@article{BrenzingerCostaHoetal.2021, author = {Brenzinger, Kristof and Costa, Ohana Y. A. and Ho, Adrian and Koorneef, Guusje and Robroek, Bjorn and Molenaar, Douwe and Korthals, Gerard and Bodelier, Paul L. E.}, title = {Steering microbiomes by organic amendments towards climate-smart agricultural soils}, series = {Biology and Fertility of Soils}, volume = {57}, journal = {Biology and Fertility of Soils}, number = {8}, doi = {10.1007/s00374-021-01599-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-326930}, pages = {1053-1074}, year = {2021}, abstract = {We steered the soil microbiome via applications of organic residues (mix of cover crop residues, sewage sludge + compost, and digestate + compost) to enhance multiple ecosystem services in line with climate-smart agriculture. Our result highlights the potential to reduce greenhouse gases (GHG) emissions from agricultural soils by the application of specific organic amendments (especially digestate + compost). Unexpectedly, also the addition of mineral fertilizer in our mesocosms led to similar combined GHG emissions than one of the specific organic amendments. However, the application of organic amendments has the potential to increase soil C, which is not the case when using mineral fertilizer. While GHG emissions from cover crop residues were significantly higher compared to mineral fertilizer and the other organic amendments, crop growth was promoted. Furthermore, all organic amendments induced a shift in the diversity and abundances of key microbial groups. We show that organic amendments have the potential to not only lower GHG emissions by modifying the microbial community abundance and composition, but also favour crop growth-promoting microorganisms. This modulation of the microbial community by organic amendments bears the potential to turn soils into more climate-smart soils in comparison to the more conventional use of mineral fertilizers.}, language = {en} } @article{D'AndreaSoriaGrotenhuisetal.2021, author = {D'Andrea, David and Soria, Francesco and Grotenhuis, Anne J. and Cha, Eugene K. and Malats, Nuria and Di Stasi, Savino and Joniau, Steven and Cai, Tommaso and Rhijn, Bas W. G. van and Irani, Jaques and Karnes, Jeffrey and Varkarakis, John and Baniel, Jack and Palou, Joan and Babjuk, Marek and Spahn, Martin and Ardelt, Peter and Colombo, Renzo and Serretta, Vincenzo and Dalbagni, Guido and Gontero, Paolo and Bartoletti, Riccardo and Larr{\´e}, Stephane and Malmstrom, Per-Uno and Sylvester, Richard and Shariat, Shahrokh F.}, title = {Association of patients' sex with treatment outcomes after intravesical bacillus Calmette-Gu{\´e}rin immunotherapy for T1G3/HG bladder cancer}, series = {World Journal of Urology}, volume = {39}, journal = {World Journal of Urology}, number = {9}, doi = {10.1007/s00345-021-03653-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-344486}, pages = {3337-3344}, year = {2021}, abstract = {Purpose To investigate the association of patients' sex with recurrence and disease progression in patients treated with intravesical bacillus Calmette-Gu{\´e}rin (BCG) for T1G3/HG urinary bladder cancer (UBC). Materials and methods We analyzed the data of 2635 patients treated with adjuvant intravesical BCG for T1 UBC between 1984 and 2019. We accounted for missing data using multiple imputations and adjusted for covariate imbalance between males and females using inverse probability weighting (IPW). Crude and IPW-adjusted Cox regression analyses were used to estimate the hazard ratios (HR) with their 95\% confidence intervals (CI) for the association of patients' sex with HG-recurrence and disease progression. Results A total of 2170 (82\%) males and 465 (18\%) females were available for analysis. Overall, 1090 (50\%) males and 244 (52\%) females experienced recurrence, and 391 (18\%) males and 104 (22\%) females experienced disease progression. On IPW-adjusted Cox regression analyses, female sex was associated with disease progression (HR 1.25, 95\%CI 1.01-1.56, p = 0.04) but not with recurrence (HR 1.06, 95\%CI 0.92-1.22, p = 0.41). A total of 1056 patients were treated with adequate BCG. In these patients, on IPW-adjusted Cox regression analyses, patients' sex was not associated with recurrence (HR 0.99, 95\%CI 0.80-1.24, p = 0.96), HG-recurrence (HR 1.00, 95\%CI 0.78-1.29, p = 0.99) or disease progression (HR 1.12, 95\%CI 0.78-1.60, p = 0.55). Conclusion Our analysis generates the hypothesis of a differential response to BCG between males and females if not adequately treated. Further studies should focus on sex-based differences in innate and adaptive immune system and their association with BCG response.}, language = {en} } @article{LinzBrandsKertelsetal.2021, author = {Linz, Christian and Brands, Roman C. and Kertels, Olivia and Dierks, Alexander and Brumberg, Joachim and Gerhard-Hartmann, Elena and Hartmann, Stefan and Schirbel, Andreas and Serfling, Sebastian and Zhi, Yingjun and Buck, Andreas K. and K{\"u}bler, Alexander and Hohm, Julian and Lapa, Constantin and Kircher, Malte}, title = {Targeting fibroblast activation protein in newly diagnosed squamous cell carcinoma of the oral cavity - initial experience and comparison to [\(^{18}\)F]FDG PET/CT and MRI}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {48}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {12}, issn = {1619-7070}, doi = {10.1007/s00259-021-05422-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307246}, pages = {3951-3960}, year = {2021}, abstract = {Purpose While [\(^{18}\)F]-fluorodeoxyglucose ([\(^{18}\)F]FDG) is the standard for positron emission tomography/computed tomography (PET/CT) imaging of oral squamous cell carcinoma (OSCC), diagnostic specificity is hampered by uptake in inflammatory cells such as neutrophils or macrophages. Recently, molecular imaging probes targeting fibroblast activation protein α (FAP), which is overexpressed in a variety of cancer-associated fibroblasts, have become available and might constitute a feasible alternative to FDG PET/CT. Methods Ten consecutive, treatment-na{\"i}ve patients (8 males, 2 females; mean age, 62 ± 9 years) with biopsy-proven OSCC underwent both whole-body [\(^{18}\)F]FDG and [\(^{68}\)Ga]FAPI-04 (FAP-directed) PET/CT for primary staging prior to tumor resection and cervical lymph node dissection. Detection of the primary tumor, as well as the presence and number of lymph node and distant metastases was analysed. Intensity of tracer accumulation was assessed by means of maximum (SUV\(_{max}\)) and peak (SUV\(_{peak}\) standardized uptake values. Histological work-up including immunohistochemical staining for FAP served as standard of reference. Results [\(^{18}\)F]FDG and FAP-directed PET/CT detected all primary tumors with a SUVmax of 25.5 ± 13.2 (FDG) and 20.5 ± 6.4 (FAP-directed) and a SUVpeak of 16.1 ± 10.3 ([\(^{18}\)F]FDG) and 13.8 ± 3.9 (FAP-directed), respectively. Regarding cervical lymph node metastases, FAP-directed PET/CT demonstrated comparable sensitivity (81.3\% vs. 87.5\%; P = 0.32) and specificity (93.3\% vs. 81.3\%; P = 0.16) to [\(^{18}\)F]FDG PET/CT. FAP expression on the cell surface of cancer-associated fibroblasts in both primary lesions as well as lymph nodes metastases was confirmed in all samples. Conclusion FAP-directed PET/CT in OSCC seems feasible. Future research to investigate its potential to improve patient staging is highly warranted.}, language = {en} } @article{GieselKratochwilSchlittenhardtetal.2021, author = {Giesel, Frederik L. and Kratochwil, Clemens and Schlittenhardt, Joel and Dendl, Katharina and Eiber, Matthias and Staudinger, Fabian and Kessler, Lukas and Fendler, Wolfgang P. and Lindner, Thomas and Koerber, Stefan A. and Cardinale, Jens and Sennung, David and Roehrich, Manuel and Debus, Juergen and Sathekge, Mike and Haberkorn, Uwe and Calais, Jeremie and Serfling, Sebastian and Buck, Andreas L.}, title = {Head-to-head intra-individual comparison of biodistribution and tumor uptake of \(^{68}\)Ga-FAPI and \(^{18}\)F-FDG PET/CT in cancer patients}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {48}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {13}, issn = {1619-7070}, doi = {10.1007/s00259-021-05307-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307252}, pages = {4377-4385}, year = {2021}, abstract = {Purpose FAPI ligands (fibroblast activation protein inhibitor), a novel class of radiotracers for PET/CT imaging, demonstrated in previous studies rapid and high tumor uptake. The purpose of this study is the head-to-head intra-individual comparison of \(^{68}\)Ga-FAPI versus standard-of-care \(^{18}\)F-FDG in PET/CT in organ biodistribution and tumor uptake in patients with various cancers. Material and Methods This international retrospective multicenter analysis included PET/CT data from 71 patients from 6 centers who underwent both \(^{68}\)Ga-FAPI and \(^{18}\)F-FDG PET/CT within a median time interval of 10 days (range 1-89 days). Volumes of interest (VOIs) were manually drawn in normal organs and tumor lesions to quantify tracer uptake by SUVmax and SUVmean. Furthermore, tumor-to-background ratios (TBR) were generated (SUVmax tumor/ SUVmax organ). Results A total of 71 patients were studied of, which 28 were female and 43 male (median age 60). In 41 of 71 patients, the primary tumor was present. Forty-three of 71 patients exhibited 162 metastatic lesions. \(^{68}\)Ga-FAPI uptake in primary tumors and metastases was comparable to 18F-FDG in most cases. The SUVmax was significantly lower for \(^{68}\)Ga-FAPI than \(^{18}\)F-FDG in background tissues such as the brain, oral mucosa, myocardium, blood pool, liver, pancreas, and colon. Thus, \(^{68}\)Ga-FAPI TBRs were significantly higher than 18F-FDG TBRs in some sites, including liver and bone metastases. Conclusion Quantitative tumor uptake is comparable between \(^{68}\)Ga-FAPI and \(^{18}\)F-FDG, but lower background uptake in most normal organs results in equal or higher TBRs for \(^{68}\)Ga-FAPI. Thus, \(^{68}\)Ga-FAPI PET/CT may yield improved diagnostic information in various cancers and especially in tumor locations with high physiological \(^{18}\)F-FDG uptake.}, language = {en} } @article{PennigHoyerKrauskopfetal.2021, author = {Pennig, Lenhard and Hoyer, Ulrike Cornelia Isabel and Krauskopf, Alexandra and Shahzad, Rahil and J{\"u}nger, Stephanie T. and Thiele, Frank and Laukamp, Kai Roman and Grunz, Jan-Peter and Perkuhn, Michael and Schlamann, Marc and Kabbasch, Christoph and Borggrefe, Jan and Goertz, Lukas}, title = {Deep learning assistance increases the detection sensitivity of radiologists for secondary intracranial aneurysms in subarachnoid hemorrhage}, series = {Neuroradiology}, volume = {63}, journal = {Neuroradiology}, number = {12}, issn = {0028-3940}, doi = {10.1007/s00234-021-02697-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308117}, pages = {1985-1994}, year = {2021}, abstract = {Purpose To evaluate whether a deep learning model (DLM) could increase the detection sensitivity of radiologists for intracranial aneurysms on CT angiography (CTA) in aneurysmal subarachnoid hemorrhage (aSAH). Methods Three different DLMs were trained on CTA datasets of 68 aSAH patients with 79 aneurysms with their outputs being combined applying ensemble learning (DLM-Ens). The DLM-Ens was evaluated on an independent test set of 104 aSAH patients with 126 aneuryms (mean volume 129.2 ± 185.4 mm3, 13.0\% at the posterior circulation), which were determined by two radiologists and one neurosurgeon in consensus using CTA and digital subtraction angiography scans. CTA scans of the test set were then presented to three blinded radiologists (reader 1: 13, reader 2: 4, and reader 3: 3 years of experience in diagnostic neuroradiology), who assessed them individually for aneurysms. Detection sensitivities for aneurysms of the readers with and without the assistance of the DLM were compared. Results In the test set, the detection sensitivity of the DLM-Ens (85.7\%) was comparable to the radiologists (reader 1: 91.2\%, reader 2: 86.5\%, and reader 3: 86.5\%; Fleiss κ of 0.502). DLM-assistance significantly increased the detection sensitivity (reader 1: 97.6\%, reader 2: 97.6\%,and reader 3: 96.0\%; overall P=.024; Fleiss κ of 0.878), especially for secondary aneurysms (88.2\% of the additional aneurysms provided by the DLM). Conclusion Deep learning significantly improved the detection sensitivity of radiologists for aneurysms in aSAH, especially for secondary aneurysms. It therefore represents a valuable adjunct for physicians to establish an accurate diagnosis in order to optimize patient treatment.}, language = {en} } @article{FeketeEgbertsPreissleretal.2021, author = {Fekete, Stefanie and Egberts, K. and Preissler, T. and Wewetzer, C. and Mehler-Wex, C. and Romanos, M. and Gerlach, M.}, title = {Estimation of a preliminary therapeutic reference range for children and adolescents with tic disorders treated with tiapride}, series = {European Journal of Clinical Pharmacology}, volume = {77}, journal = {European Journal of Clinical Pharmacology}, number = {2}, doi = {10.1007/s00228-020-03000-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-279893}, pages = {163-170}, year = {2021}, abstract = {Purpose Tiapride is commonly used in Europe for the treatment of tics. The aim of this study was to examine the relationship between dose and serum concentrations of tiapride and potential influential pharmacokinetic factors in children and adolescents. In addition, a preliminary therapeutic reference range for children and adolescents with tics treated with tiapride was calculated. Methods Children and adolescents treated with tiapride at three university hospitals and two departments of child and adolescents psychiatry in Germany and Austria were included in the study. Patient characteristics, doses, serum concentrations, and therapeutic outcome were assessed during clinical routine care using standardised measures. Results In the 49 paediatric patients (83.7\% male, mean age = 12.5 years), a positive correlation was found between tiapride dose (median 6.9 mg/kg, range 0.97-19.35) and serum concentration with marked inter-individual variability. The variation in dose explained 57\% of the inter-patient variability in tiapride serum concentrations; age, gender, and concomitant medication did not contribute to the variability. The symptoms improved in 83.3\% of the patients. 27.1\% of the patients had mild or moderate ADRs. No patient suffered from severe ADRs. Conclusions This study shows that tiapride treatment was effective and safe in most patients with tics. Compared with the therapeutic concentration range established for adults with Chorea Huntington, our data hinted at a lower lower limit (560 ng/ml) and similar upper limit (2000 ng/ml).}, language = {en} } @article{BarileBerryBlaauboeretal.2021, author = {Barile, Frank A. and Berry, Colin and Blaauboer, Bas and Boobis, Alan and Bolt, Herrmann M. and Borgert, Christopher and Dekant, Wolfgang and Dietrich, Daniel and Domingo, Jose L. and Galli, Corrado L. and Gori, Gio Batta and Greim, Helmut and Hengstler, Jan G. and Heslop-Harrison, Pat and Kacew, Sam and Marquardt, Hans and Mally, Angela and Pelkonen, Olavi and Savolainen, Kai and Testai, Emanuela and Tsatsakis, Aristides and Vermeulen, Nico P.}, title = {The EU chemicals strategy for sustainability: in support of the BfR position}, series = {Archives of Toxicology}, volume = {95}, journal = {Archives of Toxicology}, number = {9}, issn = {0340-5761}, doi = {10.1007/s00204-021-03125-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307154}, pages = {3133-3136}, year = {2021}, abstract = {The EU chemicals strategy for sustainability (CSS) asserts that both human health and the environment are presently threatened and that further regulation is necessary. In a recent Guest Editorial, members of the German competent authority for risk assessment, the BfR, raised concerns about the scientific justification for this strategy. The complexity and interdependence of the networks of regulation of chemical substances have ensured that public health and wellbeing in the EU have continuously improved. A continuous process of improvement in consumer protection is clearly desirable but any initiative directed towards this objective must be based on scientific knowledge. It must not confound risk with other factors in determining policy. This conclusion is fully supported in the present Commentary including the request to improve both, data collection and the time-consuming and bureaucratic procedures that delay the publication of regulations.}, language = {en} } @article{GuthHueserRothetal.2021, author = {Guth, Sabine and H{\"u}ser, Stephanie and Roth, Angelika and Degen, Gisela and Diel, Patrick and Edlund, Karolina and Eisenbrand, Gerhard and Engel, Karl-Heinz and Epe, Bernd and Grune, Tilman and Heinz, Volker and Henle, Thomas and Humpf, Hans-Ulrich and J{\"a}ger, Henry and Joost, Hans-Georg and Kulling, Sabine E. and Lampen, Alfonso and Mally, Angela and Marchan, Rosemarie and Marko, Doris and M{\"u}hle, Eva and Nitsche, Michael A. and R{\"o}hrdanz, Elke and Stadler, Richard and van Thriel, Christoph and Vieths, Stefan and Vogel, Rudi F. and Wascher, Edmund and Watzl, Carsten and N{\"o}thlings, Ute and Hengstler, Jan G.}, title = {Contribution to the ongoing discussion on fluoride toxicity}, series = {Archives of Toxicology}, volume = {95}, journal = {Archives of Toxicology}, number = {7}, issn = {0340-5761}, doi = {10.1007/s00204-021-03072-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307161}, pages = {2571-2587}, year = {2021}, abstract = {Since the addition of fluoride to drinking water in the 1940s, there have been frequent and sometimes heated discussions regarding its benefits and risks. In a recently published review, we addressed the question if current exposure levels in Europe represent a risk to human health. This review was discussed in an editorial asking why we did not calculate benchmark doses (BMD) of fluoride neurotoxicity for humans. Here, we address the question, why it is problematic to calculate BMDs based on the currently available data. Briefly, the conclusions of the available studies are not homogeneous, reporting negative as well as positive results; moreover, the positive studies lack control of confounding factors such as the influence of well-known neurotoxicants. We also discuss the limitations of several further epidemiological studies that did not meet the inclusion criteria of our review. Finally, it is important to not only focus on epidemiological studies. Rather, risk analysis should consider all available data, including epidemiological, animal, as well as in vitro studies. Despite remaining uncertainties, the totality of evidence does not support the notion that fluoride should be considered a human developmental neurotoxicant at current exposure levels in European countries.}, language = {en} } @article{ChumduriTurco2021, author = {Chumduri, Cindrilla and Turco, Margherita Y.}, title = {Organoids of the female reproductive tract}, series = {Journal of Molecular Medicine}, volume = {99}, journal = {Journal of Molecular Medicine}, number = {4}, doi = {10.1007/s00109-020-02028-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-328374}, pages = {531-553}, year = {2021}, abstract = {Healthy functioning of the female reproductive tract (FRT) depends on balanced and dynamic regulation by hormones during the menstrual cycle, pregnancy and childbirth. The mucosal epithelial lining of different regions of the FRT—ovaries, fallopian tubes, uterus, cervix and vagina—facilitates the selective transport of gametes and successful transfer of the zygote to the uterus where it implants and pregnancy takes place. It also prevents pathogen entry. Recent developments in three-dimensional (3D) organoid systems from the FRT now provide crucial experimental models that recapitulate the cellular heterogeneity and physiological, anatomical and functional properties of the organ in vitro. In this review, we summarise the state of the art on organoids generated from different regions of the FRT. We discuss the potential applications of these powerful in vitro models to study normal physiology, fertility, infections, diseases, drug discovery and personalised medicine.}, language = {en} } @article{PinkawaAebersoldBoehmeretal.2021, author = {Pinkawa, Michael and Aebersold, Daniel M. and B{\"o}hmer, Dirk and Flentje, Michael and Ghadjar, Pirus and Schmidt-Hegemann, Nina-Sophie and H{\"o}cht, Stefan and H{\"o}lscher, Tobias and M{\"u}ller, Arndt-Christian and Niehoff, Peter and Sedlmayer, Felix and Wolf, Frank and Zamboglou, Constantinos and Zips, Daniel and Wiegel, Thomas}, title = {Radiotherapy in nodal oligorecurrent prostate cancer}, series = {Strahlentherapie und Onkologie}, volume = {197}, journal = {Strahlentherapie und Onkologie}, number = {7}, issn = {0179-7158}, doi = {10.1007/s00066-021-01778-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307763}, pages = {575-580}, year = {2021}, abstract = {Objective The current article encompasses a literature review and recommendations for radiotherapy in nodal oligorecurrent prostate cancer. Materials and methods A literature review focused on studies comparing metastasis-directed stereotactic ablative radiotherapy (SABR) vs. external elective nodal radiotherapy (ENRT) and studies analyzing recurrence patterns after local nodal treatment was performed. The DEGRO Prostate Cancer Expert Panel discussed the results and developed treatment recommendations. Results Metastasis-directed radiotherapy results in high local control (often > 90\% within a follow-up of 1-2 years) and can be used to improve progression-free survival or defer androgen deprivation therapy (ADT) according to prospective randomized phase II data. Distant progression after involved-node SABR only occurs within a few months in the majority of patients. ENRT improves metastases-free survival rates with increased toxicity in comparison to SABR according to retrospective comparative studies. The majority of nodal recurrences after initial local treatment of pelvic nodal metastasis are detected within the true pelvis and common iliac vessels. Conclusion ENRT with or without a boost should be preferred to SABR in pelvic nodal recurrences. In oligometastatic prostate cancer with distant (extrapelvic) nodal recurrences, SABR alone can be performed in selected cases. Application of additional systemic treatments should be based on current guidelines, with ADT as first-line treatment for hormone-sensitive prostate cancer. Only in carefully selected patients can radiotherapy be initially used without additional ADT outside of the current standard recommendations. Results of (randomized) prospective studies are needed for definitive recommendations.}, language = {en} } @article{DornHerzberg2021, author = {Dorn, Franziska and Herzberg, Moriz}, title = {Response to Letter to the Editor "Keeping Late Thrombectomy Imaging Protocols Simple to Avoid Analysis Paralysis"}, series = {Clinical Neuroradiology}, volume = {31}, journal = {Clinical Neuroradiology}, number = {3}, issn = {1869-1439}, doi = {10.1007/s00062-021-01091-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307023}, pages = {813-814}, year = {2021}, language = {en} } @article{MorisChristmannWirtgenetal.2021, author = {Moris, Victoria C. and Christmann, Katharina and Wirtgen, Aline and Belokobylskij, Sergey A. and Berg, Alexander and Liebig, Wolf-Harald and Soon, Villu and Baur, Hannes and Schmitt, Thomas and Niehuis, Oliver}, title = {Cuticular hydrocarbons on old museum specimens of the spiny mason wasp, Odynerus spinipes (Hymenoptera: Vespidae: Eumeninae), shed light on the distribution and on regional frequencies of distinct chemotypes}, series = {Chemoecology}, volume = {31}, journal = {Chemoecology}, number = {5}, issn = {0937-7409}, doi = {10.1007/s00049-021-00350-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-306999}, pages = {311-322}, year = {2021}, abstract = {The mason wasp Odynerus spinipes shows an exceptional case of intrasexual cuticular hydrocarbon (CHC) profile dimorphism. Females of this species display one of two CHC profiles (chemotypes) that differ qualitatively and quantitatively from each other. The ratio of the two chemotypes was previously shown to be close to 1:1 at three sites in Southern Germany, which might not be representative given the Palearctic distribution of the species. To infer the frequency of the two chemotypes across the entire distributional range of the species, we analyzed with GC-MS the CHC profile of 1042 dry-mounted specimens stored in private and museum collections. We complemented our sampling by including 324 samples collected and preserved specifically for studying their CHCs. We were capable of reliably identifying the chemotypes in 91\% of dry-mounted samples, some of which collected almost 200 years ago. We found both chemotypes to occur in the Far East, the presumed glacial refuge of the species, and their frequency to differ considerably between sites and geographic regions. The geographic structure in the chemotype frequencies could be the result of differential selection regimes and/or different dispersal routes during the colonization of the Western Palearctic. The presented data pave the route for disentangling these factors by providing information where to geographically sample O. spinipes for population genetic analyses. They also form the much-needed basis for future studies aiming to understand the evolutionary and geographic origin as well as the genetics of the astounding CHC profile dimorphism that O. spinipes females exhibit.}, language = {en} } @article{BaurRamserKelleretal.2021, author = {Baur, Johannes and Ramser, Michaela and Keller, Nicola and Muysoms, Filip and D{\"o}rfer, J{\"o}rg and Wiegering, Armin and Eisner, Lukas and Dietz, Ulrich A.}, title = {Robotic hernia repair II. English version}, series = {Der Chirurg}, volume = {92}, journal = {Der Chirurg}, number = {Suppl 1}, doi = {10.1007/s00104-021-01479-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323866}, pages = {S15-S26}, year = {2021}, abstract = {Endoscopic management of umbilical and incisional hernias has adapted to the limitations of conventional laparoscopic instruments over the past 30 years. This includes the development of meshes for intraperitoneal placement (intraperitoneal onlay mesh, IPOM), with antiadhesive coatings; however, adhesions do occur in a significant proportion of these patients. Minimally invasive procedures result in fewer perioperative complications, but with a slightly higher recurrence rate. With the ergonomic resources of robotics, which offers angled instruments, it is now possible to implant meshes in a minimally invasively manner in different abdominal wall layers while achieving morphologic and functional reconstruction of the abdominal wall. This video article presents the treatment of ventral and incisional hernias with mesh implantation into the preperitoneal space (robot-assisted transabdominal preperitoneal ventral hernia repair, r‑ventral TAPP) as well as into the retrorectus space (r-Rives and robotic transabdominal retromuscular umbilical prosthetic repair, r‑TARUP, respectively). The results of a cohort study of 118 consecutive patients are presented and discussed with regard to the added value of the robotic technique in extraperitoneal mesh implantation and in the training of residents.}, language = {en} } @article{RamserBaurKelleretal.2021, author = {Ramser, Michaela and Baur, Johannes and Keller, Nicola and Kukleta, Jan F. and D{\"o}rfer, J{\"o}rg and Wiegering, Armin and Eisner, Lukas and Dietz, Ulrich A.}, title = {Robotic hernia surgery I. English version}, series = {Der Chirurg}, volume = {92}, journal = {Der Chirurg}, number = {Suppl 1}, doi = {10.1007/s00104-021-01446-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323934}, pages = {S1-S13}, year = {2021}, abstract = {The treatment of inguinal hernias with open and minimally invasive procedures has reached a high standard in terms of outcome over the past 30 years. However, there is still need for further improvement, mainly in terms of reduction of postoperative seroma, chronic pain, and recurrence. This video article presents the endoscopic anatomy of the groin with regard to robotic transabdominal preperitoneal patch plasty (r‑TAPP) and illustrates the surgical steps of r‑TAPP with respective video sequences. The results of a cohort study of 302 consecutive hernias operated by r‑TAPP are presented and discussed in light of the added value of the robotic technique, including advantages for surgical training. r‑TAPP is the natural evolution of conventional TAPP and has the potential to become a new standard as equipment availability increases and material costs decrease. Future studies will also have to refine the multifaceted added value of r‑TAPP with new parameters.}, language = {en} } @article{DietzKudsiGarciaUrenaetal.2021, author = {Dietz, Ulrich A. and Kudsi, O. Yusef and Garcia-Ure{\~n}a, Miguel and Baur, Johannes and Ramser, Michaela and Maksimovic, Sladjana and Keller, Nicola and D{\"o}rfer, J{\"o}rg and Eisner, Lukas and Wiegering, Armin}, title = {Robotic hernia repair III. English version}, series = {Der Chirurg}, volume = {92}, journal = {Der Chirurg}, number = {Suppl 1}, doi = {10.1007/s00104-021-01500-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323896}, pages = {S28-S39}, year = {2021}, abstract = {The principle of targeted separation or weakening of individual components of the abdominal wall to relieve tension in the median line during major abdominal reconstruction has been known for over 30 years as anterior component separation (aCS) and is an established procedure. In search of alternatives with lower complication rates, posterior component separation (pCS) was developed; transversus abdominis release (TAR) is a nerve-sparing modification of pCS. With the ergonomic resources of robotics (e.g., angled instruments), TAR can be performed in a minimally invasive manner (r-TAR): hernia gaps of up to 14 cm can be closed and a large extraperitoneal mesh implanted. In this video article, the treatment of large incisional hernias using the r‑TAR technique is presented. Exemplary results of a cohort study in 13 consecutive patients are presented. The procedure is challenging, but our own results—as well as reports from the literature—are encouraging. The r‑TAR is becoming the pinnacle procedure for abdominal wall reconstruction.}, language = {en} } @article{NavarroStegnerNieswandtetal.2021, author = {Navarro, Stefano and Stegner, David and Nieswandt, Bernhard and Heemskerk, Johan W. M. and Kuijpers, Marijke J. E.}, title = {Temporal roles of platelet and coagulation pathways in collagen- and tissue factor-induced thrombus formation}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {1}, issn = {1422-0067}, doi = {10.3390/ijms23010358}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284219}, year = {2021}, abstract = {In hemostasis and thrombosis, the complex process of thrombus formation involves different molecular pathways of platelet and coagulation activation. These pathways are considered as operating together at the same time, but this has not been investigated. The objective of our study was to elucidate the time-dependency of key pathways of thrombus and clot formation, initiated by collagen and tissue factor surfaces, where coagulation is triggered via the extrinsic route. Therefore, we adapted a microfluidics whole-blood assay with the Maastricht flow chamber to acutely block molecular pathways by pharmacological intervention at desired time points. Application of the technique revealed crucial roles of glycoprotein VI (GPVI)-induced platelet signaling via Syk kinase as well as factor VIIa-induced thrombin generation, which were confined to the first minutes of thrombus buildup. A novel anti-GPVI Fab EMF-1 was used for this purpose. In addition, platelet activation with the protease-activating receptors 1/4 (PAR1/4) and integrin αIIbβ3 appeared to be prolongedly active and extended to later stages of thrombus and clot formation. This work thereby revealed a more persistent contribution of thrombin receptor-induced platelet activation than of collagen receptor-induced platelet activation to the thrombotic process.}, language = {en} } @article{BauerMallyLiedtke2021, author = {Bauer, Benedikt and Mally, Angela and Liedtke, Daniel}, title = {Zebrafish embryos and larvae as alternative animal models for toxicity testing}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {24}, issn = {1422-0067}, doi = {10.3390/ijms222413417}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284225}, year = {2021}, abstract = {Prerequisite to any biological laboratory assay employing living animals is consideration about its necessity, feasibility, ethics and the potential harm caused during an experiment. The imperative of these thoughts has led to the formulation of the 3R-principle, which today is a pivotal scientific standard of animal experimentation worldwide. The rising amount of laboratory investigations utilizing living animals throughout the last decades, either for regulatory concerns or for basic science, demands the development of alternative methods in accordance with 3R to help reduce experiments in mammals. This demand has resulted in investigation of additional vertebrate species displaying favourable biological properties. One prominent species among these is the zebrafish (Danio rerio), as these small laboratory ray-finned fish are well established in science today and feature outstanding biological characteristics. In this review, we highlight the advantages and general prerequisites of zebrafish embryos and larvae before free-feeding stages for toxicological testing, with a particular focus on cardio-, neuro, hepato- and nephrotoxicity. Furthermore, we discuss toxicokinetics, current advances in utilizing zebrafish for organ toxicity testing and highlight how advanced laboratory methods (such as automation, advanced imaging and genetic techniques) can refine future toxicological studies in this species.}, language = {en} } @article{RamirezRodriguezPereiraHerrmannetal.2021, author = {Ram{\´i}rez-Rodr{\´i}guez, Gloria Bel{\´e}n and Pereira, Ana Rita and Herrmann, Marietta and Hansmann, Jan and Delgado-L{\´o}pez, Jos{\´e} Manuel and Sprio, Simone and Tampieri, Anna and Sandri, Monica}, title = {Biomimetic mineralization promotes viability and differentiation of human mesenchymal stem cells in a perfusion bioreactor}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {3}, issn = {1422-0067}, doi = {10.3390/ijms22031447}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285804}, year = {2021}, abstract = {In bone tissue engineering, the design of 3D systems capable of recreating composition, architecture and micromechanical environment of the native extracellular matrix (ECM) is still a challenge. While perfusion bioreactors have been proposed as potential tool to apply biomechanical stimuli, its use has been limited to a low number of biomaterials. In this work, we propose the culture of human mesenchymal stem cells (hMSC) in biomimetic mineralized recombinant collagen scaffolds with a perfusion bioreactor to simultaneously provide biochemical and biophysical cues guiding stem cell fate. The scaffolds were fabricated by mineralization of recombinant collagen in the presence of magnesium (RCP.MgAp). The organic matrix was homogeneously mineralized with apatite nanocrystals, similar in composition to those found in bone. X-Ray microtomography images revealed isotropic porous structure with optimum porosity for cell ingrowth. In fact, an optimal cell repopulation through the entire scaffolds was obtained after 1 day of dynamic seeding in the bioreactor. Remarkably, RCP.MgAp scaffolds exhibited higher cell viability and a clear trend of up-regulation of osteogenic genes than control (non-mineralized) scaffolds. Results demonstrate the potential of the combination of biomimetic mineralization of recombinant collagen in presence of magnesium and dynamic culture of hMSC as a promising strategy to closely mimic bone ECM.}, language = {en} } @article{SchlechtThienWolfetal.2021, author = {Schlecht, Anja and Thien, Adrian and Wolf, Julian and Prinz, Gabriele and Agostini, Hansj{\"u}rgen and Schlunck, G{\"u}nther and Wieghofer, Peter and Boneva, Stefaniya and Lange, Clemens}, title = {Immunosenescence in choroidal neovascularization (CNV) — Transcriptional profiling of na{\"i}ve and CNV-associated retinal myeloid cells during aging}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {24}, issn = {1422-0067}, doi = {10.3390/ijms222413318}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284342}, year = {2021}, abstract = {Immunosenescence is considered a possible factor in the development of age-related macular degeneration and choroidal neovascularization (CNV). However, age-related changes of myeloid cells (MCs), such as microglia and macrophages, in the healthy retina or during CNV formation are ill-defined. In this study, Cx3cr1-positive MCs were isolated by fluorescence-activated cell sorting from six-week (young) and two-year-old (old) Cx3cr1\(^{GFP/+}\) mice, both during physiological aging and laser-induced CNV development. High-throughput RNA-sequencing was performed to define the age-dependent transcriptional differences in MCs during physiological aging and CNV development, complemented by immunohistochemical characterization and the quantification of MCs, as well as CNV size measurements. These analyses revealed that myeloid cells change their transcriptional profile during both aging and CNV development. In the steady state, senescent MCs demonstrated an upregulation of factors contributing to cell proliferation and chemotaxis, such as Cxcl13 and Cxcl14, as well as the downregulation of microglial signature genes. During CNV formation, aged myeloid cells revealed a significant upregulation of angiogenic factors such as Arg1 and Lrg1 concomitant with significantly enlarged CNV and an increased accumulation of MCs in aged mice in comparison to young mice. Future studies need to clarify whether this observation is an epiphenomenon or a causal relationship to determine the role of immunosenescence in CNV formation.}, language = {en} } @article{SedaghatHamedaniRebsElBattrawyetal.2021, author = {Sedaghat-Hamedani, Farbod and Rebs, Sabine and El-Battrawy, Ibrahim and Chasan, Safak and Krause, Tobias and Haas, Jan and Zhong, Rujia and Liao, Zhenxing and Xu, Qiang and Zhou, Xiaobo and Akin, Ibrahim and Zitron, Edgar and Frey, Norbert and Streckfuss-B{\"o}meke, Katrin and Kayvanpour, Elham}, title = {Identification of SCN5a p.C335R variant in a large family with dilated cardiomyopathy and conduction disease}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {23}, issn = {1422-0067}, doi = {10.3390/ijms222312990}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284442}, year = {2021}, abstract = {Introduction: Familial dilated cardiomyopathy (DCM) is clinically variable and has been associated with mutations in more than 50 genes. Rapid improvements in DNA sequencing have led to the identification of diverse rare variants with unknown significance (VUS), which underlines the importance of functional analyses. In this study, by investigating human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we evaluated the pathogenicity of the p.C335R sodium voltage-gated channel alpha subunit 5 (SCN5a) variant in a large family with familial DCM and conduction disease. Methods: A four-generation family with autosomal dominant familial DCM was investigated. Next-generation sequencing (NGS) was performed in all 16 family members. Clinical deep phenotyping, including endomyocardial biopsy, was performed. Skin biopsies from two patients and one healthy family member were used to generate human-induced pluripotent stem cells (iPSCs), which were then differentiated into cardiomyocytes. Patch-clamp analysis with Xenopus oocytes and iPSC-CMs were performed. Results: A SCN5a variant (c.1003T>C; p.C335R) could be detected in all family members with DCM or conduction disease. A novel truncating TTN variant (p.Ser24998LysfsTer28) could also be identified in two family members with DCM. Family members with the SCN5a variant (p.C335R) showed significantly longer PQ and QRS intervals and lower left ventricular ejection fractions (LV-EF). All four patients who received CRT-D were non-responders. Electrophysiological analysis with Xenopus oocytes showed a loss of function in SCN5a p.C335R. Na\(^+\) channel currents were also reduced in iPSC-CMs from DCM patients. Furthermore, iPSC-CM with compound heterozygosity (SCN5a p.C335R and TTNtv) showed significant dysregulation of sarcomere structures, which may be contributed to the severity of the disease and earlier onset of DCM. Conclusion: The SCN5a p.C335R variant is causing a loss of function of peak INa in patients with DCM and cardiac conduction disease. The co-existence of genetic variants in channels and structural genes (e.g., SCN5a p.C335R and TTNtv) increases the severity of the DCM phenotype.}, language = {en} } @article{GuptaSrivastavaMinochaetal.2021, author = {Gupta, Shishir K. and Srivastava, Mugdha and Minocha, Rashmi and Akash, Aman and Dangwal, Seema and Dandekar, Thomas}, title = {Alveolar regeneration in COVID-19 patients: a network perspective}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {20}, issn = {1422-0067}, doi = {10.3390/ijms222011279}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284307}, year = {2021}, abstract = {A viral infection involves entry and replication of viral nucleic acid in a host organism, subsequently leading to biochemical and structural alterations in the host cell. In the case of SARS-CoV-2 viral infection, over-activation of the host immune system may lead to lung damage. Albeit the regeneration and fibrotic repair processes being the two protective host responses, prolonged injury may lead to excessive fibrosis, a pathological state that can result in lung collapse. In this review, we discuss regeneration and fibrosis processes in response to SARS-CoV-2 and provide our viewpoint on the triggering of alveolar regeneration in coronavirus disease 2019 (COVID-19) patients.}, language = {en} } @article{TelesYanoVillarinhoetal.2021, author = {Teles, Ramon Handerson Gomes and Yano, Rafael Sussumu and Villarinho, Nicolas Jones and Yamagata, Ana Sayuri and Jaeger, Ruy Gastaldoni and Meybohm, Patrick and Burek, Malgorzata and Freitas, Vanessa Morais}, title = {Advances in breast cancer management and extracellular vesicle research, a bibliometric analysis}, series = {Current Oncology}, volume = {28}, journal = {Current Oncology}, number = {6}, issn = {1718-7729}, doi = {10.3390/curroncol28060382}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284321}, pages = {4504 -- 4520}, year = {2021}, abstract = {Extracellular vesicles transport variable content and have crucial functions in cell-cell communication. The role of extracellular vesicles in cancer is a current hot topic, and no bibliometric study has ever analyzed research production regarding their role in breast cancer and indicated the trends in the field. In this way, we aimed to investigate the trends in breast cancer management involved with extracellular vesicle research. Articles were retrieved from Scopus, including all the documents published concerning breast cancer and extracellular vesicles. We analyzed authors, journals, citations, affiliations, and keywords, besides other bibliometric analyses, using R Studio version 3.6.2. and VOSviewer version 1.6.0. A total of 1151 articles were retrieved, and as the main result, our analysis revealed trending topics on biomarkers of liquid biopsy, drug delivery, chemotherapy, autophagy, and microRNA. Additionally, research related to extracellular vesicles in breast cancer has been focused on diagnosis, treatment, and mechanisms of action of breast tumor-derived vesicles. Future studies are expected to explore the role of extracellular vesicles on autophagy and microRNA, besides investigating the application of extracellular vesicles from liquid biopsies for biomarkers and drug delivery, enabling the development and validation of therapeutic strategies for specific cancers.}, language = {en} } @article{KadeOttoLuxenhoferetal.2021, author = {Kade, Juliane C. and Otto, Paul F. and Luxenhofer, Robert and Dalton, Paul D.}, title = {Melt electrowriting of poly(vinylidene difluoride) using a heated collector}, series = {Polymers for Advanced Technologies}, volume = {32}, journal = {Polymers for Advanced Technologies}, number = {12}, issn = {1042-7147}, doi = {10.1002/pat.5463}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318493}, pages = {4951 -- 4955}, year = {2021}, abstract = {Previous research on the melt electrowriting (MEW) of poly(vinylidene difluoride) (PVDF) resulted in electroactive fibers, however, printing more than five layers is challenging. Here, we investigate the influence of a heated collector to adjust the solidification rate of the PVDF jet so that it adheres sufficiently to each layer. A collector temperature of 110°C is required to improve fiber processing, resulting in a total of 20 fiber layers. For higher temperatures and higher layers, an interesting phenomenon occurred, where the intersection points of the fibers coalesced into periodic spheres of diameter 206 ± 52 μm (26G, 150°C collector temperature, 2000 mm/min, 10 layers in x- and y-direction).The heated collector is an important component of a MEW printer that allows polymers with a high melting point to be processable with increased layers.}, language = {en} } @article{WamserSeufertHalletal.2021, author = {Wamser, Florian and Seufert, Anika and Hall, Andrew and Wunderer, Stefan and Hoßfeld, Tobias}, title = {Valid statements by the crowd: statistical measures for precision in crowdsourced mobile measurements}, series = {Network}, volume = {1}, journal = {Network}, number = {2}, issn = {2673-8732}, doi = {10.3390/network1020013}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284154}, pages = {215 -- 232}, year = {2021}, abstract = {Crowdsourced network measurements (CNMs) are becoming increasingly popular as they assess the performance of a mobile network from the end user's perspective on a large scale. Here, network measurements are performed directly on the end-users' devices, thus taking advantage of the real-world conditions end-users encounter. However, this type of uncontrolled measurement raises questions about its validity and reliability. The problem lies in the nature of this type of data collection. In CNMs, mobile network subscribers are involved to a large extent in the measurement process, and collect data themselves for the operator. The collection of data on user devices in arbitrary locations and at uncontrolled times requires means to ensure validity and reliability. To address this issue, our paper defines concepts and guidelines for analyzing the precision of CNMs; specifically, the number of measurements required to make valid statements. In addition to the formal definition of the aspect, we illustrate the problem and use an extensive sample data set to show possible assessment approaches. This data set consists of more than 20.4 million crowdsourced mobile measurements from across France, measured by a commercial data provider.}, language = {en} } @article{GaryLenhardLenhard2021, author = {Gary, Sebastian and Lenhard, Wolfgang and Lenhard, Alexandra}, title = {Modelling norm scores with the cNORM package in R}, series = {Psych}, volume = {3}, journal = {Psych}, number = {3}, issn = {2624-8611}, doi = {10.3390/psych3030033}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284143}, pages = {501 -- 521}, year = {2021}, abstract = {In this article, we explain and demonstrate how to model norm scores with the cNORM package in R. This package is designed specifically to determine norm scores when the latent ability to be measured covaries with age or other explanatory variables such as grade level. The mathematical method used in this package draws on polynomial regression to model a three-dimensional hyperplane that smoothly and continuously captures the relation between raw scores, norm scores and the explanatory variable. By doing so, it overcomes the typical problems of classical norming methods, such as overly large age intervals, missing norm scores, large amounts of sampling error in the subsamples or huge requirements with regard to the sample size. After a brief introduction to the mathematics of the model, we describe the individual methods of the package. We close the article with a practical example using data from a real reading comprehension test.}, language = {en} } @article{GehrmannFiedlerLeutritzetal.2021, author = {Gehrmann, Andrea and Fiedler, Katrin and Leutritz, Anna Linda and Koreny, Carolin and Kittel-Schneider, Sarah}, title = {Lithium medication in pregnancy and breastfeeding — a case series}, series = {Medicina}, volume = {57}, journal = {Medicina}, number = {6}, issn = {1648-9144}, doi = {10.3390/medicina57060634}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285640}, year = {2021}, abstract = {Lithium salts are the first-line prophylaxis treatment for bipolar disorder in most guidelines. The majority of bipolar women are treated with mood stabilizers at the time they wish to get pregnant. One reason for this is the rising average age at first childbirth, at least in the high-income countries, which increases in general the likelihood of a medication with psychotropic drugs. Previously, lithium exposition during pregnancy was thought to strongly increase the risk of severe cardiac malformation. However, recent studies only point to a low teratogenic risk, so nowadays an increasing number of women are getting pregnant with ongoing lithium treatment. Regarding lithium medication during breastfeeding, there is evidence that lithium transfers to the breastmilk and can also be detected in the infants' serum. The influence on the infant is still a largely understudied topic. Regular monitoring of the infants' renal clearance, thyroid function, and lithium levels is warranted when breastfeeding under lithium exposure. In this case series, we present three case reports of bipolar mothers who were treated with lithium during pregnancy and breastfeeding to add to the scarce literature on this important topic. In short, we strengthen the importance of therapeutic drug monitoring due to fluctuating plasma levels during pregnancy and after birth, and we can report the birth and development of three healthy infants despite lithium medication during pregnancy and breastfeeding.}, language = {en} } @article{BaumToykaBlueheretal.2021, author = {Baum, Petra and Toyka, Klaus V. and Bl{\"u}her, Matthias and Kosacka, Joanna and Nowicki, Marcin}, title = {Inflammatory mechanisms in the pathophysiology of diabetic peripheral neuropathy (DN) — new aspects}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {19}, issn = {1422-0067}, doi = {10.3390/ijms221910835}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284556}, year = {2021}, abstract = {The pathogenesis of diabetic neuropathy is complex, and various pathogenic pathways have been proposed. A better understanding of the pathophysiology is warranted for developing novel therapeutic strategies. Here, we summarize recent evidence from experiments using animal models of type 1 and type 2 diabetes showing that low-grade intraneural inflammation is a facet of diabetic neuropathy. Our experimental data suggest that these mild inflammatory processes are a likely common terminal pathway in diabetic neuropathy associated with the degeneration of intraepidermal nerve fibers. In contrast to earlier reports claiming toxic effects of high-iron content, we found the opposite, i.e., nutritional iron deficiency caused low-grade inflammation and fiber degeneration while in normal or high non-heme iron nutrition no or only extremely mild inflammatory signs were identified in nerve tissue. Obesity and dyslipidemia also appear to trigger mild inflammation of peripheral nerves, associated with neuropathy even in the absence of overt diabetes mellitus. Our finding may be the experimental analog of recent observations identifying systemic proinflammatory activity in human sensorimotor diabetic neuropathy. In a rat model of type 1 diabetes, a mild neuropathy with inflammatory components could be induced by insulin treatment causing an abrupt reduction in HbA1c. This is in line with observations in patients with severe diabetes developing a small fiber neuropathy upon treatment-induced rapid HbA1c reduction. If the inflammatory pathogenesis could be further substantiated by data from human tissues and intervention studies, anti-inflammatory compounds with different modes of action may become candidates for the treatment or prevention of diabetic neuropathy.}, language = {en} } @article{VogelsangEichlerHuntemannetal.2021, author = {Vogelsang, Anna and Eichler, Susann and Huntemann, Niklas and Masanneck, Lars and B{\"o}hnlein, Hannes and Sch{\"u}ngel, Lisa and Willison, Alice and Loser, Karin and Nieswandt, Bernhard and Kehrel, Beate E. and Zarbock, Alexander and G{\"o}bel, Kerstin and Meuth, Sven G.}, title = {Platelet inhibition by low-dose acetylsalicylic acid reduces neuroinflammation in an animal model of multiple sclerosis}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {18}, issn = {1422-0067}, doi = {10.3390/ijms22189915}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284535}, year = {2021}, abstract = {Aside from the established immune-mediated etiology of multiple sclerosis (MS), compelling evidence implicates platelets as important players in disease pathogenesis. Specifically, numerous studies have highlighted that activated platelets promote the central nervous system (CNS)-directed adaptive immune response early in the disease course. Platelets, therefore, present a novel opportunity for modulating the neuroinflammatory process that characterizes MS. We hypothesized that the well-known antiplatelet agent acetylsalicylic acid (ASA) could inhibit neuroinflammation by affecting platelets if applied at low-dose and investigated its effect during experimental autoimmune encephalomyelitis (EAE) as a model to study MS. We found that oral administration of low-dose ASA alleviates symptoms of EAE accompanied by reduced inflammatory infiltrates and less extensive demyelination. Remarkably, the percentage of CNS-infiltrated CD4\(^+\) T cells, the major drivers of neuroinflammation, was decreased to 40.98 ± 3.28\% in ASA-treated mice compared to 56.11 ± 1.46\% in control animals at the disease maximum as revealed by flow cytometry. More interestingly, plasma levels of thromboxane A\(_2\) were decreased, while concentrations of platelet factor 4 and glycoprotein VI were not affected by low-dose ASA treatment. Overall, we demonstrate that low-dose ASA could ameliorate the platelet-dependent neuroinflammatory response in vivo, thus indicating a potential treatment approach for MS.}, language = {en} } @article{BieberFoersterHaefelietal.2021, author = {Bieber, Michael and Foerster, Kathrin I. and Haefeli, Walter E. and Pham, Mirko and Schuhmann, Michael K. and Kraft, Peter}, title = {Treatment with edoxaban attenuates acute stroke severity in mice by reducing blood-brain barrier damage and inflammation}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {18}, issn = {1422-0067}, doi = {10.3390/ijms22189893}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284481}, year = {2021}, abstract = {Patients with atrial fibrillation and previous ischemic stroke (IS) are at increased risk of cerebrovascular events despite anticoagulation. In these patients, treatment with non-vitamin K oral anticoagulants (NOAC) such as edoxaban reduced the probability and severity of further IS without increasing the risk of major bleeding. However, the detailed protective mechanism of edoxaban has not yet been investigated in a model of ischemia/reperfusion injury. Therefore, in the current study we aimed to assess in a clinically relevant setting whether treatment with edoxaban attenuates stroke severity, and whether edoxaban has an impact on the local cerebral inflammatory response and blood-brain barrier (BBB) function after experimental IS in mice. Focal cerebral ischemia was induced by transient middle cerebral artery occlusion in male mice receiving edoxaban, phenprocoumon or vehicle. Infarct volumes, functional outcome and the occurrence of intracerebral hemorrhage were assessed. BBB damage and the extent of local inflammatory response were determined. Treatment with edoxaban significantly reduced infarct volumes and improved neurological outcome and BBB function on day 1 and attenuated brain tissue inflammation. In summary, our study provides evidence that edoxaban might exert its protective effect in human IS by modulating different key steps of IS pathophysiology, but further studies are warranted.}, language = {en} } @article{ShemerMekiesBenJehudaetal.2021, author = {Shemer, Yuval and Mekies, Lucy N. and Ben Jehuda, Ronen and Baskin, Polina and Shulman, Rita and Eisen, Binyamin and Regev, Danielle and Arbustini, Eloisa and Gerull, Brenda and Gherghiceanu, Mihaela and Gottlieb, Eyal and Arad, Michael and Binah, Ofer}, title = {Investigating LMNA-related dilated cardiomyopathy using human induced Pluripotent Stem Cell-derived cardiomyocytes}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {15}, issn = {1422-0067}, doi = {10.3390/ijms22157874}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285673}, year = {2021}, abstract = {LMNA-related dilated cardiomyopathy is an inherited heart disease caused by mutations in the LMNA gene encoding for lamin A/C. The disease is characterized by left ventricular enlargement and impaired systolic function associated with conduction defects and ventricular arrhythmias. We hypothesized that LMNA-mutated patients' induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) display electrophysiological abnormalities, thus constituting a suitable tool for deciphering the arrhythmogenic mechanisms of the disease, and possibly for developing novel therapeutic modalities. iPSC-CMs were generated from two related patients (father and son) carrying the same E342K mutation in the LMNA gene. Compared to control iPSC-CMs, LMNA-mutated iPSC-CMs exhibited the following electrophysiological abnormalities: (1) decreased spontaneous action potential beat rate and decreased pacemaker current (I\(_f\)) density; (2) prolonged action potential duration and increased L-type Ca\(^{2+}\) current (I\(_{Ca,L}\)) density; (3) delayed afterdepolarizations (DADs), arrhythmias and increased beat rate variability; (4) DADs, arrhythmias and cessation of spontaneous firing in response to β-adrenergic stimulation and rapid pacing. Additionally, compared to healthy control, LMNA-mutated iPSC-CMs displayed nuclear morphological irregularities and gene expression alterations. Notably, KB-R7943, a selective inhibitor of the reverse-mode of the Na\(^+\)/Ca\(^{2+}\) exchanger, blocked the DADs in LMNA-mutated iPSC-CMs. Our findings demonstrate cellular electrophysiological mechanisms underlying the arrhythmias in LMNA-related dilated cardiomyopathy.}, language = {en} } @article{RajendranRajendranGiraldoVelasquezetal.2021, author = {Rajendran, Ranjithkumar and Rajendran, Vinothkumar and Giraldo-Velasquez, Mario and Megalofonou, Fevronia-Foivi and Gurski, Fynn and Stadelmann, Christine and Karnati, Srikanth and Berghoff, Martin}, title = {Oligodendrocyte-specific deletion of FGFR1 reduces cerebellar inflammation and neurodegeneration in MOG\(_{35-55}\)-induced EAE}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {17}, issn = {1422-0067}, doi = {10.3390/ijms22179495}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284296}, year = {2021}, abstract = {Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). MS commonly affects the cerebellum causing acute and chronic symptoms. Cerebellar signs significantly contribute to clinical disability, and symptoms such as tremor, ataxia, and dysarthria are difficult to treat. Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies such as MS. In autopsy tissue from patients with MS, increased expression of FGF1, FGF2, FGF9, and FGFR1 was found in lesion areas. Recent research using mouse models has focused on regions such as the spinal cord, and data on the expression of FGF/FGFR in the cerebellum are not available. In recent EAE studies, we detected that oligodendrocyte-specific deletion of FGFRs results in a milder disease course, less cellular infiltrates, and reduced neurodegeneration in the spinal cord. The objective of this study was to characterize the role of FGFR1 in oligodendrocytes in the cerebellum. Conditional deletion of FGFR1 in oligodendrocytes (Fgfr1\(^{ind-/-}\) was achieved by tamoxifen application, EAE was induced using the MOG\(_{35-55}\) peptide. The cerebellum was analyzed by histology, immunohistochemistry, and western blot. At day 62 p.i., Fgfr1\(^{ind-/-}\) mice showed less myelin and axonal degeneration compared to FGFR1-competent mice. Infiltration of CD3(+) T cells, Mac3(+) cells, B220(+) B cells and IgG(+) plasma cells in cerebellar white matter lesions (WML) was less in Fgfr1\(^{ind-/-}\)mice. There were no effects on the number of OPC or mature oligodendrocytes in white matter lesion (WML). Expression of FGF2 and FGF9 associated with less myelin and axonal degeneration, and of the pro-inflammatory cytokines IL-1β, IL-6, and CD200 was downregulated in Fgfr1\(^{ind-/-}\) mice. The FGF/FGFR signaling protein pAkt, BDNF, and TrkB were increased in Fgfr1\(^{ind-/-}\) mice. These data suggest that cell-specific deletion of FGFR1 in oligodendrocytes has anti-inflammatory and neuroprotective effects in the cerebellum in the EAE disease model of MS.}, language = {en} } @article{StrinitzPhamMaerzetal.2021, author = {Strinitz, Marc and Pham, Mirko and M{\"a}rz, Alexander G. and Feick, J{\"o}rn and Weidner, Franziska and Vogt, Marius L. and Essig, Fabian and Neugebauer, Hermann and Stoll, Guido and Schuhmann, Michael K. and Kollikowski, Alexander M.}, title = {Immune cells invade the collateral circulation during human stroke: prospective replication and extension}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {17}, issn = {1422-0067}, doi = {10.3390/ijms22179161}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284281}, year = {2021}, abstract = {It remains unclear if principal components of the local cerebral stroke immune response can be reliably and reproducibly observed in patients with acute large-vessel-occlusion (LVO) stroke. We prospectively studied a large independent cohort of n = 318 consecutive LVO stroke patients undergoing mechanical thrombectomy during which cerebral blood samples from within the occluded anterior circulation and systemic control samples from the ipsilateral cervical internal carotid artery were obtained. An extensive protocol was applied to homogenize the patient cohort and to standardize the procedural steps of endovascular sample collection, sample processing, and laboratory analyses. N = 58 patients met all inclusion criteria. (1) Mean total leukocyte counts were significantly higher within the occluded ischemic cerebral vasculature (I) vs. intraindividual systemic controls (S): +9.6\%, I: 8114/µL ± 529 vs. S: 7406/µL ± 468, p = 0.0125. (2) This increase was driven by neutrophils: +12.1\%, I: 7197/µL ± 510 vs. S: 6420/µL ± 438, p = 0.0022. Leukocyte influx was associated with (3) reduced retrograde collateral flow (R\(^2\) = 0.09696, p = 0.0373) and (4) greater infarct extent (R\(^2\) = 0.08382, p = 0.032). Despite LVO, leukocytes invade the occluded territory via retrograde collateral pathways early during ischemia, likely compromising cerebral hemodynamics and tissue integrity. This inflammatory response can be reliably observed in human stroke by harvesting immune cells from the occluded cerebral vascular compartment.}, language = {en} } @article{KiemLeischNeureiteretal.2021, author = {Kiem, Dominik and Leisch, Michael and Neureiter, Daniel and Haslauer, Theresa and Egle, Alexander and Melchardt, Thomas and Topp, Max S. and Greil, Richard}, title = {Two cases of pancytopenia with Coombs-negative hemolytic anemia after chimeric antigen receptor T-cell therapy}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {11}, issn = {1422-0067}, doi = {10.3390/ijms22115449}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284977}, year = {2021}, abstract = {Background: Chimeric antigen receptor (CAR) T-cells are changing the therapeutic landscape of hematologic malignancies. Severe side effects include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), but prolonged cytopenia has also been reported. The underlying mechanism for prolonged cytopenia is poorly understood so far. Cases: Severe pancytopenia with grade 2-3 anemia was marked 2-3 months after treatment. Laboratory evaluation revealed undetectable levels of haptoglobin with increased reticulocyte counts. Coomb's tests were negative, no schistocytes were detected on blood smear, and infectious causes were ruled out. Increased erythropoiesis without lymphoma infiltration was noted on bone marrow biopsy. A spontaneous increase in haptoglobin and hemoglobin levels was observed after several weeks. For one patient, peripheral CAR-T levels were monitored over time. We observed a decline at the same time as hemoglobin levels began to rise, implying a potential causality. Conclusion: To our knowledge, we describe the first two cases of Coombs-negative hemolytic anemia after CAR-T treatment for B-cell lymphoma. We encourage routine monitoring for hemolytic anemia after CAR-T treatment and also encourage further investigations on the underlying mechanism.}, language = {en} } @article{StetterLopezCaperuchipiHoppKraemeretal.2021, author = {Stetter, Christian and Lopez-Caperuchipi, Simon and Hopp-Kr{\"a}mer, Sarah and Bieber, Michael and Kleinschnitz, Christoph and Sir{\´e}n, Anna-Leena and Albert-Weißenberger, Christiane}, title = {Amelioration of cognitive and behavioral deficits after traumatic brain injury in coagulation factor XII deficient mice}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {9}, issn = {1422-0067}, doi = {10.3390/ijms22094855}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284959}, year = {2021}, abstract = {Based on recent findings that show that depletion of factor XII (FXII) leads to better posttraumatic neurological recovery, we studied the effect of FXII-deficiency on post-traumatic cognitive and behavioral outcomes in female and male mice. In agreement with our previous findings, neurological deficits on day 7 after weight-drop traumatic brain injury (TBI) were significantly reduced in FXII\(^{-/-}\) mice compared to wild type (WT) mice. Also, glycoprotein Ib (GPIb)-positive platelet aggregates were more frequent in brain microvasculature of WT than FXII\(^{-/-}\) mice 3 months after TBI. Six weeks after TBI, memory for novel object was significantly reduced in both female and male WT but not in FXII\(^{-/-}\) mice compared to sham-operated mice. In the setting of automated home-cage monitoring of socially housed mice in IntelliCages, female WT mice but not FXII\(^{-/-}\) mice showed decreased exploration and reacted negatively to reward extinction one month after TBI. Since neuroendocrine stress after TBI might contribute to trauma-induced cognitive dysfunction and negative emotional contrast reactions, we measured peripheral corticosterone levels and the ration of heart, lung, and spleen weight to bodyweight. Three months after TBI, plasma corticosterone levels were significantly suppressed in both female and male WT but not in FXII\(^{-/-}\) mice, while the relative heart weight increased in males but not in females of both phenotypes when compared to sham-operated mice. Our results indicate that FXII deficiency is associated with efficient post-traumatic behavioral and neuroendocrine recovery.}, language = {en} } @article{WagnerSadekDybkovaetal.2021, author = {Wagner, Michael and Sadek, Mirna S. and Dybkova, Nataliya and Mason, Fleur E. and Klehr, Johann and Firneburg, Rebecca and Cachorro, Eleder and Richter, Kurt and Klapproth, Erik and Kuenzel, Stephan R. and Lorenz, Kristina and Heijman, Jordi and Dobrev, Dobromir and El-Armouche, Ali and Sossalla, Samuel and K{\"a}mmerer, Susanne}, title = {Cellular mechanisms of the anti-arrhythmic effect of cardiac PDE2 overexpression}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {9}, issn = {1422-0067}, doi = {10.3390/ijms22094816}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285888}, year = {2021}, abstract = {Background: Phosphodiesterases (PDE) critically regulate myocardial cAMP and cGMP levels. PDE2 is stimulated by cGMP to hydrolyze cAMP, mediating a negative crosstalk between both pathways. PDE2 upregulation in heart failure contributes to desensitization to β-adrenergic overstimulation. After isoprenaline (ISO) injections, PDE2 overexpressing mice (PDE2 OE) were protected against ventricular arrhythmia. Here, we investigate the mechanisms underlying the effects of PDE2 OE on susceptibility to arrhythmias. Methods: Cellular arrhythmia, ion currents, and Ca\(^{2+}\)-sparks were assessed in ventricular cardiomyocytes from PDE2 OE and WT littermates. Results: Under basal conditions, action potential (AP) morphology were similar in PDE2 OE and WT. ISO stimulation significantly increased the incidence of afterdepolarizations and spontaneous APs in WT, which was markedly reduced in PDE2 OE. The ISO-induced increase in I\(_{CaL}\) seen in WT was prevented in PDE2 OE. Moreover, the ISO-induced, Epac- and CaMKII-dependent increase in I\(_{NaL}\) and Ca\(^{2+}\)-spark frequency was blunted in PDE2 OE, while the effect of direct Epac activation was similar in both groups. Finally, PDE2 inhibition facilitated arrhythmic events in ex vivo perfused WT hearts after reperfusion injury. Conclusion: Higher PDE2 abundance protects against ISO-induced cardiac arrhythmia by preventing the Epac- and CaMKII-mediated increases of cellular triggers. Thus, activating myocardial PDE2 may represent a novel intracellular anti-arrhythmic therapeutic strategy in HF.}, language = {en} } @article{LotzHerrmannNotzetal.2021, author = {Lotz, Christopher and Herrmann, Johannes and Notz, Quirin and Meybohm, Patrick and Kehl, Franz}, title = {Mitochondria and pharmacologic cardiac conditioning — At the heart of ischemic injury}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {6}, issn = {1422-0067}, doi = {10.3390/ijms22063224}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285368}, year = {2021}, abstract = {Pharmacologic cardiac conditioning increases the intrinsic resistance against ischemia and reperfusion (I/R) injury. The cardiac conditioning response is mediated via complex signaling networks. These networks have been an intriguing research field for decades, largely advancing our knowledge on cardiac signaling beyond the conditioning response. The centerpieces of this system are the mitochondria, a dynamic organelle, almost acting as a cell within the cell. Mitochondria comprise a plethora of functions at the crossroads of cell death or survival. These include the maintenance of aerobic ATP production and redox signaling, closely entwined with mitochondrial calcium handling and mitochondrial permeability transition. Moreover, mitochondria host pathways of programmed cell death impact the inflammatory response and contain their own mechanisms of fusion and fission (division). These act as quality control mechanisms in cellular ageing, release of pro-apoptotic factors and mitophagy. Furthermore, recently identified mechanisms of mitochondrial regeneration can increase the capacity for oxidative phosphorylation, decrease oxidative stress and might help to beneficially impact myocardial remodeling, as well as invigorate the heart against subsequent ischemic insults. The current review highlights different pathways and unresolved questions surrounding mitochondria in myocardial I/R injury and pharmacological cardiac conditioning.}, language = {en} } @article{ZioutiRummlerSteynetal.2021, author = {Ziouti, Fani and Rummler, Maximilian and Steyn, Beatrice and Thiele, Tobias and Seliger, Anne and Duda, Georg N. and Bogen, Bjarne and Willie, Bettina M. and Jundt, Franziska}, title = {Prevention of bone destruction by mechanical loading is not enhanced by the Bruton's tyrosine kinase inhibitor CC-292 in myeloma bone disease}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {8}, issn = {1422-0067}, doi = {10.3390/ijms22083840}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284943}, year = {2021}, abstract = {Limiting bone resorption and regenerating bone tissue are treatment goals in myeloma bone disease (MMBD). Physical stimuli such as mechanical loading prevent bone destruction and enhance bone mass in the MOPC315.BM.Luc model of MMBD. It is unknown whether treatment with the Bruton's tyrosine kinase inhibitor CC-292 (spebrutinib), which regulates osteoclast differentiation and function, augments the anabolic effect of mechanical loading. CC-292 was administered alone and in combination with axial compressive tibial loading in the MOPC315.BM.Luc model for three weeks. However, neither CC-292 alone nor its use in combination with mechanical loading was more effective in reducing osteolytic bone disease or rescuing bone mass than mechanical stimuli alone, as evidenced by microcomputed tomography (microCT) and histomorphometric analysis. Further studies are needed to investigate novel anti-myeloma and anti-resorptive strategies in combination with physical stimuli to improve treatment of MMBD.}, language = {en} } @article{BrodehlMeshkovMyasnikovetal.2021, author = {Brodehl, Andreas and Meshkov, Alexey and Myasnikov, Roman and Kiseleva, Anna and Kulikova, Olga and Klauke, B{\"a}rbel and Sotnikova, Evgeniia and Stanasiuk, Caroline and Divashuk, Mikhail and Pohl, Greta Marie and Kudryavtseva, Maria and Klingel, Karin and Gerull, Brenda and Zharikova, Anastasia and Gummert, Jan and Koretskiy, Sergey and Schubert, Stephan and Mershina, Elena and G{\"a}rtner, Anna and Pilus, Polina and Laser, Kai Thorsten and Sinitsyn, Valentin and Boytsov, Sergey and Drapkina, Oxana and Milting, Hendrik}, title = {Hemi- and homozygous loss-of-function mutations in DSG2 (desmoglein-2) cause recessive arrhythmogenic cardiomyopathy with an early onset}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {7}, issn = {1422-0067}, doi = {10.3390/ijms22073786}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285279}, year = {2021}, abstract = {About 50\% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2-c.378+1G>T) in the first patient and a nonsense mutation (DSG2-p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.}, language = {en} } @article{BaumKojKloetingetal.2021, author = {Baum, Petra and Koj, Severin and Kl{\"o}ting, Nora and Bl{\"u}her, Matthias and Classen, Joseph and Paeschke, Sabine and Gericke, Martin and Toyka, Klaus V. and Nowicki, Marcin and Kosacka, Joanna}, title = {Treatment-induced neuropathy in diabetes (TIND) — Developing a disease model in type 1 diabetic rats}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {4}, issn = {1422-0067}, doi = {10.3390/ijms22041571}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285793}, year = {2021}, abstract = {Treatment-induced neuropathy in diabetes (TIND) is defined by the occurrence of an acute neuropathy within 8 weeks of an abrupt decrease in glycated hemoglobin-A1c (HbA1c). The underlying pathogenic mechanisms are still incompletely understood with only one mouse model being explored to date. The aim of this study was to further explore the hypothesis that an abrupt insulin-induced fall in HbA1c may be the prime causal factor of developing TIND. BB/OKL (bio breeding/OKL, Ottawa Karlsburg Leipzig) diabetic rats were randomized in three groups, receiving insulin treatment by implanted subcutaneous osmotic insulin pumps for 3 months, as follows: Group one received 2 units per day; group two 1 unit per day: and group three 1 unit per day in the first month, followed by 2 units per day in the last two months. We serially examined blood glucose and HbA1c levels, motor- and sensory/mixed afferent conduction velocities (mNCV and csNCV) and peripheral nerve morphology, including intraepidermal nerve fiber density and numbers of Iba-1 (ionized calcium binding adaptor molecule 1) positive macrophages in the sciatic nerve. Only in BB/OKL rats of group three, with a rapid decrease in HbA1c of more than 2\%, did we find a significant decrease in mNCV in sciatic nerves (81\% of initial values) after three months of treatment as compared to those group three rats with a less marked decrease in HbA1c <2\% (mNCV 106\% of initial values, p ≤ 0.01). A similar trend was observed for sensory/mixed afferent nerve conduction velocities: csNCV were reduced in BB/OKL rats with a rapid decrease in HbA1c >2\% (csNCV 90\% of initial values), compared to those rats with a mild decrease <2\% (csNCV 112\% of initial values, p ≤ 0.01). Moreover, BB/OKL rats of group three with a decrease in HbA1c >2\% showed significantly greater infiltration of macrophages by about 50\% (p ≤ 0.01) and a decreased amount of calcitonin gene related peptide (CGRP) positive nerve fibers as compared to the animals with a milder decrease in HbA1c. We conclude that a mild acute neuropathy with inflammatory components was induced in BB/OKL rats as a consequence of an abrupt decrease in HbA1c caused by high-dose insulin treatment. This experimentally induced neuropathy shares some features with TIND in humans and may be further explored in studies into the pathogenesis and treatment of TIND.}, language = {en} } @article{KorkmazPuladiGalleretal.2021, author = {Korkmaz, Y{\"u}ksel and Puladi, Behrus and Galler, Kerstin and K{\"a}mmerer, Peer W. and Schr{\"o}der, Agnes and G{\"o}lz, Lina and Sparwasser, Tim and Bloch, Wilhelm and Friebe, Andreas and Deschner, James}, title = {Inflammation in the human periodontium induces downregulation of the α\(_1\)- and β\(_1\)-subunits of the sGC in cementoclasts}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {2}, issn = {1422-0067}, doi = {10.3390/ijms22020539}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285783}, year = {2021}, abstract = {Nitric oxide (NO) binds to soluble guanylyl cyclase (sGC), activates it in a reduced oxidized heme iron state, and generates cyclic Guanosine Monophosphate (cGMP), which results in vasodilatation and inhibition of osteoclast activity. In inflammation, sGC is oxidized and becomes insensitive to NO. NO- and heme-independent activation of sGC requires protein expression of the α\(_1\)- and β\(_1\)-subunits. Inflammation of the periodontium induces the resorption of cementum by cementoclasts and the resorption of the alveolar bone by osteoclasts, which can lead to tooth loss. As the presence of sGC in cementoclasts is unknown, we investigated the α\(_1\)- and β\(_1\)-subunits of sGC in cementoclasts of healthy and inflamed human periodontium using double immunostaining for CD68 and cathepsin K and compared the findings with those of osteoclasts from the same sections. In comparison to cementoclasts in the healthy periodontium, cementoclasts under inflammatory conditions showed a decreased staining intensity for both α\(_1\)- and β\(_1\)-subunits of sGC, indicating reduced protein expression of these subunits. Therefore, pharmacological activation of sGC in inflamed periodontal tissues in an NO- and heme-independent manner could be considered as a new treatment strategy to inhibit cementum resorption.}, language = {en} } @article{RasouliKianiPouyaShabalaetal.2021, author = {Rasouli, Fatemeh and Kiani-Pouya, Ali and Shabala, Lana and Li, Leiting and Tahir, Ayesha and Yu, Min and Hedrich, Rainer and Chen, Zhonghua and Wilson, Richard and Zhang, Heng and Shabala, Sergey}, title = {Salinity effects on guard cell proteome in Chenopodium quinoa}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {1}, issn = {1422-0067}, doi = {10.3390/ijms22010428}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285625}, year = {2021}, abstract = {Epidermal fragments enriched in guard cells (GCs) were isolated from the halophyte quinoa (Chenopodium quinoa Wild.) species, and the response at the proteome level was studied after salinity treatment of 300 mM NaCl for 3 weeks. In total, 2147 proteins were identified, of which 36\% were differentially expressed in response to salinity stress in GCs. Up and downregulated proteins included signaling molecules, enzyme modulators, transcription factors and oxidoreductases. The most abundant proteins induced by salt treatment were desiccation-responsive protein 29B (50-fold), osmotin-like protein OSML13 (13-fold), polycystin-1, lipoxygenase, alpha-toxin, and triacylglycerol lipase (PLAT) domain-containing protein 3-like (eight-fold), and dehydrin early responsive to dehydration (ERD14) (eight-fold). Ten proteins related to the gene ontology term "response to ABA" were upregulated in quinoa GC; this included aspartic protease, phospholipase D and plastid-lipid-associated protein. Additionally, seven proteins in the sucrose-starch pathway were upregulated in the GC in response to salinity stress, and accumulation of tryptophan synthase and L-methionine synthase (enzymes involved in the amino acid biosynthesis) was observed. Exogenous application of sucrose and tryptophan, L-methionine resulted in reduction in stomatal aperture and conductance, which could be advantageous for plants under salt stress. Eight aspartic proteinase proteins were highly upregulated in GCs of quinoa, and exogenous application of pepstatin A (an inhibitor of aspartic proteinase) was accompanied by higher oxidative stress and extremely low stomatal aperture and conductance, suggesting a possible role of aspartic proteinase in mitigating oxidative stress induced by saline conditions.}, language = {en} } @article{HolfelderMulanskySchleeetal.2021, author = {Holfelder, Marc and Mulansky, Lena and Schlee, Winfried and Baumeister, Harald and Schobel, Johannes and Greger, Helmut and Hoff, Andreas and Pryss, R{\"u}diger}, title = {Medical device regulation efforts for mHealth apps during the COVID-19 pandemic — an experience report of Corona Check and Corona Health}, series = {J — Multidisciplinary Scientific Journal}, volume = {4}, journal = {J — Multidisciplinary Scientific Journal}, number = {2}, issn = {2571-8800}, doi = {10.3390/j4020017}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285434}, pages = {206 -- 222}, year = {2021}, abstract = {Within the healthcare environment, mobile health (mHealth) applications (apps) are becoming more and more important. The number of new mHealth apps has risen steadily in the last years. Especially the COVID-19 pandemic has led to an enormous amount of app releases. In most countries, mHealth applications have to be compliant with several regulatory aspects to be declared a "medical app". However, the latest applicable medical device regulation (MDR) does not provide more details on the requirements for mHealth applications. When developing a medical app, it is essential that all contributors in an interdisciplinary team — especially software engineers — are aware of the specific regulatory requirements beforehand. The development process, however, should not be stalled due to integration of the MDR. Therefore, a developing framework that includes these aspects is required to facilitate a reliable and quick development process. The paper at hand introduces the creation of such a framework on the basis of the Corona Health and Corona Check apps. The relevant regulatory guidelines are listed and summarized as a guidance for medical app developments during the pandemic and beyond. In particular, the important stages and challenges faced that emerged during the entire development process are highlighted.}, language = {en} } @article{FoehrenbacherKrahfussZapfetal.2021, author = {F{\"o}hrenbacher, Steffen A. and Krahfuss, Mirjam J. and Zapf, Ludwig and Friedrich, Alexandra and Ignat'ev, Nikolai V. and Finze, Maik and Radius, Udo}, title = {Tris(pentafluoroethyl)difluorophosphorane: a versatile fluoride acceptor for transition metal chemistry}, series = {Chemistry Europe}, volume = {27}, journal = {Chemistry Europe}, number = {10}, doi = {10.1002/chem.202004885}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-256665}, pages = {3504-3516}, year = {2021}, abstract = {Fluoride abstraction from different types of transition metal fluoride complexes [L\(_n\)MF] (M=Ti, Ni, Cu) by the Lewis acid tris(pentafluoroethyl)difluorophosphorane (C\(_2\)F\(_5\))\(_3\)PF\(_2\) to yield cationic transition metal complexes with the tris(pentafluoroethyl)trifluorophosphate counterion (FAP anion, [(C\(_2\)F\(_5\))\(_3\)PF\(_3\)]\(^-\)) is reported. (C\(_2\)F\(_5\))\(_3\)PF\(_2\) reacted with trans-[Ni(iPr\(_2\)Im)\(_2\)(Ar\(^F\))F] (iPr2Im=1,3-diisopropylimidazolin-2-ylidene; Ar\(^F\)=C\(_6\)F\(_5\), 1 a; 4-CF\(_3\)-C\(_6\)F\(_4\), 1 b; 4-C\(_6\)F\(_5\)-C\(_6\)F\(_4\), 1 c) through fluoride transfer to form the complex salts trans-[Ni(iPr\(_2\)Im)\(_2\)(solv)(Ar\(^F\))]FAP (2 a-c[solv]; solv=Et\(_2\)O, CH\(_2\)Cl\(_2\), THF) depending on the reaction medium. In the presence of stronger Lewis bases such as carbenes or PPh\(_3\), solvent coordination was suppressed and the complexes trans-[Ni(iPr\(_2\)Im)\(_2\)(PPh\(_3\))(C\(_6\)F\(_5\))]FAP (trans-2 a[PPh\(_3\)]) and cis-[Ni(iPr\(_2\)Im)\(_2\)(Dipp\(_2\)Im)(C\(_6\)F\(_5\))]FAP (cis-2 a[Dipp\(_2\)Im]) (Dipp\(_2\)Im=1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene) were isolated. Fluoride abstraction from [(Dipp\(_2\)Im)CuF] (3) in CH\(_2\)Cl\(_2\) or 1,2-difluorobenzene led to the isolation of [{(Dipp\(_2\)Im)Cu}\(_2\)]\(^2\)\(^+\)2 FAP\(^-\) (4). Subsequent reaction of 4 with PPh\(_3\) and different carbenes resulted in the complexes [(Dipp\(_2\)Im)Cu(LB)]FAP (5 a-e, LB=Lewis base). In the presence of C6Me6, fluoride transfer afforded [(Dipp\(_2\)Im)Cu(C\(_6\)Me\(_6\))]FAP (5 f), which serves as a source of [(Dipp\(_2\)Im)Cu)]\(^+\). Fluoride abstraction of [Cp\(_2\)TiF\(_2\)] (7) resulted in the formation of dinuclear [FCp\(_2\)Ti(μ-F)TiCp\(_2\)F]FAP (8) (Cp=η\(^5\)-C\(_5\)H\(_5\)) with one terminal fluoride ligand at each titanium atom and an additional bridging fluoride ligand.}, language = {en} } @article{StrilciucVecseiBoeringetal.2021, author = {Strilciuc, Stefan and V{\´e}csei, L{\´a}szl{\´o} and Boering, Dana and Pražnikar, Aleš and Kaut, Oliver and Riederer, Peter and Battistin, Leontino}, title = {Safety of Cerebrolysin for neurorecovery after acute ischemic stroke: a systematic review and meta-analysis of twelve randomized-controlled trials}, series = {Pharmaceuticals}, volume = {14}, journal = {Pharmaceuticals}, number = {12}, issn = {1424-8247}, doi = {10.3390/ph14121297}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252403}, year = {2021}, abstract = {We performed a systematic search and meta-analysis of available literature to determine the safety profile of Cerebrolysin in acute ischemic stroke, filling existing safety information gaps and inconsistent results. We searched EMBASE, PubMed, and Cochrane Databases of Systematic Reviews and Clinical Trials up to the end of February 2021. Data collection and analysis were conducted using methods described in the Cochrane Handbook for Systematic Reviews of Interventions. All safety outcomes were analyzed based on risk ratios (RR) and their 95\% confidence intervals. The meta-analysis pooled 2202 patients from twelve randomized clinical trials, registering non-statistically significant (p > 0.05) differences between Cerebrolysin and placebo throughout main and subgroup analyses. The lowest rate of Serious Adverse Events (SAE), as compared to placebo, was observed for the highest dose of Cerebrolysin (50 mL), highlighting a moderate reduction (RR = 0.6). We observed a tendency of superiority of Cerebrolysin regarding SAE in high dose treatment courses for moderate-severe ischemic stroke, suggesting some effect of the agent against adverse events. This comprehensive safety meta-analysis confirms the safety profile for patients treated with Cerebrolysin after acute ischemic stroke, as compared to placebo.}, language = {en} } @article{DischingerHeckelBischleretal.2021, author = {Dischinger, Ulrich and Heckel, Tobias and Bischler, Thorsten and Hasinger, Julia and K{\"o}nigsrainer, Malina and Schmitt-B{\"o}hrer, Angelika and Otto, Christoph and Fassnacht, Martin and Seyfried, Florian and Hankir, Mohammed Khair}, title = {Roux-en-Y gastric bypass and caloric restriction but not gut hormone-based treatments profoundly impact the hypothalamic transcriptome in obese rats}, series = {Nutrients}, volume = {14}, journal = {Nutrients}, number = {1}, issn = {2072-6643}, doi = {10.3390/nu14010116}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252392}, year = {2021}, abstract = {Background: The hypothalamus is an important brain region for the regulation of energy balance. Roux-en-Y gastric bypass (RYGB) surgery and gut hormone-based treatments are known to reduce body weight, but their effects on hypothalamic gene expression and signaling pathways are poorly studied. Methods: Diet-induced obese male Wistar rats were randomized into the following groups: RYGB, sham operation, sham + body weight-matched (BWM) to the RYGB group, osmotic minipump delivering PYY3-36 (0.1 mg/kg/day), liraglutide s.c. (0.4 mg/kg/day), PYY3-36 + liraglutide, and saline. All groups (except BWM) were kept on a free choice of high- and low-fat diets. Four weeks after interventions, hypothalami were collected for RNA sequencing. Results: While rats in the RYGB, BWM, and PYY3-36 + liraglutide groups had comparable reductions in body weight, only RYGB and BWM treatment had a major impact on hypothalamic gene expression. In these groups, hypothalamic leptin receptor expression as well as the JAK-STAT, PI3K-Akt, and AMPK signaling pathways were upregulated. No significant changes could be detected in PYY3-36 + liraglutide-, liraglutide-, and PYY-treated groups. Conclusions: Despite causing similar body weight changes compared to RYGB and BWM, PYY3-36 + liraglutide treatment does not impact hypothalamic gene expression. Whether this striking difference is favorable or unfavorable to metabolic health in the long term requires further investigation.}, language = {en} } @article{FernandezCastilloCabanaDominguezKappeletal.2021, author = {Fern{\`a}ndez-Castillo, No{\`e}lia and Cabana-Dom{\´i}nguez, Judit and Kappel, Djenifer B. and Torrico, B{\`a}rbara and Weber, Heike and Lesch, Klaus-Peter and Lao, Oscar and Reif, Andreas and Cormand, Bru}, title = {Exploring the contribution to ADHD of genes involved in Mendelian disorders presenting with hyperactivity and/or inattention}, series = {Genes}, volume = {13}, journal = {Genes}, number = {1}, issn = {2073-4425}, doi = {10.3390/genes13010093}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252346}, year = {2021}, abstract = {Attention-deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by hyperactivity, impulsivity, and/or inattention, which are symptoms also observed in many rare genetic disorders. We searched for genes involved in Mendelian disorders presenting with ADHD symptoms in the Online Mendelian Inheritance in Man (OMIM) database, to curate a list of new candidate risk genes for ADHD. We explored the enrichment of functions and pathways in this gene list, and tested whether rare or common variants in these genes are associated with ADHD or with its comorbidities. We identified 139 genes, causal for 137 rare disorders, mainly related to neurodevelopmental and brain function. Most of these Mendelian disorders also present with other psychiatric traits that are often comorbid with ADHD. Using whole exome sequencing (WES) data from 668 ADHD cases, we found rare variants associated with the dimension of the severity of inattention symptoms in three genes: KIF11, WAC, and CRBN. Then, we focused on common variants and identified six genes associated with ADHD (in 19,099 cases and 34,194 controls): MANBA, UQCC2, HIVEP2, FOPX1, KANSL1, and AUH. Furthermore, HIVEP2, FOXP1, and KANSL1 were nominally associated with autism spectrum disorder (ASD) (18,382 cases and 27,969 controls), as well as HIVEP2 with anxiety (7016 cases and 14,475 controls), and FOXP1 with aggression (18,988 individuals), which is in line with the symptomatology of the rare disorders they are responsible for. In conclusion, inspecting Mendelian disorders and the genes responsible for them constitutes a valuable approach for identifying new risk genes and the mechanisms of complex disorders.}, language = {en} } @article{PrakashUnnikrishnanPryssetal.2021, author = {Prakash, Subash and Unnikrishnan, Vishnu and Pryss, R{\"u}diger and Kraft, Robin and Schobel, Johannes and Hannemann, Ronny and Langguth, Berthold and Schlee, Winfried and Spiliopoulou, Myra}, title = {Interactive system for similarity-based inspection and assessment of the well-being of mHealth users}, series = {Entropy}, volume = {23}, journal = {Entropy}, number = {12}, issn = {1099-4300}, doi = {10.3390/e23121695}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252333}, year = {2021}, abstract = {Recent digitization technologies empower mHealth users to conveniently record their Ecological Momentary Assessments (EMA) through web applications, smartphones, and wearable devices. These recordings can help clinicians understand how the users' condition changes, but appropriate learning and visualization mechanisms are required for this purpose. We propose a web-based visual analytics tool, which processes clinical data as well as EMAs that were recorded through a mHealth application. The goals we pursue are (1) to predict the condition of the user in the near and the far future, while also identifying the clinical data that mostly contribute to EMA predictions, (2) to identify users with outlier EMA, and (3) to show to what extent the EMAs of a user are in line with or diverge from those users similar to him/her. We report our findings based on a pilot study on patient empowerment, involving tinnitus patients who recorded EMAs with the mHealth app TinnitusTips. To validate our method, we also derived synthetic data from the same pilot study. Based on this setting, results for different use cases are reported.}, language = {en} } @article{SteinMarufMuelleretal.2021, author = {Stein, Kiera and Maruf, Abdullah Al and M{\"u}ller, Daniel J. and Bishop, Jeffrey R. and Bousman, Chad A.}, title = {Serotonin transporter genetic variation and antidepressant response and tolerability: a systematic review and meta-analysis}, series = {Journal of Personalized Medicine}, volume = {11}, journal = {Journal of Personalized Medicine}, number = {12}, issn = {2075-4426}, doi = {10.3390/jpm11121334}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252294}, year = {2021}, abstract = {Antidepressants are used to treat several psychiatric disorders; however, a large proportion of patients do not respond to their first antidepressant therapy and often experience adverse drug reactions (ADR). A common insertion-deletion polymorphism in the promoter region (5-HTTLPR) of the serotonin transporter (SLC6A4) gene has been frequently investigated for its association with antidepressant outcomes. Here, we performed a systematic review and meta-analysis to assess 5-HTTLPR associations with antidepressants: (1) response in psychiatric disorders other than major depressive disorder (MDD) and (2) tolerability across all psychiatric disorders. Literature searches were performed up to January 2021, yielding 82 studies that met inclusion criteria, and 16 of these studies were included in the meta-analyses. Carriers of the 5-HTTLPR LL or LS genotypes were more likely to respond to antidepressant therapy, compared to the SS carriers in the total and European ancestry-only study populations. Long (L) allele carriers taking selective serotonin reuptake inhibitors (SSRIs) reported fewer ADRs relative to short/short (SS) carriers. European L carriers taking SSRIs had lower ADR rates than S carriers. These results suggest the 5-HTTLPR polymorphism may serve as a marker for antidepressant outcomes in psychiatric disorders and may be particularly relevant to SSRI treatment among individuals of European descent.}, language = {en} } @article{KhareDeslauriersMorinetal.2021, author = {Khare, Siddhartha and Deslauriers, Annie and Morin, Hubert and Latifi, Hooman and Rossi, Sergio}, title = {Comparing time-lapse PhenoCams with satellite observations across the boreal forest of Quebec, Canada}, series = {Remote Sensing}, volume = {14}, journal = {Remote Sensing}, number = {1}, issn = {2072-4292}, doi = {10.3390/rs14010100}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252213}, year = {2021}, abstract = {Intercomparison of satellite-derived vegetation phenology is scarce in remote locations because of the limited coverage area and low temporal resolution of field observations. By their reliable near-ground observations and high-frequency data collection, PhenoCams can be a robust tool for intercomparison of land surface phenology derived from satellites. This study aims to investigate the transition dates of black spruce (Picea mariana (Mill.) B.S.P.) phenology by comparing fortnightly the MODIS normalized difference vegetation index (NDVI) and the enhanced vegetation index (EVI) extracted using the Google Earth Engine (GEE) platform with the daily PhenoCam-based green chromatic coordinate (GCC) index. Data were collected from 2016 to 2019 by PhenoCams installed in six mature stands along a latitudinal gradient of the boreal forests of Quebec, Canada. All time series were fitted by double-logistic functions, and the estimated parameters were compared between NDVI, EVI, and GCC. The onset of GCC occurred in the second week of May, whereas the ending of GCC occurred in the last week of September. We demonstrated that GCC was more correlated with EVI (R\(^2\) from 0.66 to 0.85) than NDVI (R\(^2\) from 0.52 to 0.68). In addition, the onset and ending of phenology were shown to differ by 3.5 and 5.4 days between EVI and GCC, respectively. Larger differences were detected between NDVI and GCC, 17.05 and 26.89 days for the onset and ending, respectively. EVI showed better estimations of the phenological dates than NDVI. This better performance is explained by the higher spectral sensitivity of EVI for multiple canopy leaf layers due to the presence of an additional blue band and an optimized soil factor value. Our study demonstrates that the phenological observations derived from PhenoCam are comparable with the EVI index. We conclude that EVI is more suitable than NDVI to assess phenology in evergreen species of the northern boreal region, where PhenoCam data are not available. The EVI index could be used as a reliable proxy of GCC for monitoring evergreen species phenology in areas with reduced access, or where repeated data collection from remote areas are logistically difficult due to the extreme weather.}, language = {en} } @article{NguemeniHiewKoegleretal.2021, author = {Nguemeni, Carine and Hiew, Shawn and K{\"o}gler, Stefanie and Homola, Gy{\"o}rgy A. and Volkmann, Jens and Zeller, Daniel}, title = {Split-belt training but not cerebellar anodal tDCS improves stability control and reduces risk of fall in patients with multiple sclerosis}, series = {Brain Sciences}, volume = {12}, journal = {Brain Sciences}, number = {1}, issn = {2076-3425}, doi = {10.3390/brainsci12010063}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252179}, year = {2021}, abstract = {The objective of this study was to examine the therapeutic potential of multiple sessions of training on a split-belt treadmill (SBT) combined with cerebellar anodal transcranial direct current stimulation (tDCS) on gait and balance in People with Multiple Sclerosis (PwMS). Twenty-two PwMS received six sessions of anodal (PwMS\(_{real}\), n = 12) or sham (PwMS\(_{sham}\), n = 10) tDCS to the cerebellum prior to performing the locomotor adaptation task on the SBT. To evaluate the effect of the intervention, functional gait assessment (FGA) scores and distance walked in 2 min (2MWT) were measured at the baseline (T0), day 6 (T5), and at the 4-week follow up (T6). Locomotor performance and changes of motor outcomes were similar in PwMS\(_{real}\) and PwMS\(_{sham}\) independently from tDCS mode applied to the cerebellum (anodal vs. sham, on FGA, p = 0.23; and 2MWT, p = 0.49). When the data were pooled across the groups to investigate the effects of multiple sessions of SBT training alone, significant improvement of gait and balance was found on T5 and T6, respectively, relative to baseline (FGA, p < 0.001 for both time points). The FGA change at T6 was significantly higher than at T5 (p = 0.01) underlining a long-lasting improvement. An improvement of the distance walked during the 2MWT was also observed on T5 and T6 relative to T0 (p = 0.002). Multiple sessions of SBT training resulted in a lasting improvement of gait stability and endurance, thus potentially reducing the risk of fall as measured by FGA and 2MWT. Application of cerebellar tDCS during SBT walking had no additional effect on locomotor outcomes.}, language = {en} } @article{SchuemannGrossBaueretal.2021, author = {Sch{\"u}mann, Franziska Lea and Groß, Elisabeth and Bauer, Marcus and Rohde, Christian and Sandmann, Sarah and Terziev, Denis and M{\"u}ller, Lutz P. and Posern, Guido and Wienke, Andreas and Fend, Falko and Hansmann, Martin-Leo and Klapper, Wolfram and Rosenwald, Andreas and Stein, Harald and Dugas, Martin and M{\"u}ller-Tidow, Carsten and Wickenhauser, Claudia and Binder, Mascha and Weber, Thomas}, title = {Divergent effects of EZH1 and EZH2 protein expression on the prognosis of patients with T-cell lymphomas}, series = {Biomedicines}, volume = {9}, journal = {Biomedicines}, number = {12}, issn = {2227-9059}, doi = {10.3390/biomedicines9121842}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252155}, year = {2021}, abstract = {T-cell lymphomas are highly heterogeneous and their prognosis is poor under the currently available therapies. Enhancers of zeste homologue 1 and 2 (EZH1/2) are histone H3 lysine-27 trimethyltransferases (H3K27me3). Despite the rapid development of new drugs inhibiting EZH2 and/or EZH1, the molecular interplay of these proteins and the impact on disease progression and prognosis of patients with T-cell lymphomas remains insufficiently understood. In this study, EZH1/2 mutation status was evaluated in 33 monomorphic epitheliotropic intestinal T-cell lymphomas by next generation sequencing and EZH1/2 and H3K27me3 protein expression levels were detected by immunohistochemistry in 46 T-cell lymphomas. Correlations with clinicopathologic features were analyzed and survival curves generated. No EZH1 mutations and one (3\%) EZH2 missense mutation were identified. In univariable analysis, high EZH1 expression was associated with an improved overall survival (OS) and progression-free survival (PFS) whereas high EZH2 and H3K27me3 expression were associated with poorer OS and PFS. Multivariable analysis revealed EZH1 (hazard ratio (HR) = 0.183; 95\% confidence interval (CI): 0.044-0.767; p = 0.020;) and EZH2 (HR = 8.245; 95\% CI: 1.898-35.826; p = 0.005) to be independent, divergent prognostic markers for OS. In conclusion, EZH1/2 protein expression had opposing effects on the prognosis of T-cell lymphoma patients.}, language = {en} } @article{LibreSeisslerGuerreroetal.2021, author = {Libre, Camille and Seissler, Tanja and Guerrero, Santiago and Batisse, Julien and Verriez, C{\´e}dric and Stupfler, Benjamin and Gilmer, Orian and Cabrera-Rodriguez, Romina and Weber, Melanie M. and Valenzuela-Fernandez, Agustin and Cimarelli, Andrea and Etienne, Lucie and Marquet, Roland and Paillart, Jean-Christophe}, title = {A conserved uORF regulates APOBEC3G translation and is targeted by HIV-1 Vif protein to repress the antiviral factor}, series = {Biomedicines}, volume = {10}, journal = {Biomedicines}, number = {1}, issn = {2227-9059}, doi = {10.3390/biomedicines10010013}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252147}, year = {2021}, abstract = {The HIV-1 Vif protein is essential for viral fitness and pathogenicity. Vif decreases expression of cellular restriction factors APOBEC3G (A3G), A3F, A3D and A3H, which inhibit HIV-1 replication by inducing hypermutation during reverse transcription. Vif counteracts A3G at several levels (transcription, translation, and protein degradation) that altogether reduce the levels of A3G in cells and prevent its incorporation into viral particles. How Vif affects A3G translation remains unclear. Here, we uncovered the importance of a short conserved uORF (upstream ORF) located within two critical stem-loop structures of the 5′ untranslated region (5′-UTR) of A3G mRNA for this process. A3G translation occurs through a combination of leaky scanning and translation re-initiation and the presence of an intact uORF decreases the extent of global A3G translation under normal conditions. Interestingly, the uORF is also absolutely required for Vif-mediated translation inhibition and redirection of A3G mRNA into stress granules. Overall, we discovered that A3G translation is regulated by a small uORF conserved in the human population and that Vif uses this specific feature to repress its translation.}, language = {en} } @article{BrosterReixFlorimondCayreletal.2021, author = {Broster Reix, Christine E. and Florimond, C{\´e}lia and Cayrel, Anne and Mailh{\´e}, Am{\´e}lie and Agnero-Rigot, Corentin and Landrein, Nicolas and Dacheux, Denis and Havlicek, Katharina and Bonhivers, M{\´e}lanie and Morriswood, Brooke and Robinson, Derrick R.}, title = {Bhalin, an essential cytoskeleton-associated protein of Trypanosoma brucei linking TbBILBO1 of the flagellar pocket collar with the hook complex}, series = {Microorganisms}, volume = {9}, journal = {Microorganisms}, number = {11}, issn = {2076-2607}, doi = {10.3390/microorganisms9112334}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250301}, year = {2021}, abstract = {Background: In most trypanosomes, endo and exocytosis only occur at a unique organelle called the flagellar pocket (FP) and the flagellum exits the cell via the FP. Investigations of essential cytoskeleton-associated structures located at this site have revealed a number of essential proteins. The protein TbBILBO1 is located at the neck of the FP in a structure called the flagellar pocket collar (FPC) and is essential for biogenesis of the FPC and parasite survival. TbMORN1 is a protein that is present on a closely linked structure called the hook complex (HC) and is located anterior to and overlapping the collar. TbMORN1 is essential in the bloodstream form of T. brucei. We now describe the location and function of BHALIN, an essential, new FPC-HC protein. Methodology/Principal Findings: Here, we show that a newly characterised protein, BHALIN (BILBO1 Hook Associated LINker protein), is localised to both the FPC and HC and has a TbBILBO1 binding domain, which was confirmed in vitro. Knockdown of BHALIN by RNAi in the bloodstream form parasites led to cell death, indicating an essential role in cell viability. Conclusions/Significance: Our results demonstrate the essential role of a newly characterised hook complex protein, BHALIN, that influences flagellar pocket organisation and function in bloodstream form T. brucei parasites.}, language = {en} } @article{RoellRameshaLinketal.2021, author = {R{\"o}ll, Alexander and Ramesha, Mundre N. and Link, Roman M. and Hertel, Dietrich and Schuldt, Bernhard and Patil, Shekhargouda L. and H{\"o}lscher, Dirk}, title = {Water availability controls the biomass increment of Melia dubia in South India}, series = {Forests}, volume = {12}, journal = {Forests}, number = {12}, issn = {1999-4907}, doi = {10.3390/f12121675}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250150}, year = {2021}, abstract = {Farmland tree cultivation is considered an important option for enhancing wood production. In South India, the native leaf-deciduous tree species Melia dubia is popular for short-rotation plantations. Across a rainfall gradient from 420 to 2170 mm year\(^{-1}\), we studied 186 farmland woodlots between one and nine years in age. The objectives were to identify the main factors controlling aboveground biomass (AGB) and growth rates. A power-law growth model predicts an average stand-level AGB of 93.8 Mg ha\(^{-1}\) for nine-year-old woodlots. The resulting average annual AGB increment over the length of the rotation cycle is 10.4 Mg ha\(^{-1}\) year\(^{-1}\), which falls within the range reported for other tropical tree plantations. When expressing the parameters of the growth model as functions of management, climate and soil variables, it explains 65\% of the variance in AGB. The results indicate that water availability is the main driver of the growth of M. dubia. Compared to the effects of water availability, the effects of soil nutrients are 26\% to 60\% smaller. We conclude that because of its high biomass accumulation rates in farm forestry, M. dubia is a promising candidate for short-rotation plantations in South India and beyond.}, language = {en} } @article{WelterWagnerFurtwaengleretal.2021, author = {Welter, Nils and Wagner, Angelo and Furtw{\"a}ngler, Rhoikos and Melchior, Patrick and Kager, Leo and Vokuhl, Christian and Schenk, Jens-Peter and Meier, Clemens Magnus and Siemer, Stefan and Gessler, Manfred and Graf, Norbert}, title = {Correction: Welter et al. Characteristics of nephroblastoma/nephroblastomatosis in children with a clinically reported underlying malformation or cancer predisposition syndrome. Cancers 2021, 13, 5016}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {22}, issn = {2072-6694}, doi = {10.3390/cancers13225743}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250135}, year = {2021}, abstract = {In the original article [1] there was a mistake in Table 2 as published. Table 2 contains wrong percentages in lines Bilateral disease and Patients with CPS or GU. For this reason the table should be replaced with the correct one as shown below.}, language = {en} } @article{WobserRothAppenzelleretal.2021, author = {Wobser, Marion and Roth, Sabine and Appenzeller, Silke and Houben, Roland and Schrama, David and Goebeler, Matthias and Geissinger, Eva and Rosenwald, Andreas and Maurus, Katja}, title = {Targeted deep sequencing of mycosis fungoides reveals intracellular signaling pathways associated with aggressiveness and large cell transformation}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {21}, issn = {2072-6694}, doi = {10.3390/cancers13215512}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250094}, year = {2021}, abstract = {Introduction: Large-cell transformation (LCT) of mycosis fungoides (MF) has been associated with a higher risk of relapse and progression and, consequently, restricted prognosis. Its molecular pathogenesis has not been elucidated yet. Materials and Methods: In order to address molecular mechanisms of LCT, we performed hybrid capture panel-based sequencing of skin biopsies from 10 patients suffering from MF with LCT versus 17 patients without LCT including follow-up biopsies during clinical course, respectively (51 samples in total). The analyzed patients were attributed to three different groups based on the presence of LCT and clinical behavior. Results: While indolent MF cases without LCT did not show pathogenic driver mutations, a high rate of oncogenic alterations was detected in patients with LCT and aggressive clinical courses. Various genes of different oncogenic signaling pathways, including the MAPK and JAK-STAT signaling pathways, as well as epigenetic modifiers were affected. A high inter-individual and distinctive intra-individual mutation diversity was observed. Oncogenic RAS mutations were exclusively detected in patients with LCT. Conclusion: Our data demonstrate that LCT transition of MF is associated with increased frequency of somatic mutations in cancer-associated genes. In particular, the activation of RAS signaling — together with epigenetic dysregulation — may crucially contribute to the molecular pathogenesis of the LCT phenotype, thus conveying its adverse clinical behavior.}, language = {en} } @article{StrekalovaVeniaminovaSvirinetal.2021, author = {Strekalova, Tatyana and Veniaminova, Ekaterina and Svirin, Evgeniy and Kopeikina, Ekaterina and Veremeyko, Tatyana and Yung, Amanda W. Y. and Proshin, Andrey and Tan, Shawn Zheng Kai and Khairuddin, Sharafuddin and Lim, Lee Wei and Lesch, Klaus-Peter and Walitza, Susanne and Anthony, Daniel C. and Ponomarev, Eugene D.}, title = {Sex-specific ADHD-like behaviour, altered metabolic functions, and altered EEG activity in sialyltransferase ST3GAL5-deficient mice}, series = {Biomolecules}, volume = {11}, journal = {Biomolecules}, number = {12}, issn = {2218-273X}, doi = {10.3390/biom11121759}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250071}, year = {2021}, abstract = {A deficiency in GM3-derived gangliosides, resulting from a lack of lactosylceramide-alpha-2,3-sialyltransferase (ST3GAL5), leads to severe neuropathology, including epilepsy and metabolic abnormalities. Disruption of ganglioside production by this enzyme may also have a role in the development of neuropsychiatric disorders. ST3Gal5 knock-out (St3gal5\(^{-/-}\)) mice lack a-, b-, and c-series gangliosides, but exhibit no overt neuropathology, possibly owing to the production of compensatory 0-series glycosphingolipids. Here, we sought to investigate the possibility that St3gal5\(^{-/-}\) mice might exhibit attention-deficit/hyperactivity disorder (ADHD)-like behaviours. In addition, we evaluated potential metabolic and electroencephalogram (EEG) abnormalities. St3gal5\(^{-/-}\) mice were subjected to behavioural testing, glucose tolerance tests, and the levels of expression of brain and peripheral A and B isoforms of the insulin receptor (IR) were measured. We found that St3gal5\(^{-/-}\) mice exhibit locomotor hyperactivity, impulsivity, neophobia, and anxiety-like behavior. The genotype also altered blood glucose levels and glucose tolerance. A sex bias was consistently found in relation to body mass and peripheral IR expression. Analysis of the EEG revealed an increase in amplitude in St3gal5\(^{-/-}\) mice. Together, St3gal5\(^{-/-}\) mice exhibit ADHD-like behaviours, altered metabolic and EEG measures providing a useful platform for better understanding of the contribution of brain gangliosides to ADHD and associated comorbidities.}, language = {en} } @article{JustSchollBoehmeetal.2021, author = {Just, Katja S. and Scholl, Catharina and Boehme, Miriam and Kastenm{\"u}ller, Kathrin and Just, Johannes M. and Bleckwenn, Markus and Holdenrieder, Stefan and Meier, Florian and Weckbecker, Klaus and Stingl, Julia C.}, title = {Individualized versus standardized risk assessment in patients at high risk for adverse drug reactions (the IDrug randomized controlled trial) - never change a running system?}, series = {Pharmaceuticals}, volume = {14}, journal = {Pharmaceuticals}, number = {10}, issn = {1424-8247}, doi = {10.3390/ph14101056}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248557}, year = {2021}, abstract = {The aim of this study was to compare effects of an individualized with a standardized risk assessment for adverse drug reactions to improve drug treatment with antithrombotic drugs in older adults. A randomized controlled trial was conducted in general practitioner (GP) offices. Patients aged 60 years and older, multi-morbid, taking antithrombotic drugs and at least one additional drug continuously were randomized to individualized and standardized risk assessment groups. Patients were followed up for nine months. A composite endpoint defined as at least one bleeding, thromboembolic event or death reported via a trigger list was used. Odds ratios (OR) and 95\% confidence intervals (CI) were calculated. In total, N = 340 patients were enrolled from 43 GP offices. Patients in the individualized risk assessment group met the composite endpoint more often than in the standardized group (OR 1.63 [95\%CI 1.02-2.63]) with multiple adjustments. The OR was higher in patients on phenprocoumon treatment (OR 1.99 [95\%CI 1.05-3.76]), and not significant on DOAC treatment (OR 1.52 [95\%CI 0.63-3.69]). Pharmacogenenetic variants of CYP2C9, 2C19 and VKORC1 were not observed to be associated with the composite endpoint. The results of this study may indicate that the time point for implementing individualized risk assessments is of importance.}, language = {en} } @article{RiedmeierDecarolisHaubitzetal.2021, author = {Riedmeier, Maria and Decarolis, Boris and Haubitz, Imme and M{\"u}ller, Sophie and Uttinger, Konstantin and B{\"o}rner, Kevin and Reibetanz, Joachim and Wiegering, Armin and H{\"a}rtel, Christoph and Schlegel, Paul-Gerhardt and Fassnacht, Martin and Wiegering, Verena}, title = {Adrenocortical carcinoma in childhood: a systematic review}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {21}, issn = {2072-6694}, doi = {10.3390/cancers13215266}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248507}, year = {2021}, abstract = {Adrenocortical tumors are rare in children. This systematic review summarizes the published evidence on pediatric adrenocortical carcinoma (ACC) to provide a basis for a better understanding of the disease, investigate new molecular biomarkers and therapeutic targets, and define which patients may benefit from a more aggressive therapeutic approach. We included 137 studies with 3680 ACC patients (~65\% female) in our analysis. We found no randomized controlled trials, so this review mainly reflects retrospective data. Due to a specific mutation in the TP53 gene in ~80\% of Brazilian patients, that cohort was analyzed separately from series from other countries. Hormone analysis was described in 2569 of the 2874 patients (89\%). Most patients were diagnosed with localized disease, whereas 23\% had metastasis at primary diagnosis. Only 72\% of the patients achieved complete resection. In 334 children (23\%), recurrent disease was reported: 81\% — local recurrence, 19\% (n = 65) — distant metastases at relapse. Patients < 4 years old had a different distribution of tumor stages and hormone activity and better overall survival (p < 0.001). Although therapeutic approaches are typically multimodal, no consensus is available on effective standard treatments for advanced ACC. Thus, knowledge regarding pediatric ACC is still scarce and international prospective studies are needed to implement standardized clinical stratifications and risk-adapted therapeutic strategies.}, language = {en} } @article{SchlevogtBoekerMaussetal.2021, author = {Schlevogt, Bernhard and Boeker, Klaus H. W. and Mauss, Stefan and Klinker, Hartwig and Heyne, Renate and Link, Ralph and Simon, Karl-Georg and Sarrazin, Christoph and Serfert, Yvonne and Manns, Michael P. and Wedemeyer, Heiner}, title = {Weight gain after interferon-free treatment of chronic hepatitis C — results from the German Hepatitis C-Registry (DHC-R)}, series = {Biomedicines}, volume = {9}, journal = {Biomedicines}, number = {10}, issn = {2227-9059}, doi = {10.3390/biomedicines9101495}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248476}, year = {2021}, abstract = {Chronic hepatitis C can be treated very effectively with direct-acting antivirals (DAA) with only minor side effects compared to an interferon-containing treatment regimen. The significance of metabolic comorbidities after HCV cure is not well defined. This study aims to investigate short- and long-term weight change of patients receiving interferon-free antiviral treatment for chronic hepatitis C. The German Hepatitis C-registry (DHC-R) is a national multicenter real-world cohort. A total of 5111 patients were followed prospectively after DAA treatment for up to 3 years. Weight change compared to baseline was analyzed at end of treatment and at years 1, 2, and 3 after completion of antiviral therapy. Regression analysis was performed to identify baseline predictors for weight change. While there was no relevant mean weight change (-0.2 kg, SD 4.3 kg) at the end of antiviral treatment, weight started to increase during long-term follow-up reaching +1.7 kg (SD 8.0 kg, p < 0.001) compared to baseline at 3 years (follow-up year 3, FU3) after completion of antiviral therapy. 48\%, 31\%, and 22\% of patients had a weight gain greater than 1, 3, and 5 kg at FU3, respectively. During follow-up, a body mass index (BMI) <30 proved to be the only consistent predictor for weight gain. DAA treatment is followed by a substantial weight gain (+3 kg or more) in one-third of the patients during long-term follow-up. Non-obese patients seemed to be most vulnerable to weight gain. The body compartment involved in weight gain as well as the mechanism of weight gain remain to be elucidated.}, language = {en} } @article{BaumgaertnerKernLevenetal.2021, author = {Baumg{\"a}rtner, Ingrid and Kern, Manfred and Leven, Karl-Heinz and Toepfer, Regina}, title = {Mittelalter erschließen}, series = {Das Mittelalter}, volume = {26}, journal = {Das Mittelalter}, number = {1}, issn = {0949-0345}, doi = {0.17885/heiup.1mial.2021.1.24310}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-299110}, pages = {68-86}, year = {2021}, abstract = {Research communication has been gaining public attention in recent years. Therefore, medievalists also need to focus on the transfer of their research topics to the public both within and outside the university. Based on current political demands calling for a change in communication culture, the article first of all deals theoretically with two different concepts of research communication, by distinguishing between forms of translation and those of popularization. Numerous public events, exhibitions, and cooperative projects with cities, schools, adult education centres, museums, and other educational institutions show that knowledge about the Middle Ages has been trans-mitted to interested laypersons for a long time. The authors see a particular challenge in the alterity of medieval culture, which at the same time provides an excellent opportunity for transferring research findings into society. The fascination with medieval materiality facilitates the transfer of knowledge by those disciplines that work with concrete objects, addressing issues of visuality and aesthetic experience. The article pinpoints conditions, strategies, and perspectives of successful research communication in medieval studies, and when focussing on cur-rent topics, the authors refer to concrete occasions and regional examples, showing why medieval research is still relevant today.}, subject = {Wissenschaftskommunikation}, language = {de} } @article{LiangRiosMiguelJaricketal.2021, author = {Liang, Chunguang and Rios-Miguel, Ana B. and Jarick, Marcel and Neurgaonkar, Priya and Girard, Myriam and Fran{\c{c}}ois, Patrice and Schrenzel, Jacques and Ibrahim, Eslam S. and Ohlsen, Knut and Dandekar, Thomas}, title = {Staphylococcus aureus transcriptome data and metabolic modelling investigate the interplay of Ser/Thr kinase PknB, its phosphatase Stp, the glmR/yvcK regulon and the cdaA operon for metabolic adaptation}, series = {Microorganisms}, volume = {9}, journal = {Microorganisms}, number = {10}, issn = {2076-2607}, doi = {10.3390/microorganisms9102148}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248459}, year = {2021}, abstract = {Serine/threonine kinase PknB and its corresponding phosphatase Stp are important regulators of many cell functions in the pathogen S. aureus. Genome-scale gene expression data of S. aureus strain NewHG (sigB\(^+\)) elucidated their effect on physiological functions. Moreover, metabolic modelling from these data inferred metabolic adaptations. We compared wild-type to deletion strains lacking pknB, stp or both. Ser/Thr phosphorylation of target proteins by PknB switched amino acid catabolism off and gluconeogenesis on to provide the cell with sufficient components. We revealed a significant impact of PknB and Stp on peptidoglycan, nucleotide and aromatic amino acid synthesis, as well as catabolism involving aspartate transaminase. Moreover, pyrimidine synthesis was dramatically impaired by stp deletion but only slightly by functional loss of PknB. In double knockouts, higher activity concerned genes involved in peptidoglycan, purine and aromatic amino acid synthesis from glucose but lower activity of pyrimidine synthesis from glucose compared to the wild type. A second transcriptome dataset from S. aureus NCTC 8325 (sigB\(^-\)) validated the predictions. For this metabolic adaptation, PknB was found to interact with CdaA and the yvcK/glmR regulon. The involved GlmR structure and the GlmS riboswitch were modelled. Furthermore, PknB phosphorylation lowered the expression of many virulence factors, and the study shed light on S. aureus infection processes.}, language = {en} } @article{WielandStrisselSchorleetal.2021, author = {Wieland, Annalena and Strissel, Pamela L. and Schorle, Hannah and Bakirci, Ezgi and Janzen, Dieter and Beckmann, Matthias W. and Eckstein, Markus and Dalton, Paul D. and Strick, Reiner}, title = {Brain and breast cancer cells with PTEN loss of function reveal enhanced durotaxis and RHOB dependent amoeboid migration utilizing 3D scaffolds and aligned microfiber tracts}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {20}, issn = {2072-6694}, doi = {10.3390/cancers13205144}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248443}, year = {2021}, abstract = {Background: Glioblastoma multiforme (GBM) and metastatic triple-negative breast cancer (TNBC) with PTEN mutations often lead to brain dissemination with poor patient outcome, thus new therapeutic targets are needed. To understand signaling, controlling the dynamics and mechanics of brain tumor cell migration, we implemented GBM and TNBC cell lines and designed 3D aligned microfibers and scaffolds mimicking brain structures. Methods: 3D microfibers and scaffolds were printed using melt electrowriting. GBM and TNBC cell lines with opposing PTEN genotypes were analyzed with RHO-ROCK-PTEN inhibitors and PTEN rescue using live-cell imaging. RNA-sequencing and qPCR of tumor cells in 3D with microfibers were performed, while scanning electron microscopy and confocal microscopy addressed cell morphology. Results: In contrast to the PTEN wildtype, GBM and TNBC cells with PTEN loss of function yielded enhanced durotaxis, topotaxis, adhesion, amoeboid migration on 3D microfibers and significant high RHOB expression. Functional studies concerning RHOB-ROCK-PTEN signaling confirmed the essential role for the above cellular processes. Conclusions: This study demonstrates a significant role of the PTEN genotype and RHOB expression for durotaxis, adhesion and migration dependent on 3D. GBM and TNBC cells with PTEN loss of function have an affinity for stiff brain structures promoting metastasis. 3D microfibers represent an important tool to model brain metastasizing tumor cells, where RHO-inhibitors could play an essential role for improved therapy.}, language = {en} } @article{WelterWagnerFurtwaengleretal.2021, author = {Welter, Nils and Wagner, Angelo and Furtw{\"a}ngler, Rhoikos and Melchior, Patrick and Kager, Leo and Vokuhl, Christian and Schenk, Jens-Peter and Meier, Clemens Magnus and Siemer, Stefan and Gessler, Manfred and Graf, Norbert}, title = {Characteristics of nephroblastoma/nephroblastomatosis in children with a clinically reported underlying malformation or cancer predisposition syndrome}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {19}, issn = {2072-6694}, doi = {10.3390/cancers13195016}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248434}, year = {2021}, abstract = {(1) Background: about 10\% of Wilms Tumor (WT) patients have a malformation or cancer predisposition syndrome (CPS) with causative germline genetic or epigenetic variants. Knowledge on CPS is essential for genetic counselling. (2) Methods: this retrospective analysis focused on 2927 consecutive patients with WTs registered between 1989 and 2017 in the SIOP/GPOH studies. (3) Results: Genitourinary malformations (GU, N = 66, 2.3\%), Beckwith-Wiedemann spectrum (BWS, N = 32, 1.1\%), isolated hemihypertrophy (IHH, N = 29, 1.0\%), Denys-Drash syndrome (DDS, N = 24, 0.8\%) and WAGR syndrome (N = 20, 0.7\%) were reported most frequently. Compared to others, these patients were younger at WT diagnosis (median age 24.5 months vs. 39.0 months), had smaller tumors (349.4 mL vs. 487.5 mL), less often metastasis (8.2\% vs. 18\%), but more often nephroblastomatosis (12.9\% vs. 1.9\%). WT with IHH was associated with blastemal WT and DDS with stromal subtype. Bilateral WTs were common in WAGR (30\%), DDS (29\%) and BWS (31\%). Chemotherapy induced reduction in tumor volume was poor in DDS (0.4\% increase) and favorable in BWS (86.9\% reduction). The event-free survival (EFS) of patients with BWS was significantly (p = 0.002) worse than in others. (4) Conclusions: CPS should be considered in WTs with specific clinical features resulting in referral to a geneticist. Their outcome was not always favorable.}, language = {en} } @article{KhareLatifiKhare2021, author = {Khare, Suyash and Latifi, Hooman and Khare, Siddhartha}, title = {Vegetation growth analysis of UNESCO World Heritage Hyrcanian forests using multi-sensor optical remote sensing data}, series = {Remote Sensing}, volume = {13}, journal = {Remote Sensing}, number = {19}, issn = {2072-4292}, doi = {10.3390/rs13193965}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248398}, year = {2021}, abstract = {Freely available satellite data at Google Earth Engine (GEE) cloud platform enables vegetation phenology analysis across different scales very efficiently. We evaluated seasonal and annual phenology of the old-growth Hyrcanian forests (HF) of northern Iran covering an area of ca. 1.9 million ha, and also focused on 15 UNESCO World Heritage Sites. We extracted bi-weekly MODIS-NDVI between 2017 and 2020 in GEE, which was used to identify the range of NDVI between two temporal stages. Then, changes in phenology and growth were analyzed by Sentinel 2-derived Temporal Normalized Phenology Index. We modelled between seasonal phenology and growth by additionally considering elevation, surface temperature, and monthly precipitation. Results indicated considerable difference in onset of forests along the longitudinal gradient of the HF. Faster growth was observed in low- and uplands of the western zone, whereas it was lower in both the mid-elevations and the western outskirts. Longitudinal range was a major driver of vegetation growth, to which environmental factors also differently but significantly contributed (p < 0.0001) along the west-east gradient. Our study developed at GEE provides a benchmark to examine the effects of environmental parameters on the vegetation growth of HF, which cover mountainous areas with partly no or limited accessibility.}, language = {en} } @article{MonteagudoMartinezLeandroGarciaetal.2021, author = {Monteagudo, Mar{\´i}a and Mart{\´i}nez, Paula and Leandro-Garc{\´i}a, Luis J. and Mart{\´i}nez-Montes, {\´A}ngel M. and Calsina, Bruna and Pulgar{\´i}n-Alfaro, Marta and D{\´i}az-Talavera, Alberto and Mellid, Sara and Let{\´o}n, Roc{\´i}o and Gil, Eduardo and P{\´e}rez-Mart{\´i}nez, Manuel and Meg{\´i}as, Diego and Torres-Ruiz, Ra{\´u}l and Rodriguez-Perales, Sandra and Gonz{\´a}lez, Patricia and Caleiras, Eduardo and Jim{\´e}nez-Villa, Scherezade and Roncador, Giovanna and {\´A}lvarez-Escol{\´a}, Cristina and Regojo, Rita M. and Calatayud, Mar{\´i}a and Guadalix, Sonsoles and Curr{\´a}s-Freixes, Maria and Rapizzi, Elena and Canu, Letizia and N{\"o}lting, Svenja and Remde, Hanna and Fassnacht, Martin and Bechmann, Nicole and Eisenhofer, Graeme and Mannelli, Massimo and Beuschlein, Felix and Quinkler, Marcus and Rodr{\´i}guez-Antona, Cristina and Casc{\´o}n, Alberto and Blasco, Mar{\´i}a A. and Montero-Conde, Cristina and Robledo, Mercedes}, title = {Analysis of telomere maintenance related genes reveals NOP10 as a new metastatic-risk marker in pheochromocytoma/paraganglioma}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {19}, issn = {2072-6694}, doi = {10.3390/cancers13194758}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246321}, year = {2021}, abstract = {One of the main problems we face with PPGL is the lack of molecular markers capable of predicting the development of metastases in patients. Telomere-related genes, such as TERT and ATRX, have been recently described in PPGL, supporting the association between the activation of immortalization mechanisms and disease progression. However, the contribution of other genes involving telomere preservation machinery has not been previously investigated. In this work, we aimed to analyze the prognostic value of a comprehensive set of genes involved in telomere maintenance. For this study, we collected 165 PPGL samples (97 non-metastatic/63 metastatic), genetically characterized, in which the expression of 29 genes of interest was studied by NGS. Three of the 29 genes studied, TERT, ATRX and NOP10, showed differential expression between metastatic and non-metastatic cases, and alterations in these genes were associated with a shorter time to progression, independent of SDHB-status. We studied telomere length by Q-FISH in patient samples and in an in vitro model. NOP10 overexpressing tumors displayed an intermediate-length telomere phenotype without ALT, and in vitro results suggest that NOP10 has a role in telomerase-dependent telomere maintenance. We also propose the implementation of NOP10 IHC to better stratify PPGL patients.}, language = {en} } @article{GuptaSrivastavaOsmanogluetal.2021, author = {Gupta, Shishir K. and Srivastava, Mugdha and Osmanoglu, {\"O}zge and Xu, Zhuofei and Brakhage, Axel A. and Dandekar, Thomas}, title = {Aspergillus fumigatus versus genus Aspergillus: conservation, adaptive evolution and specific virulence genes}, series = {Microorganisms}, volume = {9}, journal = {Microorganisms}, number = {10}, issn = {2076-2607}, doi = {10.3390/microorganisms9102014}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246318}, year = {2021}, abstract = {Aspergillus is an important fungal genus containing economically important species, as well as pathogenic species of animals and plants. Using eighteen fungal species of the genus Aspergillus, we conducted a comprehensive investigation of conserved genes and their evolution. This also allows us to investigate the selection pressure driving the adaptive evolution in the pathogenic species A. fumigatus. Among single-copy orthologs (SCOs) for A. fumigatus and the closely related species A. fischeri, we identified 122 versus 50 positively selected genes (PSGs), respectively. Moreover, twenty conserved genes of unknown function were established to be positively selected and thus important for adaption. A. fumigatus PSGs interacting with human host proteins show over-representation of adaptive, symbiosis-related, immunomodulatory and virulence-related pathways, such as the TGF-β pathway, insulin receptor signaling, IL1 pathway and interfering with phagosomal GTPase signaling. Additionally, among the virulence factor coding genes, secretory and membrane protein-coding genes in multi-copy gene families, 212 genes underwent positive selection and also suggest increased adaptation, such as fungal immune evasion mechanisms (aspf2), siderophore biosynthesis (sidD), fumarylalanine production (sidE), stress tolerance (atfA) and thermotolerance (sodA). These genes presumably contribute to host adaptation strategies. Genes for the biosynthesis of gliotoxin are shared among all the close relatives of A. fumigatus as an ancient defense mechanism. Positive selection plays a crucial role in the adaptive evolution of A. fumigatus. The genome-wide profile of PSGs provides valuable targets for further research on the mechanisms of immune evasion, antimycotic targeting and understanding fundamental virulence processes.}, language = {en} } @article{KurotschkaTiedemannWolfetal.2021, author = {Kurotschka, Peter Konstantin and Tiedemann, Elena and Wolf, Dominik and Thier, Nicola and Forster, Johannes and Liese, Johannes G. and Gagyor, Ildiko}, title = {Management of common infections in German primary care: a cross-sectional survey of knowledge and confidence among General Practitioners and outpatient pediatricians}, series = {Antibiotics}, volume = {10}, journal = {Antibiotics}, number = {9}, issn = {2079-6382}, doi = {10.3390/antibiotics10091131}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246272}, year = {2021}, abstract = {Outpatient antibiotic use is closely related to antimicrobial resistance and in Germany, almost 70\% of antibiotic prescriptions in human health are issued by primary care physicians (PCPs). The aim of this study was to explore PCPs, namely General Practitioners' (GPs) and outpatient pediatricians' (PDs) knowledge of guideline recommendations on rational antimicrobial treatment, the determinants of confidence in treatment decisions and the perceived need for training in this topic in a large sample of PCPs from southern Germany. Out of 3753 reachable PCPs, 1311 completed the survey (overall response rate = 34.9\%). Knowledge of guideline recommendations and perceived confidence in making treatment decisions were high in both GPs and PDs. The two highest rated influencing factors on prescribing decisions were reported to be guideline recommendations and own clinical experiences, hence patients' demands and expectations were judged as not influencing treatment decisions. The majority of physicians declared to have attended at least one specific training course on antibiotic use, yet almost all the participating PCPs declared to need more training on this topic. More studies are needed to explore how consultation-related and context-specific factors could influence antibiotic prescriptions in general and pediatric primary care in Germany beyond knowledge. Moreover, efforts should be undertaken to explore the training needs of PCPs in Germany, as this would serve the development of evidence-based educational interventions targeted to the improvement of antibiotic prescribing decisions rather than being focused solely on knowledge of guidelines.}, language = {en} } @article{HeilingKnuttiScherretal.2021, author = {Heiling, Sven and Knutti, Nadine and Scherr, Franziska and Geiger, J{\"o}rg and Weikert, Juliane and Rose, Michael and Jahns, Roland and Ceglarek, Uta and Scherag, Andr{\´e} and Kiehntopf, Michael}, title = {Metabolite ratios as quality indicators for pre-analytical variation in serum and EDTA plasma}, series = {Metabolites}, volume = {11}, journal = {Metabolites}, number = {9}, issn = {2218-1989}, doi = {10.3390/metabo11090638}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246261}, year = {2021}, abstract = {In clinical diagnostics and research, blood samples are one of the most frequently used materials. Nevertheless, exploring the chemical composition of human plasma and serum is challenging due to the highly dynamic influence of pre-analytical variation. A prominent example is the variability in pre-centrifugation delay (time-to-centrifugation; TTC). Quality indicators (QI) reflecting sample TTC are of utmost importance in assessing sample history and resulting sample quality, which is essential for accurate diagnostics and conclusive, reproducible research. In the present study, we subjected human blood to varying TTCs at room temperature prior to processing for plasma or serum preparation. Potential sample QIs were identified by Ultra high pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) based metabolite profiling in samples from healthy volunteers (n = 10). Selected QIs were validated by a targeted MS/MS approach in two independent sets of samples from patients (n = 40 and n = 70). In serum, the hypoxanthine/guanosine (HG) and hypoxanthine/inosine (HI) ratios demonstrated high diagnostic performance (Sensitivity/Specificity > 80\%) for the discrimination of samples with a TTC > 1 h. We identified several eicosanoids, such as 12-HETE, 15-(S)-HETE, 8-(S)-HETE, 12-oxo-HETE, (±)13-HODE and 12-(S)-HEPE as QIs for a pre-centrifugation delay > 2 h. 12-HETE, 12-oxo-HETE, 8-(S)-HETE, and 12-(S)-HEPE, and the HI- and HG-ratios could be validated in patient samples.}, language = {en} } @article{KristDornquastReinholdetal.2021, author = {Krist, Lilian and Dornquast, Christina and Reinhold, Thomas and Icke, Katja and Danquah, Ina and Willich, Stefan N. and Becher, Heiko and Keil, Thomas}, title = {Predictors of changes in physical activity and sedentary behavior during the COVID-19 pandemic in a Turkish migrant cohort in Germany}, series = {International Journal of Environmental Research and Public Health}, volume = {18}, journal = {International Journal of Environmental Research and Public Health}, number = {18}, issn = {1660-4601}, doi = {10.3390/ijerph18189682}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246176}, year = {2021}, abstract = {The new coronavirus (COVID-19) pandemic and the resulting response measures have led to severe limitations of people's exercise possibilities with diminished physical activity (PA) and increased sedentary behavior (SB). Since for migrant groups in Germany, no data is available, this study aimed to investigate factors associated with changes in PA and SB in a sample of Turkish descent. Participants of a prospective cohort study (adults of Turkish descent, living in Berlin, Germany) completed a questionnaire regarding COVID-19 related topics including PA and SB since February 2020. Changes in PA and SB were described, and sociodemographic, migrant-related, and health-related predictors of PA decrease and SB increase were determined using multivariable regression analyses. Of 106 participants, 69\% reported a decline of PA, 36\% reported an increase in SB. PA decrease and SB increase seemed to be associated with inactivity before the pandemic as well as with the female sex. SB increase appeared to be additionally associated with educational level and BMI. The COVID-19 pandemic and the response measures had persistent detrimental effects on this migrant population. Since sufficient PA before the pandemic had the strongest association with maintaining PA and SB during the crisis, the German government and public health professionals should prioritize PA promotion in this vulnerable group.}, language = {en} } @article{DechHolzwarthAsametal.2021, author = {Dech, Stefan and Holzwarth, Stefanie and Asam, Sarah and Andresen, Thorsten and Bachmann, Martin and Boettcher, Martin and Dietz, Andreas and Eisfelder, Christina and Frey, Corinne and Gesell, Gerhard and Gessner, Ursula and Hirner, Andreas and Hofmann, Matthias and Kirches, Grit and Klein, Doris and Klein, Igor and Kraus, Tanja and Krause, Detmar and Plank, Simon and Popp, Thomas and Reinermann, Sophie and Reiners, Philipp and Roessler, Sebastian and Ruppert, Thomas and Scherbachenko, Alexander and Vignesh, Ranjitha and Wolfmueller, Meinhard and Zwenzner, Hendrik and Kuenzer, Claudia}, title = {Potential and challenges of harmonizing 40 years of AVHRR data: the TIMELINE experience}, series = {Remote Sensing}, volume = {13}, journal = {Remote Sensing}, number = {18}, issn = {2072-4292}, doi = {10.3390/rs13183618}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246134}, year = {2021}, abstract = {Earth Observation satellite data allows for the monitoring of the surface of our planet at predefined intervals covering large areas. However, there is only one medium resolution sensor family in orbit that enables an observation time span of 40 and more years at a daily repeat interval. This is the AVHRR sensor family. If we want to investigate the long-term impacts of climate change on our environment, we can only do so based on data that remains available for several decades. If we then want to investigate processes with respect to climate change, we need very high temporal resolution enabling the generation of long-term time series and the derivation of related statistical parameters such as mean, variability, anomalies, and trends. The challenges to generating a well calibrated and harmonized 40-year-long time series based on AVHRR sensor data flown on 14 different platforms are enormous. However, only extremely thorough pre-processing and harmonization ensures that trends found in the data are real trends and not sensor-related (or other) artefacts. The generation of European-wide time series as a basis for the derivation of a multitude of parameters is therefore an extremely challenging task, the details of which are presented in this paper.}, language = {en} } @article{BrunkhorstKanaanTrautmannSchreiberetal.2021, author = {Brunkhorst-Kanaan, Nathalie and Trautmann, Sandra and Schreiber, Yannick and Thomas, Dominique and Kittel-Schneider, Sarah and Gurke, Robert and Geisslinger, Gerd and Reif, Andreas and Tegeder, Irmgard}, title = {Sphingolipid and endocannabinoid profiles in adult attention deficit hyperactivity disorder}, series = {Biomedicines}, volume = {9}, journal = {Biomedicines}, number = {9}, issn = {2227-9059}, doi = {10.3390/biomedicines9091173}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246080}, year = {2021}, abstract = {Genes encoding endocannabinoid and sphingolipid metabolism pathways were suggested to contribute to the genetic risk towards attention deficit hyperactivity disorder (ADHD). The present pilot study assessed plasma concentrations of candidate endocannabinoids, sphingolipids and ceramides in individuals with adult ADHD in comparison with healthy controls and patients with affective disorders. Targeted lipid analyses of 23 different lipid species were performed in 71 mental disorder patients and 98 healthy controls (HC). The patients were diagnosed with adult ADHD (n = 12), affective disorder (major depression, MD n = 16 or bipolar disorder, BD n = 6) or adult ADHD with comorbid affective disorders (n = 37). Canonical discriminant analysis and CHAID analyses were used to identify major components that predicted the diagnostic group. ADHD patients had increased plasma concentrations of sphingosine-1-phosphate (S1P d18:1) and sphinganine-1-phosphate (S1P d18:0). In addition, the endocannabinoids, anandamide (AEA) and arachidonoylglycerol were increased. MD/BD patients had increased long chain ceramides, most prominently Cer22:0, but low endocannabinoids in contrast to ADHD patients. Patients with ADHD and comorbid affective disorders displayed increased S1P d18:1 and increased Cer22:0, but the individual lipid levels were lower than in the non-comorbid disorders. Sphingolipid profiles differ between patients suffering from ADHD and affective disorders, with overlapping patterns in comorbid patients. The S1P d18:1 to Cer22:0 ratio may constitute a diagnostic or prognostic tool.}, language = {en} } @article{SchneiderKruseBernardellideMattosetal.2021, author = {Schneider, Verena and Kruse, Daniel and Bernardelli de Mattos, Ives and Z{\"o}phel, Saskia and Tiltmann, Kendra-Kathrin and Reigl, Amelie and Khan, Sarah and Funk, Martin and Bodenschatz, Karl and Groeber-Becker, Florian}, title = {A 3D in vitro model for burn wounds: monitoring of regeneration on the epidermal level}, series = {Biomedicines}, volume = {9}, journal = {Biomedicines}, number = {9}, issn = {2227-9059}, doi = {10.3390/biomedicines9091153}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246068}, year = {2021}, abstract = {Burns affect millions every year and a model to mimic the pathophysiology of such injuries in detail is required to better understand regeneration. The current gold standard for studying burn wounds are animal models, which are under criticism due to ethical considerations and a limited predictiveness. Here, we present a three-dimensional burn model, based on an open-source model, to monitor wound healing on the epidermal level. Skin equivalents were burned, using a preheated metal cylinder. The healing process was monitored regarding histomorphology, metabolic changes, inflammatory response and reepithelialization for 14 days. During this time, the wound size decreased from 25\% to 5\% of the model area and the inflammatory response (IL-1β, IL-6 and IL-8) showed a comparable course to wounding and healing in vivo. Additionally, the topical application of 5\% dexpanthenol enhanced tissue morphology and the number of proliferative keratinocytes in the newly formed epidermis, but did not influence the overall reepithelialization rate. In summary, the model showed a comparable healing process to in vivo, and thus, offers the opportunity to better understand the physiology of thermal burn wound healing on the keratinocyte level.}, language = {en} } @article{ReinersAsamFreyetal.2021, author = {Reiners, Philipp and Asam, Sarah and Frey, Corinne and Holzwarth, Stefanie and Bachmann, Martin and Sobrino, Jose and G{\"o}ttsche, Frank-M. and Bendix, J{\"o}rg and Kuenzer, Claudia}, title = {Validation of AVHRR Land Surface Temperature with MODIS and in situ LST — a TIMELINE thematic processor}, series = {Remote Sensing}, volume = {13}, journal = {Remote Sensing}, number = {17}, issn = {2072-4292}, doi = {10.3390/rs13173473}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246051}, year = {2021}, abstract = {Land Surface Temperature (LST) is an important parameter for tracing the impact of changing climatic conditions on our environment. Describing the interface between long- and shortwave radiation fluxes, as well as between turbulent heat fluxes and the ground heat flux, LST plays a crucial role in the global heat balance. Satellite-derived LST is an indispensable tool for monitoring these changes consistently over large areas and for long time periods. Data from the AVHRR (Advanced Very High-Resolution Radiometer) sensors have been available since the early 1980s. In the TIMELINE project, LST is derived for the entire operating period of AVHRR sensors over Europe at a 1 km spatial resolution. In this study, we present the validation results for the TIMELINE AVHRR daytime LST. The validation approach consists of an assessment of the temporal consistency of the AVHRR LST time series, an inter-comparison between AVHRR LST and in situ LST, and a comparison of the AVHRR LST product with concurrent MODIS (Moderate Resolution Imaging Spectroradiometer) LST. The results indicate the successful derivation of stable LST time series from multi-decadal AVHRR data. The validation results were investigated regarding different LST, TCWV and VA, as well as land cover classes. The comparisons between the TIMELINE LST product and the reference datasets show seasonal and land cover-related patterns. The LST level was found to be the most determinative factor of the error. On average, an absolute deviation of the AVHRR LST by 1.83 K from in situ LST, as well as a difference of 2.34 K from the MODIS product, was observed.}, language = {en} } @article{LauruschkatEtterSchnacketal.2021, author = {Lauruschkat, Chris D. and Etter, Sonja and Schnack, Elisabeth and Ebel, Frank and Sch{\"a}uble, Sascha and Page, Lukas and R{\"u}mens, Dana and Dragan, Mariola and Schlegel, Nicolas and Panagiotou, Gianni and Kniemeyer, Olaf and Brakhage, Axel A. and Einsele, Hermann and Wurster, Sebastian and Loeffler, Juergen}, title = {Chronic occupational mold exposure drives expansion of Aspergillus-reactive type 1 and type 2 T-helper cell responses}, series = {Journal of Fungi}, volume = {7}, journal = {Journal of Fungi}, number = {9}, issn = {2309-608X}, doi = {10.3390/jof7090698}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245202}, year = {2021}, abstract = {Occupational mold exposure can lead to Aspergillus-associated allergic diseases including asthma and hypersensitivity pneumonitis. Elevated IL-17 levels or disbalanced T-helper (Th) cell expansion were previously linked to Aspergillus-associated allergic diseases, whereas alterations to the Th cell repertoire in healthy occupationally exposed subjects are scarcely studied. Therefore, we employed functional immunoassays to compare Th cell responses to A. fumigatus antigens in organic farmers, a cohort frequently exposed to environmental molds, and non-occupationally exposed controls. Organic farmers harbored significantly higher A. fumigatus-specific Th-cell frequencies than controls, with comparable expansion of Th1- and Th2-cell frequencies but only slightly elevated Th17-cell frequencies. Accordingly, Aspergillus antigen-induced Th1 and Th2 cytokine levels were strongly elevated, whereas induction of IL-17A was minimal. Additionally, increased levels of some innate immune cell-derived cytokines were found in samples from organic farmers. Antigen-induced cytokine release combined with Aspergillus-specific Th-cell frequencies resulted in high classification accuracy between organic farmers and controls. Aspf22, CatB, and CipC elicited the strongest differences in Th1 and Th2 responses between the two cohorts, suggesting these antigens as potential candidates for future bio-effect monitoring approaches. Overall, we found that occupationally exposed agricultural workers display a largely balanced co-expansion of Th1 and Th2 immunity with only minor changes in Th17 responses.}, language = {en} } @article{HaydenLimbachSchuleretal.2021, author = {Hayden, Markus C. and Limbach, Matthias and Schuler, Michael and Merkl, Steffen and Schwarzl, Gabriele and Jakab, Katalin and Nowak, Dennis and Schultz, Konrad}, title = {Effectiveness of a three-week inpatient pulmonary rehabilitation program for patients after COVID-19: a prospective observational study}, series = {International Journal of Environmental Research and Public Health}, volume = {18}, journal = {International Journal of Environmental Research and Public Health}, number = {17}, issn = {1660-4601}, doi = {10.3390/ijerph18179001}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245170}, year = {2021}, abstract = {For COVID-19 patients who remain symptomatic after the acute phase, pulmonary rehabilitation (PR) is recommended. However, only a few studies have investigated the effectiveness of PR, especially considering the duration between the acute phase of COVID-19 and the onset of rehabilitation, as well as the initial severity. This prospective observational study evaluated the efficacy of PR in patients after COVID-19. A total of 120 still-symptomatic patients referred for PR after overcoming acute COVID-19 were asked to participate, of whom 108 (mean age 55.6 ± 10.1 years, 45.4\% female) consented. The patients were assigned to three groups according to the time of referral and initial disease severity (severe acute; severe after interval; mild after interval). The primary outcome was dyspnea. Secondary outcomes included other respiratory disease symptoms, physical capacity, lung function, fatigue, quality of life (QoL), depression, and anxiety. Furthermore, patients rated the overall effectiveness of PR and their subjective change in health status. At the end of PR, we detected improvements with large effect sizes in exertional dyspnea, physical capacity, QoL, fatigue, and depression in the overall group. Other parameters changed with small to medium effect sizes. PR was effective after acute COVID-19 in all three groups analyzed.}, language = {en} } @article{ScheinerLimMeixneretal.2021, author = {Scheiner, Ricarda and Lim, Kayun and Meixner, Marina D. and Gabel, Martin S.}, title = {Comparing the appetitive learning performance of six European honeybee subspecies in a common apiary}, series = {Insects}, volume = {12}, journal = {Insects}, number = {9}, issn = {2075-4450}, doi = {10.3390/insects12090768}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245180}, year = {2021}, abstract = {The Western honeybee (Apis mellifera L.) is one of the most widespread insects with numerous subspecies in its native range. How far adaptation to local habitats has affected the cognitive skills of the different subspecies is an intriguing question that we investigate in this study. Naturally mated queens of the following five subspecies from different parts of Europe were transferred to Southern Germany: A. m. iberiensis from Portugal, A. m. mellifera from Belgium, A. m. macedonica from Greece, A. m. ligustica from Italy, and A. m. ruttneri from Malta. We also included the local subspecies A. m. carnica in our study. New colonies were built up in a common apiary where the respective queens were introduced. Worker offspring from the different subspecies were compared in classical olfactory learning performance using the proboscis extension response. Prior to conditioning, we measured individual sucrose responsiveness to investigate whether possible differences in learning performances were due to differential responsiveness to the sugar water reward. Most subspecies did not differ in their appetitive learning performance. However, foragers of the Iberian honeybee, A. m. iberiensis, performed significantly more poorly, despite having a similar sucrose responsiveness. We discuss possible causes for the poor performance of the Iberian honeybees, which may have been shaped by adaptation to the local habitat.}, language = {en} } @article{DekantLangerLuppetal.2021, author = {Dekant, Raphael and Langer, Michael and Lupp, Maria and Adaku Chilaka, Cynthia and Mally, Angela}, title = {In vitro and in vivo analysis of ochratoxin A-derived glucuronides and mercapturic acids as biomarkers of exposure}, series = {Toxins}, volume = {13}, journal = {Toxins}, number = {8}, issn = {2072-6651}, doi = {10.3390/toxins13080587}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245146}, year = {2021}, abstract = {Ochratoxin A (OTA) is a widespread food contaminant, with exposure estimated to range from 0.64 to 17.79 ng/kg body weight (bw) for average consumers and from 2.40 to 51.69 ng/kg bw per day for high consumers. Current exposure estimates are, however, associated with considerable uncertainty. While biomarker-based approaches may contribute to improved exposure assessment, there is yet insufficient data on urinary metabolites of OTA and their relation to external dose to allow reliable estimates of daily intake. This study was designed to assess potential species differences in phase II biotransformation in vitro and to establish a correlation between urinary OTA-derived glucuronides and mercapturic acids and external exposure in rats in vivo. In vitro analyses of OTA metabolism using the liver S9 of rats, humans, rabbits and minipigs confirmed formation of an OTA glucuronide but provided no evidence for the formation of OTA-derived mercapturic acids to support their use as biomarkers. Similarly, OTA-derived mercapturic acids were not detected in urine of rats repeatedly dosed with OTA, while indirect analysis using enzymatic hydrolysis of the urine samples prior to LC-MS/MS established a linear relationship between urinary glucuronide excretion and OTA exposure. These results support OTA-derived glucuronides but not mercapturic acids as metabolites suitable for biomonitoring.}, language = {en} } @article{BothouSharmaOoetal.2021, author = {Bothou, Christina and Sharma, Ashish and Oo, Adrian and Kim, Baek and Perge, Pal and Igaz, Peter and Ronchi, Cristina L. and Shapiro, Igor and Hantel, Constanze}, title = {Novel insights into the molecular regulation of ribonucleotide reductase in adrenocortical carcinoma treatment}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {16}, issn = {2072-6694}, doi = {10.3390/cancers13164200}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245132}, year = {2021}, abstract = {Current systemic treatment options for patients with adrenocortical carcinomas (ACCs) are far from being satisfactory. DNA damage/repair mechanisms, which involve, e.g., ataxia-telangiectasia-mutated (ATM) and ataxia-telangiectasia/Rad3-related (ATR) protein signaling or ribonucleotide reductase subunits M1/M2 (RRM1/RRM2)-encoded ribonucleotide reductase (RNR) activation, commonly contribute to drug resistance. Moreover, the regulation of RRM2b, the p53-induced alternative to RRM2, is of unclear importance for ACC. Upon extensive drug screening, including a large panel of chemotherapies and molecular targeted inhibitors, we provide strong evidence for the anti-tumoral efficacy of combined gemcitabine (G) and cisplatin (C) treatment against the adrenocortical cell lines NCI-H295R and MUC-1. However, accompanying induction of RRM1, RRM2, and RRM2b expression also indicated developing G resistance, a frequent side effect in clinical patient care. Interestingly, this effect was partially reversed upon addition of C. We confirmed our findings for RRM2 protein, RNR-dependent dATP levels, and modulations of related ATM/ATR signaling. Finally, we screened for complementing inhibitors of the DNA damage/repair system targeting RNR, Wee1, CHK1/2, ATR, and ATM. Notably, the combination of G, C, and the dual RRM1/RRM2 inhibitor COH29 resulted in previously unreached total cell killing. In summary, we provide evidence that RNR-modulating therapies might represent a new therapeutic option for ACC.}, language = {en} } @article{WagnerSlaghuisGoebeletal.2021, author = {Wagner, Martin and Slaghuis, J{\"o}rg and G{\"o}bel, Werner and V{\´a}zquez-Boland, Jos{\´e} Antonio and Rychli, Kathrin and Schmitz-Esser, Stephan}, title = {Virulence pattern analysis of three Listeria monocytogenes lineage I epidemic strains with distinct outbreak histories}, series = {Microorganisms}, volume = {9}, journal = {Microorganisms}, number = {8}, issn = {2076-2607}, doi = {10.3390/microorganisms9081745}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245093}, year = {2021}, abstract = {Strains of the food-borne pathogen Listeria (L.) monocytogenes have diverse virulence potential. This study focused on the virulence of three outbreak strains: the CC1 strain PF49 (serovar 4b) from a cheese-associated outbreak in Switzerland, the clinical CC2 strain F80594 (serovar 4b), and strain G6006 (CC3, serovar 1/2a), responsible for a large gastroenteritis outbreak in the USA due to chocolate milk. We analysed the genomes and characterized the virulence in vitro and in vivo. Whole-genome sequencing revealed a high conservation of the major virulence genes. Minor deviations of the gene contents were found in the autolysins Ami, Auto, and IspC. Moreover, different ActA variants were present. Strain PF49 and F80594 showed prolonged survival in the liver of infected mice. Invasion and intracellular proliferation were similar for all strains, but the CC1 and CC2 strains showed increased spreading in intestinal epithelial Caco2 cells compared to strain G6006. Overall, this study revealed long-term survival of serovar 4b strains F80594 and PF49 in the liver of mice. Future work will be needed to determine the genes and molecular mechanism behind the long-term survival of L. monocytogenes strains in organs.}, language = {en} } @article{WillekeJansonZinketal.2021, author = {Willeke, Kristina and Janson, Patrick and Zink, Katharina and Stupp, Carolin and Kittel-Schneider, Sarah and Bergh{\"o}fer, Anne and Ewert, Thomas and King, Ryan and Heuschmann, Peter U. and Zapf, Andreas and Wildner, Manfred and Keil, Thomas}, title = {Occurrence of mental illness and mental health risks among the self-employed: a systematic review}, series = {International Journal of Environmental Research and Public Health}, volume = {18}, journal = {International Journal of Environmental Research and Public Health}, number = {16}, issn = {1660-4601}, doi = {10.3390/ijerph18168617}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245085}, year = {2021}, abstract = {We aimed to systematically identify and evaluate all studies of good quality that compared the occurrence of mental disorders in the self-employed versus employees. Adhering to the Cochrane guidelines, we conducted a systematic review and searched three major medical databases (MEDLINE, Web of Science, Embase), complemented by hand search. We included 26 (three longitudinal and 23 cross-sectional) population-based studies of good quality (using a validated quality assessment tool), with data from 3,128,877 participants in total. The longest of these studies, a Swedish national register evaluation with 25 years follow-up, showed a higher incidence of mental illness among the self-employed compared to white-collar workers, but a lower incidence compared to blue-collar workers. In the second longitudinal study from Sweden the self-employed had a lower incidence of mental illness compared to both blue- and white-collar workers over 15 years, whereas the third longitudinal study (South Korea) did not find a difference regarding the incidence of depressive symptoms over 6 years. Results from the cross-sectional studies showed associations between self-employment and poor general mental health and stress, but were inconsistent regarding other mental outcomes. Most studies from South Korea found a higher prevalence of mental disorders among the self-employed compared to employees, whereas the results of cross-sectional studies from outside Asia were less consistent. In conclusion, we found evidence from population-based studies for a link between self-employment and increased risk of mental illness. Further longitudinal studies are needed examining the potential risk for the development of mental disorders in specific subtypes of the self-employed.}, language = {en} } @article{BanKaračićTomićetal.2021, author = {Ban, Željka and Karačić, Zrinka and Tomić, Sanja and Amini, Hashem and Marder, Todd B. and Piantanida, Ivo}, title = {Triarylborane dyes as a novel non-covalent and non-inhibitive fluorimetric markers for DPP III enzyme}, series = {Molecules}, volume = {26}, journal = {Molecules}, number = {16}, issn = {1420-3049}, doi = {10.3390/molecules26164816}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245046}, year = {2021}, abstract = {Novel dyes were prepared by simple "click CuAAC" attachment of a triarylborane-alkyne to the azide side chain of an amino acid yielding triarylborane dye 1 which was conjugated with pyrene (dye 2) forming a triarylborane-pyrene FRET pair. In contrast to previous cationic triarylboranes, the novel neutral dyes interact only with proteins, while their affinity to DNA/RNA is completely abolished. Both the reference triarylborane amino acid and triarylborane-pyrene conjugate bind to BSA and the hDPP III enzyme with high affinities, exhibiting a strong (up to 100-fold) fluorescence increase, whereby the triarylborane-pyrene conjugate additionally retained FRET upon binding to the protein. Furthermore, the triarylborane dyes, upon binding to the hDPP III enzyme, did not impair its enzymatic activity under a wide range of experimental conditions, thus being the first non-covalent fluorimetric markers for hDPP III, also applicable during enzymatic reactions with hDPP III substrates.}, language = {en} } @article{OpolkaMuellerFellaetal.2021, author = {Opolka, Alexander and M{\"u}ller, Dominik and Fella, Christian and Balles, Andreas and Mohr, J{\"u}rgen and Last, Arndt}, title = {Multi-lens array full-field X-ray microscopy}, series = {Applied Sciences}, volume = {11}, journal = {Applied Sciences}, number = {16}, issn = {2076-3417}, doi = {10.3390/app11167234}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-244974}, year = {2021}, abstract = {X-ray full-field microscopy at laboratory sources for photon energies above 10 keV suffers from either long exposure times or low resolution. The photon flux is mainly limited by the objectives used, having a limited numerical aperture NA. We show that this can be overcome by making use of the cone-beam illumination of laboratory sources by imaging the same field of view (FoV) several times under slightly different angles using an array of X-ray lenses. Using this technique, the exposure time can be reduced drastically without any loss in terms of resolution. A proof-of-principle is given using an existing laboratory metal-jet source at the 9.25 keV Ga K\(_α\)-line and compared to a ray-tracing simulation of the setup.}, language = {en} } @article{FoeckerTimmesfeldBuehlmeieretal.2021, author = {F{\"o}cker, Manuel and Timmesfeld, Nina and B{\"u}hlmeier, Judith and Zwanziger, Denise and F{\"u}hrer, Dagmar and Grasemann, Corinna and Ehrlich, Stefan and Egberts, Karin and Fleischhaker, Christian and Wewetzer, Christoph and Wessing, Ida and Seitz, Jochen and Herpertz-Dahlmann, Beate and Hebebrand, Johannes and Libuda, Lars}, title = {Vitamin D level trajectories of adolescent patients with anorexia nervosa at inpatient admission, during treatment, and at one year follow up: association with depressive symptoms}, series = {Nutrients}, volume = {13}, journal = {Nutrients}, number = {7}, issn = {2072-6643}, doi = {10.3390/nu13072356}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242662}, year = {2021}, abstract = {(1) Background: Evidence has accumulated that patients with anorexia nervosa (AN) are at higher risk for vitamin D deficiency than healthy controls. In epidemiologic studies, low 25(OH) vitamin D (25(OH)D) levels were associated with depression. This study analyzed the relationship between 25(OH)D serum levels in adolescent patients and AN and depressive symptoms over the course of treatment. (2) Methods: 25(OH)D levels and depressive symptoms were analyzed in 93 adolescent (in-)patients with AN from the Anorexia Nervosa Day patient versus Inpatient (ANDI) multicenter trial at clinic admission, discharge, and 1 year follow up. Mixed regression models were used to analyze the relationship between 25(OH)D levels and depressive symptoms assessed by the Beck Depression Inventory (BDI-II). (3) Results: Although mean 25(OH)D levels constantly remained in recommended ranges (≥50 nmol/L) during AN treatment, levels decreased from (in)patient admission to 1 year follow up. Levels of 25(OH)D were neither cross-sectionally, prospectively, nor longitudinally associated with the BDI-II score. (4) Conclusions: This study did not confirm that 25(OH)D levels are associated with depressive symptoms in patients with AN. However, increasing risks of vitamin D deficiency over the course of AN treatment indicate that clinicians should monitor 25(OH)D levels.}, language = {en} } @article{KochPetzoldWesselyetal.2021, author = {Koch, Elias A. T. and Petzold, Anne and Wessely, Anja and Dippel, Edgar and Gesierich, Anja and Gutzmer, Ralf and Hassel, Jessica C. and Haferkamp, Sebastian and Hohberger, Bettina and K{\"a}hler, Katharina C. and Knorr, Harald and Kreuzberg, Nicole and Leiter, Ulrike and Loquai, Carmen and Meier, Friedegund and Meissner, Markus and Mohr, Peter and Pf{\"o}hler, Claudia and Rahimi, Farnaz and Schadendorf, Dirk and Schell, Beatrice and Schlaak, Max and Terheyden, Patrick and Thoms, Kai-Martin and Schuler-Thurner, Beatrice and Ugurel, Selma and Ulrich, Jens and Utikal, Jochen and Weichenthal, Michael and Ziller, Fabian and Berking, Carola and Heppt, Markus}, title = {Immune checkpoint blockade for metastatic uveal melanoma: patterns of response and survival according to the presence of hepatic and extrahepatic metastasis}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {13}, issn = {2072-6694}, doi = {10.3390/cancers13133359}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242603}, year = {2021}, abstract = {Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan-Meier method. Log-rank tests, χ\(^2\) tests, and t-tests were performed to detect significant differences between both cohorts. Results: The median OS of the overall population was 16 months (95\% CI 13.4-23.7) and the median PFS, 2.8 months (95\% CI 2.5-3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8\% and to anti-PD-1 monotherapy 8.9\% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7\% vs. cohort B 16.7\%; p = 0.45). Adverse events (AE) occurred in 41.6\%. Severe AE were observed in 26.3\% and evenly distributed between both cohorts. Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only.}, language = {en} } @article{WaltherZimmermannTheuersbacheretal.2021, author = {Walther, Grit and Zimmermann, Anna and Theuersbacher, Johanna and Kaerger, Kerstin and Lilienfeld-Toal, Marie von and Roth, Mathias and Kampik, Daniel and Geerling, Gerd and Kurzai, Oliver}, title = {Eye infections caused by filamentous fungi: spectrum and antifungal susceptibility of the prevailing agents in Germany}, series = {Journal of Fungi}, volume = {7}, journal = {Journal of Fungi}, number = {7}, issn = {2309-608X}, doi = {10.3390/jof7070511}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241810}, year = {2021}, abstract = {Fungal eye infections can lead to loss of vision and blindness. The disease is most prevalent in the tropics, although case numbers in moderate climates are increasing as well. This study aimed to determine the dominating filamentous fungi causing eye infections in Germany and their antifungal susceptibility profiles in order to improve treatment, including cases with unidentified pathogenic fungi. As such, we studied all filamentous fungi isolated from the eye or associated materials that were sent to the NRZMyk between 2014 and 2020. All strains were molecularly identified and antifungal susceptibility testing according to the EUCAST protocol was performed for common species. In total, 242 strains of 66 species were received. Fusarium was the dominating genus, followed by Aspergillus, Purpureocillium, Alternaria, and Scedosporium. The most prevalent species in eye samples were Fusarium petroliphilum, F. keratoplasticum, and F. solani of the Fusarium solani species complex. The spectrum of species comprises less susceptible taxa for amphotericin B, natamycin, and azoles, including voriconazole. Natamycin is effective for most species but not for Aspergillus flavus or Purpureocillium spp. Some strains of F. solani show MICs higher than 16 mg/L. Our data underline the importance of species identification for correct treatment.}, language = {en} } @article{HaiderAhmadYangetal.2021, author = {Haider, Malik Salman and Ahmad, Taufiq and Yang, Mengshi and Hu, Chen and Hahn, Lukas and Stahlhut, Philipp and Groll, J{\"u}rgen and Luxenhofer, Robert}, title = {Tuning the thermogelation and rheology of poly(2-oxazoline)/poly(2-oxazine)s based thermosensitive hydrogels for 3D bioprinting}, series = {Gels}, volume = {7}, journal = {Gels}, number = {3}, issn = {2310-2861}, doi = {10.3390/gels7030078}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241781}, year = {2021}, abstract = {As one kind of "smart" material, thermogelling polymers find applications in biofabrication, drug delivery and regenerative medicine. In this work, we report a thermosensitive poly(2-oxazoline)/poly(2-oxazine) based diblock copolymer comprising thermosensitive/moderately hydrophobic poly(2-N-propyl-2-oxazine) (pPrOzi) and thermosensitive/moderately hydrophilic poly(2-ethyl-2-oxazoline) (pEtOx). Hydrogels were only formed when block length exceeded certain length (≈100 repeat units). The tube inversion and rheological tests showed that the material has then a reversible sol-gel transition above 25 wt.\% concentration. Rheological tests further revealed a gel strength around 3 kPa, high shear thinning property and rapid shear recovery after stress, which are highly desirable properties for extrusion based three-dimensional (3D) (bio) printing. Attributed to the rheology profile, well resolved printability and high stackability (with added laponite) was also possible. (Cryo) scanning electron microscopy exhibited a highly porous, interconnected, 3D network. The sol-state at lower temperatures (in ice bath) facilitated the homogeneous distribution of (fluorescently labelled) human adipose derived stem cells (hADSCs) in the hydrogel matrix. Post-printing live/dead assays revealed that the hADSCs encapsulated within the hydrogel remained viable (≈97\%). This thermoreversible and (bio) printable hydrogel demonstrated promising properties for use in tissue engineering applications.}, language = {en} } @article{Scholz2021, author = {Scholz, Janek}, title = {S{\´e}rgio Zimbas Covid-19-Karikaturen im Kontext {\"o}ffentlicher Gesundheitsf{\"u}rsorge in Mosambik}, series = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, volume = {7}, journal = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, issn = {2364-6705}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-305692}, pages = {133-155}, year = {2021}, abstract = {The article deals with the educational comics of the Mozambican artist S{\´e}rgio Zimba, especially in the context of the current pandemic situation caused by Covid-19. First, comics from and comic research on Africa will be presented, especially in their repercussion within the German-language comics landscape. This will be followed by a discussion of the special situation in lusophone Africa, exemplified and illustrated by the works of the Mozambican cartoonist S{\´e}rgio Zimba. The article closes with a brief comparison of Zimba's work with the cartoons of S{\´e}rgio Pi{\c{c}}arra from Angola, to better classify the artist's work.}, language = {de} } @article{Klamp2021, author = {Klamp, Yannic}, title = {Alma und {\´a}nima in spanisch-zapotekischen Evangelisierungswerken: die Translation des Konzepts Seele im kolonialen Missionskontext (Neu-Spanien, 16.-18. Jh.)}, series = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, volume = {7}, journal = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, issn = {2364-6705}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-305681}, pages = {111-130}, year = {2021}, abstract = {The arrival of the Spanish in present-day Oaxaca, Mexico, led to manifold communicative challenges and was the origin of the first written documents in the local indigenous languages. This paper focuses on Spanish-Zapotec translations produced by Christian missionaries during the colonial period. In this context, it aims to investigate the expression of the concept of soul in their catechisms and confesionarios by analyzing chronologically how different authors apply the Spanish synonyms alma and {\´a}nima. On the one hand, we can observe some similar tendencies in central Mexican documents for the early colonial period so that we can assume that the corpus was influenced by Nahuatl translations. On the other hand, there is an independent development in Spanish-Zapotec translations not only regarding the target text but also the source text.}, language = {de} } @article{Kneifel2021, author = {Kneifel, Malte}, title = {Futur-Formen und ihre Funktionen im Portugu{\^e}s Arcaico}, series = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, volume = {7}, journal = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, issn = {2364-6705}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-305673}, pages = {91-109}, year = {2021}, abstract = {This article aims to trace the development of different verb forms that express future tense of Old Portuguese from the 13th to the 15th century by analyzing a historical text corpus. During this period, Portuguese future tense could be expressed through one synthetical as well as two analytical morphological verb constructions. Adapting an analytic model formerly employed by the Mexican researcher Concepci{\´o}n Company Company for an investigation of similar future tense forms in Old Spanish, this article seeks to point out that the use of the different verb forms in Portuguese followed distinct functions regarding aspects of both information structure as well as modality.}, language = {de} } @article{Henk2021, author = {Henk, Lars Thorben}, title = {«We're on the road to nowhere» - Felwine Sarrs narrativer Weg in die Afrotopie}, series = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, volume = {7}, journal = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, issn = {2364-6705}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-305662}, pages = {73-90}, year = {2021}, abstract = {According to the Senegalesian scholar Felwine Sarr who conceives an African utopia in his programmatic essay Afrotopia (2016), this Afrotopos has already germinated in contemporary African literature. However, it still needs to be enquired to what extent the narrated topos of the street in Sarr's own anthology 105 Rue Carnot (2011) has already realized the Afrotopos. In order to respond to this question, we would like to mobilise Michel Foucault's concept of heterotopia, which elaborates on the interactions between truth production/knowledge, power and space, and permits us to conceive of «les lieux utopiques» (Foucault 2005: 40) as actually locatable on the map and real other places outside of all places (cf. Foucault 1994: 755). Thus, in the street, a different relationship between global North and South is founded, which becomes legible as an African «utopie localis{\´e}e» (Foucault 2005: 41) that Sarr calls for in Afrotopia (2016).}, language = {de} } @article{Dittmann2021, author = {Dittmann, Lara A.}, title = {Sprach- und Kommunikationsnuancen in literarischen Interspeziesbegegnungen - Juan Ram{\´o}n Jim{\´e}nezʼ Platero y yo (1914/1917) und Thomas Manns Herr und Hund (1919)}, series = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, volume = {7}, journal = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, issn = {2364-6705}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-305658}, pages = {55-71}, year = {2021}, abstract = {The encounter with non-human animals has always been a major preoccupation in the (philosophical) quest of understanding the human (condition). Of course, they are not only present in literary texts, but also in other media such as music and art. We consider ourselves aware of their selves, natures and skills as well as their sensory perceptions. Indeed, the ways we interact with non-human animals in everyday life and in the fictional world, how we perceive, think and talk about them as well as how we communicate with them are often related to our own self-perceptions in the social collective and in social-historical discourse. If we take a closer look at literary interspecies relations, we can detect clear shades in language and communication. Based on the approaches of Human-Animal Studies, this article deals with those nuances regarding animal-human encounters in Juan Ram{\´o}n Jim{\´e}nez' Platero y yo (1914/1917) and Thomas Mann's Herr und Hund (1919) in a comparative perspective. In addition to this, a special focus is placed on the effect these elements can have on (inter)acting literary subjects as well as on extra-textual recipients.}, language = {de} } @article{deCringis2021, author = {de Cringis, Patricia}, title = {100 Jahre Vokalschw{\"a}chung in den tierras altas: historische Perspektiven eines (zu) wenig beachteten Aussprachemerkmal}, series = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, volume = {7}, journal = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, issn = {2364-6705}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-305638}, pages = {35-52}, year = {2021}, abstract = {This paper deals with the origin of the hundred-year old theory of tierras bajas and tierras altas, focusing on the description of vowel weakening within that theory developed in 1921 by Henr{\´i}quez Ure{\~n}a. I argue that the early conception of vowel weakening and its dialectal distribution has strongly influenced the kind of research we have been conducting about this phonetic feature to this day. The aim of this study therefore, is to sharpen our understanding of the former zeitgeist of research and to stimulate further big data-based studies on vowel weakening overcoming the traditional dialectal division of tierras bajas and tierras altas.}, language = {de} } @article{Christmann2021, author = {Christmann, Tim}, title = {Grenzerfahrung, Grenz{\"u}berschreitung, Grenz{\"u}berwindung: Das Falkland/Malvinas Malvinas-Trauma in Lola Arias' Film Teatro de Guerra (2018)}, series = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, volume = {7}, journal = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, issn = {2364-6705}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-305577}, pages = {17-33}, year = {2021}, abstract = {This article will examine the cinematic approach to the trauma of the Falklands/Malvinas War in Lola Ariasʼ film Teatro de Guerra (AR/ES, 2018). The armed conflict between Ar-gentina and Great Britain in 1982 can be understood as a traumatic liminal experience, whose artistic reception pushes conventional aesthetics to their limits and calls for innova-tive representational strategies. Based on a cultural studies approach to the Falklands/Mal-vinas War as a collective trauma, this contribution will highlight selected moments of aes-thetic border crossing in Teatro de Guerra, by which the film succeeds in transcending boundaries between former enemies of the war.}, language = {de} } @article{Weinreich2021, author = {Weinreich, Oliver}, title = {Zwei lange vergessene Kilianslieder aus zwei Epochen: "Adoranda veneranda" und "Sankt Kilian ein edler Schott"}, series = {W{\"u}rzburger Di{\"o}zesangeschichtsbl{\"a}tter}, volume = {84}, journal = {W{\"u}rzburger Di{\"o}zesangeschichtsbl{\"a}tter}, issn = {0342-3093}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-303766}, pages = {237-248}, year = {2021}, abstract = {Es werden zwei Kirchenlieder zum W{\"u}rzburger Bistumspatron Kilian vorgestellt: eines aus dem 12. und eines aus dem 17. Jahrhundert. Beide waren lange aus dem Bewußtsein und dem Alltagsgebrauch verschwunden.}, subject = {Kilian }, language = {de} } @article{BreilKanskePittigetal.2021, author = {Breil, Christina and Kanske, Philipp and Pittig, Roxana and B{\"o}ckler, Anne}, title = {A revised instrument for the assessment of empathy and Theory of Mind in adolescents: Introducing the EmpaToM-Y}, series = {Behavior Research Methods}, volume = {53}, journal = {Behavior Research Methods}, doi = {10.3758/s13428-021-01589-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-302877}, pages = {2487-2501}, year = {2021}, abstract = {Empathy and Theory of Mind (ToM) are two core components of social understanding. The EmpaToM is a validated social video task that allows for independent manipulation and assessment of the two capacities. First applications revealed that empathy and ToM are dissociable constructs on a neuronal as well as on a behavioral level. As the EmpaToM has been designed for the assessment of social understanding in adults, it has a high degree of complexity and comprises topics that are inadequate for minors. For this reason, we designed a new version of the EmpaToM that is especially suited to measure empathy and ToM in youths. In experiment 1, we successfully validated the EmpaToM-Y on the original EmpaToM in an adult sample (N = 61), revealing a similar pattern of results across tasks and strong correlations of all constructs. As intended, the performance measure for ToM and the control condition of the EmpaToM-Y showed reduced difficulty. In experiment 2, we tested the feasibility of the EmpaToM-Y in a group of teenagers (N = 36). Results indicate a reliable empathy induction and higher demands of ToM questions for adolescents. We provide a promising task for future research targeting inter-individual variability of socio-cognitive and socio-affective capacities as well as their precursors and outcomes in healthy minors and clinical populations.}, language = {en} } @article{SchraderRieseKurlbaumetal.2021, author = {Schrader, Nikolas and Riese, Thorsten and Kurlbaum, Max and Meybohm, Patrick and Kredel, Markus and Surat, G{\"u}zin and Scherf-Clavel, Oliver and Strate, Alexander and Pospiech, Andreas and Hoppe, Kerstin}, title = {Personalized antibiotic therapy for the critically ill: Implementation strategies and effects on clinical outcome of piperacillin therapeutic drug monitoring — a descriptive retrospective analysis}, series = {Antibiotics}, volume = {10}, journal = {Antibiotics}, number = {12}, issn = {2079-6382}, doi = {10.3390/antibiotics10121452}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250052}, year = {2021}, abstract = {Therapeutic drug monitoring (TDM) is increasingly relevant for an individualized antibiotic therapy and subsequently a necessary tool to reduce multidrug-resistant pathogens, especially in light of diminishing antimicrobial capabilities. Critical illness is associated with profound pharmacokinetic and pharmacodynamic alterations, which challenge dose finding and the application of particularly hydrophilic drugs such as β-lactam antibiotics. Methods: Implementation strategy, potential benefit, and practicability of the developed standard operating procedures were retrospectively analyzed from January to December 2020. Furthermore, the efficacy of the proposed dosing target of piperacillin in critically ill patients was evaluated. Results: In total, 160 patients received piperacillin/tazobactam therapy and were subsequently included in the study. Of them, 114 patients received piperacillin/tazobactam by continuous infusion and had at least one measurement of piperacillin serum level according to the standard operating procedure. In total, 271 measurements were performed with an average level of 79.0 ± 46.0 mg/L. Seventy-one piperacillin levels exceeded 100 mg/L and six levels were lower than 22.5 mg/L. The high-level and the low-level group differed significantly in infection laboratory parameters (CRP (mg/dL) 20.18 ± 11.71 vs. 5.75 ± 5.33) and renal function [glomerular filtration rate (mL/min/1.75 m2) 40.85 ± 26.74 vs. 120.50 ± 70.48]. Conclusions: Piperacillin levels are unpredictable in critically ill patients. TDM during piperacillin/tazobactam therapy is highly recommended for all patients. Although our implementation strategy was effective, further strategies implemented into the daily clinical workflow might support the health care staff and increase the clinicians' alertness.}, language = {en} } @article{SchlauersbachHanioLenzetal.2021, author = {Schlauersbach, Jonas and Hanio, Simon and Lenz, Bettina and Vemulapalli, Sahithya P. B. and Griesinger, Christian and P{\"o}ppler, Ann-Christin and Harlacher, Cornelius and Galli, Bruno and Meinel, Lorenz}, title = {Leveraging bile solubilization of poorly water-soluble drugs by rational polymer selection}, series = {Journal of Controlled Release}, volume = {330}, journal = {Journal of Controlled Release}, edition = {Accepted Version}, doi = {10.1016/j.jconrel.2020.12.016}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-296957}, pages = {36-48}, year = {2021}, abstract = {Poorly water-soluble drugs frequently solubilize into bile colloids and this natural mechanism is key for efficient bioavailability. We tested the impact of pharmaceutical polymers on this solubilization interplay using proton nuclear magnetic resonance spectroscopy, dynamic light scattering, and by assessing the flux across model membranes. Eudragit E, Soluplus, and a therapeutically used model polymer, Colesevelam, impacted the bile-colloidal geometry and molecular interaction. These polymer-induced changes reduced the flux of poorly water-soluble and bile interacting drugs (Perphenazine, Imatinib) but did not impact the flux of bile non-interacting Metoprolol. Non-bile interacting polymers (Kollidon VA 64, HPMC-AS) neither impacted the flux of colloid-interacting nor colloid-non-interacting drugs. These insights into the drug substance/polymer/bile colloid interplay potentially point towards a practical optimization parameter steering formulations to efficient bile-solubilization by rational polymer selection.}, language = {en} } @article{TongsompornWananiyakulSteuding2021, author = {Tongsomporn, Janyarak and Wananiyakul, Saeree and Steuding, J{\"o}rn}, title = {The values of the periodic zeta-function at the nontrivial zeros of Riemann's zeta-function}, series = {Symmetry}, volume = {13}, journal = {Symmetry}, number = {12}, issn = {2073-8994}, doi = {10.3390/sym13122410}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252261}, year = {2021}, abstract = {In this paper, we prove an asymptotic formula for the sum of the values of the periodic zeta-function at the nontrivial zeros of the Riemann zeta-function (up to some height) which are symmetrical on the real line and the critical line. This is an extension of the previous results due to Garunkštis, Kalpokas, and, more recently, Sowa. Whereas Sowa's approach was assuming the yet unproved Riemann hypothesis, our result holds unconditionally.}, language = {en} } @article{RodriguesMarzbanHewig2021, author = {Rodrigues, Johannes and Marzban, Dorna and Hewig, Johannes}, title = {The influence of mental imagery expertise of pen and paper players versus computer gamers upon performance and electrocortical correlates in a difficult mental rotation task}, series = {Symmetry}, volume = {13}, journal = {Symmetry}, number = {12}, issn = {2073-8994}, doi = {10.3390/sym13122337}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252253}, year = {2021}, abstract = {We investigated the influence of mental imagery expertise in 15 pen and paper role-players as an expert group compared to the gender-matched control group of computer role-players in the difficult Vandenberg and Kuse mental rotation task. In this task, the participants have to decide which two of four rotated figures match the target figure. The dependent measures were performance speed and accuracy. In our exploratory investigation, we further examined midline frontal theta band activation, parietal alpha band activation, and parietal alpha band asymmetry in EEG as indicator for the chosen rotation strategy. Additionally, we explored the gender influence on performance and EEG activation, although a very small female sample section was given. The expected gender difference concerning performance accuracy was negated by expertise in pen and paper role-playing women, while the gender-specific difference in performance speed was preserved. Moreover, gender differences concerning electro-cortical measures revealed differences in rotation strategy, with women using top-down strategies compared to men, who were using top-down strategies and active inhibition of associative cortical areas. These strategy uses were further moderated by expertise, with higher expertise leading to more pronounced activation patters, especially during successful performance. However, due to the very limited sample size, the findings of this explorative study have to be interpreted cautiously.}, language = {en} }