TY - JOUR A1 - Welter, Nils A1 - Wagner, Angelo A1 - Furtwängler, Rhoikos A1 - Melchior, Patrick A1 - Kager, Leo A1 - Vokuhl, Christian A1 - Schenk, Jens-Peter A1 - Meier, Clemens Magnus A1 - Siemer, Stefan A1 - Gessler, Manfred A1 - Graf, Norbert T1 - Characteristics of nephroblastoma/nephroblastomatosis in children with a clinically reported underlying malformation or cancer predisposition syndrome JF - Cancers N2 - (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. KW - nephroblastoma KW - clinical malformations KW - cancer predisposition syndromes KW - tumor surveillance KW - outcome Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248434 SN - 2072-6694 VL - 13 IS - 19 ER - TY - JOUR A1 - Khare, Suyash A1 - Latifi, Hooman A1 - Khare, Siddhartha T1 - Vegetation growth analysis of UNESCO World Heritage Hyrcanian forests using multi-sensor optical remote sensing data JF - Remote Sensing N2 - 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. KW - Hyrcanian forest KW - NDVI KW - phenology KW - Sentinel-2 KW - TNPI KW - World Heritage Sites KW - Google Earth Engine Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248398 SN - 2072-4292 VL - 13 IS - 19 ER - TY - JOUR A1 - Monteagudo, María A1 - Martínez, Paula A1 - Leandro-García, Luis J. A1 - Martínez-Montes, Ángel M. A1 - Calsina, Bruna A1 - Pulgarín-Alfaro, Marta A1 - Díaz-Talavera, Alberto A1 - Mellid, Sara A1 - Letón, Rocío A1 - Gil, Eduardo A1 - Pérez-Martínez, Manuel A1 - Megías, Diego A1 - Torres-Ruiz, Raúl A1 - Rodriguez-Perales, Sandra A1 - González, Patricia A1 - Caleiras, Eduardo A1 - Jiménez-Villa, Scherezade A1 - Roncador, Giovanna A1 - Álvarez-Escolá, Cristina A1 - Regojo, Rita M. A1 - Calatayud, María A1 - Guadalix, Sonsoles A1 - Currás-Freixes, Maria A1 - Rapizzi, Elena A1 - Canu, Letizia A1 - Nölting, Svenja A1 - Remde, Hanna A1 - Fassnacht, Martin A1 - Bechmann, Nicole A1 - Eisenhofer, Graeme A1 - Mannelli, Massimo A1 - Beuschlein, Felix A1 - Quinkler, Marcus A1 - Rodríguez-Antona, Cristina A1 - Cascón, Alberto A1 - Blasco, María A. A1 - Montero-Conde, Cristina A1 - Robledo, Mercedes T1 - Analysis of telomere maintenance related genes reveals NOP10 as a new metastatic-risk marker in pheochromocytoma/paraganglioma JF - Cancers N2 - 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. KW - pheochromocytoma KW - paraganglioma KW - PPGL KW - telomeres KW - prognostic biomarker KW - ALT KW - TERT KW - ATRX KW - NOP10 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246321 SN - 2072-6694 VL - 13 IS - 19 ER - TY - JOUR A1 - Gupta, Shishir K. A1 - Srivastava, Mugdha A1 - Osmanoglu, Özge A1 - Xu, Zhuofei A1 - Brakhage, Axel A. A1 - Dandekar, Thomas T1 - Aspergillus fumigatus versus genus Aspergillus: conservation, adaptive evolution and specific virulence genes JF - Microorganisms N2 - 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. KW - molecular evolution KW - phylogenetic analysis KW - adaptation KW - recombination KW - positive selection KW - human pathogenic fungi KW - genus Aspergillus KW - Aspergillus fumigatus Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246318 SN - 2076-2607 VL - 9 IS - 10 ER - TY - JOUR A1 - Kurotschka, Peter Konstantin A1 - Tiedemann, Elena A1 - Wolf, Dominik A1 - Thier, Nicola A1 - Forster, Johannes A1 - Liese, Johannes G. A1 - Gagyor, Ildiko T1 - Management of common infections in German primary care: a cross-sectional survey of knowledge and confidence among General Practitioners and outpatient pediatricians JF - Antibiotics N2 - 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. KW - infectious diseases management KW - general practitioner KW - pediatrician KW - primary care KW - outpatient KW - antibiotic use KW - antimicrobial resistance KW - antimicrobial stewardship KW - survey KW - knowledge Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246272 SN - 2079-6382 VL - 10 IS - 9 ER - TY - JOUR A1 - Heiling, Sven A1 - Knutti, Nadine A1 - Scherr, Franziska A1 - Geiger, Jörg A1 - Weikert, Juliane A1 - Rose, Michael A1 - Jahns, Roland A1 - Ceglarek, Uta A1 - Scherag, André A1 - Kiehntopf, Michael T1 - Metabolite ratios as quality indicators for pre-analytical variation in serum and EDTA plasma JF - Metabolites N2 - 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. KW - quality indicators KW - biomarker KW - hypoxanthine KW - inosine KW - guanosine KW - eicosanoids KW - time-to-centrifugation KW - pre-analytical variation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246261 SN - 2218-1989 VL - 11 IS - 9 ER - TY - JOUR A1 - Krist, Lilian A1 - Dornquast, Christina A1 - Reinhold, Thomas A1 - Icke, Katja A1 - Danquah, Ina A1 - Willich, Stefan N. A1 - Becher, Heiko A1 - Keil, Thomas T1 - Predictors of changes in physical activity and sedentary behavior during the COVID-19 pandemic in a Turkish migrant cohort in Germany JF - International Journal of Environmental Research and Public Health N2 - 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. KW - physical activity KW - sedentary behavior KW - COVID-19 KW - migrants KW - public health Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246176 SN - 1660-4601 VL - 18 IS - 18 ER - TY - JOUR A1 - Dech, Stefan A1 - Holzwarth, Stefanie A1 - Asam, Sarah A1 - Andresen, Thorsten A1 - Bachmann, Martin A1 - Boettcher, Martin A1 - Dietz, Andreas A1 - Eisfelder, Christina A1 - Frey, Corinne A1 - Gesell, Gerhard A1 - Gessner, Ursula A1 - Hirner, Andreas A1 - Hofmann, Matthias A1 - Kirches, Grit A1 - Klein, Doris A1 - Klein, Igor A1 - Kraus, Tanja A1 - Krause, Detmar A1 - Plank, Simon A1 - Popp, Thomas A1 - Reinermann, Sophie A1 - Reiners, Philipp A1 - Roessler, Sebastian A1 - Ruppert, Thomas A1 - Scherbachenko, Alexander A1 - Vignesh, Ranjitha A1 - Wolfmueller, Meinhard A1 - Zwenzner, Hendrik A1 - Kuenzer, Claudia T1 - Potential and challenges of harmonizing 40 years of AVHRR data: the TIMELINE experience JF - Remote Sensing N2 - 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. KW - AVHRR KW - Earth Observation KW - harmonization KW - time series analysis KW - climate related trends KW - automatic processing KW - Europe KW - TIMELINE Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246134 SN - 2072-4292 VL - 13 IS - 18 ER - TY - JOUR A1 - Brunkhorst-Kanaan, Nathalie A1 - Trautmann, Sandra A1 - Schreiber, Yannick A1 - Thomas, Dominique A1 - Kittel-Schneider, Sarah A1 - Gurke, Robert A1 - Geisslinger, Gerd A1 - Reif, Andreas A1 - Tegeder, Irmgard T1 - Sphingolipid and endocannabinoid profiles in adult attention deficit hyperactivity disorder JF - Biomedicines N2 - 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. KW - attention deficit hyperactivity disorder KW - endocannabinoids KW - ceramides KW - bipolar disorder KW - major depression KW - tandem mass spectrometry Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246080 SN - 2227-9059 VL - 9 IS - 9 ER - TY - JOUR A1 - Schneider, Verena A1 - Kruse, Daniel A1 - Bernardelli de Mattos, Ives A1 - Zöphel, Saskia A1 - Tiltmann, Kendra-Kathrin A1 - Reigl, Amelie A1 - Khan, Sarah A1 - Funk, Martin A1 - Bodenschatz, Karl A1 - Groeber-Becker, Florian T1 - A 3D in vitro model for burn wounds: monitoring of regeneration on the epidermal level JF - Biomedicines N2 - 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. KW - skin models KW - open-source epidermis KW - wound model KW - impedance spectroscopy KW - wound physiology KW - burn wound Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246068 SN - 2227-9059 VL - 9 IS - 9 ER - TY - JOUR A1 - Reiners, Philipp A1 - Asam, Sarah A1 - Frey, Corinne A1 - Holzwarth, Stefanie A1 - Bachmann, Martin A1 - Sobrino, Jose A1 - Göttsche, Frank-M. A1 - Bendix, Jörg A1 - Kuenzer, Claudia T1 - Validation of AVHRR Land Surface Temperature with MODIS and in situ LST — a TIMELINE thematic processor JF - Remote Sensing N2 - 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. KW - Land Surface Temperature KW - AVHRR KW - MODIS KW - time series KW - Europe KW - validation KW - TIMELINE Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246051 SN - 2072-4292 VL - 13 IS - 17 ER - TY - JOUR A1 - Lauruschkat, Chris D. A1 - Etter, Sonja A1 - Schnack, Elisabeth A1 - Ebel, Frank A1 - Schäuble, Sascha A1 - Page, Lukas A1 - Rümens, Dana A1 - Dragan, Mariola A1 - Schlegel, Nicolas A1 - Panagiotou, Gianni A1 - Kniemeyer, Olaf A1 - Brakhage, Axel A. A1 - Einsele, Hermann A1 - Wurster, Sebastian A1 - Loeffler, Juergen T1 - Chronic occupational mold exposure drives expansion of Aspergillus-reactive type 1 and type 2 T-helper cell responses JF - Journal of Fungi N2 - 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. KW - mold exposure KW - immunoassay KW - biomarker KW - Aspergillus KW - cytokines KW - inflammation KW - adaptive immunity KW - hypersensitivity Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245202 SN - 2309-608X VL - 7 IS - 9 ER - TY - JOUR A1 - Hayden, Markus C. A1 - Limbach, Matthias A1 - Schuler, Michael A1 - Merkl, Steffen A1 - Schwarzl, Gabriele A1 - Jakab, Katalin A1 - Nowak, Dennis A1 - Schultz, Konrad T1 - Effectiveness of a three-week inpatient pulmonary rehabilitation program for patients after COVID-19: a prospective observational study JF - International Journal of Environmental Research and Public Health N2 - 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. KW - COVID-19 KW - pulmonary rehabilitation KW - course of recovery KW - inpatient rehabilitation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245170 SN - 1660-4601 VL - 18 IS - 17 ER - TY - JOUR A1 - Scheiner, Ricarda A1 - Lim, Kayun A1 - Meixner, Marina D. A1 - Gabel, Martin S. T1 - Comparing the appetitive learning performance of six European honeybee subspecies in a common apiary JF - Insects N2 - 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. KW - adaptation KW - Apis mellifera KW - olfactory learning KW - proboscis extension response KW - sucrose responsiveness KW - genetic diversity Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245180 SN - 2075-4450 VL - 12 IS - 9 ER - TY - JOUR A1 - Dekant, Raphael A1 - Langer, Michael A1 - Lupp, Maria A1 - Adaku Chilaka, Cynthia A1 - Mally, Angela T1 - In vitro and in vivo analysis of ochratoxin A-derived glucuronides and mercapturic acids as biomarkers of exposure JF - Toxins N2 - 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. KW - ochratoxin A KW - biomarker of exposure KW - glucuronide KW - mercapturic acid KW - mycotoxin Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245146 SN - 2072-6651 VL - 13 IS - 8 ER - TY - JOUR A1 - Bothou, Christina A1 - Sharma, Ashish A1 - Oo, Adrian A1 - Kim, Baek A1 - Perge, Pal A1 - Igaz, Peter A1 - Ronchi, Cristina L. A1 - Shapiro, Igor A1 - Hantel, Constanze T1 - Novel insights into the molecular regulation of ribonucleotide reductase in adrenocortical carcinoma treatment JF - Cancers N2 - 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. KW - adrenocortical carcinoma KW - adrenocortical cell line KW - RRM2 KW - RNR KW - COH29 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245132 SN - 2072-6694 VL - 13 IS - 16 ER - TY - JOUR A1 - Wagner, Martin A1 - Slaghuis, Jörg A1 - Göbel, Werner A1 - Vázquez-Boland, José Antonio A1 - Rychli, Kathrin A1 - Schmitz-Esser, Stephan T1 - Virulence pattern analysis of three Listeria monocytogenes lineage I epidemic strains with distinct outbreak histories JF - Microorganisms N2 - 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. KW - pathogenicity KW - whole-genome analysis KW - prolonged survival Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245093 SN - 2076-2607 VL - 9 IS - 8 ER - TY - JOUR A1 - Willeke, Kristina A1 - Janson, Patrick A1 - Zink, Katharina A1 - Stupp, Carolin A1 - Kittel-Schneider, Sarah A1 - Berghöfer, Anne A1 - Ewert, Thomas A1 - King, Ryan A1 - Heuschmann, Peter U. A1 - Zapf, Andreas A1 - Wildner, Manfred A1 - Keil, Thomas T1 - Occurrence of mental illness and mental health risks among the self-employed: a systematic review JF - International Journal of Environmental Research and Public Health N2 - 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. KW - incidence KW - mental disorders KW - mental health KW - mental illness KW - prevalence KW - self-employed KW - small business KW - systematic review Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245085 SN - 1660-4601 VL - 18 IS - 16 ER - TY - JOUR A1 - Ban, Željka A1 - Karačić, Zrinka A1 - Tomić, Sanja A1 - Amini, Hashem A1 - Marder, Todd B. A1 - Piantanida, Ivo T1 - Triarylborane dyes as a novel non-covalent and non-inhibitive fluorimetric markers for DPP III enzyme JF - Molecules N2 - 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. KW - triarylborane KW - pyrene KW - click CuAAC synthesis KW - DPP III enzyme KW - BSA KW - fluorescence Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245046 SN - 1420-3049 VL - 26 IS - 16 ER - TY - JOUR A1 - Opolka, Alexander A1 - Müller, Dominik A1 - Fella, Christian A1 - Balles, Andreas A1 - Mohr, Jürgen A1 - Last, Arndt T1 - Multi-lens array full-field X-ray microscopy JF - Applied Sciences N2 - 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. KW - X-ray microscopy KW - full-field microscopy KW - compound refractive X-ray lenses KW - CRLs Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244974 SN - 2076-3417 VL - 11 IS - 16 ER - TY - JOUR A1 - Föcker, Manuel A1 - Timmesfeld, Nina A1 - Bühlmeier, Judith A1 - Zwanziger, Denise A1 - Führer, Dagmar A1 - Grasemann, Corinna A1 - Ehrlich, Stefan A1 - Egberts, Karin A1 - Fleischhaker, Christian A1 - Wewetzer, Christoph A1 - Wessing, Ida A1 - Seitz, Jochen A1 - Herpertz-Dahlmann, Beate A1 - Hebebrand, Johannes A1 - Libuda, Lars T1 - 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 JF - Nutrients N2 - (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. KW - vitamin D KW - supplements KW - anorexia nervosa KW - depressive symptoms KW - adolescents Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242662 SN - 2072-6643 VL - 13 IS - 7 ER - TY - JOUR A1 - Koch, Elias A. T. A1 - Petzold, Anne A1 - Wessely, Anja A1 - Dippel, Edgar A1 - Gesierich, Anja A1 - Gutzmer, Ralf A1 - Hassel, Jessica C. A1 - Haferkamp, Sebastian A1 - Hohberger, Bettina A1 - Kähler, Katharina C. A1 - Knorr, Harald A1 - Kreuzberg, Nicole A1 - Leiter, Ulrike A1 - Loquai, Carmen A1 - Meier, Friedegund A1 - Meissner, Markus A1 - Mohr, Peter A1 - Pföhler, Claudia A1 - Rahimi, Farnaz A1 - Schadendorf, Dirk A1 - Schell, Beatrice A1 - Schlaak, Max A1 - Terheyden, Patrick A1 - Thoms, Kai-Martin A1 - Schuler-Thurner, Beatrice A1 - Ugurel, Selma A1 - Ulrich, Jens A1 - Utikal, Jochen A1 - Weichenthal, Michael A1 - Ziller, Fabian A1 - Berking, Carola A1 - Heppt, Markus T1 - Immune checkpoint blockade for metastatic uveal melanoma: patterns of response and survival according to the presence of hepatic and extrahepatic metastasis JF - Cancers N2 - 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. KW - uveal melanoma KW - immune checkpoint blockade KW - PD-1 KW - CTLA-4 KW - liver metastasis KW - treatment resistance Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242603 SN - 2072-6694 VL - 13 IS - 13 ER - TY - JOUR A1 - Walther, Grit A1 - Zimmermann, Anna A1 - Theuersbacher, Johanna A1 - Kaerger, Kerstin A1 - Lilienfeld-Toal, Marie von A1 - Roth, Mathias A1 - Kampik, Daniel A1 - Geerling, Gerd A1 - Kurzai, Oliver T1 - Eye infections caused by filamentous fungi: spectrum and antifungal susceptibility of the prevailing agents in Germany JF - Journal of Fungi N2 - 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. KW - eye infection KW - fungal infection KW - keratitis KW - antifungal susceptibility KW - natamycin KW - Fusarium KW - Purpureocillium KW - Aspergillus KW - Alternaria KW - Scedosporium Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241810 SN - 2309-608X VL - 7 IS - 7 ER - TY - JOUR A1 - Haider, Malik Salman A1 - Ahmad, Taufiq A1 - Yang, Mengshi A1 - Hu, Chen A1 - Hahn, Lukas A1 - Stahlhut, Philipp A1 - Groll, Jürgen A1 - Luxenhofer, Robert T1 - Tuning the thermogelation and rheology of poly(2-oxazoline)/poly(2-oxazine)s based thermosensitive hydrogels for 3D bioprinting JF - Gels N2 - 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. KW - poly(2-ethyl-2-oxazoline) KW - shear thinning KW - shape fidelity KW - cyto-compatibility KW - bio-printability Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241781 SN - 2310-2861 VL - 7 IS - 3 ER - TY - JOUR A1 - Breil, Christina A1 - Kanske, Philipp A1 - Pittig, Roxana A1 - Böckler, Anne T1 - A revised instrument for the assessment of empathy and Theory of Mind in adolescents: Introducing the EmpaToM-Y JF - Behavior Research Methods N2 - 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. KW - empathy KW - Theory of Mind KW - social cognition KW - social understanding KW - mentalizing KW - asolescence KW - development Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-302877 VL - 53 ER - TY - JOUR A1 - Schrader, Nikolas A1 - Riese, Thorsten A1 - Kurlbaum, Max A1 - Meybohm, Patrick A1 - Kredel, Markus A1 - Surat, Güzin A1 - Scherf-Clavel, Oliver A1 - Strate, Alexander A1 - Pospiech, Andreas A1 - Hoppe, Kerstin T1 - Personalized antibiotic therapy for the critically ill: Implementation strategies and effects on clinical outcome of piperacillin therapeutic drug monitoring — a descriptive retrospective analysis JF - Antibiotics N2 - 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. KW - therapeutic drug monitoring KW - piperacillin/tazobactam KW - personalized antimicrobial therapy KW - antimicrobial stewardship Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250052 SN - 2079-6382 VL - 10 IS - 12 ER - TY - JOUR A1 - Schlauersbach, Jonas A1 - Hanio, Simon A1 - Lenz, Bettina A1 - Vemulapalli, Sahithya P. B. A1 - Griesinger, Christian A1 - Pöppler, Ann-Christin A1 - Harlacher, Cornelius A1 - Galli, Bruno A1 - Meinel, Lorenz T1 - Leveraging bile solubilization of poorly water-soluble drugs by rational polymer selection JF - Journal of Controlled Release N2 - 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. KW - polymer drug interaction KW - flux KW - bile salt KW - simulated intestinal fluid KW - colloid Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-296957 VL - 330 ET - Accepted Version ER - TY - JOUR A1 - Tongsomporn, Janyarak A1 - Wananiyakul, Saeree A1 - Steuding, Jörn T1 - The values of the periodic zeta-function at the nontrivial zeros of Riemann's zeta-function JF - Symmetry N2 - 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. KW - zeta-functions KW - Riemann hypothesis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252261 SN - 2073-8994 VL - 13 IS - 12 ER - TY - JOUR A1 - Rodrigues, Johannes A1 - Marzban, Dorna A1 - Hewig, Johannes T1 - 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 JF - Symmetry N2 - 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. KW - mental rotation KW - expertise in visual imagery KW - pen and paper vs. computer role-players KW - midline frontal theta band frequency activation KW - parietal alpha band frequency activation KW - gender influence KW - EEG Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252253 SN - 2073-8994 VL - 13 IS - 12 ER - TY - JOUR A1 - Stanley, Jean-Daniel A1 - Ullmann, Tobias A1 - Lange-Athinodorou, Eva T1 - Holocene aridity-induced interruptions of human activity along a fluvial channel in Egypt's northern delta JF - Quaternary N2 - Geoarchaeological information presented here pertains to a subsidiary Nile channel that once flowed west of the main Sebennitic distributary and discharged its water and sediments at Egypt’s then north-central deltaic coast. Periodical paleoclimatic episodes during the later Middle and Upper Holocene included decreased rainfall and increased aridity that reduced the Nile’s flow levels and thus likely disrupted nautical transport and anthropogenic activity along this channel. Such changes in this deltaic sector, positioned adjacent to the Levantine Basin in the Eastern Mediterranean, can be attributed to climatic shifts triggered as far as the North Atlantic to the west, and African highland source areas of the Egyptian Nile to the south. Of special interest in a study core recovered along the channel are several sediment sequences without anthropogenic material that are interbedded between strata comprising numerous potsherds. The former are interpreted here as markers of increased regional aridity and reduced Nile flow which could have periodically disrupted the regional distribution of goods and nautical activities. Such times occurred ~5000 years B.P., ~4200–4000 years B.P., ~3200–2800 years B.P., ~2300–2200 years B.P., and more recently. Periods comparable to these are also identified by altered proportions of pollen, isotopic and compositional components in different radiocarbon-dated Holocene cores recovered elsewhere in the Nile delta, the Levantine region to the east and north of Egypt, and in the Faiyum depression south of the delta. KW - Nile delta KW - Sebennitic KW - paleoenvironment KW - paleoclimate KW - Nile flow KW - geoarchaeology Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250285 SN - 2571-550X VL - 4 IS - 4 ER - TY - JOUR A1 - Jakuscheit, Axel A1 - Schaefer, Nina A1 - Roedig, Johannes A1 - Luedemann, Martin A1 - Hertzberg-Boelch, Sebastian Philipp von A1 - Weissenberger, Manuel A1 - Schmidt, Karsten A1 - Holzapfel, Boris Michael A1 - Rudert, Maximilian T1 - Modifiable individual risks of perioperative blood transfusions and acute postoperative complications in total hip and knee arthroplasty JF - Journal of Personalized Medicine N2 - Background: The primary aim of this study was to identify modifiable patient-related predictors of blood transfusions and perioperative complications in total hip and knee arthroplasty. Individual predictor-adjusted risks can be used to define preoperative treatment thresholds. Methods: We performed this retrospective monocentric study in orthopaedic patients who underwent primary total knee or hip arthroplasty. Multivariate logistic regression models were used to assess the predictive value of patient-related characteristics. Predictor-adjusted individual risks of blood transfusions and the occurrence of any perioperative adverse event were calculated for potentially modifiable risk factors. Results: 3754 patients were included in this study. The overall blood transfusion and complication rates were 4.8% and 6.4%, respectively. Haemoglobin concentration (Hb, p < 0.001), low body mass index (BMI, p < 0.001) and estimated glomerular filtration rate (eGFR, p = 0.004) were the strongest potentially modifiable predictors of a blood transfusion. EGFR (p = 0.001) was the strongest potentially modifiable predictor of a complication. Predictor-adjusted risks of blood transfusions and acute postoperative complications were calculated for Hb and eGFR. Hb = 12.5 g/dL, BMI = 17.6 kg/m\(^2\), and eGFR = 54 min/mL were associated, respectively, with a 10% risk of a blood transfusion, eGFR = 59 mL/min was associated with a 10% risk of a complication. Conclusion: The individual risks for blood transfusions and acute postoperative complications are strongly increased in patients with a low preoperative Hb, low BMI or low eGFR. We recommend aiming at a preoperative Hb ≥ 13g/dL, an eGFR ≥ 60 mL/min and to avoid a low BMI. Future studies must show if a preoperative increase of eGFR and BMI is feasible and truly beneficial. KW - patient blood management KW - total joint arthroplasty KW - haemoglobin KW - perioperative management Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250290 SN - 2075-4426 VL - 11 IS - 11 ER - TY - JOUR A1 - Ziegler, Mirjam A1 - Kaiser, Anna A1 - Igel, Christine A1 - Geissler, Julia A1 - Mechler, Konstantin A1 - Holz, Nathalie E. A1 - Becker, Katja A1 - Döpfner, Manfred A1 - Romanos, Marcel A1 - Brandeis, Daniel A1 - Hohmann, Sarah A1 - Millenet, Sabina A1 - Banaschewski, Tobias T1 - Actigraphy-derived sleep profiles of children with and without attention-deficit/hyperactivity disorder (ADHD) over two weeks — comparison, precursor symptoms, and the chronotype JF - Brain Sciences N2 - Although sleep problems are common in children with ADHD, their extent, preceding risk factors, and the association between neurocognitive performance and neurobiological processes in sleep and ADHD, are still largely unknown. We examined sleep variables in school-aged children with ADHD, addressing their intra-individual variability (IIV) and considering potential precursor symptoms as well as the chronotype. Additionally, in a subgroup of our sample, we investigated associations with neurobehavioral functioning (n = 44). A total of 57 children (6–12 years) with (n = 24) and without ADHD (n = 33) were recruited in one center of the large ESCAlife study to wear actigraphs for two weeks. Actigraphy-derived dependent variables, including IIV, were analyzed using linear mixed models in order to find differences between the groups. A stepwise regression model was used to investigate neuropsychological function. Overall, children with ADHD showed longer sleep onset latency (SOL), higher IIV in SOL, more movements during sleep, lower sleep efficiency, and a slightly larger sleep deficit on school days compared with free days. No group differences were observed for chronotype or sleep onset time. Sleep problems in infancy predicted later SOL and the total number of movements during sleep in children with and without ADHD. No additional effect of sleep problems, beyond ADHD symptom severity, on neuropsychological functioning was found. This study highlights the importance of screening children with ADHD for current and early childhood sleep disturbances in order to prevent long-term sleep problems and offer individualized treatments. Future studies with larger sample sizes should examine possible biological markers to improve our understanding of the underlying mechanisms. KW - sleep KW - actigraphy KW - attention-deficit/hyperactivity disorder (ADHD) KW - intra-individual variability (IIV) KW - chronotype KW - children KW - continuous performance task (CPT) KW - precursor symptoms KW - ESCAlife Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250084 SN - 2076-3425 VL - 11 IS - 12 ER - TY - JOUR A1 - Schmitt, T. A1 - Egu, D.T. A1 - Walter, E. A1 - Sigmund, A.M. A1 - Eichkorn, R. A1 - Yazdi, A. A1 - Schmidt, E. A1 - Sárdy, M. A1 - Eming, R. A1 - Goebeler, M. A1 - Waschke, J. T1 - Ca\(^{2+}\) signalling is critical for autoantibody‐induced blistering of human epidermis in pemphigus JF - British Journal of Dermatology N2 - Background Pemphigus is a severe bullous autoimmune skin disease. Pemphigus foliaceus (PF) is characterized by antidesmoglein (Dsg) 1 IgG causing epidermal blistering; mucosal pemphigus vulgaris (mPV) by anti‐Dsg3 IgG inducing erosions in the mucosa; and mucocutaneous pemphigus vulgaris (PV) by affecting both, with autoantibodies targeting Dsg1 and Dsg3. Objectives To characterize the Ca\(^{2+}\) flux pathway and delineate its importance in pemphigus pathogenesis and clinical phenotypes caused by different antibody profiles. Methods Immunoprecipitation, Ca\(^{2+}\) flux analysis, Western blotting, immunofluorescence staining, dissociation assays and a human skin ex vivo model were used. Results PV IgG and PF IgG, but neither Dsg3‐specific monoclonal antibody (AK23) nor mPV IgG, caused Ca\(^{2+}\) influx in primary human keratinocytes. Phosphatidylinositol 4‐kinase α interacts with Dsg1 but not with Dsg3. Its downstream target – phospholipase‐C‐γ1 (PLC) – was activated by PV IgG and PF IgG but not AK23 or mPV IgG. PLC releases inositol 1,4,5‐trisphosphate (IP3) causing IP3 receptor (IP3R) activation and Ca2+ flux from the endoplasmic reticulum into the cytosol, which stimulates Ca2+ release‐activated channels (CRAC)‐mediated Ca\(^{2+}\) influx. Inhibitors against PLC, IP3R and CRAC effectively blocked PV IgG and PF IgG‐induced Ca\(^{2+}\) influx; ameliorated alterations of Dsg1 and Dsg3 localization, and reorganization of keratin and actin filaments; and inhibited loss of cell adhesion in vitro. Finally, inhibiting PLC or IP3R was protective against PV IgG‐induced blister formation and redistribution of Dsg1 and Dsg3 in human skin ex vivo. Conclusions Ca2+‐mediated signalling is important for epidermal blistering and dependent on the autoantibody profile, which indicates different roles for signalling complexes organized by Dsg1 and Dsg3. Interfering with PLC and Ca\(^{2+}\) signalling may be a promising approach to treat epidermal manifestations of pemphigus. KW - pemphigus KW - epidermis KW - Ca\(^{2+}\) signalling Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262810 VL - 185 IS - 3 SP - 595 EP - 604 ER - TY - JOUR A1 - Reif, Magnus A1 - Tesfaselassie, Mewael F. A1 - Wolters, Maik H. T1 - Technological Growth and Hours in the Long Run: Theory and Evidence JF - Economica N2 - Over the last few decades, hours worked per capita have declined substantially in many OECD economies. Using the standard neoclassical growth model with endogenous work–leisure choice, we assess the role of trend growth slowdown in accounting for the decline in hours worked. In the model, a permanent reduction in technological growth decreases steady‐state hours worked by increasing the consumption–output ratio. Our empirical analysis exploits cross‐country variation in the timing and size of the decline in technological growth to show that technological growth has a highly significant positive effect on hours. A decline in the long‐run trend of technological growth by 1 percentage point is associated with a decline in trend hours worked in the range of 1–3%. This result is robust to controlling for taxes, which have been found in previous studies to be an important determinant of hours. Our empirical finding is quantitatively in line with the one implied by a calibrated version of the model, though evidence for the model’s implication that the effect on hours works via changes in the consumption–output ratio is rather mixed. KW - technological growth KW - working hours KW - neoclassical growth model Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262801 VL - 88 IS - 352 SP - 1016 EP - 1053 ER - TY - JOUR A1 - Dorner, Daniela A1 - Mostafá, Miguel A1 - Satalecka, Konstancja T1 - High-energy alerts in the multi-messenger era JF - Universe N2 - The observation of electromagnetic counterparts to both high energy neutrinos and gravitational waves marked the beginning of a new era in astrophysics. The multi-messenger approach allows us to gain new insights into the most energetic events in the Universe such as gamma-ray bursts, supernovas, and black hole mergers. Real-time multi-messenger alerts are the key component of the observational strategies to unravel the transient signals expected from astrophysical sources. Focusing on the high-energy regime, we present a historical perspective of multi-messenger observations, the detectors and observational techniques used to study them, the status of the multi-messenger alerts and the most significant results, together with an overview of the future prospects in the field. KW - multi-messenger KW - real-time KW - high-energy KW - alerts Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248496 SN - 2218-1997 VL - 7 IS - 11 ER - TY - JOUR A1 - Morais, António P. A1 - Pasechnik, Roman A1 - Porod, Werner T1 - Grand Unified origin of gauge interactions and families replication in the Standard Model JF - Universe N2 - The tremendous phenomenological success of the Standard Model (SM) suggests that its flavor structure and gauge interactions may not be arbitrary but should have a fundamental first-principle explanation. In this work, we explore how the basic distinctive properties of the SM dynamically emerge from a unified New Physics framework tying together both flavor physics and Grand Unified Theory (GUT) concepts. This framework is suggested by a novel anomaly-free supersymmetric chiral E\(_6\)×SU(2)\(_F\)×U(1)\(_F\) GUT containing the SM. Among the most appealing emergent properties of this theory is the Higgs-matter unification with a highly-constrained massless chiral sector featuring two universal Yukawa couplings close to the GUT scale. At the electroweak scale, the minimal SM-like effective field theory limit of this GUT represents a specific flavored three-Higgs doublet model consistent with the observed large hierarchies in the quark mass spectra and mixing already at tree level. KW - grand unified theories KW - supersymmetry KW - phenomenology of New Physics Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250237 SN - 2218-1997 VL - 7 IS - 12 ER - TY - JOUR A1 - Boulos, Joelle C. A1 - Saeed, Mohamed E. M. A1 - Chatterjee, Manik A1 - Bülbül, Yagmur A1 - Crudo, Francesco A1 - Marko, Doris A1 - Munder, Markus A1 - Klauck, Sabine M. A1 - Efferth, Thomas T1 - Repurposing of the ALK inhibitor crizotinib for acute leukemia and multiple myeloma cells JF - Pharmaceuticals N2 - Crizotinib was a first generation of ALK tyrosine kinase inhibitor approved for the treatment of ALK-positive non-small-cell lung carcinoma (NSCLC) patients. COMPARE and cluster analyses of transcriptomic data of the NCI cell line panel indicated that genes with different cellular functions regulated the sensitivity or resistance of cancer cells to crizotinib. Transcription factor binding motif analyses in gene promoters divulged two transcription factors possibly regulating the expression of these genes, i.e., RXRA and GATA1, which are important for leukemia and erythroid development, respectively. COMPARE analyses also implied that cell lines of various cancer types displayed varying degrees of sensitivity to crizotinib. Unexpectedly, leukemia but not lung cancer cells were the most sensitive cells among the different types of NCI cancer cell lines. Re-examining this result in another panel of cell lines indeed revealed that crizotinib exhibited potent cytotoxicity towards acute myeloid leukemia and multiple myeloma cells. P-glycoprotein-overexpressing CEM/ADR5000 leukemia cells were cross-resistant to crizotinib. NCI-H929 multiple myeloma cells were the most sensitive cells. Hence, we evaluated the mode of action of crizotinib on these cells. Although crizotinib is a TKI, it showed highest correlation rates with DNA topoisomerase II inhibitors and tubulin inhibitors. The altered gene expression profiles after crizotinib treatment predicted several networks, where TOP2A and genes related to cell cycle were downregulated. Cell cycle analyses showed that cells incubated with crizotinib for 24 h accumulated in the G\(_2\)M phase. Crizotinib also increased the number of p-H3(Ser10)-positive NCI-H929 cells illustrating crizotinib's ability to prevent mitotic exit. However, cells accumulated in the sub-G\(_0\)G\(_1\) fraction with longer incubation periods, indicating apoptosis induction. Additionally, crizotinib disassembled the tubulin network of U2OS cells expressing an α-tubulin-GFP fusion protein, preventing migration of cancer cells. This result was verified by in vitro tubulin polymerization assays. In silico molecular docking also revealed a strong binding affinity of crizotinib to the colchicine and Vinca alkaloid binding sites. Taken together, these results demonstrate that crizotinib destabilized microtubules. Additionally, the decatenation assay showed that crizotinib partwise inhibited the catalytic activity of DNA topoisomerase II. In conclusion, crizotinib exerted kinase-independent cytotoxic effects through the dual inhibition of tubulin polymerization and topoisomerase II and might be used to treat not only NSCLC but also multiple myeloma. KW - acute myeloid leukemia KW - drug repurposing KW - multiple myeloma KW - network pharmacology KW - transcriptomics KW - tyrosine kinase inhibitors Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250258 SN - 1424-8247 VL - 14 IS - 11 ER - TY - JOUR A1 - Pirner, Marlies T1 - A review on BGK models for gas mixtures of mono and polyatomic molecules JF - Fluids N2 - We consider the Bathnagar–Gross–Krook (BGK) model, an approximation of the Boltzmann equation, describing the time evolution of a single momoatomic rarefied gas and satisfying the same two main properties (conservation properties and entropy inequality). However, in practical applications, one often has to deal with two additional physical issues. First, a gas often does not consist of only one species, but it consists of a mixture of different species. Second, the particles can store energy not only in translational degrees of freedom but also in internal degrees of freedom such as rotations or vibrations (polyatomic molecules). Therefore, here, we will present recent BGK models for gas mixtures for mono- and polyatomic particles and the existing mathematical theory for these models. KW - multi-fluid mixture KW - kinetic model KW - BGK approximation KW - degrees of freedom in internal energy KW - existence of solutions KW - large-time behaviour Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250161 SN - 2311-5521 VL - 6 IS - 11 ER - TY - JOUR A1 - Hellmuth, Kathrin A1 - Klingenberg, Christian A1 - Li, Qin A1 - Tang, Min T1 - Multiscale convergence of the inverse problem for chemotaxis in the Bayesian setting JF - Computation N2 - Chemotaxis describes the movement of an organism, such as single or multi-cellular organisms and bacteria, in response to a chemical stimulus. Two widely used models to describe the phenomenon are the celebrated Keller–Segel equation and a chemotaxis kinetic equation. These two equations describe the organism's movement at the macro- and mesoscopic level, respectively, and are asymptotically equivalent in the parabolic regime. The way in which the organism responds to a chemical stimulus is embedded in the diffusion/advection coefficients of the Keller–Segel equation or the turning kernel of the chemotaxis kinetic equation. Experiments are conducted to measure the time dynamics of the organisms' population level movement when reacting to certain stimulation. From this, one infers the chemotaxis response, which constitutes an inverse problem. In this paper, we discuss the relation between both the macro- and mesoscopic inverse problems, each of which is associated with two different forward models. The discussion is presented in the Bayesian framework, where the posterior distribution of the turning kernel of the organism population is sought. We prove the asymptotic equivalence of the two posterior distributions. KW - inverse problems KW - Bayesian approach KW - kinetic chemotaxis equation KW - Keller–Segel model KW - multiscale modeling KW - asymptotic analysis KW - velocity jump process KW - mathematical biology Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250216 SN - 2079-3197 VL - 9 IS - 11 ER - TY - JOUR A1 - Rokhafrouz, Mohammad A1 - Latifi, Hooman A1 - Abkar, Ali A. A1 - Wojciechowski, Tomasz A1 - Czechlowski, Mirosław A1 - Naieni, Ali Sadeghi A1 - Maghsoudi, Yasser A1 - Niedbała, Gniewko T1 - Simplified and hybrid remote sensing-based delineation of management zones for nitrogen variable rate application in wheat JF - Agriculture N2 - Enhancing digital and precision agriculture is currently inevitable to overcome the economic and environmental challenges of the agriculture in the 21st century. The purpose of this study was to generate and compare management zones (MZ) based on the Sentinel-2 satellite data for variable rate application of mineral nitrogen in wheat production, calculated using different remote sensing (RS)-based models under varied soil, yield and crop data availability. Three models were applied, including (1) a modified “RS- and threshold-based clustering”, (2) a “hybrid-based, unsupervised clustering”, in which data from different sources were combined for MZ delineation, and (3) a “RS-based, unsupervised clustering”. Various data processing methods including machine learning were used in the model development. Statistical tests such as the Paired Sample T-test, Kruskal–Wallis H-test and Wilcoxon signed-rank test were applied to evaluate the final delineated MZ maps. Additionally, a procedure for improving models based on information about phenological phases and the occurrence of agricultural drought was implemented. The results showed that information on agronomy and climate enables improving and optimizing MZ delineation. The integration of prior knowledge on new climate conditions (drought) in image selection was tested for effective use of the models. Lack of this information led to the infeasibility of obtaining optimal results. Models that solely rely on remote sensing information are comparatively less expensive than hybrid models. Additionally, remote sensing-based models enable delineating MZ for fertilizer recommendations that are temporally closer to fertilization times. KW - precision agriculture KW - management zones KW - remote sensing KW - Sentinel-2 KW - clustering KW - winter wheat KW - drought KW - digital agriculture Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250033 SN - 2077-0472 VL - 11 IS - 11 ER - TY - JOUR A1 - Rapp, Christina K. A1 - Van Dijck, Ine A1 - Laugwitz, Lucia A1 - Boon, Mieke A1 - Briassoulis, George A1 - Ilia, Stavroula A1 - Kammer, Birgit A1 - Reu, Simone A1 - Hornung, Stefanie A1 - Buchert, Rebecca A1 - Sofan, Linda A1 - Froukh, Tawfiq A1 - Witters, Peter A1 - Rymen, Daisy A1 - Haack, Tobias B. A1 - Proesmans, Marijke A1 - Griese, Matthias T1 - Expanding the phenotypic spectrum of FINCA (fibrosis, neurodegeneration, and cerebral angiomatosis) syndrome beyond infancy JF - Clinical Genetics N2 - Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA, MIM#618278) is a rare clinical condition caused by bi‐allelic variants in NHL repeat containing protein 2 (NHLRC2, MIM*618277). Pulmonary disease may be the presenting sign and the few patients reported so far, all deceased in early infancy. Exome sequencing was performed on patients with childhood interstitial lung disease (chILD) and additional neurological features. The chILD‐EU register database and an in‐house database were searched for patients with NHLRC2 variants and clinical features overlapping FINCA syndrome. Six patients from three families were identified with bi‐allelic variants in NHLRC2. Two of these children died before the age of two while four others survived until childhood. Interstitial lung disease was pronounced in almost all patients during infancy and stabilized over the course of the disease with neurodevelopmental delay (NDD) evolving as the key clinical finding. We expand the phenotype of FINCA syndrome to a multisystem disorder with variable severity. FINCA syndrome should also be considered in patients beyond infancy with NDD and a history of distinct interstitial lung disease. Managing patients in registers for rare diseases helps identifying new diagnostic entities and advancing care for these patients. KW - cerebropulmonary disease KW - childhood interstitial lung disease KW - cholesterol pneumonia KW - FINCA KW - lung fibrosis KW - lipoid pneumonitis KW - multi‐organ disease KW - NHLRC2 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262732 VL - 100 IS - 4 SP - 453 EP - 461 ER - TY - JOUR A1 - Kann, Simone A1 - Blessmann, Joerg A1 - Winkelmann, Yvonne A1 - Hansen, Jessica A1 - Maya Amaya, Leonardo J. A1 - Rivera Salcedo, Gadith E. A1 - Halas, Hussein El A1 - Schmidt‐Chanasit, Jonas A1 - Keoviengkhone, Latdamone A1 - Sopraseuth, Vatsana A1 - Deschermeier, Christina A1 - Mika, Angela T1 - Dengue virus detection in Lao PDR and Colombia: Comparative evaluation of PCR tests JF - Tropical Medicine & International Health N2 - Objectives Dengue virus (DENV) detection by polymerase chain reaction (PCR) facilitates diagnosis of dengue fever, which is the most frequent arboviral disease globally. Two studies were performed in countries with high dengue incidence, to assess the diagnostic performance of different PCR techniques. Methods/Results Two hundred and seventy‐nine acute phase blood samples from febrile patients were analyzed for DENV by the RealStar Dengue RT‐PCR kit (Altona Diagnostics) as gold standard in comparison with the Tropical Fever Core multiplex PCR (Fast Track Diagnostics). In total, 102 samples collected in Savannakhet Province (Lao PDR, Southeast Asia) in 2013 and 35 samples from Valledupar (Colombia, South America) tested positive for DENV by RealStar RT‐PCR. In comparison, the Tropical Fever Core multiplex PCR detected 65.0% (65/102) and 68.6% (24/35) of these samples as positive for DENV in Savannakhet and Valledupar, respectively. Diagnostic sensitivity of the multiplex PCR strongly correlated with viral load. A subset of DENV PCR‐confirmed samples was additionally tested by BNITM in house Dengue Type RT‐PCR in comparison with two commercial test kits (RealStar Dengue Type RT‐PCR [Altona Diagnostics], Dengue differentiation PCR [Fast Track Diagnostics]). The leading dengue serotype in Savannakhet was DENV‐3 (58% [29/50]), while DENV‐1 (53.8% [14/26]) was the predominant serotype found in samples collected in Valledupar by BNITM‐type PCR. However, three DENV serotypes were circulating in Valledupar and in Savannakhet. In 2015, additional studies found predominantly DENV‐4 (71% [12/17]) in Savannakhet. Conclusions Both studies emphasized that routine diagnostics in both regions will benefit from an expanded use of highly sensitive pan‐dengue PCRs. KW - Colombia KW - dengue infections KW - dengue serotypes KW - Lao PDR KW - PCR diagnostics Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262703 VL - 26 IS - 10 SP - 1296 EP - 1302 ER - TY - JOUR A1 - Asch, Silke A1 - Kaufmann, Tobias Peter A1 - Walter, Michaela A1 - Leistner, Marcus A1 - Danner, Bernd C. A1 - Perl, Thorsten A1 - Kutschka, Ingo A1 - Niehaus, Heidi T1 - The effect of perioperative hemadsorption in patients operated for acute infective endocarditis—A randomized controlled study JF - Artificial Organs N2 - Patients operated for infective endocarditis (IE) are at high risk of developing an excessive systemic hyperinflammatory state, resulting in systemic inflammatory response syndrome and septic shock. Hemoadsorption (HA) by cytokine adsorbers has been successfully applied to remove inflammatory mediators. This randomized controlled trial investigates the effect of perioperative HA therapy on inflammatory parameters and hemodynamic status in patients operated for IE. A total of 20 patients were randomly assigned to either HA therapy or the control group. HA therapy was initiated intraoperatively and continued for 24 hours postoperatively. Cytokine levels (IL‐6, IL‐1b, TNF‐α), leukocytes, C‐reactive protein (CRP), and Procalcitonin (PCT) as well as catecholamine support, and volume requirement were compared between both groups. Operative procedures included aortic (n = 7), mitral (n = 6), and multiple valve surgery (n = 7). All patients survived to discharge. No significant differences concerning median cytokine levels (IL‐6 and TNF‐α) were observed between both groups. CRP and PCT baseline levels were significantly higher in the HA group (59.5 vs. 26.3 mg/dL, P = .029 and 0.17 vs. 0.05 µg/L, P = .015) equalizing after surgery. Patients in the HA group required significantly higher doses of vasopressors (0.093 vs. 0.025 µg/kg/min norepinephrine, P = .029) at 12 hours postoperatively as well as significantly more overall volume replacement (7217 vs. 4185 mL at 12 hours, P = .015; 12 021 vs. 4850 mL at 48 hours, P = .015). HA therapy did neither result in a reduction of inflammatory parameters nor result in an improvement of hemodynamic parameters in patients operated for IE. For a more targeted use of HA therapy, appropriate selection criteria are required. KW - cytokines KW - endocarditis KW - hemadsorption KW - sepsis KW - SIRS Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262681 VL - 45 IS - 11 SP - 1328 EP - 1337 ER - TY - JOUR A1 - Glöggler, Julia C. A1 - Hellmann, Daniel A1 - Von Manstein, Maja A1 - Jäger, Rudolph A1 - Repky, Stefan A1 - Beyersmann, Jan A1 - Lapatki, Bernd G. T1 - Motor learning might contribute to a therapeutic anterior shift of the habitual mandibular position—An exploratory study JF - Journal of Oral Rehabilitation N2 - Background Passive mandibular advancement with functional appliances is commonly used to treat juvenile patients with mandibular retrognathism. Objective The aim of this study was to investigate whether active repetitive training of the mandible into an anterior position would result in a shift of the habitual mandibular position (HMP). Methods Twenty adult healthy subjects were randomly assigned to one of two groups: a training group receiving six supervised functional training sessions of 10 min each and a control group without training. Bonded lateral biteplates disengaged occlusion among both groups throughout the 15‐day experiment. Customised registration‐training appliances consisted of a maxillary component with an anterior plane and a mandibular component with an attached metal sphere. Training sessions consisted of repeated mouth‐opening/closing cycles (frequency: 30/min) to hit an anteriorly positioned hemispherical target notch with this metal sphere. The HMP was registered at defined times during the experiment. Results The HMP in the training group showed a statistically significant anterior shift of 1.6 mm (interquartile range [IQR]: 1.2 mm), compared with a significant posterior shift of −0.8 mm (IQR: 2.8 mm) in the control group (p < .05). Although the anterior shift among the training group showed a partial relapse 4 days after the first training block, it then advanced slightly in the 4‐day interval after the second training block, which might indicate neuroplasticity of the masticatory motor system. Conclusions Motor learning by repetitive training of the mandible into an anterior position might help to improve the results of functional appliance therapy among patients with mandibular retrognathism. KW - mandibular advancement KW - mandibular shift KW - masticatory system KW - motor training KW - mandibular resting position KW - habitual mandibular position KW - masticatory muscles KW - motor skill learning Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262644 VL - 48 IS - 8 SP - 891 EP - 900 ER - TY - JOUR A1 - Schulz, Ninja T1 - Auxiliary DO in Asian Englishes JF - World Englishes N2 - To indicate emphasis, auxiliary do is used in affirmative contexts (do+) when no other auxiliary is present. It is thus rooted in the grammatical system of do‐support; however, do+ does not always bear stress and can fulfil various discourse‐marking functions (Nevalainen & Rissanen, 1986). Positioned at the intersection of grammar and discourse, do+ constitutes an interesting study for its use in ‘non‐native’ varieties of English since it can be assumed that the more salient grammatical functions are easier to master for learners. Focusing on Asian Englishes in contrast to Inner Circle varieties, this exploratory paper assesses the frequency and distribution of do+ in the spoken and written parts of eight ICE components. KW - auxiliary DO KW - Asian Englishes KW - grammar Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262630 VL - 40 IS - 4 SP - 502 EP - 518 ER - TY - JOUR A1 - Lombardi, Jolina A1 - Mayer, Benjamin A1 - Semler, Elisa A1 - Anderl‐Straub, Sarah A1 - Uttner, Ingo A1 - Kassubek, Jan A1 - Diehl‐Schmid, Janine A1 - Danek, Adrian A1 - Levin, Johannes A1 - Fassbender, Klaus A1 - Fliessbach, Klaus A1 - Schneider, Anja A1 - Huppertz, Hans‐Jürgen A1 - Jahn, Holger A1 - Volk, Alexander A1 - Kornhuber, Johannes A1 - Landwehrmeyer, Bernhard A1 - Lauer, Martin A1 - Prudlo, Johannes A1 - Wiltfang, Jens A1 - Schroeter, Matthias L. A1 - Ludolph, Albert A1 - Otto, Markus T1 - Quantifying progression in primary progressive aphasia with structural neuroimaging JF - Alzheimer's & Dementia N2 - Introduction The term primary progressive aphasia (PPA) sums up the non‐fluent (nfv), the semantic (sv), and the logopenic (lv) variant. Up to now, there is only limited data available concerning magnetic resonance imaging volumetry to monitor disease progression. Methods Structural brain imaging and an extensive assessment were applied at baseline and up to 4‐year(s) follow‐up in 269 participants. With automated atlas‐based volumetry 56 brain regions were assessed. Atrophy progression served to calculate sample sizes for therapeutic trials. Results At baseline highest atrophy appeared in parts of the left frontal lobe for nfvPPA (–17%) and of the left temporal lobe for svPPA (–34%) and lvPPA (–24%). Severest progression within 1‐year follow‐up occurred in the basal ganglia in nfvPPA (–7%), in the hippocampus/amygdala in svPPA (–9%), and in (medial) temporal regions in lvPPA (–6%). Conclusion PPA presents as a left‐dominant, mostly gray matter sensitive disease with considerable atrophy at baseline that proceeds variant‐specific. KW - atlas‐based volumetry KW - disease progression KW - frontotemporal dementia KW - longitudinal magnetic resonance imaging KW - primary progressive aphasia KW - sample size calculation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262605 VL - 17 IS - 10 SP - 1595 EP - 1609 ER - TY - JOUR A1 - Krämer, Felix A1 - Luff, Martin S. A1 - Radius, Udo A1 - Weigend, Florian A1 - Breher, Frank T1 - NON‐Ligated N‐Heterocyclic Tetrylenes JF - European Journal of Inorganic Chemistry N2 - We report on the synthesis of N‐heterocyclic tetrylenes ligated by the NON‐donor framework 4,5‐bis(2,6‐diisopropylphenyl‐amino)‐2,7‐di‐tert‐butyl‐9,9‐dimethylxanthene. The molecular structures of the germylene (3), stannylene (4) and plumbylene (5) where determined by X‐ray diffraction studies. Furthermore, we present quantum chemical studies on the σ‐donor and π‐acceptor properties of 3–5. Additionally, we report on the reactivity of the tetrylenes towards the transition metal carbonyls [Rh(CO)\(_{2}\)Cl]\(_{2}\), [W(CO)\(_{6}\)] and [Ni(CO)\(_{4}\)]. The isolated complexes (6 and 7) show the differing reactivity of NHTs compared to NHCs. Instead of just forming the anticipated complex [(NON)Sn−Rh(CO)\(_{2}\)Cl], 4 inserts into the Rh−Cl bond to afford [(NON)Sn(Cl)Rh(CO)(C\(_{6}\)H\(_{6}\))] (6, additional CO/C6H6 exchange) and [(NON)Sn(Cl)Rh\(_{2}\)(CO)\(_{4}\)Cl] (7). By avoiding halogenated transition metal precursors in order to prevent insertion reactions, germylene 3 shows “classical” coordination chemistry towards {Ni(CO)3} forming the complex [(NON)Ge−Ni(CO)\(_{3}\)] (8). KW - Germylenes KW - heterocyclic tetrylenes KW - hetrocyclic tetrylene complexes KW - Plumbylenes KW - Stannylenes Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262586 VL - 2021 IS - 35 SP - 3591 EP - 3600 ER - TY - JOUR A1 - Alnusaire, Taghreed S. A1 - Sayed, Ahmed M. A1 - Elmaidomy, Abeer H. A1 - Al-Sanea, Mohammad M. A1 - Albogami, Sarah A1 - Albqmi, Mha A1 - Alowaiesh, Bassam F. A1 - Mostafa, Ehab M. A1 - Musa, Arafa A1 - Youssif, Khayrya A. A1 - Refaat, Hesham A1 - Othman, Eman M. A1 - Dandekar, Thomas A1 - Alaaeldin, Eman A1 - Ghoneim, Mohammed M. A1 - Abdelmohsen, Usama Ramadan T1 - An in vitro and in silico study of the enhanced antiproliferative and pro-oxidant potential of Olea europaea L. cv. Arbosana leaf extract via elastic nanovesicles (spanlastics) JF - Antioxidants N2 - The olive tree is a venerable Mediterranean plant and often used in traditional medicine. The main aim of the present study was to evaluate the effect of Olea europaea L. cv. Arbosana leaf extract (OLE) and its encapsulation within a spanlastic dosage form on the improvement of its pro-oxidant and antiproliferative activity against HepG-2, MCF-7, and Caco-2 human cancer cell lines. The LC-HRESIMS-assisted metabolomic profile of OLE putatively annotated 20 major metabolites and showed considerable in vitro antiproliferative activity against HepG-2, MCF-7, and Caco-2 cell lines with IC\(_{50}\) values of 9.2 ± 0.8, 7.1 ± 0.9, and 6.5 ± 0.7 µg/mL, respectively. The encapsulation of OLE within a (spanlastic) nanocarrier system, using a spraying method and Span 40 and Tween 80 (4:1 molar ratio), was successfully carried out (size 41 ± 2.4 nm, zeta potential 13.6 ± 2.5, and EE 61.43 ± 2.03%). OLE showed enhanced thermal stability, and an improved in vitro antiproliferative effect against HepG-2, MCF-7, and Caco-2 (IC\(_{50}\) 3.6 ± 0.2, 2.3 ± 0.1, and 1.8 ± 0.1 µg/mL, respectively) in comparison to the unprocessed extract. Both preparations were found to exhibit pro-oxidant potential inside the cancer cells, through the potential inhibitory activity of OLE against glutathione reductase and superoxide dismutase (IC\(_{50}\) 1.18 ± 0.12 and 2.33 ± 0.19 µg/mL, respectively). These inhibitory activities were proposed via a comprehensive in silico study to be linked to the presence of certain compounds in OLE. Consequently, we assume that formulating such a herbal extract within a suitable nanocarrier would be a promising improvement of its therapeutic potential. KW - olive KW - metabolomic profiling KW - antiproliferative KW - pro-oxidant KW - encapsulation KW - spanlastic KW - nanocarrier KW - docking KW - molecular dynamics simulation KW - Olea Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250064 SN - 2076-3921 VL - 10 IS - 12 ER - TY - JOUR A1 - Friedmann, Anton A1 - Fickl, Stefan A1 - Fischer, Kai R. A1 - Dalloul, Milad A1 - Goetz, Werner A1 - Kauffmann, Frederic T1 - Horizontal augmentation of chronic mandibular defects by the Guided Bone Regeneration approach: a randomized study in dogs JF - Materials N2 - Various biomaterial combinations have been studied focusing on their ability to stabilize blood clots and maintain space under soft tissue to support new bone formation. A popular combination is Deproteinized Bovine Bone Mineral (DBBM) placed with a native collagen membrane (NCM) tacked to native bone. In this study, we compared the outcome of this treatment option to those achieved with three different graft/membrane combinations with respect to total newly occupied area and the mineralized compound inside. After bi-lateral extraction of two mandibular premolars in five adult beagles L-shaped alveolar defects were created. A total of 20 defects healed for 6 weeks resulting in chronic type bone defects. At baseline, four options were randomly allocated to five defects each: a. DBBM + NCM with a four-pin fixation across the ridge; b. DBBM + RCLC (ribose cross-linked collagen membrane); c. DBBM + NPPM (native porcine pericardium membrane); and d. Ca-sulfate (CS) + RCLC membrane. Membranes in b/c/d were not fixed; complete tensionless wound closure was achieved by CAF. Termination after 3 months and sampling followed, and non-decalcified processing and toluidine blue staining were applied. Microscopic images obtained at standardized magnification were histomorphometrically assessed by ImageJ software (NIH). An ANOVA post hoc test was applied; histomorphometric data are presented in this paper as medians and interquartile ranges (IRs). All sites healed uneventfully, all sites were sampled and block separation followed before Technovit embedding. Two central sections per block for each group were included. Two of five specimen were lost due to processing error and were excluded from group b. New bone area was significantly greater for option b. compared to a. (p = 0.001), c. (p = 0.002), and d. (p = 0.046). Residual non-bone graft area was significantly less for option d. compared to a. (p = 0.026) or c. (p = 0.021). We conclude that collagen membranes with a prolonged resorption/barrier profile combined with bone substitutes featuring different degradation profiles sufficiently support new bone formation. Tacking strategy/membrane fixation appears redundant when using these biomaterials. KW - lateral augmentation KW - histomorphometry KW - collagen membranes KW - degradation profile KW - bone substitutes KW - guided bone regeneration (GBR) KW - animal study Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252351 SN - 1996-1944 VL - 15 IS - 1 ER - TY - JOUR A1 - Dauer née Joppe, Karina A1 - Tatenhorst, Lars A1 - Caldi Gomes, Lucas A1 - Zhang, Shuyu A1 - Parvaz, Mojan A1 - Carboni, Eleonora A1 - Roser, Anna‐Elisa A1 - El DeBakey, Hazem A1 - Bähr, Mathias A1 - Vogel‐Mikuš, Katarina A1 - Wang Ip, Chi A1 - Becker, Stefan A1 - Zweckstetter, Markus A1 - Lingor, Paul T1 - Brain iron enrichment attenuates α‐synuclein spreading after injection of preformed fibrils JF - Journal of Neurochemistry N2 - Regional iron accumulation and α‐synuclein (α‐syn) spreading pathology within the central nervous system are common pathological findings in Parkinson's disease (PD). Whereas iron is known to bind to α‐syn, facilitating its aggregation and regulating α‐syn expression, it remains unclear if and how iron also modulates α‐syn spreading. To elucidate the influence of iron on the propagation of α‐syn pathology, we investigated α‐syn spreading after stereotactic injection of α‐syn preformed fibrils (PFFs) into the striatum of mouse brains after neonatal brain iron enrichment. C57Bl/6J mouse pups received oral gavage with 60, 120, or 240 mg/kg carbonyl iron or vehicle between postnatal days 10 and 17. At 12 weeks of age, intrastriatal injections of 5‐µg PFFs were performed to induce seeding of α‐syn aggregates. At 90 days post‐injection, PFFs‐injected mice displayed long‐term memory deficits, without affection of motor behavior. Interestingly, quantification of α‐syn phosphorylated at S129 showed reduced α‐syn pathology and attenuated spreading to connectome‐specific brain regions after brain iron enrichment. Furthermore, PFFs injection caused intrastriatal microglia accumulation, which was alleviated by iron in a dose‐dependent way. In primary cortical neurons in a microfluidic chamber model in vitro, iron application did not alter trans‐synaptic α‐syn propagation, possibly indicating an involvement of non‐neuronal cells in this process. Our study suggests that α‐syn PFFs may induce cognitive deficits in mice independent of iron. However, a redistribution of α‐syn aggregate pathology and reduction of striatal microglia accumulation in the mouse brain may be mediated via iron‐induced alterations of the brain connectome. KW - alpha‐synuclein KW - alpha‐synuclein propagation KW - alpha‐synuclein seeding KW - iron dyshomeostasis KW - Parkinson's disease Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262544 VL - 159 IS - 3 SP - 554 EP - 573 ER -