with normalized LVEF or heart failure with midrange LVEF subgroups showed greater reductions in LV end-diastolic/end-systolic diameters (both P<0.001), and left atrial systolic diameter (P=0.002), more increased septal/posterior end-diastolic wall-thickness (both P<0.001), and significantly greater improvement in diastolic function, biomarkers, symptoms, and health status. Heart failure duration <1 year, female sex, higher predischarge blood pressure, and baseline LVEF were independent predictors of LVEF improvement. Mortality and event-free survival rates were lower in patients with heart failure with normalized LVEF (P=0.002). Overall, LVEF increased further at 18-months' follow-up (P<0.001), while LV end-diastolic diameter decreased (P=0.048). However, LVEF worsened (P=0.002) and LV end-diastolic diameter increased (P=0.047) in patients with heart failure with normalized LVEF hospitalized between 6-months' follow-up and 18-months' follow-up. Conclusions Six-month survivors of acute cardiac decompensation for systolic heart failure showed variable LVEF trajectories, with >50\% showing improvements by ≥1 LVEF category. LVEF changes correlated with various parameters, suggesting multilevel reverse remodeling, were predictable from several baseline characteristics, and were associated with clinical outcomes at 18-months' follow-up. Repeat hospitalizations were associated with attenuation of reverse remodeling."}, language = {en} } @article{BaeuerleinQureischiMokhtarietal.2021, author = {B{\"a}uerlein, Carina A. and Qureischi, Musga and Mokhtari, Zeinab and Tabares, Paula and Brede, Christian and Jord{\´a}n Garrote, Ana-Laura and Riedel, Simone S. and Chopra, Martin and Reu, Simone and Mottok, Anja and Arellano-Viera, Estibaliz and Graf, Carolin and Kurzwart, Miriam and Schmiedgen, Katharina and Einsele, Hermann and W{\"o}lfl, Matthias and Schlegel, Paul-Gerhardt and Beilhack, Andreas}, title = {A T-Cell Surface Marker Panel Predicts Murine Acute Graft-Versus-Host Disease}, series = {Frontiers in Immunology}, volume = {11}, journal = {Frontiers in Immunology}, issn = {1664-3224}, doi = {10.3389/fimmu.2020.593321}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224290}, year = {2021}, abstract = {Acute graft-versus-host disease (aGvHD) is a severe and often life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). AGvHD is mediated by alloreactive donor T-cells targeting predominantly the gastrointestinal tract, liver, and skin. Recent work in mice and patients undergoing allo-HCT showed that alloreactive T-cells can be identified by the expression of α4β7 integrin on T-cells even before manifestation of an aGvHD. Here, we investigated whether the detection of a combination of the expression of T-cell surface markers on peripheral blood (PB) CD8\(^+\) T-cells would improve the ability to predict aGvHD. To this end, we employed two independent preclinical models of minor histocompatibility antigen mismatched allo-HCT following myeloablative conditioning. Expression profiles of integrins, selectins, chemokine receptors, and activation markers of PB donor T-cells were measured with multiparameter flow cytometry at multiple time points before the onset of clinical aGvHD symptoms. In both allo-HCT models, we demonstrated a significant upregulation of α4β7 integrin, CD162E, CD162P, and conversely, a downregulation of CD62L on donor T-cells, which could be correlated with the development of aGvHD. Other surface markers, such as CD25, CD69, and CC-chemokine receptors were not found to be predictive markers. Based on these preclinical data from mouse models, we propose a surface marker panel on peripheral blood T-cells after allo-HCT combining α4β7 integrin with CD62L, CD162E, and CD162P (cutaneous lymphocyte antigens, CLA, in humans) to identify patients at risk for developing aGvHD early after allo-HCT.}, language = {en} } @article{KuckaWajant2021, author = {Kucka, Kirstin and Wajant, Harald}, title = {Receptor Oligomerization and Its Relevance for Signaling by Receptors of the Tumor Necrosis Factor Receptor Superfamily}, series = {Frontiers in Cell and Developmental Biology}, volume = {8}, journal = {Frontiers in Cell and Developmental Biology}, issn = {2296-634X}, doi = {10.3389/fcell.2020.615141}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227180}, year = {2021}, abstract = {With the exception of a few signaling incompetent decoy receptors, the receptors of the tumor necrosis factor receptor superfamily (TNFRSF) are signaling competent and engage in signaling pathways resulting in inflammation, proliferation, differentiation, and cell migration and also in cell death induction. TNFRSF receptors (TNFRs) become activated by ligands of the TNF superfamily (TNFSF). TNFSF ligands (TNFLs) occur as trimeric type II transmembrane proteins but often also as soluble ligand trimers released from the membrane-bound form by proteolysis. The signaling competent TNFRs are efficiently activated by the membrane-bound TNFLs. The latter recruit three TNFR molecules, but there is growing evidence that this is not sufficient to trigger all aspects of TNFR signaling; rather, the formed trimeric TNFL-TNFR complexes have to cluster secondarily in the cell-to-cell contact zone for full TNFR activation. With respect to their response to soluble ligand trimers, the signaling competent TNFRs can be subdivided into two groups. TNFRs of one group, designated as category I TNFRs, are robustly activated by soluble ligand trimers. The receptors of a second group (category II TNFRs), however, failed to become properly activated by soluble ligand trimers despite high affinity binding. The limited responsiveness of category II TNFRs to soluble TNFLs can be overcome by physical linkage of two or more soluble ligand trimers or, alternatively, by anchoring the soluble ligand molecules to the cell surface or extracellular matrix. This suggests that category II TNFRs have a limited ability to promote clustering of trimeric TNFL-TNFR complexes outside the context of cell-cell contacts. In this review, we will focus on three aspects on the relevance of receptor oligomerization for TNFR signaling: (i) the structural factors which promote clustering of free and liganded TNFRs, (ii) the signaling pathway specificity of the receptor oligomerization requirement, and (iii) the consequences for the design and development of TNFR agonists.}, language = {en} } @article{BianchiSivarajanWallesetal.2021, author = {Bianchi, Maria and Sivarajan, Rinu and Walles, Thorsten and Hackenberg, Stephan and Steinke, Maria}, title = {Susceptibility of primary human airway epithelial cells to Bordetella pertussis adenylate cyclase toxin in two- and three-dimensional culture conditions}, series = {Innate Immunity}, volume = {27}, journal = {Innate Immunity}, number = {1}, issn = {1753-4259}, doi = {10.1177/1753425920979354}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219849}, pages = {89-98}, year = {2021}, abstract = {The human pathogen Bordetella pertussis targets the respiratory epithelium and causes whooping cough. Its virulence factor adenylate cyclase toxin (CyaA) plays an important role in the course of infection. Previous studies on the impact of CyaA on human epithelial cells have been carried out using cell lines derived from the airways or the intestinal tract. Here, we investigated the interaction of CyaA and its enzymatically inactive but fully pore-forming toxoid CyaA-AC- with primary human airway epithelial cells (hAEC) derived from different anatomical sites (nose and tracheo-bronchial region) in two-dimensional culture conditions. To assess possible differences between the response of primary hAEC and respiratory cell lines directly, we included HBEC3-KT in our studies. In comparative analyses, we studied the impact of both the toxin and the toxoid on cell viability, intracellular cAMP concentration and IL-6 secretion. We found that the selected hAEC, which lack CD11b, were differentially susceptible to both CyaA and CyaA-AC-. HBEC3-KT appeared not to be suitable for subsequent analyses. Since the nasal epithelium first gets in contact with airborne pathogens, we further studied the effect of CyaA and its toxoid on the innate immunity of three-dimensional tissue models of the human nasal mucosa. The present study reveals first insights in toxin-cell interaction using primary hAEC.}, language = {en} } @article{LehenbergerBenkertBiedermann2021, author = {Lehenberger, Maximilian and Benkert, Markus and Biedermann, Peter H. W.}, title = {Ethanol-Enriched Substrate Facilitates Ambrosia Beetle Fungi, but Inhibits Their Pathogens and Fungal Symbionts of Bark Beetles}, series = {Frontiers in Microbiology}, volume = {11}, journal = {Frontiers in Microbiology}, issn = {1664-302X}, doi = {10.3389/fmicb.2020.590111}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222222}, year = {2021}, abstract = {Bark beetles (sensu lato) colonize woody tissues like phloem or xylem and are associated with a broad range of micro-organisms. Specific fungi in the ascomycete orders Hypocreales, Microascales and Ophistomatales as well as the basidiomycete Russulales have been found to be of high importance for successful tree colonization and reproduction in many species. While fungal mutualisms are facultative for most phloem-colonizing bark beetles (sensu stricto), xylem-colonizing ambrosia beetles are long known to obligatorily depend on mutualistic fungi for nutrition of adults and larvae. Recently, a defensive role of fungal mutualists for their ambrosia beetle hosts was revealed: Few tested mutualists outcompeted other beetle-antagonistic fungi by their ability to produce, detoxify and metabolize ethanol, which is naturally occurring in stressed and/or dying trees that many ambrosia beetle species preferentially colonize. Here, we aim to test (i) how widespread beneficial effects of ethanol are among the independently evolved lineages of ambrosia beetle fungal mutualists and (ii) whether it is also present in common fungal symbionts of two bark beetle species (Ips typographus, Dendroctonus ponderosae) and some general fungal antagonists of bark and ambrosia beetle species. The majority of mutualistic ambrosia beetle fungi tested benefited (or at least were not harmed) by the presence of ethanol in terms of growth parameters (e.g., biomass), whereas fungal antagonists were inhibited. This confirms the competitive advantage of nutritional mutualists in the beetle's preferred, ethanol-containing host material. Even though most bark beetle fungi are found in the same phylogenetic lineages and ancestral to the ambrosia beetle (sensu stricto) fungi, most of them were highly negatively affected by ethanol and only a nutritional mutualist of Dendroctonus ponderosae benefited, however. This suggests that ethanol tolerance is a derived trait in nutritional fungal mutualists, particularly in ambrosia beetles that show cooperative farming of their fungi.}, language = {en} } @article{EckertRibechiniJaricketal.2021, author = {Eckert, Ina N. and Ribechini, Eliana and Jarick, Katja J. and Strozniak, Sandra and Potter, Sarah J. and Beilhack, Andreas and Lutz, Manfred B.}, title = {VLA-1 Binding to Collagen IV Controls Effector T Cell Suppression by Myeloid-Derived Suppressor Cells in the Splenic Red Pulp}, series = {Frontiers in Immunology}, volume = {11}, journal = {Frontiers in Immunology}, issn = {1664-3224}, doi = {10.3389/fimmu.2020.616531}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222671}, year = {2021}, abstract = {Myeloid-derived suppressor cells (MDSCs) represent a major population controlling T cell immune responses. However, little is known about their molecular requirements for homing and T cell interaction to mediate suppression. Here, we investigated the functional role of the homing and collagen IV receptor VLA-1 (α1β1-integrin) on in vitro GM-CSF generated murine MDSCs from wild-type (WT) and CD49a/α1-integrin (Itga1\(^{-/-}\)) gene-deficient mice. Here, we found that effector (Teff) but not naive (Tn) CD4\(^+\) T cells express VLA-1 and monocytes further up-regulated their expression after culture in GM-CSF when they differentiated into the monocytic subset of resting MDSCs (R-MDSCs). Subsequent activation of R-MDSCs by LPS+IFN-γ (A-MDSCs) showed increased in vitro suppressor potential, which was independent of VLA-1. Surprisingly, VLA-1 deficiency did not influence A-MDSC motility or migration on collagen IV in vitro. However, interaction times of Itga1\(^{-/-}\) A-MDSCs with Teff were shorter than with WT A-MDSCs on collagen IV but not on fibronectin substrate in vitro. After injection, A-MDSCs homed to the splenic red pulp where they co-localized with Teff and showed immediate suppression already after 6 h as shown by inhibition of T cell proliferation and induction of apoptosis. Injection of A-MDSCs from Itga1\(^{-/-}\) mice showed equivalent homing into the spleen but a reduced suppressive effect. Interaction studies of A-MDSCs with Teff in the subcapsular red pulp with intravital two-photon microscopy revealed also here that MDSC motility and migration parameters were not altered by VLA-1 deficiency, but the interaction times with Teff were reduced. Together, our data point to a new role of VLA-1 adhesion to collagen IV as a prerequisite for extended contact times with Teff required for suppression.}, language = {en} } @article{AdolfiHerpinMartinezBengocheaetal.2021, author = {Adolfi, Mateus C. and Herpin, Amaury and Martinez-Bengochea, Anabel and Kneitz, Susanne and Regensburger, Martina and Grunwald, David J. and Schartl, Manfred}, title = {Crosstalk Between Retinoic Acid and Sex-Related Genes Controls Germ Cell Fate and Gametogenesis in Medaka}, series = {Frontiers in Cell and Developmental Biology}, volume = {8}, journal = {Frontiers in Cell and Developmental Biology}, issn = {2296-634X}, doi = {10.3389/fcell.2020.613497}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222669}, year = {2021}, abstract = {Sex determination (SD) is a highly diverse and complex mechanism. In vertebrates, one of the first morphological differences between the sexes is the timing of initiation of the first meiosis, where its initiation occurs first in female and later in male. Thus, SD is intimately related to the responsiveness of the germ cells to undergo meiosis in a sex-specific manner. In some vertebrates, it has been reported that the timing for meiosis entry would be under control of retinoic acid (RA), through activation of Stra8. In this study, we used a fish model species for sex determination and lacking the stra8 gene, the Japanese medaka (Oryzias latipes), to investigate the connection between RA and the sex determination pathway. Exogenous RA treatments act as a stress factor inhibiting germ cell differentiation probably by activation of dmrt1a and amh. Disruption of the RA degrading enzyme gene cyp26a1 induced precocious meiosis and oogenesis in embryos/hatchlings of female and even some males. Transcriptome analyzes of cyp26a1-/-adult gonads revealed upregulation of genes related to germ cell differentiation and meiosis, in both ovaries and testes. Our findings show that germ cells respond to RA in a stra8 independent model species. The responsiveness to RA is conferred by sex-related genes, restricting its action to the sex differentiation period in both sexes.}, language = {en} } @article{KessieLodesOberwinkleretal.2021, author = {Kessie, David K. and Lodes, Nina and Oberwinkler, Heike and Goldman, William E. and Walles, Thorsten and Steinke, Maria and Gross, Roy}, title = {Activity of Tracheal Cytotoxin of Bordetella pertussis in a Human Tracheobronchial 3D Tissue Model}, series = {Frontiers in Cellular and Infection Microbiology}, volume = {10}, journal = {Frontiers in Cellular and Infection Microbiology}, issn = {2235-2988}, doi = {10.3389/fcimb.2020.614994}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222736}, year = {2021}, abstract = {Bordetella pertussis is a highly contagious pathogen which causes whooping cough in humans. A major pathophysiology of infection is the extrusion of ciliated cells and subsequent disruption of the respiratory mucosa. Tracheal cytotoxin (TCT) is the only virulence factor produced by B. pertussis that has been able to recapitulate this pathology in animal models. This pathophysiology is well characterized in a hamster tracheal model, but human data are lacking due to scarcity of donor material. We assessed the impact of TCT and lipopolysaccharide (LPS) on the functional integrity of the human airway mucosa by using in vitro airway mucosa models developed by co-culturing human tracheobronchial epithelial cells and human tracheobronchial fibroblasts on porcine small intestinal submucosa scaffold under airlift conditions. TCT and LPS either alone and in combination induced blebbing and necrosis of the ciliated epithelia. TCT and LPS induced loss of ciliated epithelial cells and hyper-mucus production which interfered with mucociliary clearance. In addition, the toxins had a disruptive effect on the tight junction organization, significantly reduced transepithelial electrical resistance and increased FITC-Dextran permeability after toxin incubation. In summary, the results indicate that TCT collaborates with LPS to induce the disruption of the human airway mucosa as reported for the hamster tracheal model.}, language = {en} } @article{HerrmannDiederichsMelniketal.2021, author = {Herrmann, Marietta and Diederichs, Solvig and Melnik, Svitlana and Riegger, Jana and Trivanović, Drenka and Li, Shushan and Jenei-Lanzl, Zsuzsa and Brenner, Rolf E. and Huber-Lang, Markus and Zaucke, Frank and Schildberg, Frank A. and Gr{\"a}ssel, Susanne}, title = {Extracellular Vesicles in Musculoskeletal Pathologies and Regeneration}, series = {Frontiers in Bioengineering and Biotechnology}, volume = {8}, journal = {Frontiers in Bioengineering and Biotechnology}, issn = {2296-4185}, doi = {10.3389/fbioe.2020.624096}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222882}, year = {2021}, abstract = {The incidence of musculoskeletal diseases is steadily increasing with aging of the population. In the past years, extracellular vesicles (EVs) have gained attention in musculoskeletal research. EVs have been associated with various musculoskeletal pathologies as well as suggested as treatment option. EVs play a pivotal role in communication between cells and their environment. Thereby, the EV cargo is highly dependent on their cellular origin. In this review, we summarize putative mechanisms by which EVs can contribute to musculoskeletal tissue homeostasis, regeneration and disease, in particular matrix remodeling and mineralization, pro-angiogenic effects and immunomodulatory activities. Mesenchymal stromal cells (MSCs) present the most frequently used cell source for EV generation for musculoskeletal applications, and herein we discuss how the MSC phenotype can influence the cargo and thus the regenerative potential of EVs. Induced pluripotent stem cell-derived mesenchymal progenitor cells (iMPs) may overcome current limitations of MSCs, and iMP-derived EVs are discussed as an alternative strategy. In the last part of the article, we focus on therapeutic applications of EVs and discuss both practical considerations for EV production and the current state of EV-based therapies.}, language = {en} } @article{DischingerHasingerKoenigsraineretal.2021, author = {Dischinger, Ulrich and Hasinger, Julia and K{\"o}nigsrainer, Malina and Corteville, Carolin and Otto, Christoph and Fassnacht, Martin and Hankir, Mohamed and Seyfried, Florian Johannes David}, title = {Toward a Medical Gastric Bypass: Chronic Feeding Studies With Liraglutide + PYY\(_{3-36}\) Combination Therapy in Diet-Induced Obese Rats}, series = {Frontiers in Endocrinology}, volume = {11}, journal = {Frontiers in Endocrinology}, issn = {1664-2392}, doi = {10.3389/fendo.2020.598843}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223113}, year = {2021}, abstract = {Background Combination therapies of anorectic gut hormones partially mimic the beneficial effects of bariatric surgery. Thus far, the effects of a combined chronic systemic administration of Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\)) have not been directly compared to Roux-en-Y gastric bypass (RYGB) in a standardized experimental setting. Methods High-fat diet (HFD)-induced obese male Wistar rats were randomized into six treatment groups: (1) RYGB, (2) sham-operation (shams), (3) liraglutide, (4) PYY\(_{3-36}\), (5) PYY\(_{3-36}\)+liraglutide (6), saline. Animals were kept on a free choice high- and low-fat diet. Food intake, preference, and body weight were measured daily for 4 weeks. Open field (OP) and elevated plus maze (EPM) tests were performed. Results RYGB reduced food intake and achieved sustained weight loss. Combined PYY\(_{3-36}\)+liraglutide treatment led to similar and plateaued weight loss compared to RYGB. Combined PYY\(_{3-36}\)+liraglutide treatment was superior to PYY\(_{3-36}\) (p ≤ 0.0001) and liraglutide (p ≤ 0.05 or p ≤ 0.01) mono-therapy. PYY\(_{3-36}\)+liraglutide treatment and RYGB also reduced overall food intake and (less pronounced) high-fat preference compared to controls. The animals showed no signs of abnormal behavior in OF or EPM. Conclusions Liraglutide and PYY\(_{3-36}\) combination therapy vastly mimics reduced food intake, food choice and weight reducing benefits of RYGB.}, language = {en} } @article{OehlerBrackBlumetal.2021, author = {Oehler, Beatrice and Brack, Alexander and Blum, Robert and Rittner, Heike L.}, title = {Pain Control by Targeting Oxidized Phospholipids: Functions, Mechanisms, Perspectives}, series = {Frontiers in Endocrinology}, volume = {11}, journal = {Frontiers in Endocrinology}, issn = {1664-2392}, doi = {10.3389/fendo.2020.613868}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223432}, year = {2021}, abstract = {Within the lipidome oxidized phospholipids (OxPL) form a class of chemically highly reactive metabolites. OxPL are acutely produced in inflamed tissue and act as endogenous, proalgesic (pain-inducing) metabolites. They excite sensory, nociceptive neurons by activating transient receptor potential ion channels, specifically TRPA1 and TRPV1. Under inflammatory conditions, OxPL-mediated receptor potentials even potentiate the action potential firing rate of nociceptors. Targeting OxPL with D-4F, an apolipoprotein A-I mimetic peptide or antibodies like E06, specifically binding oxidized headgroups of phospholipids, can be used to control acute, inflammatory pain syndromes, at least in rodents. With a focus on proalgesic specificities of OxPL, this article discusses, how targeting defined substances of the epilipidome can contribute to mechanism-based therapies against primary and secondary chronic inflammatory or possibly also neuropathic pain.}, language = {en} } @article{WuerthnerNoll2021, author = {W{\"u}rthner, Frank and Noll, Niklas}, title = {A Calix[4]arene-Based Cyclic Dinuclear Ruthenium Complex for Light-Driven Catalytic Water Oxidation}, series = {Chemistry - A European Journal}, volume = {27}, journal = {Chemistry - A European Journal}, number = {1}, doi = {10.1002/chem.202004486}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230030}, pages = {444-450}, year = {2021}, abstract = {A cyclic dinuclear ruthenium(bda) (bda: 2,2'-bipyridine-6,6'-dicarboxylate) complex equipped with oligo(ethylene glycol)-functionalized axial calix[4]arene ligands has been synthesized for homogenous catalytic water oxidation. This novel Ru(bda) macrocycle showed significantly increased catalytic activity in chemical and photocatalytic water oxidation compared to the archetype mononuclear reference [Ru(bda)(pic)\(_2\)]. Kinetic investigations, including kinetic isotope effect studies, disclosed a unimolecular water nucleophilic attack mechanism of this novel dinuclear water oxidation catalyst (WOC) under the involvement of the second coordination sphere. Photocatalytic water oxidation with this cyclic dinuclear Ru complex using [Ru(bpy)\(_3\)]Cl\(_2\) as a standard photosensitizer revealed a turnover frequency of 15.5 s\(^{-1}\) and a turnover number of 460. This so far highest photocatalytic performance reported for a Ru(bda) complex underlines the potential of this water-soluble WOC for artificial photosynthesis.}, language = {en} } @article{WuerthnerMezaChinchaSchindleretal.2021, author = {W{\"u}rthner, Frank and Meza-Chincha, Ana-Lucia and Schindler, Dorothee and Natali, Mirco}, title = {Effects of Photosensitizers and Reaction Media on Light-Driven Water Oxidation with Trinuclear Ruthenium Macrocycles}, series = {ChemPhotoChem}, volume = {5}, journal = {ChemPhotoChem}, number = {2}, doi = {10.1002/cptc.202000133}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230116}, pages = {173-183}, year = {2021}, abstract = {Photocatalytic water oxidation is a promising process for the production of solar fuels and the elucidation of factors that influence this process is of high significance. Thus, we have studied in detail light-driven water oxidation with a trinuclear Ru(bda) (bda: 2,2'-bipyridine-6,6'-dicarboxylate) macrocycle MC3 and its highly water soluble derivative m-CH\(_2\)NMe\(_2\)-MC3 using a series of ruthenium tris(bipyridine) complexes as photosensitizers under varied reaction conditions. Our investigations showed that the catalytic activities of these Ru macrocycles are significantly affected by the choice of photosensitizer (PS) and reaction media, in addition to buffer concentration, light intensity and concentration of the sensitizer. Our steady-state and transient spectroscopic studies revealed that the photocatalytic performance of trinuclear Ru(bda) macrocycles is not limited by their intrinsic catalytic activities but rather by the efficiency of photogeneration of oxidant PS\(^+\) and its ability to act as an oxidizing agent to the catalysts as both are strongly dependent on the choice of photosensitizer and the amount of employed organic co-solvent.}, language = {en} } @article{KokicHillenTegunovetal.2021, author = {Kokic, Goran and Hillen, Hauke S. and Tegunov, Dimitry and Dienermann, Christian and Seitz, Florian and Schmitzova, Jana and Farnung, Lucas and Siewert, Aaron and H{\"o}bartner, Claudia and Cramer, Patrick}, title = {Mechanism of SARS-CoV-2 polymerase stalling by remdesivir}, series = {Nature Communications}, volume = {12}, journal = {Nature Communications}, doi = {10.1038/s41467-020-20542-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220979}, year = {2021}, abstract = {Remdesivir is the only FDA-approved drug for the treatment of COVID-19 patients. The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-2. Remdesivir is incorporated by the RdRp into the growing RNA product and allows for addition of three more nucleotides before RNA synthesis stalls. Here we use synthetic RNA chemistry, biochemistry and cryoelectron microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling. We show that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation. This translocation barrier causes retention of the RNA 3ʹ-nucleotide in the substrate-binding site of the RdRp and interferes with entry of the next nucleoside triphosphate, thereby stalling RdRp. In the structure of the remdesivir-stalled state, the 3ʹ-nucleotide of the RNA product is matched and located with the template base in the active center, and this may impair proofreading by the viral 3ʹ-exonuclease. These mechanistic insights should facilitate the quest for improved antivirals that target coronavirus replication.}, language = {en} }