@article{AbdelLatifFathyAnwaretal.2022, author = {Abdel-Latif, Rania and Fathy, Moustafa and Anwar, Hend Ali and Naseem, Muhammad and Dandekar, Thomas and Othman, Eman M.}, title = {Cisplatin-induced reproductive toxicity and oxidative stress: ameliorative effect of kinetin}, series = {Antioxidants}, volume = {11}, journal = {Antioxidants}, number = {5}, issn = {2076-3921}, doi = {10.3390/antiox11050863}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-271223}, year = {2022}, abstract = {Cisplatin is a commonly used chemotherapeutic agent; however, its potential side effects, including gonadotoxicity and infertility, are a critical problem. Oxidative stress has been implicated in the pathogenesis of cisplatin-induced testicular dysfunction. We investigated whether kinetin use at different concentrations could alleviate gonadal injury associated with cisplatin treatment, with an exploration of the involvement of its antioxidant capacity. Kinetin was administered in different doses of 0.25, 0.5, and 1 mg/kg, alone or along with cisplatin for 10 days. Cisplatin toxicity was induced via a single IP dose of 7 mg/kg on day four. In a dose-dependent manner, concomitant administration of kinetin with cisplatin significantly restored testicular oxidative stress parameters, corrected the distorted sperm quality parameters and histopathological changes, enhanced levels of serum testosterone and testicular StAR protein expression, as well as reduced the up-regulation of testicular TNF-α, IL-1β, Il-6, and caspase-3, caused by cisplatin. It is worth noting that the testicular protective effect of the highest kinetin dose was comparable/more potent and significantly higher than the effects of vitamin C and the lowest kinetin dose, respectively. Overall, these data indicate that kinetin may offer a promising approach for alleviating cisplatin-induced reproductive toxicity and organ damage, via ameliorating oxidative stress and reducing inflammation and apoptosis.}, language = {en} } @article{AbendrothNaurothRichteretal.2022, author = {Abendroth, Johanna and Nauroth, Peter and Richter, Tobias and Gollwitzer, Mario}, title = {Non-strategic detection of identity-threatening information: Epistemic validation and identity defense may share a common cognitive basis}, series = {PLoS ONE}, volume = {17}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0261535}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301019}, year = {2022}, abstract = {Readers use prior knowledge to evaluate the validity of statements and detect false information without effort and strategic control. The present study expands this research by exploring whether people also non-strategically detect information that threatens their social identity. Participants (N = 77) completed a task in which they had to respond to a "True" or "False" probe after reading true, false, identity-threatening, or non-threatening sentences. Replicating previous studies, participants reacted more slowly to a positive probe ("True") after reading false (vs. true) sentences. Notably, participants also reacted more slowly to a positive probe after reading identity-threatening (vs. non-threatening) sentences. These results provide first evidence that identity-threatening information, just as false information, is detected at a very early stage of information processing and lends support to the notion of a routine, non-strategic identity-defense mechanism.}, language = {en} } @article{AchenbachHuppertzZemanetal.2022, author = {Achenbach, Leonard and Huppertz, Gunnar and Zeman, Florian and Weber, Johannes and Luig, Patrick and Rudert, Maximilian and Krutsch, Werner}, title = {Multicomponent stretching and rubber band strengthening exercises do not reduce overuse shoulder injuries: a cluster randomised controlled trial with 579 handball athletes}, series = {BMJ Open Sport \& Exercise Medicine}, volume = {8}, journal = {BMJ Open Sport \& Exercise Medicine}, number = {1}, issn = {2055-7647}, doi = {10.1136/bmjsem-2021-001270}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300770}, year = {2022}, abstract = {Objectives Handball is associated with a high risk of overuse shoulder injury. This study investigated if an injury prevention programme effectively reduces overuse injury to the throwing shoulder of handball athletes. Methods 61 men's and women's handball teams (u-19 and senior athletes) were cluster-randomised into an intervention and a control group in the 2019-2020 season. Players of the intervention group regularly carried out an injury prevention programme. Both groups documented overuse shoulder injuries via an online questionnaire every second week. The primary endpoint was the prevalence of overuse injury to the throwing shoulder. Secondary endpoints were the influence of compliance on the primary endpoint and intensity of overuse shoulder symptoms measured by a shortened, handball-specific Western Ontario Shoulder Index (WOSI). Results 31 teams (295 players) in the intervention group and 30 teams (284 players) in the control group were included for analyses. The overall questionnaire response rate was 61\%. The average prevalence of overuse shoulder injury did not significantly differ between the intervention group (n=109, 38.4\% (95\% CI 32.9\% to 44.2\%)) and the control group (n=106, 35.9\% (95\% CI 30.7\% to 41.6\%), p=0.542). Compliance with the intervention programme did not significantly affect overuse shoulder injury (p=0.893). Using generalised estimating equations for WOSI, the estimated mean for the intervention group was 44.6 points (95\% CI 42.0 to 47.1) and 47.6 points for the control group (95\% CI 44.9 to 50.3, p=0.111). Conclusions A multicomponent exercise programme using rubber bands and stretching did not significantly reduce the prevalence or symptoms of overuse throwing shoulder injury in handball athletes of both sexes. Randomised controlled study; level of evidence I.}, language = {en} } @article{AchenbachLeHanneurCamenzindetal.2022, author = {Achenbach, Leonard and Le Hanneur, Malo and Camenzind, Roland S. and Bouyer, Michael and Pottecher, Pierre and Lafosse, Thibault}, title = {Systematic bifocal decompression for isolated long thoracic nerve paresis: A case series of 12 patients}, series = {Interdisciplinary Neurosurgery}, volume = {27}, journal = {Interdisciplinary Neurosurgery}, doi = {10.1016/j.inat.2021.101384}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265085}, year = {2022}, abstract = {To date, no consensus exists regarding the best surgical management of isolated, micro-traumatic long thoracic nerve (LTN) paresis. Our hypothesis was that a combined decompression of the LTN at two potential locations for entrapment would be effective in the management of dynamic LTN paresis. We report on twelve patients with isolated LTN parersis, with tenderness at two entrapment sites, who underwent bifocal LTN decompression after undergoing unsuccessful conservative treatment for at least 6 months; all patients had preoperative electrodiagnostic studies that confirmed the paresis and ruled out peripheral neuritis. Clinical and electrical improvements were observed in eight patients (67\%) regarding shoulder flexion, shoulder abduction, and Quick-DASH scores. Four patients (33\%) did not improve after surgery. The results corroborate our hypothesis that a bifocal LTN decompression can be an effective and reliable therapeutic option in more than half of a very selective patient population suffering from serratus anterior muscle deficiency.}, language = {en} } @article{AdemmerHornQuast2022, author = {Ademmer, Martin and Horn, Wolfram and Quast, Josefine}, title = {Stock market dynamics and the relative importance of domestic, foreign, and common shocks}, series = {International Journal of Finance \& Economics}, volume = {27}, journal = {International Journal of Finance \& Economics}, number = {4}, doi = {10.1002/ijfe.2194}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225729}, pages = {3911 -- 3923}, year = {2022}, abstract = {We quantify the contemporaneous relationships among stock markets in the euro area, the United States, and a group of emerging economies over the period from 2008 to 2017. Exploiting the heteroskedasticity in the stock market data, we identify shocks that originated in the respective domestic markets and shocks that are common to all markets. Our results underline the leading role of the United States in international equity markets, but also point to the importance of indirect spillovers for all economies. Variance decompositions show that while domestic shocks explain the bigger part of the variation in each stock market, a substantial part of the variation in the euro area and the emerging economies can be attributed to foreign shocks. A comparison with a sample covering the pre-crisis period from 1999 to 2007 suggests a strengthening of the linkages among global stock markets in recent years. In particular, the spillovers from advanced to emerging economies have become more pronounced.}, language = {en} } @article{AlHejailanWeigelSchuerleinetal.2022, author = {Al-Hejailan, Reem and Weigel, Tobias and Sch{\"u}rlein, Sebastian and Berger, Constantin and Al-Mohanna, Futwan and Hansmann, Jan}, title = {Decellularization of full heart — optimizing the classical sodium-dodecyl-sulfate-based decellularization protocol}, series = {Bioengineering}, volume = {9}, journal = {Bioengineering}, number = {4}, issn = {2306-5354}, doi = {10.3390/bioengineering9040147}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270781}, year = {2022}, abstract = {Compared to cell therapy, where cells are injected into a defect region, the treatment of heart infarction with cells seeded in a vascularized scaffold bears advantages, such as an immediate nutrient supply or a controllable and persistent localization of cells. For this purpose, decellularized native tissues are a preferable choice as they provide an in vivo-like microenvironment. However, the quality of such scaffolds strongly depends on the decellularization process. Therefore, two protocols based on sodium dodecyl sulfate or sodium deoxycholate were tailored and optimized for the decellularization of a porcine heart. The obtained scaffolds were tested for their applicability to generate vascularized cardiac patches. Decellularization with sodium dodecyl sulfate was found to be more suitable and resulted in scaffolds with a low amount of DNA, a highly preserved extracellular matrix composition, and structure shown by GAG quantification and immunohistochemistry. After seeding human endothelial cells into the vasculature, a coagulation assay demonstrated the functionality of the endothelial cells to minimize the clotting of blood. Human-induced pluripotent-stem-cell-derived cardiomyocytes in co-culture with fibroblasts and mesenchymal stem cells transferred the scaffold into a vascularized cardiac patch spontaneously contracting with a frequency of 25.61 ± 5.99 beats/min for over 16 weeks. The customized decellularization protocol based on sodium dodecyl sulfate renders a step towards a preclinical evaluation of the scaffolds.}, language = {en} } @article{AlWarhiElmaidomyMaheretal.2022, author = {Al-Warhi, Tarfah and Elmaidomy, Abeer H. and Maher, Sherif A. and Abu-Baih, Dalia H. and Selim, Samy and Albqmi, Mha and Al-Sanea, Mohammad M. and Alnusaire, Taghreed S. and Ghoneim, Mohammed M. and Mostafa, Ehab M. and Hussein, Shaimaa and El-Damasy, Ashraf K. and Saber, Entesar Ali and Elrehany, Mahmoud A. and Sayed, Ahmed M. and Othman, Eman M. and El-Sherbiny, Mohamed and Abdelmohsen, Usama Ramadan}, title = {The wound-healing potential of Olea europaea L. Cv. Arbequina leaves extract: an integrated in vitro, in silico, and in vivo investigation}, series = {Metabolites}, volume = {12}, journal = {Metabolites}, number = {9}, issn = {2218-1989}, doi = {10.3390/metabo12090791}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286150}, year = {2022}, abstract = {Olea europaea L. Cv. Arbequina (OEA) (Oleaceae) is an olive variety species that has received little attention. Besides our previous work for the chemical profiling of OEA leaves using LC-HRESIMS, an additional 23 compounds are identified. An excision wound model is used to measure wound healing action. Wounds are provided with OEA (2\% w/v) or MEBO\(^®\) cream (marketed treatment). The wound closure rate related to vehicle-treated wounds is significantly increased by OEA. Comparing to vehicle wound tissues, significant levels of TGF-β in OEA and MEBO\(^®\) (p < 0.05) are displayed by gene expression patterns, with the most significant levels in OEA-treated wounds. Proinflammatory TNF-α and IL-1β levels are substantially reduced in OEA-treated wounds. The capability of several lignan-related compounds to interact with MMP-1 is revealed by extensive in silico investigation of the major OEA compounds (i.e., inverse docking, molecular dynamics simulation, and ΔG calculation), and their role in the wound-healing process is also characterized. The potential of OEA as a potent MMP-1 inhibitor is shown in subsequent in vitro testing (IC\(_{50}\) = 88.0 ± 0.1 nM). In conclusion, OEA is introduced as an interesting therapeutic candidate that can effectively manage wound healing because of its anti-inflammatory and antioxidant properties.}, language = {en} } @article{AldejohannWiesePosseltGastmeieretal.2022, author = {Aldejohann, Alexander Maximilian and Wiese-Posselt, Miriam and Gastmeier, Petra and Kurzai, Oliver}, title = {Expert recommendations for prevention and management of Candida auris transmission}, series = {Mycoses}, volume = {65}, journal = {Mycoses}, number = {6}, doi = {10.1111/myc.13445}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318570}, pages = {590 -- 598}, year = {2022}, abstract = {Candida auris was first described as a yeast pathogen in 2009. Since then, the species has emerged worldwide. In contrast to most other Candida spp., C. auris frequently exhibits multi-drug resistance and is readily transmitted in hospital settings. While most detections so far are from colonised patients, C. auris does cause superficial and life-threatening invasive infections. During management of the first documented C. auris transmission in a German hospital, experts from the National Reference Centers for Invasive Fungal Infections (NRZMyk) and the National Reference Center for Surveillance of Nosocomial Infections screened available literature and integrated available knowledge on infection prevention and C. auris epidemiology and biology to enable optimal containment. Relevant recommendations developed during this process are summarised in this guidance document, intended to assist in management of C. auris transmission and potential outbreak situations. Rapid and effective measures to contain C. auris spread require a multi-disciplinary approach that includes clinical specialists of the affected unit, nursing staff, hospital hygiene, diagnostic microbiology, cleaning staff, hospital management and experts in diagnostic mycology / fungal infections. Action should be initiated in a step-wise process and relevant interventions differ between management of singular C. auris colonised / infected patients and detection of potential C. auris transmission or nosocomial outbreaks.}, language = {en} } @article{AllgaierSchleeProbstetal.2022, author = {Allgaier, Johannes and Schlee, Winfried and Probst, Thomas and Pryss, R{\"u}diger}, title = {Prediction of tinnitus perception based on daily life mHealth data using country origin and season}, series = {Journal of Clinical Medicine}, volume = {11}, journal = {Journal of Clinical Medicine}, number = {15}, issn = {2077-0383}, doi = {10.3390/jcm11154270}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-281812}, year = {2022}, abstract = {Tinnitus is an auditory phantom perception without external sound stimuli. This chronic perception can severely affect quality of life. Because tinnitus symptoms are highly heterogeneous, multimodal data analyses are increasingly used to gain new insights. MHealth data sources, with their particular focus on country- and season-specific differences, can provide a promising avenue for new insights. Therefore, we examined data from the TrackYourTinnitus (TYT) mHealth platform to create symptom profiles of TYT users. We used gradient boosting engines to classify momentary tinnitus and regress tinnitus loudness, using country of origin and season as features. At the daily assessment level, tinnitus loudness can be regressed with a mean absolute error rate of 7.9\% points. In turn, momentary tinnitus can be classified with an F1 score of 93.79\%. Both results indicate differences in the tinnitus of TYT users with respect to season and country of origin. The significance of the features was evaluated using statistical and explainable machine learning methods. It was further shown that tinnitus varies with temperature in certain countries. The results presented show that season and country of origin appear to be valuable features when combined with longitudinal mHealth data at the level of daily assessment.}, language = {en} } @phdthesis{Amatobi2022, author = {Amatobi, Kelechi Michael}, title = {Circadian clocks determine transport and membrane lipid oscillation in \(Drosophila\) hemolymph in complex interactions between nutrient-type, photic conditions and feeding behaviour}, doi = {10.25972/OPUS-24446}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-244462}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {The interaction between circadian clocks and metabolism is of increasing interest, since clock dysfunction often correlates with metabolic pathologies. Many research articles have been published analysing the impact of factors such as circadian clock, light, feeding time and diet-type on energy homeostasis in various tissues/organs of organisms with most of the findings done in mammals. Little is known about the impact of circadian clock and the above-mentioned factors on circulating lipids, especially the transport form of lipids - diacylglycerol (DG) and membrane lipids such as phosphatidylethanolamine (PE) and phosphatidylcholine (PC) in the Drosophila hemolymph. The fruit fly Drosophila is a prime model organism in circadian, behaviour and metabolism research. To study the role of circadian clock and behaviour in metabolism, we performed an extensive comparative hemolymph lipid (diacylglycerol: DG, phosphatidylethanolamine: PE, phosphatidylcholine: PC) analysis using ultra performance liquid chromatography coupled to time-of-flight mass spectrometry (UPLC-MS) between wild-type flies (WTCS) and clock disrupted mutants (per01). In addition, clock controlled food intake- feeding behaviour was investigated. Time-dependent variation of transport (DG) and membrane lipids (PE and PC) were not rhythmic in WTCS under constant darkness and in per01 under LD, suggesting an impact of light and clock genes on daily lipid oscillations. Day-time and night-time restriction of food led to comparable lipid profiles, suggesting that lipid oscillations are not exclusively entrained by feeding but rather are endogenously regulated. Ultradian oscillations in lipid levels in WTCS under LD were masked by digested fatty acids since lipid levels peaked more robustly at the beginning and end of light phase when flies were fed a lipid- and protein-free diet. These results suggest that metabolite (DG, PE and PC) oscillation is influenced by complex interactions between nutrient-type, photic conditions, circadian clock and feeding time. In conclusion, the results of this thesis suggest that circadian clocks determine transport and membrane lipid oscillation in Drosophila hemolymph in complex interactions between nutrient-type, photic conditions and feeding behaviour.}, subject = {Pharmaceutische Biologie}, language = {en} } @article{AmbrožovaFinnbergFeldmannetal.2022, author = {Ambrožov{\´a}, Lucie and Finnberg, Sven and Feldmann, Benedikt and Buse, J{\"o}rn and Preuss, Henry and Ewald, J{\"o}rg and Thorn, Simon}, title = {Coppicing and topsoil removal promote diversity of dung-inhabiting beetles (Coleoptera: Scarabaeidae, Geotrupidae, Staphylinidae) in forests}, series = {Agricultural and Forest Entomology}, volume = {24}, journal = {Agricultural and Forest Entomology}, number = {1}, doi = {10.1111/afe.12472}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258296}, pages = {104-113}, year = {2022}, abstract = {Central European forests experience a substantial loss of open-forest organisms due to forest management and increasing nitrogen deposition. However, management strategies, removing different levels of nitrogen, have been rarely evaluated simultaneously. We tested the additive effects of coppicing and topsoil removal on communities of dung-inhabiting beetles compared to closed forests. We sampled 57 021 beetles, using baited pitfall traps exposed on 27 plots. Experimental treatments resulted in significantly different communities by promoting open-habitat species. While alpha diversity did not differ among treatments, gamma diversity of Geotrupidae and Scarabaeidae and beta diversity of Staphylinidae were higher in coppice than in forest. Functional diversity of rove beetles was higher in both, coppice and topsoil-removed plots, compared to control plots. This was likely driven by higher habitat heterogeneity in established forest openings. Five dung beetle species and four rove beetle species benefitted from coppicing, one red-listed dung beetle and two rove beetle species benefitted from topsoil removal. Our results demonstrate that dung-inhabiting beetles related to open forest patches can be promoted by both, coppicing and additional topsoil removal. A mosaic of coppice and bare-soil-rich patches can hence promote landscape-level gamma diversity of dung and rove beetles within forests.}, language = {en} } @article{AmerellerDeutschbeinJoshietal.2022, author = {Amereller, Felix and Deutschbein, Timo and Joshi, Mamta and Schopohl, Jochen and Schilbach, Katharina and Detomas, Mario and Duffy, Leo and Carroll, Paul and Papa, Sophie and St{\"o}rmann, Sylv{\`e}re}, title = {Differences between immunotherapy-induced and primary hypophysitis—a multicenter retrospective study}, series = {Pituitary}, volume = {25}, journal = {Pituitary}, number = {1}, issn = {1386-341X}, doi = {10.1007/s11102-021-01182-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308704}, pages = {152-158}, year = {2022}, abstract = {Objective Immune checkpoint inhibitors can cause various immune-related adverse events including secondary hypophysitis. We compared clinical characteristics of immunotherapy-induced hypophysitis (IIH) and primary hypophysitis (PH) Design Retrospective multicenter cohort study including 56 patients with IIH and 60 patients with PH. Methods All patients underwent extensive endocrine testing. Data on age, gender, symptoms, endocrine dysfunction, MRI, immunotherapeutic agents and autoimmune diseases were collected. Results Median time of follow-up was 18 months in IIH and 69 months in PH. The median time from initiation of immunotherapy to IIH diagnosis was 3 months. IIH affected males more frequently than PH (p < 0.001) and led to more impaired pituitary axes in males (p < 0.001). The distribution of deficient adenohypophysial axes was comparable between both entities, however, central hypocortisolism was more frequent (p < 0.001) and diabetes insipidus considerably less frequent in IIH (p < 0.001). Symptoms were similar except that visual impairment occurred more rarely in IIH (p < 0.001). 20 \% of IIH patients reported no symptoms at all. Regarding MRI, pituitary stalk thickening was less frequent in IIH (p = 0.009). Concomitant autoimmune diseases were more prevalent in PH patients before the diagnosis of hypophysitis (p = 0.003) and more frequent in IIH during follow-up (p = 0.002). Conclusions Clinically, IIH and PH present with similar symptoms. Diabetes insipidus very rarely occurs in IIH. Central hypocortisolism, in contrast, is a typical feature of IIH. Preexisting autoimmunity seems not to be indicative of developing IIH.}, language = {en} } @article{AnStrisselAlAbboodietal.2022, author = {An, Ran and Strissel, Pamela L. and Al-Abboodi, Majida and Robering, Jan W. and Supachai, Reakasame and Eckstein, Markus and Peddi, Ajay and Hauck, Theresa and B{\"a}uerle, Tobias and Boccaccini, Aldo R. and Youssef, Almoatazbellah and Sun, Jiaming and Strick, Reiner and Horch, Raymund E. and Boos, Anja M. and Kengelbach-Weigand, Annika}, title = {An innovative arteriovenous (AV) loop breast cancer model tailored for cancer research}, series = {Bioengineering}, volume = {9}, journal = {Bioengineering}, number = {7}, issn = {2306-5354}, doi = {10.3390/bioengineering9070280}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-278919}, year = {2022}, abstract = {Animal models are important tools to investigate the pathogenesis and develop treatment strategies for breast cancer in humans. In this study, we developed a new three-dimensional in vivo arteriovenous loop model of human breast cancer with the aid of biodegradable materials, including fibrin, alginate, and polycaprolactone. We examined the in vivo effects of various matrices on the growth of breast cancer cells by imaging and immunohistochemistry evaluation. Our findings clearly demonstrate that vascularized breast cancer microtissues could be engineered and recapitulate the in vivo situation and tumor-stromal interaction within an isolated environment in an in vivo organism. Alginate-fibrin hybrid matrices were considered as a highly powerful material for breast tumor engineering based on its stability and biocompatibility. We propose that the novel tumor model may not only serve as an invaluable platform for analyzing and understanding the molecular mechanisms and pattern of oncologic diseases, but also be tailored for individual therapy via transplantation of breast cancer patient-derived tumors.}, language = {en} } @article{AngerLockKleinetal.2022, author = {Anger, Friedrich and Lock, Johan Friso and Klein, Ingo and Hartlapp, Ingo and Wiegering, Armin and Germer, Christoph-Thomas and Kunzmann, Volker and L{\"o}b, Stefan}, title = {Does concurrent cholestasis alter the prognostic value of preoperatively elevated CA19-9 serum levels in patients with pancreatic head adenocarcinoma?}, series = {Annals of Surgical Oncology}, volume = {29}, journal = {Annals of Surgical Oncology}, number = {13}, doi = {10.1245/s10434-022-12460-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323854}, pages = {8523-8533}, year = {2022}, abstract = {Background Pancreatic adenocarcinoma (PDAC) patients with preoperative carbohydrate antigen 19-9 (CA19-9) serum levels higher than 500 U/ml are classified as biologically borderline resectable (BR-B). To date, the impact of cholestasis on preoperative CA19-9 serum levels in these patients has remained unquantified. Methods Data on 3079 oncologic pancreatic resections due to PDAC that were prospectively acquired by the German Study, Documentation and Quality (StuDoQ) registry were analyzed in relation to preoperative CA19-9 and bilirubin serum values. Preoperative CA19-9 values were adjusted according to the results of a multivariable linear regression analysis of pathologic parameters, bilirubin, and CA19-9 values. Results Of 1703 PDAC patients with tumor located in the pancreatic head, 420 (24.5 \%) presented with a preoperative CA19-9 level higher than 500 U/ml. Although receiver operating characteristics (ROC) analysis failed to determine exact CA19-9 cut-off values for prognostic indicators (R and N status), the T, N, and G status; the UICC stage; and the number of simultaneous vein resections increased with the level of preoperative CA19-9, independently of concurrent cholestasis. After adjustment of preoperative CA19-9 values, 18.5 \% of patients initially staged as BR-B showed CA19-9 values below 500 U/ml. However, the postoperative pathologic results for these patients did not change compared with the patients who had CA19-9 levels higher than 500 U/ml after bilirubin adjustment. Conclusions In this multicenter dataset of PDAC patients, elevation of preoperative CA19-9 correlated with well-defined prognostic pathologic parameters. Bilirubin adjustment of CA19-9 is feasible but does not affect the prognostic value of CA19-9 in jaundiced patients.}, language = {en} } @article{AnsahAbuKleemannetal.2022, author = {Ansah, Christabel Edena and Abu, Itohan-Osa and Kleemann, Janina and Mahmoud, Mahmoud Ibrahim and Thiel, Michael}, title = {Environmental contamination of a biodiversity hotspot — action needed for nature conservation in the Niger Delta, Nigeria}, series = {Sustainability}, volume = {14}, journal = {Sustainability}, number = {21}, issn = {2071-1050}, doi = {10.3390/su142114256}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297214}, year = {2022}, abstract = {The Niger Delta belongs to the largest swamp and mangrove forests in the world hosting many endemic and endangered species. Therefore, its conservation should be of highest priority. However, the Niger Delta is confronted with overexploitation, deforestation and pollution to a large extent. In particular, oil spills threaten the biodiversity, ecosystem services, and local people. Remote sensing can support the detection of spills and their potential impact when accessibility on site is difficult. We tested different vegetation indices to assess the impact of oil spills on the land cover as well as to detect accumulations (hotspots) of oil spills. We further identified which species, land cover types, and protected areas could be threatened in the Niger Delta due to oil spills. The results showed that the Enhanced Vegetation Index, the Normalized Difference Vegetation Index, and the Soil Adjusted Vegetation Index were more sensitive to the effects of oil spills on different vegetation cover than other tested vegetation indices. Forest cover was the most affected land-cover type and oil spills also occurred in protected areas. Threatened species are inhabiting the Niger Delta Swamp Forest and the Central African Mangroves that were mainly affected by oil spills and, therefore, strong conservation measures are needed even though security issues hamper the monitoring and control.}, language = {en} } @phdthesis{Anwar2022, author = {Anwar, Ammarah}, title = {Natural variation of gene regulatory networks in \(Arabidopsis\) \(thaliana\)}, doi = {10.25972/OPUS-29154}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-291549}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Understanding the causal relationship between genotype and phenotype is a major objective in biology. The main interest is in understanding trait architecture and identifying loci contributing to the respective traits. Genome-wide association mapping (GWAS) is one tool to elucidate these relationships and has been successfully used in many different species. However, most studies concentrate on marginal marker effects and ignore epistatic and gene-environment interactions. These interactions are problematic to account for, but are likely to make major contributions to many phenotypes that are not regulated by independent genetic effects, but by more sophisticated gene-regulatory networks. Further complication arises from the fact that these networks vary in different natural accessions. However, understanding the differences of gene regulatory networks and gene-gene interactions is crucial to conceive trait architecture and predict phenotypes. The basic subject of this study - using data from the Arabidopsis 1001 Genomes Project - is the analysis of pre-mature stop codons. These have been incurred in nearly one-third of the ~ 30k genes. A gene-gene interaction network of the co-occurrence of stop codons has been built and the over and under representation of different pairs has been statistically analyzed. To further classify the significant over and under- represented gene-gene interactions in terms of molecular function of the encoded proteins, gene ontology terms (GO-SLIM) have been applied. Furthermore, co- expression analysis specifies gene clusters that co-occur over different genetic and phenotypic backgrounds. To link these patterns to evolutionary constrains, spatial location of the respective alleles have been analyzed as well. The latter shows clear patterns for certain gene pairs that indicate differential selection.}, subject = {Arabidopsis thaliana}, language = {en} } @article{AppellBritoReinwand2022, author = {Appell, J{\"u}rgen and Brito, Bel{\´e}n L{\´o}pez and Reinwand, Simon}, title = {Counterexamples on compositions}, series = {Mathematische Semesterberichte}, volume = {70}, journal = {Mathematische Semesterberichte}, number = {1}, issn = {0720-728X}, doi = {10.1007/s00591-022-00318-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324306}, pages = {43-56}, year = {2022}, abstract = {We give a collection of 16 examples which show that compositions \(g\) \(\circ\) \(f\) of well-behaved functions \(f\) and \(g\) can be badly behaved. Remarkably, in 10 of the 16 examples it suffices to take as outer function \(g\) simply a power-type or characteristic function. Such a collection of examples may serve as a source of exercises for a calculus course.}, language = {en} } @article{AppeltshauserMessingerStarzetal.2022, author = {Appeltshauser, Luise and Messinger, Julia and Starz, Katharina and Heinrich, David and Brunder, Anna-Michelle and Stengel, Helena and Fiebig, Bianca and Ayzenberg, Ilya and Birklein, Frank and Dresel, Christian and Dorst, Johannes and Dvorak, Florian and Grimm, Alexander and Joerk, Alexander and Leypoldt, Frank and M{\"a}urer, Mathias and Merl, Patrick and Michels, Sebastian and Pitarokoili, Kalliopi and Rosenfeldt, Mathias and Sperfeld, Anne-Dorte and Weihrauch, Marc and Welte, Gabriel Simon and Sommer, Claudia and Doppler, Kathrin}, title = {Diabetes Mellitus Is a Possible Risk Factor for Nodo-paranodopathy With Antiparanodal Autoantibodies}, series = {Neurology: Neuroimmunology \& Neuroinflammation}, volume = {9}, journal = {Neurology: Neuroimmunology \& Neuroinflammation}, number = {3}, doi = {10.1212/NXI.0000000000001163}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300551}, year = {2022}, abstract = {Background and Objectives Nodo-paranodopathies are peripheral neuropathies with dysfunction of the node of Ranvier. Affected patients who are seropositive for antibodies against adhesion molecules like contactin-1 and neurofascin show distinct clinical features and a disruption of the paranodal complex. An axoglial dysjunction is also a characteristic finding of diabetic neuropathy. Here, we aim to investigate a possible association of antibody-mediated nodo-paranodopathy and diabetes mellitus (DM). Methods We retrospectively analyzed clinical data of 227 patients with chronic inflammatory demyelinating polyradiculoneuropathy and Guillain-Barr{\´e} syndrome from multiple centers in Germany who had undergone diagnostic testing for antiparanodal antibodies targeting neurofascin-155, pan-neurofascin, contactin-1-associated protein 1, and contactin-1. To study possible direct pathogenic effects of antiparanodal antibodies, we performed immunofluorescence binding assays on human pancreatic tissue sections. Results The frequency of DM was 33.3\% in seropositive patients and thus higher compared with seronegative patients (14.1\%, OR = 3.04, 95\% CI = 1.31-6.80). The relative risk of DM in seropositive patients was 3.4-fold higher compared with the general German population. Seropositive patients with DM most frequently harbored anti-contactin-1 antibodies and had higher antibody titers than seropositive patients without DM. The diagnosis of DM preceded the onset of neuropathy in seropositive patients. No immunoreactivity of antiparanodal antibodies against pancreatic tissue was detected. Discussion We report an association of nodo-paranodopathy and DM. Our results suggest that DM may be a potential risk factor for predisposing to developing nodo-paranodopathy and argue against DM being induced by the autoantibodies. Our findings set the basis for further research investigating underlying immunopathogenetic connections.}, language = {en} } @article{AsamGessnerAlmengorGonzalezetal.2022, author = {Asam, Sarah and Gessner, Ursula and Almengor Gonz{\´a}lez, Roger and Wenzl, Martina and Kriese, Jennifer and Kuenzer, Claudia}, title = {Mapping crop types of Germany by combining temporal statistical metrics of Sentinel-1 and Sentinel-2 time series with LPIS data}, series = {Remote Sensing}, volume = {14}, journal = {Remote Sensing}, number = {13}, issn = {2072-4292}, doi = {10.3390/rs14132981}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-278969}, year = {2022}, abstract = {Nationwide and consistent information on agricultural land use forms an important basis for sustainable land management maintaining food security, (agro)biodiversity, and soil fertility, especially as German agriculture has shown high vulnerability to climate change. Sentinel-1 and Sentinel-2 satellite data of the Copernicus program offer time series with temporal, spatial, radiometric, and spectral characteristics that have great potential for mapping and monitoring agricultural crops. This paper presents an approach which synergistically uses these multispectral and Synthetic Aperture Radar (SAR) time series for the classification of 17 crop classes at 10 m spatial resolution for Germany in the year 2018. Input data for the Random Forest (RF) classification are monthly statistics of Sentinel-1 and Sentinel-2 time series. This approach reduces the amount of input data and pre-processing steps while retaining phenological information, which is crucial for crop type discrimination. For training and validation, Land Parcel Identification System (LPIS) data were available covering 15 of the 16 German Federal States. An overall map accuracy of 75.5\% was achieved, with class-specific F1-scores above 80\% for winter wheat, maize, sugar beet, and rapeseed. By combining optical and SAR data, overall accuracies could be increased by 6\% and 9\%, respectively, compared to single sensor approaches. While no increase in overall accuracy could be achieved by stratifying the classification in natural landscape regions, the class-wise accuracies for all but the cereal classes could be improved, on average, by 7\%. In comparison to census data, the crop areas could be approximated well with, on average, only 1\% of deviation in class-specific acreages. Using this streamlined approach, similar accuracies for the most widespread crop types as well as for smaller permanent crop classes were reached as in other Germany-wide crop type studies, indicating its potential for repeated nationwide crop type mapping.}, language = {en} } @article{AsterEvdokimovBraunetal.2022, author = {Aster, H-C and Evdokimov, D. and Braun, A. and {\"U}{\c{c}}eyler, N. and Sommer, C.}, title = {Analgesic Medication in Fibromyalgia Patients: A Cross-Sectional Study}, series = {Pain Research and Management}, volume = {2022}, journal = {Pain Research and Management}, doi = {10.1155/2022/1217717}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300578}, year = {2022}, abstract = {There is no approved drug for fibromyalgia syndrome (FMS) in Europe. In the German S3 guideline, amitriptyline, duloxetine, and pregabalin are recommended for temporary use. The aim of this study was to cross-sectionally investigate the current practice of medication in FMS patients in Germany. We systematically interviewed 156 patients with FMS, while they were participating in a larger study. The patients had been stratified into subgroups with and without a decrease in intraepidermal nerve fiber density. The drugs most commonly used to treat FMS pain were nonsteroidal anti-inflammatory drugs (NSAIDs) (41.0\% of all patients), metamizole (22.4\%), and amitriptyline (12.8\%). The most frequent analgesic treatment regimen was "on demand" (53.9\%), during pain attacks, while 35.1\% of the drugs were administered daily and the remaining in other regimens. Median pain relief as self-rated by the patients on a numerical rating scale (0-10) was 2 points for NSAIDS, 2 for metamizole, and 1 for amitriptyline. Drugs that were discontinued due to lack of efficacy rather than side effects were acetaminophen, flupirtine, and selective serotonin reuptake inhibitors. Reduction in pain severity was best achieved by NSAIDs and metamizole. Our hypothesis that a decrease in intraepidermal nerve fiber density might represent a neuropathic subtype of FMS, which would be associated with better effectiveness of drugs targeting neuropathic pain, could not be confirmed in this cohort. Many FMS patients take "on-demand" medication that is not in line with current guidelines. More randomized clinical trials are needed to assess drug effects in FMS subgroups.}, language = {en} } @article{AsterEvdokimovBraunetal.2022, author = {Aster, Hans-Christoph and Evdokimov, Dimitar and Braun, Alexandra and {\"U}{\c{c}}eyler, Nurcan and Kampf, Thomas and Pham, Mirko and Homola, Gy{\"o}rgy A. and Sommer, Claudia}, title = {CNS imaging characteristics in fibromyalgia patients with and without peripheral nerve involvement}, series = {Scientific Reports}, volume = {12}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-022-10489-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300562}, year = {2022}, abstract = {We tested the hypothesis that reduced skin innervation in fibromyalgia syndrome is associated with specific CNS changes. This prospective case-control study included 43 women diagnosed with fibromyalgia syndrome and 40 healthy controls. We further compared the fibromyalgia subgroups with reduced (n = 21) and normal (n = 22) skin innervation. Brains were analysed for cortical volume, for white matter integrity, and for functional connectivity. Compared to controls, cortical thickness was decreased in regions of the frontal, temporal and parietal cortex in the fibromyalgia group as a whole, and decreased in the bilateral pericalcarine cortices in the fibromyalgia subgroup with reduced skin innervation. Diffusion tensor imaging revealed a significant increase in fractional anisotropy in the corona radiata, the corpus callosum, cingulum and fornix in patients with fibromyalgia compared to healthy controls and decreased FA in parts of the internal capsule and thalamic radiation in the subgroup with reduced skin innervation. Using resting-state fMRI, the fibromyalgia group as a whole showed functional hypoconnectivity between the right midfrontal gyrus and the posterior cerebellum and the right crus cerebellum, respectively. The subgroup with reduced skin innervation showed hyperconnectivity between the inferior frontal gyrus, the angular gyrus and the posterior parietal gyrus. Our results suggest that the subgroup of fibromyalgia patients with pronounced pathology in the peripheral nervous system shows alterations in morphology, structural and functional connectivity also at the level of the encephalon. We propose considering these subgroups when conducting clinical trials.}, language = {en} } @article{AsterRomanosWalitzaetal.2022, author = {Aster, Hans-Christoph and Romanos, Marcel and Walitza, Susanne and Gerlach, Manfred and M{\"u}hlberger, Andreas and Rizzo, Albert and Andreatta, Marta and Hasenauer, Natalie and Hartrampf, Philipp E. and Nerlich, Kai and Reiners, Christoph and Lorenz, Reinhard and Buck, Andreas K. and Deserno, Lorenz}, title = {Responsivity of the striatal dopamine system to methylphenidate — A within-subject I-123-β-CIT-SPECT study in male children and adolescents with attention-deficit/hyperactivity disorder}, series = {Frontiers in Psychiatry}, volume = {13}, journal = {Frontiers in Psychiatry}, issn = {1664-0640}, doi = {10.3389/fpsyt.2022.804730}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270862}, year = {2022}, abstract = {Background: Methylphenidate (MPH) is the first-line pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD). MPH binds to the dopamine (DA) transporter (DAT), which has high density in the striatum. Assessments of the striatal dopamine transporter by single positron emission computed tomography (SPECT) in childhood and adolescent patients are rare but can provide insight on how the effects of MPH affect DAT availability. The aim of our within-subject study was to investigate the effect of MPH on DAT availability and how responsivity to MPH in DAT availability is linked to clinical symptoms and cognitive functioning. Methods Thirteen adolescent male patients (9-16 years) with a diagnosis of ADHD according to the DSM-IV and long-term stimulant medication (for at least 6 months) with MPH were assessed twice within 7 days using SPECT after application of I-123-β-CIT to examine DAT binding potential (DAT BP). SPECT measures took place in an on- and off-MPH status balanced for order across participants. A virtual reality continuous performance test was performed at each time point. Further clinical symptoms were assessed for baseline off-MPH. Results On-MPH status was associated with a highly significant change (-29.9\%) of striatal DAT BP as compared to off-MPH (t = -4.12, p = 0.002). A more pronounced change in striatal DAT BP was associated with higher off-MPH attentional and externalizing symptom ratings (Pearson r = 0.68, p = 0.01). Striatal DAT BP off-MPH, but not on-MPH, was associated with higher symptom ratings (Pearson r = 0.56, p = 0.04). Conclusion Our findings corroborate previous reports from mainly adult samples that MPH changes striatal DAT BP availability and suggest higher off-MPH DAT BP, likely reflecting low baseline DA levels, as a marker of symptom severity.}, language = {en} } @article{AugustinKertelsWiegeringetal.2022, author = {Augustin, Anne Marie and Kertels, Olivia and Wiegering, Verena and Thurner, Annette and Kickuth, Ralph}, title = {Percutaneous implantation of peripherally inserted totally implantable venous access systems in the forearm in adolescent patients}, series = {Pediatric Radiology}, volume = {52}, journal = {Pediatric Radiology}, number = {8}, doi = {10.1007/s00247-022-05321-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324947}, pages = {1550-1558}, year = {2022}, abstract = {Background Children with different underlying malignant diseases require long-term central venous access. As for port systems in a pectoral position, peripherally implanted port systems in the forearm revealed high levels of technical and clinical success in adult cohorts. Objective To investigate the technical and clinical outcomes of percutaneous central venous port implantation in the forearm in adolescents. Materials and methods Between April 2010 and August 2020, 32 children ages 9 to 17 years with underlying malignancy received 35 totally implantable venous access ports (TIVAPs) in the forearm. All venous port systems were peripherally inserted under ultrasound guidance. Correct catheter placement was controlled by fluoroscopy. As primary endpoints, the technical success, rate of complications and catheter maintenance were analyzed. Secondary endpoints were the side of implantation, vein of catheter access, laboratory results on the day of the procedure, procedural radiation exposure, amount of contrast agent and reasons for port device removal. Results Percutaneous TIVAP placement under sonographic guidance was technically successful in 34 of 35 procedures (97.1\%). Procedure-related complications did not occur. During the follow-up, 13,684 catheter days were analyzed, revealing 11 complications (0.8 per 1,000 catheter-duration days), Of these 11 complications, 7 were major and 10 occurred late. In seven cases, the port device had to be removed; removal-related complications did not occur. Conclusion Peripheral TIVAP placement in the forearms of children is a feasible, effective and safe technique with good midterm outcome. As results are comparable with standard access routes, this technique may be offered as an alternative when intermittent venous access is required.}, language = {en} } @article{AugustinLuciusThurneretal.2022, author = {Augustin, Anne Marie and Lucius, Leonie Johanna and Thurner, Annette and Kickuth, Ralph}, title = {Malignant obstruction of the inferior vena cava: clinical experience with the self-expanding Sinus-XL stent system}, series = {Abdominal Radiology}, volume = {47}, journal = {Abdominal Radiology}, number = {10}, doi = {10.1007/s00261-022-03587-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324951}, pages = {3604-3614}, year = {2022}, abstract = {Purpose To evaluate the technical and clinical outcome of Sinus-XL stent placement in patients with malignant obstruction syndrome of the inferior vena cava. Methods Between October 2010 and January 2021, 21 patients with different malignant primary disease causing inferior vena cava obstruction were treated with Sinus-XL stent implantation. Procedural data, technical and clinical outcome parameters were retrospectively analyzed. Results Technical success was 100\%. Analysis of available manometry data revealed a significant reduction of the mean translesional pressure gradient following the procedure (p = 0.008). Reintervention rate was 4.8\% (1/21). The available follow-up imaging studies showed primary and primary-assisted stent patency rates of 93\% (13/14) and 100\% (14/14), respectively. Major complications did not occur. The clinical success regarding lower extremity edema was 82.4\% (14/17) for the first and 85.7\% (18/21) for the last follow-up. Longer lengths of IVC obstruction were associated with reduced clinical improvement after the procedure (p = 0.025). Improvement of intraprocedural manometry results and lower extremity edema revealed only minor correlation. Ascites and anasarca were not significantly positively affected by the procedure. Conclusion Sinus-XL stent placement in patients with malignant inferior vena cava obstruction showed high technical success and low complication rates. Regarding the clinical outcome, significant symptom improvement could be achieved in lower extremity edema, whereas ascites and anasarca lacked satisfying symptom relief. Based on our results, this procedure should be considered as a suitable therapy in a palliative care setting for patients with advanced malignant disease.}, language = {en} } @article{AugustinWolfschmidtElsaesseretal.2022, author = {Augustin, Anne Marie and Wolfschmidt, Franziska and Els{\"a}sser, Thilo and Sauer, Alexander and Dierks, Alexander and Bley, Thorsten Alexander and Kickuth, Ralph}, title = {Color-coded summation images for the evaluation of blood flow in endovascular aortic dissection fenestration}, series = {BMC Medical Imaging}, volume = {22}, journal = {BMC Medical Imaging}, number = {1}, doi = {10.1186/s12880-022-00744-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301107}, year = {2022}, abstract = {Background To analyze the benefit of color-coded summation images in the assessment of target lumen perfusion in patients with aortic dissection and malperfusion syndrome before and after fluoroscopy-guided aortic fenestration. Methods Between December 2011 and April 2020 25 patients with Stanford type A (n = 13) or type B dissection (n = 12) and malperfusion syndromes were treated with fluoroscopy-guided fenestration of the dissection flap using a re-entry catheter. The procedure was technically successful in 100\% of the cases and included additional iliofemoral stent implantation in four patients. Intraprocedural systolic blood pressure measurements for gradient evaluation were performed in 19 cases. Post-processed color-coded DSA images were obtained from all DSA series before and following fenestration. Differences in time to peak (dTTP) values in the compromised aortic lumen and transluminal systolic blood pressure gradients were analyzed retrospectively. Correlation analysis between dTTP and changes in blood pressure gradients was performed. Results Mean TTP prior to dissection flap fenestration was 6.85 ± 1.35 s. After fenestration, mean TTP decreased significantly to 4.96 ± 0.94 s (p < 0.001). Available systolic blood pressure gradients between the true and the false lumen were reduced by a median of 4.0 mmHg following fenestration (p = 0.031), with significant reductions in Stanford type B dissections (p = 0.013) and minor reductions in type A dissections (p = 0.530). A moderate correlation with no statistical significance was found between dTTP and the difference in systolic blood pressure (r = 0.226; p = 0.351). Conclusions Hemodynamic parameters obtained from color-coded DSA confirmed a significant reduction of TTP values in the aortic target lumen in terms of an improved perfusion in the compromised aortic region. Color-coded DSA might thus be a suitable complementary tool in the assessment of complex vascular patterns prevailing in aortic dissections, especially when blood pressure measurements are not conclusive or feasible.}, language = {en} } @phdthesis{Awadallah2022, author = {Awadallah, Abdelhaleem Aly Ahmed}, title = {The Crew of the Sun Bark in the Amduat}, doi = {10.25972/OPUS-28711}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-287115}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {The Amduat is one of the most important Netherworld Books which was recorded in various kinds of Ancient Egyptian sources since the beginning of the 18th dynasty, especially the walls of the royal tombs. The main theme of the Amduat is the journey of the sun god through the underworld where the solar bark and its crew is the central scene of the journey. The study focuses on finding the reasons of choosing the crew's members who manage the sun bark's journey in the Amduat. It also aims at illustrating the functions and responsibilities of each crew member. Following a historical approach, the study analyzes the Pyramid Texts and Coffin Texts as the most important documents before the New Kingdom, and proceeding to the inscriptions and writings of the monuments which contain portrayals and inscriptions of the Amduat in the New Kingdom. Furthermore, it sheds some light on the solar cycle's main features and primary aspects, and tries to scrutinize the date, meaning, and symbolisms of the Amduat and its indications in the earlier sources.}, language = {en} } @article{AyalaCarrilloFarfanCardenasNielsenetal.2022, author = {Ayala-Carrillo, Mariana and Farf{\´a}n, Michelle and C{\´a}rdenas-Nielsen, Anah{\´i} and Lemoine-Rodr{\´i}guez, Richard}, title = {Are wildfires in the wildland-urban interface increasing temperatures? A land surface temperature assessment in a semi-arid Mexican city}, series = {Land}, volume = {11}, journal = {Land}, number = {12}, issn = {2073-445X}, doi = {10.3390/land11122105}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297308}, year = {2022}, abstract = {High rates of land conversion due to urbanization are causing fragmented and dispersed spatial patterns in the wildland-urban interface (WUI) worldwide. The occurrence of anthropogenic fires in the WUI represents an important environmental and social issue, threatening not only vegetated areas but also periurban inhabitants, as is the case in many Latin American cities. However, research has not focused on the dynamics of the local climate in the WUI. This study analyzes whether wildfires contribute to the increase in land surface temperature (LST) in the WUI of the metropolitan area of the city of Guanajuato (MACG), a semi-arid Mexican city. We estimated the pre- and post-fire LST for 2018-2021. Spatial clusters of high LST were detected using hot spot analysis and examined using ANOVA and Tukey's post-hoc statistical tests to assess whether LST is related to the spatial distribution of wildfires during our study period. Our results indicate that the areas where the wildfires occurred, and their surroundings, show higher LST. This has negative implications for the local ecosystem and human population, which lacks adequate infrastructure and services to cope with the effects of rising temperatures. This is the first study assessing the increase in LST caused by wildfires in a WUI zone in Mexico.}, language = {en} } @article{AydinliLiangDandekar2022, author = {Aydinli, Muharrem and Liang, Chunguang and Dandekar, Thomas}, title = {Motif and conserved module analysis in DNA (promoters, enhancers) and RNA (lncRNA, mRNA) using AlModules}, series = {Scientific Reports}, volume = {12}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-022-21732-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301268}, year = {2022}, abstract = {Nucleic acid motifs consist of conserved and variable nucleotide regions. For functional action, several motifs are combined to modules. The tool AIModules allows identification of such motifs including combinations of them and conservation in several nucleic acid stretches. AIModules recognizes conserved motifs and combinations of motifs (modules) allowing a number of interesting biological applications such as analysis of promoter and transcription factor binding sites (TFBS), identification of conserved modules shared between several gene families, e.g. promoter regions, but also analysis of shared and conserved other DNA motifs such as enhancers and silencers, in mRNA (motifs or regulatory elements e.g. for polyadenylation) and lncRNAs. The tool AIModules presented here is an integrated solution for motif analysis, offered as a Web service as well as downloadable software. Several nucleotide sequences are queried for TFBSs using predefined matrices from the JASPAR DB or by using one's own matrices for diverse types of DNA or RNA motif discovery. Furthermore, AIModules can find TFBSs common to two or more sequences. Demanding high or low conservation, AIModules outperforms other solutions in speed and finds more modules (specific combinations of TFBS) than alternative available software. The application also searches RNA motifs such as polyadenylation site or RNA-protein binding motifs as well as DNA motifs such as enhancers as well as user-specified motif combinations (https://bioinfo-wuerz.de/aimodules/; alternative entry pages: https://aimodules.heinzelab.de or https://www.biozentrum.uni-wuerzburg.de/bioinfo/computing/aimodules). The application is free and open source whether used online, on-site, or locally.}, language = {en} } @article{BachmannHelbigCrumbachetal.2022, author = {Bachmann, Jonas and Helbig, Andreas and Crumbach, Merian and Krummenacher, Ivo and Braunschweig, Holger and Helten, Holger}, title = {Fusion of Aza- and Oxadiborepins with Furans in a Reversible Ring-Opening Process Furnishes Versatile Building Blocks for Extended π-Conjugated Materials}, series = {Chemistry - A European Journal}, volume = {28}, journal = {Chemistry - A European Journal}, number = {63}, doi = {10.1002/chem.202202455}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-293926}, year = {2022}, abstract = {A modular synthesis of both difurooxa- and difuroazadiborepins from a common precursor is demonstrated. Starting from 2,2′-bifuran, after protection of the positions 5 and 5' with bulky silyl groups, formation of the novel polycycles proceeds through opening of the furan rings to a dialkyne and subsequent re-cyclization in the borylation step. The resulting bifuran-fused diborepins show pronounced stability, highly planar tricyclic structures, and intense blue light emission. Deprotection and transformation into dibrominated building blocks that can be incorporated into π-extended materials can be performed in one step. Detailed DFT calculations provide information about the aromaticity of the constituent rings of this polycycle.}, language = {en} } @article{BadrMcFlederWuetal.2022, author = {Badr, Mohammad and McFleder, Rhonda L. and Wu, Jingjing and Knorr, Susanne and Koprich, James B. and H{\"u}nig, Thomas and Brotchie, Jonathan M. and Volkmann, Jens and Lutz, Manfred B. and Ip, Chi Wang}, title = {Expansion of regulatory T cells by CD28 superagonistic antibodies attenuates neurodegeneration in A53T-α-synuclein Parkinson's disease mice}, series = {Journal of Neuroinflammation}, volume = {19}, journal = {Journal of Neuroinflammation}, doi = {10.1186/s12974-022-02685-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300580}, year = {2022}, abstract = {Background Regulatory CD4\(^+\)CD25\(^+\)FoxP3\(^+\) T cells (Treg) are a subgroup of T lymphocytes involved in maintaining immune balance. Disturbance of Treg number and impaired suppressive function of Treg correlate with Parkinson's disease severity. Superagonistic anti-CD28 monoclonal antibodies (CD28SA) activate Treg and cause their expansion to create an anti-inflammatory environment. Methods Using the AAV1/2-A53T-α-synuclein Parkinson's disease mouse model that overexpresses the pathogenic human A53T-α-synuclein (hαSyn) variant in dopaminergic neurons of the substantia nigra, we assessed the neuroprotective and disease-modifying efficacy of a single intraperitoneal dose of CD28SA given at an early disease stage. Results CD28SA led to Treg expansion 3 days after delivery in hαSyn Parkinson's disease mice. At this timepoint, an early pro-inflammation was observed in vehicle-treated hαSyn Parkinson's disease mice with elevated percentages of CD8\(^+\)CD69\(^+\) T cells in brain and increased levels of interleukin-2 (IL-2) in the cervical lymph nodes and spleen. These immune responses were suppressed in CD28SA-treated hαSyn Parkinson's disease mice. Early treatment with CD28SA attenuated dopaminergic neurodegeneration in the SN of hαSyn Parkinson's disease mice accompanied with reduced brain numbers of activated CD4\(^+\), CD8\(^+\) T cells and CD11b\(^+\) microglia observed at the late disease-stage 10 weeks after AAV injection. In contrast, a later treatment 4 weeks after AAV delivery failed to reduce dopaminergic neurodegeneration. Conclusions Our data indicate that immune modulation by Treg expansion at a timepoint of overt inflammation is effective for treatment of hαSyn Parkinson's disease mice and suggest that the concept of early immune therapy could pose a disease-modifying option for Parkinson's disease patients.}, language = {en} } @article{BaeMuellerFoersteretal.2022, author = {Bae, Soyeon and M{\"u}ller, J{\"o}rg and F{\"o}rster, Bernhard and Hilmers, Torben and Hochrein, Sophia and Jacobs, Martin and Leroy, Benjamin M. L. and Pretzsch, Hans and Weisser, Wolfgang W. and Mitesser, Oliver}, title = {Tracking the temporal dynamics of insect defoliation by high-resolution radar satellite data}, series = {Methods in Ecology and Evolution}, volume = {13}, journal = {Methods in Ecology and Evolution}, number = {1}, doi = {10.1111/2041-210X.13726}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258222}, pages = {121-132}, year = {2022}, abstract = {Quantifying tree defoliation by insects over large areas is a major challenge in forest management, but it is essential in ecosystem assessments of disturbance and resistance against herbivory. However, the trajectory from leaf-flush to insect defoliation to refoliation in broadleaf trees is highly variable. Its tracking requires high temporal- and spatial-resolution data, particularly in fragmented forests. In a unique replicated field experiment manipulating gypsy moth Lymantria dispar densities in mixed-oak forests, we examined the utility of publicly accessible satellite-borne radar (Sentinel-1) to track the fine-scale temporal trajectory of defoliation. The ratio of backscatter intensity between two polarizations from radar data of the growing season constituted a canopy development index (CDI) and a normalized CDI (NCDI), which were validated by optical (Sentinel-2) and terrestrial laser scanning (TLS) data as well by intensive caterpillar sampling from canopy fogging. The CDI and NCDI strongly correlated with optical and TLS data (Spearman's ρ = 0.79 and 0.84, respectively). The ΔNCDII\(_{Defoliation(A-C)}\) significantly explained caterpillar abundance (R\(^{2}\) = 0.52). The NCDI at critical timesteps and ΔNCDI related to defoliation and refoliation well discriminated between heavily and lightly defoliated forests. We demonstrate that the high spatial and temporal resolution and the cloud independence of Sentinel-1 radar potentially enable spatially unrestricted measurements of the highly dynamic canopy herbivory. This can help monitor insect pests, improve the prediction of outbreaks and facilitate the monitoring of forest disturbance, one of the high priority Essential Biodiversity Variables, in the near future.}, language = {en} } @article{BahenaDaftarianMaroofianetal.2022, author = {Bahena, Paulina and Daftarian, Narsis and Maroofian, Reza and Linares, Paola and Villalobos, Daniel and Mirrahimi, Mehraban and Rad, Aboulfazl and Doll, Julia and Hofrichter, Michaela A. H. and Koparir, Asuman and R{\"o}der, Tabea and Han, Seungbin and Sabbaghi, Hamideh and Ahmadieh, Hamid and Behboudi, Hassan and Villanueva-Mendoza, Cristina and Cort{\´e}s-Gonzalez, Vianney and Zamora-Ortiz, Rocio and Kohl, Susanne and Kuehlewein, Laura and Darvish, Hossein and Alehabib, Elham and La Arenas-Sordo, Maria de Luz and Suri, Fatemeh and Vona, Barbara and Haaf, Thomas}, title = {Unraveling the genetic complexities of combined retinal dystrophy and hearing impairment}, series = {Human Genetics}, volume = {141}, journal = {Human Genetics}, number = {3-4}, issn = {1432-1203}, doi = {10.1007/s00439-021-02303-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267750}, pages = {785-803}, year = {2022}, abstract = {Usher syndrome, the most prevalent cause of combined hereditary vision and hearing impairment, is clinically and genetically heterogeneous. Moreover, several conditions with phenotypes overlapping Usher syndrome have been described. This makes the molecular diagnosis of hereditary deaf-blindness challenging. Here, we performed exome sequencing and analysis on 7 Mexican and 52 Iranian probands with combined retinal degeneration and hearing impairment (without intellectual disability). Clinical assessment involved ophthalmological examination and hearing loss questionnaire. Usher syndrome, most frequently due to biallelic variants in MYO7A (USH1B in 16 probands), USH2A (17 probands), and ADGRV1 (USH2C in 7 probands), was diagnosed in 44 of 59 (75\%) unrelated probands. Almost half of the identified variants were novel. Nine of 59 (15\%) probands displayed other genetic entities with dual sensory impairment, including Alstr{\"o}m syndrome (3 patients), cone-rod dystrophy and hearing loss 1 (2 probands), and Heimler syndrome (1 patient). Unexpected findings included one proband each with Scheie syndrome, coenzyme Q10 deficiency, and pseudoxanthoma elasticum. In four probands, including three Usher cases, dual sensory impairment was either modified/aggravated or caused by variants in distinct genes associated with retinal degeneration and/or hearing loss. The overall diagnostic yield of whole exome analysis in our deaf-blind cohort was 92\%. Two (3\%) probands were partially solved and only 3 (5\%) remained without any molecular diagnosis. In many cases, the molecular diagnosis is important to guide genetic counseling, to support prognostic outcomes and decisions with currently available and evolving treatment modalities.}, language = {en} } @article{BalakrishnanHemmenChoudhuryetal.2022, author = {Balakrishnan, Ashwin and Hemmen, Katherina and Choudhury, Susobhan and Krohn, Jan-Hagen and Jansen, Kerstin and Friedrich, Mike and Beliu, Gerti and Sauer, Markus and Lohse, Martin J. and Heinze, Katrin G.}, title = {Unraveling the hidden temporal range of fast β2-adrenergic receptor mobility by time-resolved fluorescence}, series = {Communications Biology}, volume = {5}, journal = {Communications Biology}, number = {1}, doi = {10.1038/s42003-022-03106-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301140}, year = {2022}, abstract = {G-protein-coupled receptors (GPCRs) are hypothesized to possess molecular mobility over a wide temporal range. Until now the temporal range has not been fully accessible due to the crucially limited temporal range of available methods. This in turn, may lead relevant dynamic constants to remain masked. Here, we expand this dynamic range by combining fluorescent techniques using a spot confocal setup. We decipher mobility constants of β\(_{2}\)-adrenergic receptor over a wide time range (nanosecond to second). Particularly, a translational mobility (10 µm\(^{2}\)/s), one order of magnitude faster than membrane associated lateral mobility that explains membrane protein turnover and suggests a wider picture of the GPCR availability on the plasma membrane. And a so far elusive rotational mobility (1-200 µs) which depicts a previously overlooked dynamic component that, despite all complexity, behaves largely as predicted by the Saffman-Delbr{\"u}ck model.}, language = {en} } @phdthesis{Bangalore2022, author = {Bangalore, Disha Mohan}, title = {Mechanistic studies of protein-DNA interactions by single molecule atomic force microscopy}, doi = {10.25972/OPUS-25204}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252047}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Protein-DNA interactions are central to many biological processes and form the bedrock of gene transcription, DNA replication, and DNA repair processes. Many proteins recognize specific sequences in DNA- a restriction enzyme must only cut at the correct sequence and a transcription factor should bind at its consensus sequence. Some proteins are designed to bind to specific structural or chemical features in DNA, such as DNA repair proteins and some DNA modifying enzymes. Target-specific DNA binding proteins initially bind to non-specific DNA and then search for their target sites through different types of diffusion mechanisms. Atomic force microscopy (AFM) is a single-molecule technique that is specifically well-suited to resolve the distinct states of target-specific as well as nonspecific protein-DNA interactions that are vital for a deeper insight into the target site search mechanisms of these enzymes. In this thesis, protein systems involved in epigenetic regulation, base excision repair (BER), and transcription are investigated by single-molecule AFM analyses complemented by biochemical and biophysical experiments. The first chapter of this thesis narrates the establishment of a novel, user-unbiased MatLab-based tool for automated DNA bend angle measurements on AFM data. This tool has then been employed to study the initial lesion detection step of several DNA glycosylases. These results promoted a model describing the altered plasticities of DNA at the target lesions of DNA glycosylases as the fundamental mechanism for their enhanced efficiency of lesion detection. In the second chapter of this thesis, the novel automated tool has been further extended to provide protein binding positions on the DNA along with corresponding DNA bend angles and applied to the study of DNMT3A DNA methyltransferase. These AFM studies revealed preferential co-methylation at specific, defined distances between two CpG sites by the enzyme and when combined with biochemical analyses and structural modelling supported novel modes of CpG co-methylation by DNMT3A. In the third chapter of this thesis, the role of 8-oxo-guanine glycosylase (hOGG1) in Myc-mediated transcription initiation has been investigated. AFM analyses revealed that in the presence of oxidative damage in DNA, Myc is recruited to its target site (E-box) by hOGG1 through direct protein-protein interactions, specifically under oxidizing conditions. Intriguingly, oxidation of hOGG1 was further observed to result in dimerization of hOGG1, which may also play a role in the mechanism of transcription regulation by hOGG1 under oxidative stress.}, subject = {Transcription}, language = {en} } @phdthesis{Bangelesa2022, author = {Bangelesa, Freddy Fefe}, title = {Impacts of climate variability and change on Maize (\(Zea\) \(mays\)) production in tropical Africa}, doi = {10.25972/OPUS-25934}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259347}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Climate change is undeniable and constitutes one of the major threats of the 21st century. It impacts sectors of our society, usually negatively, and is likely to worsen towards the middle and end of the century. The agricultural sector is of particular concern, for it is the primary source of food and is strongly dependent on the weather. Considerable attention has been given to the impact of climate change on African agriculture because of the continent's high vulnerability, which is mainly due to its low adaptation capac- ity. Several studies have been implemented to evaluate the impact of climate change on this continent. The results are sometimes controversial since the studies are based on different approaches, climate models and crop yield datasets. This study attempts to contribute substantially to this large topic by suggesting specific types of climate pre- dictors. The study focuses on tropical Africa and its maize yield. Maize is considered to be the most important crop in this region. To estimate the effect of climate change on maize yield, the study began by developing a robust cross-validated multiple linear regression model, which related climate predictors and maize yield. This statistical trans- fer function is reputed to be less prone to overfitting and multicollinearity problems. It is capable of selecting robust predictors, which have a physical meaning. Therefore, the study combined: large-scale predictors, which were derived from the principal component analysis of the monthly precipitation and temperature; traditional local-scale predictors, mainly, the mean precipitation, mean temperature, maximum temperature and minimum temperature; and the Water Requirement Satisfaction Index (WRSI), derived from the specific crop (maize) water balance model. The projected maize-yield change is forced by a regional climate model (RCM) REMO under two emission scenarios: high emission scenario (RCP8.5) and mid-range emission scenario (RCP4.5). The different effects of these groups of predictors in projecting the future maize-yield changes were also assessed. Furthermore, the study analysed the impact of climate change on the global WRSI. The results indicate that almost 27 \% of the interannual variability of maize production of the entire region is explained by climate variables. The influence of climate predictors on maize-yield production is more pronounced in West Africa, reaching 55 \% in some areas. The model projection indicates that the maize yield in the entire region is expected to decrease by the middle of the century under an RCP8.5 emission scenario, and from the middle of the century to the end of the century, the production will slightly recover but will remain negative (around -10 \%). However, in some regions of East Africa, a slight increase in maize yield is expected. The maize-yield projection under RCP4.5 remains relatively unchanged compared to the baseline period (1982-2016). The results further indicate that large-scale predictors are the most critical drivers of the global year-to-year maize-yield variability, and ENSO - which is highly correlated with the most important predictor (PC2) - seems to be the physical process underlying this variability. The effects of local predictors are more pronounced in the eastern parts of the region. The impact of the future climate change on WRSI reveals that the availability of maize water is expected to decrease everywhere, except in some parts of eastern Africa.}, language = {en} } @article{BanickaMartensPanzeretal.2022, author = {Banicka, Veronika and Martens, Marie Christine and Panzer, R{\"u}diger and Schrama, David and Emmert, Steffen and Boeckmann, Lars and Thiem, Alexander}, title = {Homozygous CRISPR/Cas9 knockout generated a novel functionally active exon 1 skipping XPA variant in melanoma cells}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {19}, issn = {1422-0067}, doi = {10.3390/ijms231911649}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290427}, year = {2022}, abstract = {Defects in DNA repair pathways have been associated with an improved response to immune checkpoint inhibition (ICI). In particular, patients with the nucleotide excision repair (NER) defect disease Xeroderma pigmentosum (XP) responded impressively well to ICI treatment. Recently, in melanoma patients, pretherapeutic XP gene expression was predictive for anti-programmed cell death-1 (PD-1) ICI response. The underlying mechanisms of this finding are still to be revealed. Therefore, we used CRISPR/Cas9 to disrupt XPA in A375 melanoma cells. The resulting subclonal cell lines were investigated by Sanger sequencing. Based on their genetic sequence, candidates from XPA exon 1 and 2 were selected and further analyzed by immunoblotting, immunofluorescence, HCR and MTT assays. In XPA exon 1, we established a homozygous (c.19delG; p.A7Lfs*8) and a compound heterozygous (c.19delG/c.19_20insG; p.A7Lfs*8/p.A7Gfs*55) cell line. In XPA exon 2, we generated a compound heterozygous mutated cell line (c.206_208delTTG/c.208_209delGA; p.I69_D70delinsN/p.D70Hfs*31). The better performance of the homozygous than the heterozygous mutated exon 1 cells in DNA damage repair (HCR) and post-UV-C cell survival (MTT), was associated with the expression of a novel XPA protein variant. The results of our study serve as the fundamental basis for the investigation of the immunological consequences of XPA disruption in melanoma.}, language = {en} } @article{BarahonadeBritoKleinHesslingSerflingetal.2022, author = {Barahona de Brito, Carlotta and Klein-Hessling, Stefan and Serfling, Edgar and Patra, Amiya Kumar}, title = {Hematopoietic stem and progenitor cell maintenance and multiple lineage differentiation is an integral function of NFATc1}, series = {Cells}, volume = {11}, journal = {Cells}, number = {13}, issn = {2073-4409}, doi = {10.3390/cells11132012}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-278809}, year = {2022}, abstract = {Hematopoietic stem and progenitor cell (HSPC) maintenance and the differentiation of various lineages is a highly complex but precisely regulated process. Multiple signaling pathways and an array of transcription factors influence HSPC maintenance and the differentiation of individual lineages to constitute a functional hematopoietic system. Nuclear factor of activated T cell (NFAT) family transcription factors have been studied in the context of development and function of multiple mature hematopoietic lineage cells. However, until now their contribution in HSPC physiology and HSPC differentiation to multiple hematopoietic lineages has remained poorly understood. Here, we show that NFAT proteins, specifically NFATc1, play an indispensable role in the maintenance of HSPCs. In the absence of NFATc1, very few HSPCs develop in the bone marrow, which are functionally defective. In addition to HSPC maintenance, NFATc1 also critically regulates differentiation of lymphoid, myeloid, and erythroid lineage cells from HSPCs. Deficiency of NFATc1 strongly impaired, while enhanced NFATc1 activity augmented, the differentiation of these lineages, which further attested to the vital involvement of NFATc1 in regulating hematopoiesis. Hematopoietic defects due to lack of NFATc1 activity can lead to severe pathologies such as lymphopenia, myelopenia, and a drastically reduced lifespan underlining the critical role NFATc1 plays in HSPC maintenance and in the differentaion of various lineages. Our findings suggest that NFATc1 is a critical component of the myriad signaling and transcriptional regulators that are essential to maintain normal hematopoiesis.}, language = {en} } @article{BarahonadeBritoPatra2022, author = {Barahona de Brito, Carlotta and Patra, Amiya Kumar}, title = {NFAT factors are dispensable for the development but are critical for the maintenance of Foxp3\(^+\) regulatory T cells}, series = {Cells}, volume = {11}, journal = {Cells}, number = {9}, issn = {2073-4409}, doi = {10.3390/cells11091397}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270668}, year = {2022}, abstract = {The transcription factors of the nuclear factor of activated T cell (NFAT) family play a crucial role in multiple aspects of T cell function. It has recently been reported that NFATs play an important role in the suppressive function of CD4\(^+\)CD25\(^+\)Foxp3\(^+\) regulatory T (T\(_{reg}\)) cells. In this study, we have investigated the role of NFATs in the thymic development of T\(_{reg}\) cells in mice. We show that NFAT factors are dispensable for the development of Foxp3\(^+\) T\(_{reg}\) cells in the thymus but are critical for the maintenance of both the phenotype and survival of T\(_{reg}\) cells in the thymus as well as in peripheral lymphoid organs. Specifically, the homeostasis of CD4\(^+\)CD25\(^+\)Foxp3\(^+\) but not the CD4\(^+\)CD25\(^-\)Foxp3\(^+\) fraction is severely perturbed when NFAT signaling is blocked, leading to a strongly reduced T\(_{reg}\) population. We underscored this intriguing effect of NFAT on CD4\(^+\)CD25\(^+\)Foxp3\(^+\) T\(_{reg}\) cells to the disruption of survival signals provided by interleukin 2 (IL-2). Accordingly, blocking T\(_{reg}\) cell death by abolishing the activity of pro-apoptotic Bcl-2 family member Bim, compensated for the survival defects induced due to a lack of NFAT-IL-2-IL-2R signaling. Inhibition of NFAT activity led to a strong reduction in the number of Foxp3\(^+\) T\(_{reg}\) cells; however, it did not influence the level of Foxp3 expression on an individual cell basis. In addition, we show a differential effect of IL-2 and IL-7 signaling on Foxp3\(^+\) T\(_{reg}\) versus CD4\(^+\)CD25\(^-\) T cell development, again underlining the dispensability of NFAT signaling in the development, but not in the maintenance of Foxp3\(^+\) T\(_{reg}\) cells.}, language = {en} } @article{BarakDhimanSturmetal.2022, author = {Barak, Arvind and Dhiman, Nishant and Sturm, Floriane and Rauch, Florian and Lakshmanna, Yapamanu Adithya and Findlay, Karen S. and Beeby, Andrew and Marder, Todd B. and Umapathy, Siva}, title = {Excited-State Intramolecular Charge-Transfer Dynamics in 4-Dimethylamino-4′-cyanodiphenylacetylene: An Ultrafast Raman Loss Spectroscopic Perspective}, series = {ChemPhotoChem}, volume = {6}, journal = {ChemPhotoChem}, number = {12}, doi = {10.1002/cptc.202200146}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312280}, year = {2022}, abstract = {Photo-initiated intramolecular charge transfer (ICT) processes play a pivotal role in the excited state reaction dynamics in donor-bridge-acceptor systems. The efficacy of such a process can be improved by modifying the extent of π-conjugation, relative orientation/twists of the donor/acceptor entities and polarity of the environment. Herein, 4-dimethylamino-4′-cyanodiphenylacetylene (DACN-DPA), a typical donor-π-bridge-acceptor system, was chosen to unravel the role of various internal coordinates that govern the extent of photo-initiated ICT dynamics. Transient absorption (TA) spectra of DACN-DPA in n-hexane exhibit a lifetime of >2 ns indicating the formation of a triplet state while, in acetonitrile, a short time-constant of ∼2 ps indicates the formation of charge transferred species. Ultrafast Raman loss spectroscopy (URLS) measurements show distinct temporal and spectral dynamics of Raman bands associated with C≡C and C=C stretching vibrations. The appearance of a new band at ∼1492 cm\(^{-1}\) in acetonitrile clearly indicates structural modification during the ultrafast ICT process. Furthermore, these observations are supported by TD-DFT computations.}, language = {en} } @phdthesis{Barth2022, author = {Barth, Dominik}, title = {Computation of multi-branch-point covers and applications in Galois theory}, doi = {10.25972/OPUS-27702}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-277025}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {We present a technique for computing multi-branch-point covers with prescribed ramification and demonstrate the applicability of our method in relatively large degrees by computing several families of polynomials with symplectic and linear Galois groups. As a first application, we present polynomials over \(\mathbb{Q}(\alpha,t)\) for the primitive rank-3 groups \(PSp_4(3)\) and \(PSp_4(3).C_2\) of degree 27 and for the 2-transitive group \(PSp_6(2)\) in its actions on 28 and 36 points, respectively. Moreover, the degree-28 polynomial for \(PSp_6(2)\) admits infinitely many totally real specializations. Next, we present the first (to the best of our knowledge) explicit polynomials for the 2-transitive linear groups \(PSL_4(3)\) and \(PGL_4(3)\) of degree 40, and the imprimitive group \(Aut(PGL_4(3))\) of degree 80. Additionally, we negatively answer a question by K{\"o}nig whether there exists a degree-63 rational function with rational coefficients and monodromy group \(PSL_6(2)\) ramified over at least four points. This is achieved due to the explicit computation of the corresponding hyperelliptic genus-3 Hurwitz curve parameterizing this family, followed by a search for rational points on it. As a byproduct of our calculations we obtain the first explicit \(Aut(PSL_6(2))\)-realizations over \(\mathbb{Q}(t)\). At last, we present a technique by Elkies for bounding the transitivity degree of Galois groups. This provides an alternative way to verify the Galois groups from the previous chapters and also yields a proof that the monodromy group of a degree-276 cover computed by Monien is isomorphic to the sporadic 2-transitive Conway group \(Co_3\).}, subject = {Galois-Theorie}, language = {en} } @phdthesis{BathePeters2022, author = {Bathe-Peters, Marc}, title = {Spectroscopic approaches for the localization and dynamics of β\(_1\)- and β\(_2\)-adrenergic receptors in cardiomyocytes}, doi = {10.25972/OPUS-25812}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258126}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {In the heart the β\(_1\)-adrenergic receptor (AR) and the β\(_2\)-AR, two prototypical G protein-coupled receptors (GPCRs), are both activated by the same hormones, namely adrenaline and noradrenaline. Both receptors couple to stimulatory G\(_s\) proteins, mediate an increase in cyclic adenosine monophosphate (cAMP) and influence the contractility and frequency of the heart upon stimulation. However, activation of the β\(_1\)-AR, not the β\(_2\)-AR, lead to other additional effects, such as changes in gene transcription resulting in cardiac hypertrophy, leading to speculations on how distinct effects can arise from receptors coupled to the same downstream signaling pathway. In this thesis the question of whether this distinct behavior may originate from a differential localization of these two receptors in adult cardiomyocytes is addressed. Therefore, fluorescence spectroscopy tools are developed and implemented in order to elucidate the presence and dynamics of these endogenous receptors at the outer plasma membrane as well as on the T-tubular network of intact adult cardiomyocytes. This allows the visualization of confined localization and diffusion of the β\(_2\)-AR to the T-tubular network at endogenous expression. In contrast, the β\(_1\)-AR is found diffusing at both the outer plasma membrane and the T-tubules. Upon overexpression of the β\(_2\)-AR in adult transgenic cardiomyocytes, the receptors experience a loss of this compartmentalization and are also found at the cell surface. These data suggest that distinct signaling and functional effects can be controlled by specific cell surface targeting of the receptor subtypes. The tools at the basis of this thesis work are a fluorescent adrenergic antagonist in combination of fluorescence fluctuation spectroscopy to monitor the localization and dynamics of the lowly expressed adrenergic receptors. Along the way to optimizing these approaches, I worked on combining widefield and confocal imaging in one setup, as well as implementing a stable autofocus mechanism using electrically tunable lenses.}, subject = {G-Protein gekoppelte Rezeptoren}, language = {en} } @article{BauerConchaMendozaKreienbrocketal.2022, author = {Bauer, Hannah and Concha Mendoza, Gustavo Andr{\´e}s and Kreienbrock, Lothar and Hartmann, Maria and Frickmann, Hagen and Kann, Simone}, title = {Prevalence of common diseases in Indigenous people in Colombia}, series = {Tropical Medicine and Infectious Disease}, volume = {7}, journal = {Tropical Medicine and Infectious Disease}, number = {6}, issn = {2414-6366}, doi = {10.3390/tropicalmed7060109}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-278953}, year = {2022}, abstract = {The Indigenous tribe called the Wiwa lives retracted in the Sierra Nevada de Santa Marta, Colombia. Little is known about their health status and whether the health care system in place covers their needs. In 2017 and 2018, a permanent physician was in charge for the Wiwa. Diseases and complaints were registered, ranked, and classified with the ICD-10 coding. Datasets from the Indigenous health care provider Dusakawi, collected from local health points and health brigades travelling sporadically into the fields for short visits, were compared. Furthermore, a list of provided medication was evaluated regarding the recorded needs. The most common complaints found were respiratory, infectious and parasitic, and digestive diseases. The top ten diagnoses collected in the health points and in the health brigade datasets were similar, although with a different ranking. The available medication showed a basic coverage only, with a critical lack of treatment for many severe, chronic, and life-threatening diseases. Most of the detected diseases in the Indigenous population are avoidable by an improvement in health care access, an expansion of the provided medication, and an increase in knowledge, hygiene, and life standards.}, language = {en} } @article{BauerSperlichHolmbergetal.2022, author = {Bauer, Nikolai and Sperlich, Billy and Holmberg, Hans-Christer and Engel, Florian A.}, title = {Effects of High-Intensity Interval Training in School on the Physical Performance and Health of Children and Adolescents: A Systematic Review with Meta-Analysis}, series = {Sports Medicine - Open}, volume = {8}, journal = {Sports Medicine - Open}, number = {1}, issn = {2199-1170}, doi = {10.1186/s40798-022-00437-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301205}, year = {2022}, abstract = {Objectives To assess the impact of HIIT performed at school, i.e. both in connection with physical education (intra-PE) and extracurricular sports activities (extra-PE), on the physical fitness and health of children and adolescents. Methods PubMed and SPORTDiscus were searched systematically utilizing the following criteria for inclusion: (1) healthy children and adolescents (5-18 years old) of normal weight; (2) HIIT performed intra- and/or extra-PE for at least 5 days at an intensity ≥ 80\% of maximal heart rate (HR\(_{max}\)) or peak oxygen uptake (VO\(_{2peak}\)) or as Functional HIIT; (3) comparison with a control (HIIT versus alternative interventions); and (4) pre- and post-analysis of parameters related to physical fitness and health. The outcomes with HIIT and the control interventions were compared utilizing Hedges' g effect size (ES) and associated 95\% confidence intervals. Results Eleven studies involving 707 participants who performed intra-PE and 388 participants extra-PE HIIT were included. In comparison with the control interventions, intra-PE HIIT improved mean ES for neuromuscular and anaerobic performance (ES jump performance: 5.89 ± 5.67 (range 1.88-9.90); ES number of push-ups: 6.22 (range n.a.); ES number of sit-ups: 2.66 ± 2.02 (range 1.24-4.09)), as well as ES fasting glucose levels (- 2.68 (range n.a.)) more effectively, with large effect sizes. Extra-PE HIIT improved mean ES for neuromuscular and anaerobic performance (ES jump performance: 1.81 (range n.a.); ES number of sit-ups: 2.60 (range n.a.)) to an even greater extent, again with large effect sizes. Neither form of HIIT was more beneficial for parameters related to cardiorespiratory fitness than the control interventions. Conclusion Compared to other forms of exercise (e.g. low-to-moderate-intensity running or walking), both intra- and extra-PE HIIT result in greater improvements in neuromuscular and anaerobic performance, as well as in fasting levels of glucose in school children.}, language = {en} } @article{BaumbachHoertererOppeltetal.2022, author = {Baumbach, Sebastian Felix and H{\"o}rterer, Hubert and Oppelt, Sonja and Szeimies, Ulrike and Polzer, Hans and Walther, Markus}, title = {Do pre-operative radiologic assessment predict postoperative outcomes in patients with insertional Achilles tendinopathy?: a retrospective database study}, series = {Archives of Orthopaedic and Trauma Surgery}, volume = {142}, journal = {Archives of Orthopaedic and Trauma Surgery}, number = {11}, issn = {1434-3916}, doi = {10.1007/s00402-021-03897-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307963}, pages = {3045-3052}, year = {2022}, abstract = {Introduction Diagnosis and treatment of insertional tendinopathy of the Achilles tendon (IAT) remains a challenge. The aim of this study was to assess the influence of pre-operative radiological pathologies on the patient-reported outcomes following open debridement of all pathologies for IAT. Materials and methods In this IRB-approved retrospective correlation and comparative study, patients with pre-operative imaging were identified from the authors' retrospective IAT database comprising of 118 patients. All were treated by a standardized surgical treatment strategy utilizing a midline, transachillary approach and debridement of all pathologies. A total of fifteen radiologic parameters were measured on radiographs (RX) and MRI. The patient-reported outcomes were assessed using the Victorian Institute of Sport Assessment-Achilles questionnaire (VISA-A-G) and the general health questionnaire SF-12 at a minimum follow-up of 12 months. The data are presented as mean ± SD (95\% CI). Results 88 patients (74.6\%) with an average age of 50 ± 12 (47-52) years were included. Radiographs were available in 68 patients and MRI in 53. The mean follow-up was 3.8 ± 1.9 (3.4-4.3) years. The overall VISA-A-G was 81 ± 22 (77-86), the SF-12 PCS 54 ± 7 (52-55), and the SF-12 MCS 52 ± 9 (50-54) points. None of the assessed radiological parameters had a significant influence on the patient-reported outcome following surgical treatment for IAT. Conclusion In this retrospective correlation study, no significant association was found between preoperative radiographic and MRI radiologic parameters for IAT and postoperative patient-reported outcomes (VISA-A-G and SF-12).}, language = {en} } @article{BazihizinaBoehmMessereretal.2022, author = {Bazihizina, Nadia and B{\"o}hm, Jennifer and Messerer, Maxim and Stigloher, Christian and M{\"u}ller, Heike M. and Cuin, Tracey Ann and Maierhofer, Tobias and Cabot, Joan and Mayer, Klaus F. X. and Fella, Christian and Huang, Shouguang and Al-Rasheid, Khaled A. S. and Alquraishi, Saleh and Breadmore, Michael and Mancuso, Stefano and Shabala, Sergey and Ache, Peter and Zhang, Heng and Zhu, Jian-Kang and Hedrich, Rainer and Scherzer, S{\"o}nke}, title = {Stalk cell polar ion transport provide for bladder-based salinity tolerance in Chenopodium quinoa}, series = {New Phytologist}, volume = {235}, journal = {New Phytologist}, number = {5}, doi = {10.1111/nph.18205}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-287222}, pages = {1822 -- 1835}, year = {2022}, abstract = {Chenopodium quinoa uses epidermal bladder cells (EBCs) to sequester excess salt. Each EBC complex consists of a leaf epidermal cell, a stalk cell, and the bladder. Under salt stress, sodium (Na\(^{+}\)), chloride (Cl\(^{-}\)), potassium (K\(^{+}\)) and various metabolites are shuttled from the leaf lamina to the bladders. Stalk cells operate as both a selectivity filter and a flux controller. In line with the nature of a transfer cell, advanced transmission electron tomography, electrophysiology, and fluorescent tracer flux studies revealed the stalk cell's polar organization and bladder-directed solute flow. RNA sequencing and cluster analysis revealed the gene expression profiles of the stalk cells. Among the stalk cell enriched genes, ion channels and carriers as well as sugar transporters were most pronounced. Based on their electrophysiological fingerprint and thermodynamic considerations, a model for stalk cell transcellular transport was derived.}, language = {en} } @phdthesis{Becht2022, author = {Becht, Alexander Ulrich}, title = {New applications for spectroscopic and chemometric studies of drugs}, doi = {10.25972/OPUS-27534}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-275342}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Spectroscopic methods were established decades ago in a wide variety of fields. This also applies to the pharmaceutical field, although they initially were mostly used for identity testing or structure elucidation only. Technical developments, such as miniaturization (NMR benchtop devices), Fourier transformations (for NMR, MIR spectroscopy) or the combination with chemometric evaluation (e.g., in Process Analytical Technology, PAT), have further increased their importance and opened up new applications. The aim of this work was to investigate further new approaches and to find new applications for already established methods and to show their benefits. By means of MIR, NIR and NMR data and their chemometric evaluation (principal component analysis, PCA; hierarchical cluster analysis, HCA; linear discriminant analysis, LDA), possibilities were presented to successfully determine the manufacturer or the pharmaceutical company of various paracetamol preparations. In the course of this, various similarities and correlations between the preparations of individual companies could also be identified. For this purpose, a suitable sample preparation was developed for each spectroscopic method, and suitable measurement parameters in order to obtain reproducible spectra for the chemometric evaluation were determined. Furthermore, the results of the two unsupervised methods (HCA, PCA) were compared with each other. The HCA was able to confirm those of the PCA for the very most part. Additionally, through these methods it was possible to characterize many of the preparations based on clusters formed by comparable tablet compositions. In order to be able to measure unmortared, whole tablets using the NIR spectrometer, an attachment was developed and manufactured using 3D printing. Its functionality was demonstrated by measuring and analyzing the tablets of two different batches of nine paracetamol preparations. The batches were clearly distinguished on the basis of a PCA and a significant difference was also demonstrated by means of statistical tests. For NMR spectroscopy, a method was developed to obtain optimized "fingerprint" spectra of drug formulations. For this purpose, a 1D DOSY measurement was elaborated, in which the signals of the active ingredient could be filtered out by the appropriate choice of measurement parameters. The chemometric evaluation can thus focus on the remaining signals of the excipients, on the basis of which the preparations of the same API can be distinguished. Especially in the case of formulations that consist largely of active ingredient, data pre processing of the spectra can thus be simplified and greater importance can be assigned to the originally very small excipient signals. A quantitative 1H NMR method was developed for the comparison of a high field spectrometer (400 MHz) with a benchtop spectrometer (80 MHz) for two finished drugs. It was shown that it is possible to obtain comparable results with both instruments, but that the influence of the excipients on the signals and the lower resolution of the benchtop instrument must be taken into account. Therefore, it was not possible to obtain comparable results without further optimization of the method for one of the active ingredients. In the investigation of various reactions between APIs and excipients using DOSY, its usefulness as a screening method in stability testing was demonstrated. For this purpose, three different APIs and excipients were stressed together and the reaction mixtures were subsequently measured using DOSY. Based on the translational diffusion coefficient, the reaction products could be identified and distinguished from the active ingredients and the excipients used. The importance of thoughtful processing could also be demonstrated. If all peak heights are selected when evaluating signals split by direct spin spin coupling, this allows the detection of hidden signals as long as not all signals have the same diffusion coefficient. The selective selection of individual peak heights in the case of split signals also enables the evaluation of signals that overlap slightly. However, the limitations of this method were also shown when two signals overlap too much and differ too little in their diffusion coefficients. Hence, it has been successfully demonstrated in the various projects that the new chemometric approaches, as well as the new applications of already established methods, enable in depth findings and thus have a clear added value.}, subject = {Instrumentelle Analytik}, language = {en} } @article{BeckEngelReimers2022, author = {Beck, Franziska and Engel, Florian A. and Reimers, Anne Kerstin}, title = {Compensation or displacement of physical activity in children and adolescents: a systematic review of empirical studies}, series = {Children}, volume = {9}, journal = {Children}, number = {3}, issn = {2227-9067}, doi = {10.3390/children9030351}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267231}, year = {2022}, abstract = {Regular physical activity during childhood and adolescence is associated with health benefits. Consequently, numerous health promotion programs for children and adolescents emphasize the enhancement of physical activity. However, the ActivityStat hypothesis states that increases in physical activity in one domain are compensated for by decreasing physical activity in another domain. Currently, little is known about how physical activity varies in children and adolescents within intervals of one day or multiple days. This systematic review provides an overview of studies that analyzed changes in (overall) physical activity, which were assessed with objective measurements, or compensatory mechanisms caused by increases or decreases in physical activity in a specific domain in children and adolescents. A systematic search of electronic databases (PubMed, Scopus, Web of Science, SportDiscus) was performed with a priori defined inclusion criteria. Two independent researchers screened the literature and identified and rated the methodological quality of the studies. A total of 77 peer-reviewed articles were included that analyzed changes in overall physical activity with multiple methodological approaches resulting in compensation or displacement. Of 40,829 participants, 16,265 indicated compensation associated with physical activity. Subgroup analyses separated by study design, participants, measurement instrument, physical activity context, and intervention duration also showed mixed results toward an indication of compensation. Quality assessment of the included studies revealed that they were of high quality (mean = 0.866). This review provides inconclusive results about compensation in relation to physical activity. A trend toward increased compensation in interventional studies and in interventions of longer duration have been observed.}, language = {en} } @article{BeerHaertelHelfrichFoerster2022, author = {Beer, Katharina and H{\"a}rtel, Stephan and Helfrich-F{\"o}rster, Charlotte}, title = {The pigment-dispersing factor neuronal network systematically grows in developing honey bees}, series = {The Journal of Comparative Neurology}, volume = {530}, journal = {The Journal of Comparative Neurology}, number = {9}, doi = {10.1002/cne.25278}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-257300}, pages = {1321-1340}, year = {2022}, abstract = {The neuropeptide pigment-dispersing factor (PDF) plays a prominent role in the circadian clock of many insects including honey bees. In the honey bee brain, PDF is expressed in about 15 clock neurons per hemisphere that lie between the central brain and the optic lobes. As in other insects, the bee PDF neurons form wide arborizations in the brain, but certain differences are evident. For example, they arborize only sparsely in the accessory medulla (AME), which serves as important communication center of the circadian clock in cockroaches and flies. Furthermore, all bee PDF neurons cluster together, which makes it impossible to distinguish individual projections. Here, we investigated the developing bee PDF network and found that the first three PDF neurons arise in the third larval instar and form a dense network of varicose fibers at the base of the developing medulla that strongly resembles the AME of hemimetabolous insects. In addition, they send faint fibers toward the lateral superior protocerebrum. In last larval instar, PDF cells with larger somata appear and send fibers toward the distal medulla and the medial protocerebrum. In the dorsal part of the medulla serpentine layer, a small PDF knot evolves from which PDF fibers extend ventrally. This knot disappears during metamorphosis and the varicose arborizations in the putative AME become fainter. Instead, a new strongly stained PDF fiber hub appears in front of the lobula. Simultaneously, the number of PDF neurons increases and the PDF neuronal network in the brain gets continuously more complex.}, language = {en} } @article{BeetzHechavarria2022, author = {Beetz, M. Jerome and Hechavarr{\´i}a, Julio C.}, title = {Neural processing of naturalistic echolocation signals in bats}, series = {Frontiers in Neural Circuits}, volume = {16}, journal = {Frontiers in Neural Circuits}, issn = {1662-5110}, doi = {10.3389/fncir.2022.899370}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-274605}, year = {2022}, abstract = {Echolocation behavior, a navigation strategy based on acoustic signals, allows scientists to explore neural processing of behaviorally relevant stimuli. For the purpose of orientation, bats broadcast echolocation calls and extract spatial information from the echoes. Because bats control call emission and thus the availability of spatial information, the behavioral relevance of these signals is undiscussable. While most neurophysiological studies, conducted in the past, used synthesized acoustic stimuli that mimic portions of the echolocation signals, recent progress has been made to understand how naturalistic echolocation signals are encoded in the bat brain. Here, we review how does stimulus history affect neural processing, how spatial information from multiple objects and how echolocation signals embedded in a naturalistic, noisy environment are processed in the bat brain. We end our review by discussing the huge potential that state-of-the-art recording techniques provide to gain a more complete picture on the neuroethology of echolocation behavior.}, language = {en} } @article{BeheraJainGangulietal.2022, author = {Behera, Ananyaashree and Jain, Preeti and Ganguli, Geetanjali and Biswas, Mainak and Padhi, Avinash and Pattanaik, Kali Prasad and Nayak, Barsa and Erg{\"u}n, S{\"u}leyman and Hagens, Kristine and Redinger, Natalja and Saqib, Mohd and Mishra, Bibhuti B. and Schaible, Ulrich E. and Karnati, Srikanth and Sonawane, Avinash}, title = {Mycobacterium tuberculosis acetyltransferase suppresses oxidative stress by inducing peroxisome formation in macrophages}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {5}, issn = {1422-0067}, doi = {10.3390/ijms23052584}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284080}, year = {2022}, abstract = {Mycobacterium tuberculosis (Mtb) inhibits host oxidative stress responses facilitating its survival in macrophages; however, the underlying molecular mechanisms are poorly understood. Here, we identified a Mtb acetyltransferase (Rv3034c) as a novel counter actor of macrophage oxidative stress responses by inducing peroxisome formation. An inducible Rv3034c deletion mutant of Mtb failed to induce peroxisome biogenesis, expression of the peroxisomal β-oxidation pathway intermediates (ACOX1, ACAA1, MFP2) in macrophages, resulting in reduced intracellular survival compared to the parental strain. This reduced virulence phenotype was rescued by repletion of Rv3034c. Peroxisome induction depended on the interaction between Rv3034c and the macrophage mannose receptor (MR). Interaction between Rv3034c and MR induced expression of the peroxisomal biogenesis proteins PEX5p, PEX13p, PEX14p, PEX11β, PEX19p, the peroxisomal membrane lipid transporter ABCD3, and catalase. Expression of PEX14p and ABCD3 was also enhanced in lungs from Mtb aerosol-infected mice. This is the first report that peroxisome-mediated control of ROS balance is essential for innate immune responses to Mtb but can be counteracted by the mycobacterial acetyltransferase Rv3034c. Thus, peroxisomes represent interesting targets for host-directed therapeutics to tuberculosis.}, language = {en} } @article{BellutPappBieberetal.2022, author = {Bellut, Maximilian and Papp, Lena and Bieber, Michael and Kraft, Peter and Stoll, Guido and Schuhmann, Michael K.}, title = {NLPR3 inflammasome inhibition alleviates hypoxic endothelial cell death in-vitro and protects blood-brain barrier integrity in murine stroke}, series = {Cell Death \& Disease}, volume = {13}, journal = {Cell Death \& Disease}, doi = {10.1038/s41419-021-04379-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265693}, year = {2022}, abstract = {In ischemic stroke (IS) impairment of the blood-brain barrier (BBB) has an important role in the secondary deterioration of neurological function. BBB disruption is associated with ischemia-induced inflammation, brain edema formation, and hemorrhagic infarct transformation, but the underlying mechanisms are incompletely understood. Dysfunction of endothelial cells (EC) may play a central role in this process. Although neuronal NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome upregulation is an established trigger of inflammation in IS, the contribution of its expression in EC is unclear. We here used brain EC, exposed them to oxygen and glucose deprivation (OGD) in vitro, and analyzed their survival depending on inflammasome inhibition with the NLRP3-specific drug MCC950. During OGD, EC death could significantly be reduced when targeting NLRP3, concomitant with diminished endothelial NLRP3 expression. Furthermore, MCC950 led to reduced levels of Caspase 1 (p20) and activated Gasdermin D as markers for pyroptosis. Moreover, inflammasome inhibition reduced the secretion of pro-inflammatory chemokines, cytokines, and matrix metalloproteinase-9 (MMP9) in EC. In a translational approach, IS was induced in C57Bl/6 mice by 60 mins transient middle cerebral artery occlusion and 23 hours of reperfusion. Stroke volume, functional outcome, the BBB integrity, and-in good agreement with the in vitro results-MMP9 secretion as well as EC survival improved significantly in MCC950-treated mice. In conclusion, our results establish the NLRP3 inflammasome as a critical pathogenic effector of stroke-induced BBB disruption by activating inflammatory signaling cascades and pyroptosis in brain EC.}, language = {en} } @article{BellutRaimondiHaarmannetal.2022, author = {Bellut, Maximilian and Raimondi, Anthony T. and Haarmann, Axel and Zimmermann, Lena and Stoll, Guido and Schuhmann, Michael K.}, title = {NLRP3 inhibition reduces rt-PA induced endothelial dysfunction under ischemic conditions}, series = {Biomedicines}, volume = {10}, journal = {Biomedicines}, number = {4}, issn = {2227-9059}, doi = {10.3390/biomedicines10040762}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267261}, year = {2022}, abstract = {Thrombolysis with recombinant tissue plasminogen activator (rt-PA) is a mainstay of acute ischemic stroke treatment but is associated with bleeding complications, especially after prolonged large vessel occlusion. Recently, inhibition of the NLRP3 inflammasome led to preserved blood-brain barrier (BBB) integrity in experimental stroke in vivo. To further address the potential of NLRP3 inflammasome inhibition as adjunct stroke treatment we used immortalized brain derived endothelial cells (bEnd5) as an in vitro model of the BBB. We treated bEnd5 with rt-PA in combination with the NLRP3 specific inhibitor MCC950 or vehicle under normoxic as well as ischemic (OGD) conditions. We found that rt-PA exerted a cytotoxic effect on bEnd5 cells under OGD confirming that rt-PA is harmful to the BBB. This detrimental effect could be significantly reduced by MCC950 treatment. Moreover, under ischemic conditions, the Cell Index — a sensible indicator for a patent BBB — and the protein expression of Zonula occludens 1 stabilized after MCC950 treatment. At the same time, the extent of endothelial cell death and NLRP3 expression decreased. In conclusion, NLRP3 inhibition can protect the BBB from rt-PA-induced damage and thereby potentially increase the narrow time window for safe thrombolysis in stroke.}, language = {en} } @article{BenKhaledHammerYeetal.2022, author = {Ben Khaled, Najib and Hammer, Katharina and Ye, Liangtao and Alnatsha, Ahmed and Widholz, Sebastian A. and Piseddu, Ignazio and Sirtl, Simon and Schneider, Julia and Munker, Stefan and Mahajan, Ujjwal Mukund and Montero, Juan Jos{\´e} and Griger, Joscha and Mayerle, Julia and Reiter, Florian P. and De Toni, Enrico N.}, title = {TRAIL receptor targeting agents potentiate PARP inhibitor efficacy in pancreatic cancer independently of BRCA2 mutation status}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {21}, issn = {2072-6694}, doi = {10.3390/cancers14215240}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290884}, year = {2022}, abstract = {Chemotherapy, the standard treatment for pancreatic ductal adenocarcinoma (PDAC), has only a modest effect on the outcome of patients with late-stage disease. Investigations of the genetic features of PDAC have demonstrated a frequent occurrence of mutations in genes involved in homologous recombination (HR), especially in the breast cancer susceptibility gene 2 (BRCA2). Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved as a maintenance treatment for patients with advanced PDAC with germline BRCA1/2 mutations following a platinum-containing first-line regimen. Limitations to the use of PARP inhibitors are represented by the relatively small proportion of patients with mutations in BRCA1/2 genes and the modest capability of these substances of inducing objective response. We have previously shown that pancreatic cancer with BRCA2 mutations exhibits a remarkably enhanced sensitivity towards tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) receptor-stimulating agents. We thus aimed to investigate the effect of combined treatment with PARP inhibitors and TRAIL receptor-stimulating agents in pancreatic cancer and its dependency on the BRCA2 gene status. The respective effects of TRAIL-targeting agents and the PARP inhibitor olaparib or of their combination were assessed in pancreatic cancer cell lines and patient-derived organoids. In addition, BRCA2-knockout and -complementation models were investigated. The effects of these agents on apoptosis, DNA damage, cell cycle, and receptor surface expression were assessed by immunofluorescence, Western blot, and flow cytometry. PARP inhibition and TRAIL synergized to cause cell death in pancreatic cancer cell lines and PDAC organoids. This effect proved independent of BRCA2 gene status in three independent models. Olaparib and TRAIL in combination caused a detectable increase in DNA damage and a concentration-dependent cell cycle arrest in the G2/M and S cell cycle phases. Olaparib also significantly increased the proportion of membrane-bound death receptor 5. Our results provide a preclinical rationale for the combination of PARP inhibitors and TRAIL receptor agonists for the treatment of pancreatic cancer and suggest that the use of PARP inhibitors could be extended to patients without BRCA2 mutations if used in combination with TRAIL agonists.}, language = {en} } @article{BencurovaShityakovSchaacketal.2022, author = {Bencurova, Elena and Shityakov, Sergey and Schaack, Dominik and Kaltdorf, Martin and Sarukhanyan, Edita and Hilgarth, Alexander and Rath, Christin and Montenegro, Sergio and Roth, G{\"u}nter and Lopez, Daniel and Dandekar, Thomas}, title = {Nanocellulose composites as smart devices with chassis, light-directed DNA Storage, engineered electronic properties, and chip integration}, series = {Frontiers in Bioengineering and Biotechnology}, volume = {10}, journal = {Frontiers in Bioengineering and Biotechnology}, issn = {2296-4185}, doi = {10.3389/fbioe.2022.869111}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-283033}, year = {2022}, abstract = {The rapid development of green and sustainable materials opens up new possibilities in the field of applied research. Such materials include nanocellulose composites that can integrate many components into composites and provide a good chassis for smart devices. In our study, we evaluate four approaches for turning a nanocellulose composite into an information storage or processing device: 1) nanocellulose can be a suitable carrier material and protect information stored in DNA. 2) Nucleotide-processing enzymes (polymerase and exonuclease) can be controlled by light after fusing them with light-gating domains; nucleotide substrate specificity can be changed by mutation or pH change (read-in and read-out of the information). 3) Semiconductors and electronic capabilities can be achieved: we show that nanocellulose is rendered electronic by iodine treatment replacing silicon including microstructures. Nanocellulose semiconductor properties are measured, and the resulting potential including single-electron transistors (SET) and their properties are modeled. Electric current can also be transported by DNA through G-quadruplex DNA molecules; these as well as classical silicon semiconductors can easily be integrated into the nanocellulose composite. 4) To elaborate upon miniaturization and integration for a smart nanocellulose chip device, we demonstrate pH-sensitive dyes in nanocellulose, nanopore creation, and kinase micropatterning on bacterial membranes as well as digital PCR micro-wells. Future application potential includes nano-3D printing and fast molecular processors (e.g., SETs) integrated with DNA storage and conventional electronics. This would also lead to environment-friendly nanocellulose chips for information processing as well as smart nanocellulose composites for biomedical applications and nano-factories.}, language = {en} } @article{BergerDemolombeHemetal.2022, author = {Berger, Nathalie and Demolombe, Vincent and Hem, Sonia and Rofidal, Val{\´e}rie and Steinmann, Laura and Krouk, Gabriel and Crabos, Amandine and Nacry, Philippe and Verdoucq, Lionel and Santoni, V{\´e}ronique}, title = {Root membrane ubiquitinome under short-term osmotic stress}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {4}, issn = {1422-0067}, doi = {10.3390/ijms23041956}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284003}, year = {2022}, abstract = {Osmotic stress can be detrimental to plants, whose survival relies heavily on proteomic plasticity. Protein ubiquitination is a central post-translational modification in osmotic-mediated stress. In this study, we used the K-Ɛ-GG antibody enrichment method integrated with high-resolution mass spectrometry to compile a list of 719 ubiquitinated lysine (K-Ub) residues from 450 Arabidopsis root membrane proteins (58\% of which are transmembrane proteins), thereby adding to the database of ubiquitinated substrates in plants. Although no ubiquitin (Ub) motifs could be identified, the presence of acidic residues close to K-Ub was revealed. Our ubiquitinome analysis pointed to a broad role of ubiquitination in the internalization and sorting of cargo proteins. Moreover, the simultaneous proteome and ubiquitinome quantification showed that ubiquitination is mostly not involved in membrane protein degradation in response to short osmotic treatment but that it is putatively involved in protein internalization, as described for the aquaporin PIP2;1. Our in silico analysis of ubiquitinated proteins shows that two E2 Ub-conjugating enzymes, UBC32 and UBC34, putatively target membrane proteins under osmotic stress. Finally, we revealed a positive role for UBC32 and UBC34 in primary root growth under osmotic stress.}, language = {en} } @phdthesis{Berger2022, author = {Berger, Sarina Maria}, title = {Influence of Charge and Its Distribution on Biological Applications of Bis-Triarylboranes and Preliminary Investigations on H\(_2\)O\(_2\)-Cleavable Aryl Boronate Esters}, doi = {10.25972/OPUS-24314}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-243147}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {This dissertation describes the synthesis of an unsymmetrically-substituted triarylborane. This term describes a three-coordinate boron atom that is bound to three different aromatic systems, namely 2,6-dimethylphenyl, mesityl, and 4-(N,N-dimethylamino)-2,6-dimethylphenyl. It is also demonstrated that the amine functionality can be converted with methyl triflate into an ammonium moiety. The investigation of photophysical and electrochemical properties of this compound in comparison with the non-aminated and di-aminated analogues of the triarylborane is described besides other investigations of e. g. singlet oxygen sensitization, rotational barriers, and fundamental DFT calculations. Based on these investigations, selectively mono-, bis- and tris-dimethylamino- and trimethylammonium-substituted bis-triarylborane bithiophene chromophores were synthesized and their photophysical, and electrochemical properties were investigated together with the water solubility and singlet oxygen sensitizing efficiency of the cationic compounds Cat1+, Cat2+, Cat(i)2+, and Cat3+. Comparing these properties with the results obtained for the mono-triarylboranes reveals a large influence of the bridging unit on the investigated properties of the bis-triarylboranes. In addition, the interaction of the cationic bis-triarylboranes with different polynucleotides were investigated in buffered solutions as well as the ability of these selectively charged compounds to enter and localize within organelles of human lung carcinoma and normal lung cells. All these investigations demonstrate that the number of charges and their distribution influences the interactions and staining properties as well as most of the other properties investigated. In addition, preliminary investigations on H2O2-cleavable boronate esters in the presence of stochiometric amounts of H2O2 are described for three different aryl boronate esters.}, subject = {Triarylborane}, language = {en} } @phdthesis{Bergmann2022, author = {Bergmann, Tim Jonas}, title = {Pathways in uremic cardiomyopathy - the intracellular orchestrator PGC-1α in cell culture and in a mouse model of uremia}, doi = {10.25972/OPUS-28706}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-287061}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {For the past 20 years, chronic kidney disease (CKD) has remained one of the major causes of death worldwide. Cardiovascular events account for approximately 50\% of deaths in CKD patients, underscoring the clinical relevance of the observed cardiac changes. These changes define uremic cardiomyopathy (UCM) and include left-ventricular hypertrophy (LVH), LV dilatation, and LV systolic and diastolic dysfunction. LVH is seen as the primary manifestation of UCM and is caused by a multitude of different systems including in-creased pre- and afterload and the renin-angiotensin system (RAS). More recent studies found that myocardial dysfunction is apparent before changes in the ventricular geome-try, like hypertrophy, occur to the uremic heart. This leads to the conclusion that LVH is not the cause of cardiac dysfunction, but one of the alterations caused by factors related to the uremic state itself. Among these factors that are independent of pressure and vol-ume overload, are cardiotonic steroids as well as the parathyroid hormone and the endo-thelin (ET-1) system. But we suggest a different substance to play an important role in UCM: Urea. Patients in end-stage renal disease (ESRD) display increased oxidative stress and urea has been found to increase levels of oxidative stress, at least in endothelial cells. Therefore, we investigated the effect that elevated urea levels, as seen in patients undergoing dialysis, have on cardiomyocytes. As the oxidative stress in a cell is regulated by mitochondrial processes, we suspected the mitochondrial orchestrator PGC-1α to play an important role. The uremic heart is in a state of elevated oxidative stress. This has been presented by multiple authors before. By conducting immunofluorescent staining for reactive oxygen species (ROS), we tried to replicate their findings and illustrate elevated levels of ROS. As the fluorescence analysis did not bear significant results, we approached oxidative stress from a different angle: Via mass spectrometry, we looked at the amino acids methionine, cysteine and betaine which are highly involved in sustaining the oxidative balance in the cell. Our findings in the media of urea-treated HL-1 cells lead us to the conclusion, that these cardiomyocytes were in a state of low antioxidative resources. Next, to find the intracellular mechanisms that connect uremia to oxidative stress and compromised energetics, we investigated possible downstream effectors of uremia. The urea-treated cardiomyocytes exhibited significant alterations regarding upstream effec-tors of PGC-1α: The protein kinases Akt and Erk were expressed and phosphorylated dif-ferently in a western blot analysis of uremic h9c2 cells and in mice with induced kidney failure. To combine these findings regarding the protein kinases Akt and Erk and oxidative stress, the Erk/p38 pathways seems conclusive (figure 20). This pathway links uremia and oxidative stress to intracellular effectors that have been found to influence the develop-ment of uremic cardiomyopathy. Another life-threatening alteration in uremic cardiomyopathy is a corrupted cardiac func-tion. The myocardium of uremic patients has shown to be more susceptible to ischemic damage and most patients receiving dialysis experience repeated episodes of intradialytic impairments in cardiac function. The urea-treated cardiomyocytes had a significantly higher oxygen consumption rate due to an inefficiently increased metabolism, most likely caused by an increased level of uncoupling. Taken together, the results of this study indicate that urea by itself plays a role in the de-velopment of uremic cardiomyopathy. So-called high-physiologic levels of urea have led to a mitochondrial inefficiency and an increase of oxidative stress in cardiomyocytes. The protein kinases Akt and Erk may work as effectors of urea to induce these changes via the Erk/p38 pathway. It seems very likely that the mitochondrial changes are mediated by the mitochondrial orchestrator PGC-1α. These observations might lead to further studies in-vestigating urea levels in dialysis patients. In the future, these might lead to a change of practice regarding tolerated urea levels in dialysis and help reduce the cardiac mortality of patients with chronic kidney disease.}, subject = {Ur{\"a}mie}, language = {en} } @article{BerlijnHildebrandtGamer2022, author = {Berlijn, Adam M. and Hildebrandt, Lea K. and Gamer, Matthias}, title = {Idiosyncratic viewing patterns of social scenes reflect individual preferences}, series = {Journal of Vision}, volume = {22}, journal = {Journal of Vision}, number = {13}, doi = {10.1167/jov.22.13.10}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301029}, year = {2022}, abstract = {In general, humans preferentially look at conspecifics in naturalistic images. However, such group-based effects might conceal systematic individual differences concerning the preference for social information. Here, we investigated to what degree fixations on social features occur consistently within observers and whether this preference generalizes to other measures of social prioritization in the laboratory as well as the real world. Participants carried out a free viewing task, a relevance taps task that required them to actively select image regions that are crucial for understanding a given scene, and they were asked to freely take photographs outside the laboratory that were later classified regarding their social content. We observed stable individual differences in the fixation and active selection of human heads and faces that were correlated across tasks and partly predicted the social content of self-taken photographs. Such relationship was not observed for human bodies indicating that different social elements need to be dissociated. These findings suggest that idiosyncrasies in the visual exploration and interpretation of social features exist and predict real-world behavior. Future studies should further characterize these preferences and elucidate how they shape perception and interpretation of social contexts in healthy participants and patients with mental disorders that affect social functioning.}, language = {en} } @article{BernhardKrumpholzKriegeretal.2022, author = {Bernhard, Lukas and Krumpholz, Roman and Krieger, Yannick and Czempiel, Tobias and Meining, Alexander and Navab, Nassir and L{\"u}th, Tim and Wilhelm, Dirk}, title = {PLAFOKON: a new concept for a patient-individual and intervention-specific flexible surgical platform}, series = {Surgical Endoscopy}, volume = {36}, journal = {Surgical Endoscopy}, number = {7}, issn = {0930-2794}, doi = {10.1007/s00464-021-08908-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307490}, pages = {5303-5312}, year = {2022}, abstract = {Background Research in the field of surgery is mainly driven by aiming for trauma reduction as well as for personalized treatment concepts. Beyond laparoscopy, other proposed approaches for further reduction of the therapeutic trauma have failed to achieve clinical translation, with few notable exceptions. We believe that this is mainly due to a lack of flexibility and high associated costs. We aimed at addressing these issues by developing a novel minimally invasive operating platform and a preoperative design workflow for patient-individual adaptation and cost-effective rapid manufacturing of surgical manipulators. In this article, we report on the first in-vitro cholecystectomy performed with our operating platform. Methods The single-port overtube (SPOT) is a snake-like surgical manipulator for minimally invasive interventions. The system layout is highly flexible and can be adapted in design and dimensions for different kinds of surgery, based on patient- and disease-specific parameters. For collecting and analyzing this data, we developed a graphical user interface, which assists clinicians during the preoperative planning phase. Other major components of our operating platform include an instrument management system and a non-sterile user interface. For the trial surgery, we used a validated phantom which was further equipped with a porcine liver including the gallbladder. Results Following our envisioned preoperative design workflow, a suitable geometry of the surgical manipulator was determined for our trial surgery and rapidly manufactured by means of 3D printing. With this setup, we successfully performed a first in-vitro cholecystectomy, which was completed in 78 min. Conclusions By conducting the trial surgery, we demonstrated the effectiveness of our PLAFOKON operating platform. While some aspects - especially regarding usability and ergonomics - can be further optimized, the overall performance of the system is highly promising, with sufficient flexibility and strength for conducting the necessary tissue manipulations.}, language = {en} } @phdthesis{Bertelsmann2022, author = {Bertelsmann, Dietmar}, title = {Analysis of the Frequency of Kidney Toxicity in Preclinical Safety Studies using the eTOX Database}, doi = {10.25972/OPUS-25710}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-257104}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {This research aimed to obtain reliable data on the frequency of different types of renal toxicity findings in 28-day oral gavage studies in Wistar rats, their consistency across species and study duration, as well as the correlation between histopathological endpoints and routinely used clinical chemistry parameters indicative of kidney injury. Analysis of renal histopathological findings was carried out through extraction of information from the IMI eTOX database. Spontaneous renal histopathological findings in 28-day oral gavage studies in control Wistar rats and beagle dogs confirmed tubular basophilia and renal dilation as the most frequent incidental findings in controls, whereas necrosis and glomerulosclerosis were not identified at all or only rarely as a background lesion. Histopathological evidence of necrosis and glomerulosclerosis was associated with changes in clinical chemistry parameters in 28-day oral gavage Wistar rat studies. Necrosis was frequently accompanied by a statistically significant rise in serum creatinine and serum urea, whereas serum albumin was frequently found to decrease statistically significantly in treatment groups in which necrosis was recorded. In contrast to necrosis, glomerulosclerosis was not associated with statistically significant changes in serum creatinine and urea in any of the 28-day oral gavage Wistar rat treatment groups, but appears to be best reflected by a pattern of statistically significantly lowered serum albumin and serum protein together with a statistically significant increase in serum cholesterol. As might have been expected based on the high background incidences of tubular basophilia and dilation, no consistent changes in any of the clinical chemistry parameters were evident in animals in which renal lesions were con� fined to renal tubular basophilia or dilation. In summary, the routinely provided clinical chemistry parameters are rather insensitive - novel kidney biomarkers such as Cystatin C, β-trace protein and Kidney injury molecule 1 should further be evaluated and integrated into routine preclinical and clinical practice. However, evaluation of clinical chemistry data was limited by the lack of individual animal data. Even though an extensive amount of preclinical studies is accessible through the eTOX database, comparison of consistency across time was limited by the limited number of shorter- and longer term studies conducted with the compounds identified as causing renal histopathological changes within a 28- day study in rats. A high consistency across time for both treatment-related tubular basophilia and treatment-related dilation cannot be confirmed for either of the two effects as these two findings were both induced only rarely in studies over a different treatment-duration other than 28 days after administration of the compounds which provoked the respective effect in a 28-day study. For the finding of necrosis consistency across time was low with the exception of "AZ_GGA_200002321", in which renal papillary necrosis was identified consist� ently throughout different treatment durations (2, 4, 26, 104 weeks). No shorter and longer-term studies were available for the compounds identified as causing glomerulosclerosis within a 28-day study in rats. No consistent findings of the selected histopathological endpoints were identified in any of the corresponding 28-day oral gavage beagle dog studies after treatment with the identical compounds, which caused the respective ef� fect after 28-day treatment in rats. However, in the overwhelming majority of cases, beagle dogs were administered lower doses in these studies in compar� ison to the corresponding 28-day Wistar rat studies. Searching the eTOX database yielded no 28-day oral gavage studies in Wistar and Wistar Han rats in which accumulation of hyaline droplets, tubular atrophy or hyperplasia was recorded. Only one 28-day oral gavage Wistar rat study was identified with the histopathological result of neutrophilic inflammation. Consequently, evaluation of these four renal findings in relation to clinical chemistry parameters and consistency across time and species cannot be made. In summary, this work contributes knowledge through mining and evaluating the eTOX database on a variety of specific renal endpoints that frequently occur after administration of trial substances in 28-day oral gavage studies in Wistar rats in the field of preclinical toxicity with specific focus on their frequency relation to background findings, as well as consistency across time and species. Targeted statistical evaluation of in vivo data within joint research ventures such as the eTOX project, presents an enormous opportunity for an innovative future way of aiding preclinical research towards a more efficient research in the preclinical stage of drug development. This could be achieved through the aug� mentation of methodological strategies and possibly novel software tools in order to predict in vivo toxicology of new molecular entities by means of information that is already available before early stages of the drug development pipeline begin.}, language = {en} } @phdthesis{Bertero2022, author = {Bertero, Edoardo}, title = {Mechano-energetic uncoupling in Barth syndrome cardiomyopathy}, doi = {10.25972/OPUS-25517}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-255176}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {In this Doctoral Thesis we investigated the consequences of perturbed mitochondrial calcium handling in the context of a rare human disease, Barth syndrome, in which the altered phospholipid composition of the inner mitochondrial membrane affects the structural organization of several protein complexes, including the mitochondrial calcium uniporter. We discovered that loss of the mitochondrial calcium uniporter in cardiac, but not skeletal muscle mitochondria hinders the calcium-induced adaptation of mitochondrial oxidative metabolism during workload transitions. This mechano-energetic uncoupling impairs the physiological increase in contractile force during physical exercise and might predispose Barth syndrome patients to the development of arrhythmias.}, language = {en} } @article{BertramBartschSodmannetal.2022, author = {Bertram, Ralph and Bartsch, Vanessa and Sodmann, Johanna and Hennig, Luca and M{\"u}jde, Engin and Stock, Jonathan and Ruedig, Vivienne and Sodmann, Philipp and Todt, Daniel and Steinmann, Eike and Hitzl, Wolfgang and Steinmann, Joerg}, title = {Risk stratification of SARS-CoV-2 breakthrough infections based on an outbreak at a student festive event}, series = {Vaccines}, volume = {10}, journal = {Vaccines}, number = {3}, issn = {2076-393X}, doi = {10.3390/vaccines10030432}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267270}, year = {2022}, abstract = {In early 2022, the Coronavirus disease 2019 (COVID-19) remains a global challenge. COVID-19 is caused by an increasing number of variants of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we report an outbreak of SARS-CoV-2 breakthrough infections related to a student festive event with 100 mostly vaccinated guests, which took place in Northern Bavaria, Germany, in October 2021. The data were obtained by retrospective guest interviews. In total, 95 students participated in the study, with 94 being fully vaccinated and 24 reporting infection by the delta variant. Correlation analyses among 15 examined variables revealed that time spent at the event, conversation with the supposed index person, and a homologous viral vector vaccination regime were significant risk factors for infection. Non-significant observations related to higher rates of infection included time since last vaccination, shared use of drinking vessels, and number of individual person-to-person contacts at the event. Our data suggest that a high rate of breakthrough infections with the delta variant occurs if no preventive measures are practiced. To limit infection risk, high-quality testing of participants should be considered a mandatory measure at gatherings, irrespective of the participants' vaccination status.}, language = {en} } @article{BetzSegerNieding2022, author = {Betz, Ann-Katrin and Seger, Benedikt T. and Nieding, Gerhild}, title = {How can carbon labels and climate-friendly default options on restaurant menus contribute to the reduction of greenhouse gas emissions associated with dining?}, series = {PLOS Climate}, volume = {1}, journal = {PLOS Climate}, number = {5}, doi = {10.1371/journal.pclm.0000028}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301039}, year = {2022}, abstract = {In this study, we aimed to understand how restaurants can contribute to climate change mitigation via menu design. We investigated two types of interventions: changing the configuration of menu entries with variable side dishes so that the most climate-friendly option is set as the default and indicating the greenhouse gas emission of each dish via carbon labels. In an online simulation experiment, 265 participants were shown the menus of nine different restaurants and had to choose exactly one dish per menu. In six menus, the main dishes were presented with different default options: the side dish was associated either with the highest or with the lowest greenhouse gas emissions. The other three menus consisted of unitary dishes for which the default rules did not apply. All menus were presented either with or without carbon labels for each dish option. The results indicated that more climate-friendly dish choices resulting in lower greenhouse gas emissions were made with the low-emission than the high-emission default condition, and when carbon labels were present rather than absent. The effects of both interventions interacted, which indicates that the interventions partly overlap with regard to cognitive predecessors of choice behavior, such as attentional focus and social norms. The results suggest that the design of restaurant menus has a considerable effect on the carbon footprint of dining.}, language = {en} } @article{BeyerGothMueller2022, author = {Beyer, Jacob and Goth, Florian and M{\"u}ller, Tobias}, title = {Better integrators for functional renormalization group calculations}, series = {The European Physical Journal B}, volume = {95}, journal = {The European Physical Journal B}, number = {7}, issn = {1434-6028}, doi = {10.1140/epjb/s10051-022-00378-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325131}, year = {2022}, abstract = {We analyze a variety of integration schemes for the momentum space functional renormalization group calculation with the goal of finding an optimized scheme. Using the square lattice t-t' Hubbard model as a testbed we define and benchmark the quality. Most notably we define an error estimate of the solution for the ordinary differential equation circumventing the issues introduced by the divergences at the end of the FRG flow. Using this measure to control for accuracy we find a threefold reduction in number of required integration steps achievable by choice of integrator. We herewith publish a set of recommended choices for the functional renormalization group, shown to decrease the computational cost for FRG calculations and representing a valuable basis for further investigations.}, language = {en} } @article{BețiuNoveanuHancuetal.2022, author = {Bețiu, Alina M. and Noveanu, Lavinia and H{\^a}ncu, Iasmina M. and Lascu, Ana and Petrescu, Lucian and Maack, Christoph and Elm{\´e}r, Eskil and Muntean, Danina M.}, title = {Mitochondrial effects of common cardiovascular medications: the good, the bad and the mixed}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {21}, issn = {1422-0067}, doi = {10.3390/ijms232113653}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297384}, year = {2022}, abstract = {Mitochondria are central organelles in the homeostasis of the cardiovascular system via the integration of several physiological processes, such as ATP generation via oxidative phosphorylation, synthesis/exchange of metabolites, calcium sequestration, reactive oxygen species (ROS) production/buffering and control of cellular survival/death. Mitochondrial impairment has been widely recognized as a central pathomechanism of almost all cardiovascular diseases, rendering these organelles important therapeutic targets. Mitochondrial dysfunction has been reported to occur in the setting of drug-induced toxicity in several tissues and organs, including the heart. Members of the drug classes currently used in the therapeutics of cardiovascular pathologies have been reported to both support and undermine mitochondrial function. For the latter case, mitochondrial toxicity is the consequence of drug interference (direct or off-target effects) with mitochondrial respiration/energy conversion, DNA replication, ROS production and detoxification, cell death signaling and mitochondrial dynamics. The present narrative review aims to summarize the beneficial and deleterious mitochondrial effects of common cardiovascular medications as described in various experimental models and identify those for which evidence for both types of effects is available in the literature.}, language = {en} } @article{BieberSchuhmannBellutetal.2022, author = {Bieber, Michael and Schuhmann, Michael K. and Bellut, Maximilian and Stegner, David and Heinze, Katrin G. and Pham, Mirko and Nieswandt, Bernhard and Stoll, Guido}, title = {Blockade of platelet glycoprotein Ibα augments neuroprotection in Orai2-deficient mice during middle cerebral artery occlusion}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {16}, issn = {1422-0067}, doi = {10.3390/ijms23169496}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286038}, year = {2022}, abstract = {During ischemic stroke, infarct growth before recanalization diminishes functional outcome. Hence, adjunct treatment options to protect the ischemic penumbra before recanalization are eagerly awaited. In experimental stroke targeting two different pathways conferred protection from penumbral tissue loss: (1) enhancement of hypoxic tolerance of neurons by deletion of the calcium channel subunit Orai2 and (2) blocking of detrimental lymphocyte-platelet responses. However, until now, no preclinical stroke study has assessed the potential of combining neuroprotective with anti-thrombo-inflammatory interventions to augment therapeutic effects. We induced focal cerebral ischemia in Orai2-deficient (Orai2\(^{-/-}\)) mice by middle cerebral artery occlusion (MCAO). Animals were treated with anti-glycoprotein Ib alpha (GPIbα) Fab fragments (p0p/B Fab) blocking GPIbα-von Willebrand factor (vWF) interactions. Rat immunoglobulin G (IgG) Fab was used as the control treatment. The extent of infarct growth before recanalization was assessed at 4 h after MCAO. Moreover, infarct volumes were determined 6 h after recanalization (occlusion time: 4 h). Orai2 deficiency significantly halted cerebral infarct progression under occlusion. Inhibition of platelet GPIbα further reduced primary infarct growth in Orai2\(^{-/-}\) mice. During ischemia-reperfusion, upon recanalization, mice were likewise protected. All in all, we show that neuroprotection in Orai2\(^{-/-}\) mice can be augmented by targeting thrombo-inflammation. This supports the clinical development of combined neuroprotective/anti-platelet strategies in hyper-acute stroke.}, language = {en} } @article{BielmeierSchmittKleefeldtetal.2022, author = {Bielmeier, Christina B. and Schmitt, Sabrina I. and Kleefeldt, Nikolai and Boneva, Stefaniya K. and Schlecht, Anja and Vallon, Mario and Tamm, Ernst R. and Hillenkamp, Jost and Erg{\"u}n, S{\"u}leyman and Neueder, Andreas and Braunger, Barbara M.}, title = {Deficiency in retinal TGFβ signaling aggravates neurodegeneration by modulating pro-apoptotic and MAP kinase pathways}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {5}, issn = {1422-0067}, doi = {10.3390/ijms23052626}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-283971}, year = {2022}, abstract = {Transforming growth factor β (TGFβ) signaling has manifold functions such as regulation of cell growth, differentiation, migration, and apoptosis. Moreover, there is increasing evidence that it also acts in a neuroprotective manner. We recently showed that TGFβ receptor type 2 (Tgfbr2) is upregulated in retinal neurons and M{\"u}ller cells during retinal degeneration. In this study we investigated if this upregulation of TGFβ signaling would have functional consequences in protecting retinal neurons. To this end, we analyzed the impact of TGFβ signaling on photoreceptor viability using mice with cell type-specific deletion of Tgfbr2 in retinal neurons and M{\"u}ller cells (Tgfbr2\(_{ΔOC}\)) in combination with a genetic model of photoreceptor degeneration (VPP). We examined retinal morphology and the degree of photoreceptor degeneration, as well as alterations of the retinal transcriptome. In summary, retinal morphology was not altered due to TGFβ signaling deficiency. In contrast, VPP-induced photoreceptor degeneration was drastically exacerbated in double mutant mice (Tgfbr2\(_{ΔOC}\); VPP) by induction of pro-apoptotic genes and dysregulation of the MAP kinase pathway. Therefore, TGFβ signaling in retinal neurons and M{\"u}ller cells exhibits a neuroprotective effect and might pose promising therapeutic options to attenuate photoreceptor degeneration in humans.}, language = {en} } @article{BieniekSadeckaSzulakowskaetal.2022, author = {Bieniek, Maciej and Sadecka, Katarzyna and Szulakowska, Ludmiła and Hawrylak, Paweł}, title = {Theory of excitons in atomically thin semiconductors: tight-binding approach}, series = {Nanomaterials}, volume = {12}, journal = {Nanomaterials}, number = {9}, issn = {2079-4991}, doi = {10.3390/nano12091582}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-275243}, year = {2022}, abstract = {Atomically thin semiconductors from the transition metal dichalcogenide family are materials in which the optical response is dominated by strongly bound excitonic complexes. Here, we present a theory of excitons in two-dimensional semiconductors using a tight-binding model of the electronic structure. In the first part, we review extensive literature on 2D van der Waals materials, with particular focus on their optical response from both experimental and theoretical points of view. In the second part, we discuss our ab initio calculations of the electronic structure of MoS\(_2\), representative of a wide class of materials, and review our minimal tight-binding model, which reproduces low-energy physics around the Fermi level and, at the same time, allows for the understanding of their electronic structure. Next, we describe how electron-hole pair excitations from the mean-field-level ground state are constructed. The electron-electron interactions mix the electron-hole pair excitations, resulting in excitonic wave functions and energies obtained by solving the Bethe-Salpeter equation. This is enabled by the efficient computation of the Coulomb matrix elements optimized for two-dimensional crystals. Next, we discuss non-local screening in various geometries usually used in experiments. We conclude with a discussion of the fine structure and excited excitonic spectra. In particular, we discuss the effect of band nesting on the exciton fine structure; Coulomb interactions; and the topology of the wave functions, screening and dielectric environment. Finally, we follow by adding another layer and discuss excitons in heterostructures built from two-dimensional semiconductors.}, language = {en} } @article{BieniussaKahramanSkornickaetal.2022, author = {Bieniussa, Linda and Kahraman, Baran and Skornicka, Johannes and Schulte, Annemarie and Voelker, Johannes and Jablonka, Sibylle and Hagen, Rudolf and Rak, Kristen}, title = {Pegylated insulin-like growth factor 1 attenuates hair cell loss and promotes presynaptic maintenance of medial olivocochlear cholinergic fibers in the cochlea of the progressive motor neuropathy mouse}, series = {Frontiers in Neurology}, volume = {13}, journal = {Frontiers in Neurology}, issn = {1664-2295}, doi = {10.3389/fneur.2022.885026}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-276669}, year = {2022}, abstract = {The progressive motor neuropathy (PMN) mouse is a model of an inherited motor neuropathy disease with progressive neurodegeneration. Axon degeneration associates with homozygous mutations of the TBCE gene encoding the tubulin chaperone E protein. TBCE is responsible for the correct dimerization of alpha and beta-tubulin. Strikingly, the PMN mouse also develops a progressive hearing loss after normal hearing onset, characterized by degeneration of the auditory nerve and outer hair cell (OHC) loss. However, the development of this neuronal and cochlear pathology is not fully understood yet. Previous studies with pegylated insulin-like growth factor 1 (peg-IGF-1) treatment in this mouse model have been shown to expand lifespan, weight, muscle strength, and motor coordination. Accordingly, peg-IGF-1 was evaluated for an otoprotective effect. We investigated the effect of peg-IGF-1 on the auditory system by treatment starting at postnatal day 15 (p15). Histological analysis revealed positive effects on OHC synapses of medial olivocochlear (MOC) neuronal fibers and a short-term attenuation of OHC loss. Peg-IGF-1 was able to conditionally restore the disorganization of OHC synapses and maintain the provision of cholinergic acetyltransferase in presynapses. To assess auditory function, frequency-specific auditory brainstem responses and distortion product otoacoustic emissions were recorded in animals on p21 and p28. However, despite the positive effect on MOC fibers and OHC, no restoration of hearing could be achieved. The present work demonstrates that the synaptic pathology of efferent MOC fibers in PMN mice represents a particular form of "efferent auditory neuropathy." Peg-IGF-1 showed an otoprotective effect by preventing the degeneration of OHCs and efferent synapses. However, enhanced efforts are needed to optimize the treatment to obtain detectable improvements in hearing performances.}, language = {en} } @article{BittnerBoonDelbancoetal.2022, author = {Bittner, Nataly and Boon, Andy and Delbanco, Evert H. and Walter, Christof and Mally, Angela}, title = {Assessment of aromatic amides in printed food contact materials: analysis of potential cleavage to primary aromatic amines during simulated passage through the gastrointestinal tract}, series = {Archives of Toxicology}, volume = {96}, journal = {Archives of Toxicology}, number = {5}, doi = {10.1007/s00204-022-03254-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324697}, pages = {1423-1435}, year = {2022}, abstract = {Recent analyses conducted by German official food control reported detection of the aromatic amides N-(2,4-dimethylphenyl)acetamide (NDPA), N-acetoacetyl-m-xylidine (NAAX) and 3-hydroxy-2-naphthanilide (Naphthol AS) in cold water extracts from certain food contact materials made from paper or cardboard, including paper straws, paper napkins, and cupcake liners. Because aromatic amides may be cleaved to potentially genotoxic primary amines upon oral intake, these findings raise concern that transfer of NDPA, NAAX and Naphthol AS from food contact materials into food may present a risk to human health. The aim of the present work was to assess the stability of NDPA, NAAX and Naphthol AS and potential cleavage to 2,4-dimethylaniline (2,4-DMA) and aniline during simulated passage through the gastrointestinal tract using static in vitro digestion models. Using the digestion model established by the National Institute for Public Health and the Environment (RIVM, Bilthoven, NL) and a protocol recommended by the European Food Safety Authority, potential hydrolysis of the aromatic amides to the respective aromatic amines was assessed by LC-MS/MS following incubation of the aromatic amides with digestive fluid simulants. Time-dependent hydrolysis of NDPA and NAAX resulting in formation of the primary aromatic amine 2,4-DMA was consistently observed in both models. The highest rate of cleavage of NDPA and NAAX was recorded following 4 h incubation with 0.07 M HCl as gastric-juice simulant, and amounted to 0.21\% and 0.053\%, respectively. Incubation of Naphthol AS with digestive fluid simulants did not give rise to an increase in the concentration of aniline above the background that resulted from the presence of aniline as an impurity of the test compound. Considering the lack of evidence for aniline formation from Naphthol AS and the extremely low rate of hydrolysis of the amide bonds of NDPA and NAAX during simulated passage through the gastrointestinal tract that gives rise to only very minor amounts of the potentially mutagenic and/or carcinogenic aromatic amine 2,4-DMA, risk assessment based on assumption of 100\% cleavage to the primary aromatic amines would appear to overestimate health risks related to the presence of aromatic amides in food contact materials.}, language = {en} } @article{BliziotisKluijtmansSotoetal.2022, author = {Bliziotis, Nikolaos G. and Kluijtmans, Leo A. J. and Soto, Sebastian and Tinnevelt, Gerjen H. and Langton, Katharina and Robledo, Mercedes and Pamporaki, Christina and Engelke, Udo F. H. and Erlic, Zoran and Engel, Jasper and Deutschbein, Timo and N{\"o}lting, Svenja and Prejbisz, Aleksander and Richter, Susan and Prehn, Cornelia and Adamski, Jerzy and Januszewicz, Andrzej and Reincke, Martin and Fassnacht, Martin and Eisenhofer, Graeme and Beuschlein, Felix and Kroiss, Matthias and Wevers, Ron A. and Jansen, Jeroen J. and Deinum, Jaap and Timmers, Henri J. L. M.}, title = {Pre- versus post-operative untargeted plasma nuclear magnetic resonance spectroscopy metabolomics of pheochromocytoma and paraganglioma}, series = {Endocrine}, volume = {75}, journal = {Endocrine}, number = {1}, doi = {10.1007/s12020-021-02858-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-326574}, pages = {254-265}, year = {2022}, abstract = {Purpose Pheochromocytomas and Paragangliomas (PPGL) result in chronic catecholamine excess and serious health complications. A recent study obtained a metabolic signature in plasma from PPGL patients; however, its targeted nature may have generated an incomplete picture and a broader approach could provide additional insights. We aimed to characterize the plasma metabolome of PPGL patients before and after surgery, using an untargeted approach, and to broaden the scope of the investigated metabolic impact of these tumors. Design A cohort of 36 PPGL patients was investigated. Blood plasma samples were collected before and after surgical tumor removal, in association with clinical and tumor characteristics. Methods Plasma samples were analyzed using untargeted nuclear magnetic resonance (NMR) spectroscopy metabolomics. The data were evaluated using a combination of uni- and multi-variate statistical methods. Results Before surgery, patients with a nonadrenergic tumor could be distinguished from those with an adrenergic tumor based on their metabolic profiles. Tyrosine levels were significantly higher in patients with high compared to those with low BMI. Comparing subgroups of pre-operative samples with their post-operative counterparts, we found a metabolic signature that included ketone bodies, glucose, organic acids, methanol, dimethyl sulfone and amino acids. Three signals with unclear identities were found to be affected. Conclusions Our study suggests that the pathways of glucose and ketone body homeostasis are affected in PPGL patients. BMI-related metabolite levels were also found to be altered, potentially linking muscle atrophy to PPGL. At baseline, patient metabolomes could be discriminated based on their catecholamine phenotype.}, language = {en} } @article{BliziotisKluijtmansTinneveltetal.2022, author = {Bliziotis, Nikolaos G. and Kluijtmans, Leo A. J. and Tinnevelt, Gerjen H. and Reel, Parminder and Reel, Smarti and Langton, Katharina and Robledo, Mercedes and Pamporaki, Christina and Pecori, Alessio and Van Kralingen, Josie and Tetti, Martina and Engelke, Udo F. H. and Erlic, Zoran and Engel, Jasper and Deutschbein, Timo and N{\"o}lting, Svenja and Prejbisz, Aleksander and Richter, Susan and Adamski, Jerzy and Januszewicz, Andrzej and Ceccato, Filippo and Scaroni, Carla and Dennedy, Michael C. and Williams, Tracy A. and Lenzini, Livia and Gimenez-Roqueplo, Anne-Paule and Davies, Eleanor and Fassnacht, Martin and Remde, Hanna and Eisenhofer, Graeme and Beuschlein, Felix and Kroiss, Matthias and Jefferson, Emily and Zennaro, Maria-Christina and Wevers, Ron A. and Jansen, Jeroen J. and Deinum, Jaap and Timmers, Henri J. L. M.}, title = {Preanalytical pitfalls in untargeted plasma nuclear magnetic resonance metabolomics of endocrine hypertension}, series = {Metabolites}, volume = {12}, journal = {Metabolites}, number = {8}, issn = {2218-1989}, doi = {10.3390/metabo12080679}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-282930}, year = {2022}, abstract = {Despite considerable morbidity and mortality, numerous cases of endocrine hypertension (EHT) forms, including primary aldosteronism (PA), pheochromocytoma and functional paraganglioma (PPGL), and Cushing's syndrome (CS), remain undetected. We aimed to establish signatures for the different forms of EHT, investigate potentially confounding effects and establish unbiased disease biomarkers. Plasma samples were obtained from 13 biobanks across seven countries and analyzed using untargeted NMR metabolomics. We compared unstratified samples of 106 PHT patients to 231 EHT patients, including 104 PA, 94 PPGL and 33 CS patients. Spectra were subjected to a multivariate statistical comparison of PHT to EHT forms and the associated signatures were obtained. Three approaches were applied to investigate and correct confounding effects. Though we found signatures that could separate PHT from EHT forms, there were also key similarities with the signatures of sample center of origin and sample age. The study design restricted the applicability of the corrections employed. With the samples that were available, no biomarkers for PHT vs. EHT could be identified. The complexity of the confounding effects, evidenced by their robustness to correction approaches, highlighted the need for a consensus on how to deal with variabilities probably attributed to preanalytical factors in retrospective, multicenter metabolomics studies.}, language = {en} } @article{BohnertTrellaPreissetal.2022, author = {Bohnert, Simone and Trella, Stefanie and Preiß, Ulrich and Heinsen, Helmut and Bohnert, Michael and Zwirner, Johann and Tremblay, Marie-{\`E}ve and Monoranu, Camelia-Maria and Ondruschka, Benjamin}, title = {Density of TMEM119-positive microglial cells in postmortem cerebrospinal fluid as a surrogate marker for assessing complex neuropathological processes in the CNS}, series = {International Journal of Legal Medicine}, volume = {136}, journal = {International Journal of Legal Medicine}, number = {6}, doi = {10.1007/s00414-022-02863-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325009}, pages = {1841-1850}, year = {2022}, abstract = {Routine coronal paraffin-sections through the dorsal frontal and parieto-occipital cortex of a total of sixty cases with divergent causes of death were immunohistochemically (IHC) stained with an antibody against TMEM119. Samples of cerebrospinal fluid (CSF) of the same cases were collected by suboccipital needle-puncture, subjected to centrifugation and processed as cytospin preparations stained with TMEM119. Both, cytospin preparations and sections were subjected to computer-assisted density measurements. The density of microglial TMEM119-positive cortical profiles correlated with that of cytospin results and with the density of TMEM119-positive microglial profiles in the medullary layer. There was no statistically significant correlation between the density of medullary TMEM119-positive profiles and the cytospin data. Cortical microglial cells were primarily encountered in supragranular layers I, II, and IIIa and in infragranular layers V and VI, the region of U-fibers and in circumscribed foci or spread in a diffuse manner and high density over the white matter. We have evidence that cortical microglia directly migrate into CSF without using the glympathic pathway. Microglia in the medullary layer shows a strong affinity to the adventitia of deep vessels in the myelin layer. Selected rapidly fatal cases including myocardial infarcts and drowning let us conclude that microglia in cortex and myelin layer can react rapidly and its reaction and migration is subject to pre-existing external and internal factors. Cytospin preparations proved to be a simple tool to analyze and assess complex changes in the CNS after rapid fatal damage. There is no statistically significant correlation between cytospin and postmortem interval. Therefore, the quantitative analyses of postmortem cytospins obviously reflect the neuropathology of the complete central nervous system. Cytospins provide forensic pathologists a rather simple and easy to perform method for the global assessment of CNS affliction.}, language = {en} } @phdthesis{Bold2022, author = {Bold, Kevin}, title = {Macrocyclic Oligothiophene Bridged Perylene Bisimide Donor-Acceptor Dyads}, doi = {10.25972/OPUS-27192}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-271926}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {A series of donor-acceptor macrocyclic architectures comprising oligothiophene strands that connect the imide positions of a perylene bisimide have been synthesized via a platinum-mediated cross-coupling strategy. The target structures were characterized by steady-state UV/Vis absorption, fluorescence and transient absorption spectroscopy, as well as cyclic and differential pulse voltammetry. Crystal structure analysis of the macrocycles revealed insights into the bridge arrangements. The properties of the macrocyclic bridges were compared to linear oligothiophene reference compounds which itself exhibited an unusual electrochemical effect.}, subject = {Perylenbisdicarboximide}, language = {en} } @article{BoldStolteShoyamaetal.2022, author = {Bold, Kevin and Stolte, Matthias and Shoyama, Kazutaka and Holzapfel, Marco and Schmiedel, Alexander and Lambert, Christoph and W{\"u}rthner, Frank}, title = {Macrocyclic donor-acceptor dyads composed of a perylene bisimide dye surrounded by oligothiophene bridges}, series = {Angewandte Chemie Internationale Edition}, volume = {61}, journal = {Angewandte Chemie Internationale Edition}, number = {1}, doi = {10.1002/anie.202113598}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-256569}, year = {2022}, abstract = {Two macrocyclic architectures comprising oligothiophene strands that connect the imide positions of a perylene bisimide (PBI) dye have been synthesized via a platinum-mediated cross-coupling strategy. The crystal structure of the double bridged PBI reveals all syn-arranged thiophene units that completely enclose the planar PBI chromophore via a 12-membered macrocycle. The target structures were characterized by steady-state UV/Vis absorption, fluorescence and transient absorption spectroscopy, as well as cyclic and differential pulse voltammetry. Both donor-acceptor dyads show ultrafast F{\"o}rster Resonance Energy Transfer and photoinduced electron transfer, thereby leading to extremely low fluorescence quantum yields even in the lowest polarity cyclohexane solvent.}, language = {en} } @article{BoldStolteShoyamaetal.2022, author = {Bold, Kevin and Stolte, Matthias and Shoyama, Kazutaka and Krause, Ana-Maria and Schmiedel, Alexander and Holzapfel, Marco and Lambert, Christoph and W{\"u}rthner, Frank}, title = {Macrocyclic Donor-Acceptor Dyads Composed of Oligothiophene Half-Cycles and Perylene Bisimides}, series = {Chemistry - A European Journal}, volume = {28}, journal = {Chemistry - A European Journal}, number = {30}, doi = {10.1002/chem.202200355}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-276435}, year = {2022}, abstract = {A series of donor-acceptor (D-A) macrocyclic dyads consisting of an electron-poor perylene bisimide (PBI) π-scaffold bridged with electron-rich α-oligothiophenes bearing four, five, six and seven thiophene units between the two phenyl-imide substituents has been synthesized and characterized by steady-state UV/Vis absorption and fluorescence spectroscopy, cyclic and differential pulse voltammetry as well as transient absorption spectroscopy. Tying the oligothiophene strands in a conformationally fixed macrocyclic arrangement leads to a more rigid π-scaffold with vibronic fine structure in the respective absorption spectra. Electrochemical analysis disclosed charged state properties in solution which are strongly dependent on the degree of rigidification within the individual macrocycle. Investigation of the excited state dynamics revealed an oligothiophene bridge size-dependent fast charge transfer process for the macrocyclic dyads upon PBI subunit excitation.}, language = {en} } @article{BolmZemskovZelleretal.2022, author = {Bolm, Louisa and Zemskov, Sergii and Zeller, Maria and Baba, Taisuke and Roldan, Jorge and Harrison, Jon M. and Petruch, Natalie and Sato, Hiroki and Petrova, Ekaterina and Lapshyn, Hryhoriy and Braun, Ruediger and Honselmann, Kim C. and Hummel, Richard and Dronov, Oleksii and Kirichenko, Alexander V. and Klinkhammer-Schalke, Monika and Kleihues-van Tol, Kees and Zeissig, Sylke R. and Rades, Dirk and Keck, Tobias and Fernandez-del Castillo, Carlos and Wellner, Ulrich F. and Wegner, Rodney E.}, title = {Concepts and outcomes of perioperative therapy in stage IA-III pancreatic cancer — a cross-validation of the National Cancer Database (NCDB) and the German Cancer Registry Group of the Society of German Tumor Centers (GCRG/ADT)}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {4}, issn = {2072-6694}, doi = {10.3390/cancers14040868}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262174}, year = {2022}, abstract = {(1) Background: The aim of this study is to assess perioperative therapy in stage IA-III pancreatic cancer cross-validating the German Cancer Registry Group of the Society of German Tumor Centers — Network for Care, Quality, and Research in Oncology, Berlin (GCRG/ADT) and the National Cancer Database (NCDB). (2) Methods: Patients with clinical stage IA-III PDAC undergoing surgery alone (OP), neoadjuvant therapy (TX) + surgery (neo + OP), surgery+adjuvantTX (OP + adj) and neoadjuvantTX + surgery + adjuvantTX (neo + OP + adj) were identified. Baseline characteristics, histopathological parameters, and overall survival (OS) were evaluated. (3) Results: 1392 patients from the GCRG/ADT and 29,081 patients from the NCDB were included. Patient selection and strategies of perioperative therapy remained consistent across the registries for stage IA-III pancreatic cancer. Combined neo + OP + adj was associated with prolonged OS as compared to neo + OP alone (17.8 m vs. 21.3 m, p = 0.012) across all stages in the GCRG/ADT registry. Similarly, OS with neo + OP + adj was improved as compared to neo + OP in the NCDB registry (26.4 m vs. 35.4 m, p < 0.001). (4) Conclusion: The cross-validation study demonstrated similar concepts and patient selection criteria of perioperative therapy across clinical stages of PDAC. Neoadjuvant therapy combined with adjuvant therapy is associated with improved overall survival as compared to either therapy alone.}, language = {en} } @article{BorojevićJaukovićKukoljetal.2022, author = {Borojević, Ana and Jauković, Aleksandra and Kukolj, Tamara and Mojsilović, Slavko and Obradović, Hristina and Trivanović, Drenka and Živanović, Milena and Zečević, Željko and Simić, Marija and Gobeljić, Borko and Vujić, Dragana and Bugarski, Diana}, title = {Vitamin D3 stimulates proliferation capacity, expression of pluripotency markers, and osteogenesis of human bone marrow mesenchymal stromal/stem cells, partly through SIRT1 signaling}, series = {Biomolecules}, volume = {12}, journal = {Biomolecules}, number = {2}, issn = {2218-273X}, doi = {10.3390/biom12020323}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262203}, year = {2022}, abstract = {The biology of vitamin D3 is well defined, as are the effects of its active metabolites on various cells, including mesenchymal stromal/stem cells (MSCs). However, the biological potential of its precursor, cholecalciferol (VD3), has not been sufficiently investigated, although its significance in regenerative medicine — mainly in combination with various biomaterial matrices — has been recognized. Given that VD3 preconditioning might also contribute to the improvement of cellular regenerative potential, the aim of this study was to investigate its effects on bone marrow (BM) MSC functions and the signaling pathways involved. For that purpose, the influence of VD3 on BM-MSCs obtained from young human donors was determined via MTT test, flow cytometric analysis, immunocytochemistry, and qRT-PCR. Our results revealed that VD3, following a 5-day treatment, stimulated proliferation, expression of pluripotency markers (NANOG, SOX2, and Oct4), and osteogenic differentiation potential in BM-MSCs, while it reduced their senescence. Moreover, increased sirtuin 1 (SIRT1) expression was detected upon treatment with VD3, which mediated VD3-promoted osteogenesis and, partially, the stemness features through NANOG and SOX2 upregulation. In contrast, the effects of VD3 on proliferation, Oct4 expression, and senescence were SIRT1-independent. Altogether, these data indicate that VD3 has strong potential to modulate BM-MSCs' features, partially through SIRT1 signaling, although the precise mechanisms merit further investigation.}, language = {en} } @article{BorovaSchluttNickeletal.2022, author = {Borova, Solomiia and Schlutt, Christine and Nickel, Joachim and Luxenhofer, Robert}, title = {A Transient Initiator for Polypeptoids Postpolymerization α-Functionalization via Activation of a Thioester Group}, series = {Macromolecular Chemistry and Physics}, volume = {223}, journal = {Macromolecular Chemistry and Physics}, number = {3}, doi = {10.1002/macp.202100331}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-257587}, year = {2022}, abstract = {Here, a postpolymerization modification method for an α-terminal functionalized poly-(N-methyl-glycine), also known as polysarcosine, is introduced. 4-(Methylthio)phenyl piperidine-4-carboxylate as an initiator for the ring-opening polymerization of N-methyl-glycine-N-carboxyanhydride followed by oxidation of the thioester group to yield an α-terminal reactive 4-(methylsulfonyl)phenyl piperidine-4-carboxylate polymer is utilized. This represents an activated carboxylic acid terminus, allowing straightforward modification with nucleophiles under mild reaction conditions and provides the possibility to introduce a wide variety of nucleophiles as exemplified using small molecules, fluorescent dyes, and model proteins. The new initiator yielded polymers with well-defined molar mass, low dispersity, and high end-group fidelity, as observed by gel permeation chromatography, nuclear magnetic resonance spectroscopy, and matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy. The introduced method can be of great interest for bioconjugation, but requires optimization, especially for protein conjugation.}, language = {en} } @article{BoschertTeuschMuellerRichteretal.2022, author = {Boschert, Verena and Teusch, Jonas and M{\"u}ller-Richter, Urs D. A. and Brands, Roman C. and Hartmann, Stefan}, title = {PKM2 modulation in head and neck squamous cell carcinoma}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {2}, issn = {1422-0067}, doi = {10.3390/ijms23020775}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284458}, year = {2022}, abstract = {The enzyme pyruvate kinase M2 (PKM2) plays a major role in the switch of tumor cells from oxidative phosphorylation to aerobic glycolysis, one of the hallmarks of cancer. Different allosteric inhibitors or activators and several posttranslational modifications regulate its activity. Head and neck squamous cell carcinoma (HNSCC) is a common disease with a high rate of recurrence. To find out more about PKM2 and its modulation in HNSCC, we examined a panel of HNSCC cells using real-time cell metabolic analysis and Western blotting with an emphasis on phosphorylation variant Tyr105 and two reagents known to impair PKM2 activity. Our results show that in HNSCC, PKM2 is commonly phosphorylated at Tyrosine 105. Its levels depended on tyrosine kinase activity, emphasizing the importance of growth factors such as EGF (epidermal growth factor) on HNSCC metabolism. Furthermore, its correlation with the expression of CD44 indicates a role in cancer stemness. Cells generally reacted with higher glycolysis to PKM2 activator DASA-58 and lower glycolysis to PKM2 inhibitor Compound 3k, but some were more susceptible to activation and others to inhibition. Our findings emphasize the need to further investigate the role of PKM2 in HNSCC, as it could aid understanding and treatment of the disease.}, language = {en} } @article{BoschetScherbaumPittig2022, author = {Boschet, Juliane M. and Scherbaum, Stefan and Pittig, Andre}, title = {Costly avoidance of Pavlovian fear stimuli and the temporal dynamics of its decision process}, series = {Scientific Reports}, volume = {12}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-022-09931-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301041}, year = {2022}, abstract = {Conflicts between avoiding feared stimuli versus approaching them for competing rewards are essential for functional behavior and anxious psychopathology. Yet, little is known about the underlying decision process. We examined approach-avoidance decisions and their temporal dynamics when avoiding Pavlovian fear stimuli conflicted with gaining rewards. First, a formerly neutral stimulus (CS+) was repeatedly paired with an aversive stimulus (US) to establish Pavlovian fear. Another stimulus (CS-) was never paired with the US. A control group received neutral tones instead of aversive USs. Next, in each of 324 trials, participants chose between a CS-/low reward and a CS+/high reward option. For the latter, probability of CS+ presentation (Pavlovian fear information) and reward magnitude (reward information) varied. Computer mouse movements were tracked to capture the decision dynamics. Although no more USs occurred, pronounced and persistent costly avoidance of the Pavlovian fear CS+ was found. Time-continuous multiple regression of movement trajectories revealed a stronger and faster impact of Pavlovian fear compared to reward information during decision-making. The impact of fear information, but not reward information, modestly decreased across trials. These findings suggest a persistently stronger weighting of fear compared to reward information during approach-avoidance decisions, which may facilitate the development of pathological avoidance.}, language = {en} } @article{BotheHaenzelmannBoehleretal.2022, author = {Bothe, Sebastian and H{\"a}nzelmann, Petra and B{\"o}hler, Stephan and Kehrein, Josef and Zehe, Markus and Wiedemann, Christoph and Hellmich, Ute A. and Brenk, Ruth and Schindelin, Hermann and Sotriffer, Christoph}, title = {Fragment screening using biolayer interferometry reveals ligands targeting the SHP-motif binding site of the AAA+ ATPase p97}, series = {Communications Chemistry}, volume = {5}, journal = {Communications Chemistry}, number = {1}, doi = {10.1038/s42004-022-00782-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300821}, year = {2022}, abstract = {Biosensor techniques have become increasingly important for fragment-based drug discovery during the last years. The AAA+ ATPase p97 is an essential protein with key roles in protein homeostasis and a possible target for cancer chemotherapy. Currently available p97 inhibitors address its ATPase activity and globally impair p97-mediated processes. In contrast, inhibition of cofactor binding to the N-domain by a protein-protein-interaction inhibitor would enable the selective targeting of specific p97 functions. Here, we describe a biolayer interferometry-based fragment screen targeting the N-domain of p97 and demonstrate that a region known as SHP-motif binding site can be targeted with small molecules. Guided by molecular dynamics simulations, the binding sites of selected screening hits were postulated and experimentally validated using protein- and ligand-based NMR techniques, as well as X-ray crystallography, ultimately resulting in the first structure of a small molecule in complex with the N-domain of p97. The identified fragments provide insights into how this region could be targeted and present first chemical starting points for the development of a protein-protein interaction inhibitor preventing the binding of selected cofactors to p97.}, language = {en} } @article{BrammerBlankeKellneretal.2022, author = {Brammer, Jan C. and Blanke, Gerd and Kellner, Claudia and Hoffmann, Alexander and Herres-Pawlis, Sonja and Schatzschneider, Ulrich}, title = {TUCAN: A molecular identifier and descriptor applicable to the whole periodic table from hydrogen to oganesson}, series = {Journal of Cheminformatics}, volume = {14}, journal = {Journal of Cheminformatics}, number = {1}, issn = {1758-2946}, doi = {10.1186/s13321-022-00640-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-299730}, year = {2022}, abstract = {TUCAN is a canonical serialization format that is independent of domain-specific concepts of structure and bonding. The atomic number is the only chemical feature that is used to derive the TUCAN format. Other than that, the format is solely based on the molecular topology. Validation is reported on a manually curated test set of molecules as well as a library of non-chemical graphs. The serialization procedure generates a canonical "tuple-style" output which is bidirectional, allowing the TUCAN string to serve as both identifier and descriptor. Use of the Python NetworkX graph library facilitated a compact and easily extensible implementation.}, language = {en} } @article{BrandForsterBoecketal.2022, author = {Brand, Jessica S. and Forster, Leonard and B{\"o}ck, Thomas and Stahlhut, Philipp and Teßmar, J{\"o}rg and Groll, J{\"u}rgen and Albrecht, Krystyna}, title = {Covalently Cross-Linked Pig Gastric Mucin Hydrogels Prepared by Radical-Based Chain-Growth and Thiol-ene Mechanisms}, series = {Macromolecular Bioscience}, volume = {22}, journal = {Macromolecular Bioscience}, number = {4}, doi = {10.1002/mabi.202100274}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318453}, year = {2022}, abstract = {Mucin, a high molecular mass hydrophilic glycoprotein, is the main component of mucus that coats every wet epithelium in animals. It is thus intrinsically biocompatible, and with its protein backbone and the o-glycosidic bound oligosaccharides, it contains a plethora of functional groups which can be used for further chemical modifications. Here, chain-growth and step-growth (thiol-ene) free-radical cross-linked hydrogels prepared from commercially available pig gastric mucin (PGM) are introduced and compared as cost-efficient and easily accessible alternative to the more broadly applied bovine submaxillary gland mucin. For this, PGM is functionalized with photoreactive acrylate groups or allyl ether moieties, respectively. Whereas homopolymerization of acrylate-functionalized polymers is performed, for thiol-ene cross-linking, the allyl-ether-functionalized PGM is cross-linked with thiol-functionalized hyaluronic acid. Morphology, mechanical properties, and cell compatibility of both kinds of PGM hydrogels are characterized and compared. Furthermore, the biocompatibility of these hydrogels can be evaluated in cell culture experiments.}, language = {en} } @article{BrandTroyaKrenzeretal.2022, author = {Brand, Markus and Troya, Joel and Krenzer, Adrian and Saßmannshausen, Zita and Zoller, Wolfram G. and Meining, Alexander and Lux, Thomas J. and Hann, Alexander}, title = {Development and evaluation of a deep learning model to improve the usability of polyp detection systems during interventions}, series = {United European Gastroenterology Journal}, volume = {10}, journal = {United European Gastroenterology Journal}, number = {5}, doi = {10.1002/ueg2.12235}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312708}, pages = {477-484}, year = {2022}, abstract = {Background The efficiency of artificial intelligence as computer-aided detection (CADe) systems for colorectal polyps has been demonstrated in several randomized trials. However, CADe systems generate many distracting detections, especially during interventions such as polypectomies. Those distracting CADe detections are often induced by the introduction of snares or biopsy forceps as the systems have not been trained for such situations. In addition, there are a significant number of non-false but not relevant detections, since the polyp has already been previously detected. All these detections have the potential to disturb the examiner's work. Objectives Development and evaluation of a convolutional neuronal network that recognizes instruments in the endoscopic image, suppresses distracting CADe detections, and reliably detects endoscopic interventions. Methods A total of 580 different examination videos from 9 different centers using 4 different processor types were screened for instruments and represented the training dataset (519,856 images in total, 144,217 contained a visible instrument). The test dataset included 10 full-colonoscopy videos that were analyzed for the recognition of visible instruments and detections by a commercially available CADe system (GI Genius, Medtronic). Results The test dataset contained 153,623 images, 8.84\% of those presented visible instruments (12 interventions, 19 instruments used). The convolutional neuronal network reached an overall accuracy in the detection of visible instruments of 98.59\%. Sensitivity and specificity were 98.55\% and 98.92\%, respectively. A mean of 462.8 frames containing distracting CADe detections per colonoscopy were avoided using the convolutional neuronal network. This accounted for 95.6\% of all distracting CADe detections. Conclusions Detection of endoscopic instruments in colonoscopy using artificial intelligence technology is reliable and achieves high sensitivity and specificity. Accordingly, the new convolutional neuronal network could be used to reduce distracting CADe detections during endoscopic procedures. Thus, our study demonstrates the great potential of artificial intelligence technology beyond mucosal assessment.}, language = {en} } @article{BraunEvdokimovFranketal.2022, author = {Braun, Alexandra and Evdokimov, Dimitar and Frank, Johanna and Pauli, Paul and Wabel, Thomas and {\"U}{\c{c}}eyler, Nurcan and Sommer, Claudia}, title = {Relevance of Religiosity for Coping Strategies and Disability in Patients with Fibromyalgia Syndrome}, series = {Journal of Religion and Health}, volume = {61}, journal = {Journal of Religion and Health}, number = {1}, issn = {1573-6571}, doi = {10.1007/s10943-020-01177-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-269135}, pages = {524-539}, year = {2022}, abstract = {Coping strategies are essential for the outcome of chronic pain. This study evaluated religiosity in a cohort of patients with fibromyalgia syndrome (FMS), its effect on pain and other symptoms, on coping and FMS-related disability. A total of 102 FMS patients were recruited who filled in questionnaires, a subgroup of 42 patients participated in a face-to-face interview, and data were evaluated by correlation and regression analyses. Few patients were traditionally religious, but the majority believed in a higher existence and described their spirituality as "transcendence conviction". The coping strategy "praying-hoping" and the ASP dimension "religious orientation" (r = 0.5, P < 0.05) showed a significant relationship independent of the grade of religiosity (P < 0.05). A high grade of belief in a higher existence was negatively associated with the choice of ignoring as coping strategy (r = - 0.4, P < 0.05). Mood and affect-related variables had the highest impact on disability (b = 0.5, P < 0.05). In this cohort, the grade of religiosity played a role in the choice of coping strategies, but had no effects on health and mood outcome.}, language = {en} } @article{BreilHuesteggeBoeckler2022, author = {Breil, Christina and Huestegge, Lynn and B{\"o}ckler, Anne}, title = {From eye to arrow: Attention capture by direct gaze requires more than just the eyes}, series = {Attention, Perception \& Psychophysics}, volume = {84}, journal = {Attention, Perception \& Psychophysics}, number = {1}, issn = {1943-393X}, doi = {10.3758/s13414-021-02382-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-273206}, pages = {64-75}, year = {2022}, abstract = {Human attention is strongly attracted by direct gaze and sudden onset motion. The sudden direct-gaze effect refers to the processing advantage for targets appearing on peripheral faces that suddenly establish eye contact. Here, we investigate the necessity of social information for attention capture by (sudden onset) ostensive cues. Six experiments involving 204 participants applied (1) naturalistic faces, (2) arrows, (3) schematic eyes, (4) naturalistic eyes, or schematic facial configurations (5) without or (6) with head turn to an attention-capture paradigm. Trials started with two stimuli oriented towards the observer and two stimuli pointing into the periphery. Simultaneous to target presentation, one direct stimulus changed to averted and one averted stimulus changed to direct, yielding a 2 × 2 factorial design with direction and motion cues being absent or present. We replicated the (sudden) direct-gaze effect for photographic faces, but found no corresponding effects in Experiments 2-6. Hence, a holistic and socially meaningful facial context seems vital for attention capture by direct gaze. STATEMENT OF SIGNIFICANCE: The present study highlights the significance of context information for social attention. Our findings demonstrate that the direct-gaze effect, that is, the prioritization of direct gaze over averted gaze, critically relies on the presentation of a meaningful holistic and naturalistic facial context. This pattern of results is evidence in favor of early effects of surrounding social information on attention capture by direct gaze.}, language = {en} } @article{BrenzingerMaihoffPetersetal.2022, author = {Brenzinger, Kristof and Maihoff, Fabienne and Peters, Marcell K. and Schimmer, Leonie and Bischler, Thorsten and Classen, Alice}, title = {Temperature and livestock grazing trigger transcriptome responses in bumblebees along an elevational gradient}, series = {iScience}, volume = {25}, journal = {iScience}, number = {10}, doi = {10.1016/j.isci.2022.105175}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301276}, year = {2022}, abstract = {Climate and land-use changes cause increasing stress to pollinators but the molecular pathways underlying stress responses are poorly understood. Here, we analyzed the transcriptomic response of Bombus lucorum workers to temperature and livestock grazing. Bumblebees sampled along an elevational gradient, and from differently managed grassland sites (livestock grazing vs unmanaged) in the German Alps did not differ in the expression of genes known for thermal stress responses. Instead, metabolic energy production pathways were upregulated in bumblebees sampled in mid- or high elevations or during cool temperatures. Extensive grazing pressure led to an upregulation of genetic pathways involved in immunoregulation and DNA-repair. We conclude that widespread bumblebees are tolerant toward temperature fluctuations in temperate mountain environments. Moderate temperature increases may even release bumblebees from metabolic stress. However, transcriptome responses to even moderate management regimes highlight the completely underestimated complexity of human influence on natural pollinators.}, language = {en} } @article{BrodehlGerull2022, author = {Brodehl, Andreas and Gerull, Brenda}, title = {Genetic insights into primary restrictive cardiomyopathy}, series = {Journal of Clinical Medicine}, volume = {11}, journal = {Journal of Clinical Medicine}, number = {8}, issn = {2077-0383}, doi = {10.3390/jcm11082094}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270621}, year = {2022}, abstract = {Restrictive cardiomyopathy is a rare cardiac disease causing severe diastolic dysfunction, ventricular stiffness and dilated atria. In consequence, it induces heart failure often with preserved ejection fraction and is associated with a high mortality. Since it is a poor clinical prognosis, patients with restrictive cardiomyopathy frequently require heart transplantation. Genetic as well as non-genetic factors contribute to restrictive cardiomyopathy and a significant portion of cases are of unknown etiology. However, the genetic forms of restrictive cardiomyopathy and the involved molecular pathomechanisms are only partially understood. In this review, we summarize the current knowledge about primary genetic restrictive cardiomyopathy and describe its genetic landscape, which might be of interest for geneticists as well as for cardiologists.}, language = {en} } @article{BroschKorsaTabanetal.2022, author = {Brosch, Philippa K. and Korsa, Tessa and Taban, Danush and Eiring, Patrick and Hildebrand, Sascha and Neubauer, Julia and Zimmermann, Heiko and Sauer, Markus and Shirakashi, Ryo and Djuzenova, Cholpon S. and Sisario, Dmitri and Sukhorukov, Vladimir L.}, title = {Glucose and inositol transporters, SLC5A1 and SLC5A3, in glioblastoma cell migration}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {23}, issn = {2072-6694}, doi = {10.3390/cancers14235794}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297498}, year = {2022}, abstract = {(1) Background: The recurrence of glioblastoma multiforme (GBM) is mainly due to invasion of the surrounding brain tissue, where organic solutes, including glucose and inositol, are abundant. Invasive cell migration has been linked to the aberrant expression of transmembrane solute-linked carriers (SLC). Here, we explore the role of glucose (SLC5A1) and inositol transporters (SLC5A3) in GBM cell migration. (2) Methods: Using immunofluorescence microscopy, we visualized the subcellular localization of SLC5A1 and SLC5A3 in two highly motile human GBM cell lines. We also employed wound-healing assays to examine the effect of SLC inhibition on GBM cell migration and examined the chemotactic potential of inositol. (3) Results: While GBM cell migration was significantly increased by extracellular inositol and glucose, it was strongly impaired by SLC transporter inhibition. In the GBM cell monolayers, both SLCs were exclusively detected in the migrating cells at the monolayer edge. In single GBM cells, both transporters were primarily localized at the leading edge of the lamellipodium. Interestingly, in GBM cells migrating via blebbing, SLC5A1 and SLC5A3 were predominantly detected in nascent and mature blebs, respectively. (4) Conclusion: We provide several lines of evidence for the involvement of SLC5A1 and SLC5A3 in GBM cell migration, thereby complementing the migration-associated transportome. Our findings suggest that SLC inhibition is a promising approach to GBM treatment.}, language = {en} } @article{BrosinskyLeisterChengetal.2022, author = {Brosinsky, Paulin and Leister, Hanna and Cheng, Nan and Varelas, Xaralabos and Visekruna, Alexander and Luu, Maik}, title = {Verteporfin protects against Th17 cell-mediated EAE independently of YAP inhibition}, series = {European Journal of Immunology}, volume = {52}, journal = {European Journal of Immunology}, number = {9}, doi = {10.1002/eji.202149564}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-287234}, pages = {1523 -- 1526}, year = {2022}, abstract = {The known YAP inhibitor verteporfin is capable of repressing IL-17A production in Th17 cells. However, this effect is mediated independently of YAP and can ameliorate Th17-mediated experimental autoimmune encephalomyelitis (EAE) upon in vivo administration. The data suggest verteprofin's mode of action for the design of novel therapeutic autoimmune disease intervention.}, language = {en} } @phdthesis{Brych2022, author = {Brych, Mareike Kimberly}, title = {How movements and cognition interact: An investigation of spontaneous blinks}, doi = {10.25972/OPUS-26737}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267376}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {During natural behavior, cognitive processes constantly coincide with body movements such as head or eye movements or blinks. However, during experimental investigations of cognitive processes, movements are often highly restricted which is rather unnatural. In order to improve our understanding of natural behavior, this thesis investigates the interaction between cognition and movements by focusing on spontaneous blinks, which naturally interact with other body movements. Spontaneous blinks are inevitably connected to vision as they shut out incoming visual information. Both sensory-based and cognitive factors, for example, stimulus occurrence and evaluation, were reported to influence blink behavior. Our first study investigated if such influences are comparable for visual and non-visual input. The chosen experimental design allowed dissociating sensory-driven and cognitive influences, which then could be compared between the visual and auditory domain. Our results show that blinks are more strongly modulated during passive observation of visual input compared to auditory input. This modulation is however enhanced for both input modalities by an increased attentional demand. In addition, the cognitively defined meaning of a stimulus changes blink latency independent of the sensory domain. Overall, our findings show that spontaneous blinks and cognitive processes are linked beyond vision. Moreover, the underlying cognitive processes that influence blinks are largely the same across different sensory input indicating that blinks are profoundly integrated into our system. When investigating natural behavior, it is important to consider that movements rarely occur in isolation, but are executed side by side. As these movements interact and have a link to cognitive processes, the complexity of our system increases. In order to take this complexity into account, the second part of the experimental research focused on movement interactions, more specifically on the interactions between blinks, pupil size and speaking. Our results reveal that speech-related motor activity increases blink rate and pupil size as well as modulates blink timing. This is in line with previous research that described a relation between different body and eye movements. Importantly, each bodily-induced change in eye movements affects visual information intake. Therefore, different movements can be tightly linked to perceptual processes through complex interactions. Altogether, the work of this thesis provides rich evidence that movements and cognitive processes are deeply intertwined. Therefore, movements should be seen as an integral part of our system. Taking the relevance of movements and their interactions into account during experimental investigations is necessary in order to reveal a more realistic and complete picture of human natural behavior.}, subject = {Kognition}, language = {en} } @article{BraeuerBurchardtMunkeltBleieretal.2022, author = {Br{\"a}uer-Burchardt, Christian and Munkelt, Christoph and Bleier, Michael and Heinze, Matthias and Gebhart, Ingo and K{\"u}hmstedt, Peter and Notni, Gunther}, title = {A new sensor system for accurate 3D surface measurements and modeling of underwater objects}, series = {Applied Sciences}, volume = {12}, journal = {Applied Sciences}, number = {9}, issn = {2076-3417}, doi = {10.3390/app12094139}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270792}, year = {2022}, abstract = {A new underwater 3D scanning device based on structured illumination and designed for continuous capture of object data in motion for deep sea inspection applications is introduced. The sensor permanently captures 3D data of the inspected surface and generates a 3D surface model in real time. Sensor velocities up to 0.7 m/s are directly compensated while capturing camera images for the 3D reconstruction pipeline. The accuracy results of static measurements of special specimens in a water basin with clear water show the high accuracy potential of the scanner in the sub-millimeter range. Measurement examples with a moving sensor show the significance of the proposed motion compensation and the ability to generate a 3D model by merging individual scans. Future application tests in offshore environments will show the practical potential of the sensor for the desired inspection tasks.}, language = {en} } @article{BucheltSkovRasmussenetal.2022, author = {Buchelt, Sebastian and Skov, Kirstine and Rasmussen, Kerstin Kr{\o}ier and Ullmann, Tobias}, title = {Sentinel-1 time series for mapping snow cover depletion and timing of snowmelt in Arctic periglacial environments: case study from Zackenberg and Kobbefjord, Greenland}, series = {The Cryosphere}, volume = {16}, journal = {The Cryosphere}, number = {2}, doi = {10.5194/tc-16-625-2022}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300139}, pages = {625 -- 646}, year = {2022}, abstract = {Snow cover (SC) and timing of snowmelt are key regulators of a wide range of Arctic ecosystem functions. Both are strongly influenced by the amplified Arctic warming and essential variables to understand environmental changes and their dynamics. This study evaluates the potential of Sentinel-1 (S-1) synthetic aperture radar (SAR) time series for monitoring SC depletion and snowmelt with high spatiotemporal resolution to capture their understudied small-scale heterogeneity. We use 97 dual-polarized S-1 SAR images acquired over northeastern Greenland and 94 over southwestern Greenland in the interferometric wide swath mode from the years 2017 and 2018. Comparison of S-1 intensity against SC fraction maps derived from orthorectified terrestrial time-lapse imagery indicates that SAR backscatter can increase before a decrease in SC fraction is observed. Hence, the increase in backscatter is related to changing snowpack properties during the runoff phase as well as decreasing SC fraction. We here present a novel empirical approach based on the temporal evolution of the SAR signal to identify start of runoff (SOR), end of snow cover (EOS) and SC extent for each S-1 observation date during melt using backscatter thresholds as well as the derivative. Comparison of SC with orthorectified time-lapse imagery indicates that HV polarization outperforms HH when using a global threshold. The derivative avoids manual selection of thresholds and adapts to different environmental settings and seasonal conditions. With a global configuration (threshold: 4 dB; polarization: HV) as well as with the derivative, the overall accuracy of SC maps was in all cases above 75 \% and in more than half of cases above 90 \%. Based on the physical principle of SAR backscatter during snowmelt, our approach is expected to work well in other low-vegetation areas and, hence, could support large-scale SC monitoring at high spatiotemporal resolution (20 m, 6 d) with high accuracy.}, language = {en} } @article{BuckSerflingLindneretal.2022, author = {Buck, Andreas K. and Serfling, Sebastian E. and Lindner, Thomas and H{\"a}nscheid, Heribert and Schirbel, Andreas and Hahner, Stefanie and Fassnacht, Martin and Einsele, Hermann and Werner, Rudolf A.}, title = {CXCR4-targeted theranostics in oncology}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {49}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {12}, doi = {10.1007/s00259-022-05849-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324545}, pages = {4133-4144}, year = {2022}, abstract = {A growing body of literature reports on the upregulation of C-X-C motif chemokine receptor 4 (CXCR4) in a variety of cancer entities, rendering this receptor as suitable target for molecular imaging and endoradiotherapy in a theranostic setting. For instance, the CXCR4-targeting positron emission tomography (PET) agent [\(^{68}\)Ga]PentixaFor has been proven useful for a comprehensive assessment of the current status quo of solid tumors, including adrenocortical carcinoma or small-cell lung cancer. In addition, [\(^{68}\)Ga]PentixaFor has also provided an excellent readout for hematological malignancies, such as multiple myeloma, marginal zone lymphoma, or mantle cell lymphoma. PET-based quantification of the CXCR4 capacities in vivo allows for selecting candidates that would be suitable for treatment using the theranostic equivalent [\(^{177}\)Lu]/[\(^{90}\)Y]PentixaTher. This CXCR4-directed theranostic concept has been used as a conditioning regimen prior to hematopoietic stem cell transplantation and to achieve sufficient anti-lymphoma/-tumor activity in particular for malignant tissues that are highly sensitive to radiation, such as the hematological system. Increasing the safety margin, pretherapeutic dosimetry is routinely performed to determine the optimal activity to enhance therapeutic efficacy and to reduce off-target adverse events. The present review will provide an overview of current applications for CXCR4-directed molecular imaging and will introduce the CXCR4-targeted theranostic concept for advanced hematological malignancies.}, language = {en} } @article{BuellesbachDiaoSchmittetal.2022, author = {Buellesbach, Jan and Diao, Wenwen and Schmitt, Thomas and Beukeboom, Leo W.}, title = {Micro-climate correlations and conserved sexual dimorphism of cuticular hydrocarbons in European populations of the jewel wasp Nasonia vitripennis}, series = {Ecological Entomology}, volume = {47}, journal = {Ecological Entomology}, number = {1}, doi = {10.1111/een.13089}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262770}, pages = {38 -- 51}, year = {2022}, abstract = {1. Protection against desiccation and chemical communication are two fundamental functions of cuticular hydrocarbons (CHCs) in insects. In the parasitoid jewel wasp Nasonia vitripennis (Walker), characterised by a cosmopolitan distribution through largely different environments, CHCs function as universally recognised female sex pheromones. However, CHC uniformity as basis for sexual recognition may conflict with the desiccation protection function, expected to display considerable flexibility through adaptation to different environmental conditions. 2. We compared male and female CHC profiles of N. vitripennis across a wide latitudinal gradient in Europe and correlated their CHC variation with climatic factors associated with desiccation. Additionally, we tested male mate discrimination behaviour between populations to detect potential variations in female sexual attractiveness. 3. Results did not conform to the general expectation that longer, straight-chain CHCs occur in higher proportions in warmer and drier climates. Instead, unexpected environmental correlations of intermediate chain-length CHCs (C31) were found exclusively in females, potentially reflecting the different life histories of the sexes in N. vitripennis. 4. Furthermore, we found no indication of population-specific male mate preference, confirming the stability of female sexual attractiveness, likely conveyed through their CHC profiles. C31 mono- and C33 di-methyl-branched alkanes were consistently and most strongly associated with sexual dimorphism, suggesting their potential role in encoding the female-specific sexual signalling function. 5. Our study sheds light on how both adaptive flexibility and conserved sexual attractiveness can potentially be integrated and encoded in CHC profiles of N. vitripennis females across a wide distribution range in Europe.}, language = {en} } @article{BuergerEmserSeideletal.2022, author = {Buerger, Arne and Emser, Theresa and Seidel, Alexandra and Scheiner, Christin and von Schoenfeld, Cornelia and Ruecker, Viktoria and Heuschmann, Peter U. and Romanos, Marcel}, title = {DUDE - a universal prevention program for non-suicidal self-injurious behavior in adolescence based on effective emotion regulation: study protocol of a cluster-randomized controlled trial}, series = {Trials}, volume = {23}, journal = {Trials}, doi = {10.1186/s13063-021-05973-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265874}, year = {2022}, abstract = {Background Non-suicidal self-injury (NSSI) has become a substantial public health problem. NSSI is a high-risk marker for the development and persistence of mental health problems, shows high rates of morbidity and mortality, and causes substantial health care costs. Thus, there is an urgent need for action to develop universal prevention programs for NSSI before adolescents begin to show this dangerous behavior. Currently, however, universal prevention programs are lacking. Methods The main objective of the present study is to evaluate a newly developed universal prevention program ("DUDE - Du und deine Emotionen / You and your emotions"), based on a skills-based approach in schools, in 3200 young adolescents (age 11-14 years). The effectiveness of DUDE will be investigated in a cluster-randomized controlled trial (RCT) in schools (N = 16). All groups will receive a minimal intervention called "Stress-free through the school day" as a mental health literacy program to prevent burnout in school. The treatment group (N = 1600; 8 schools) will additionally undergo the universal prevention program DUDE and will be divided into treatment group 1 (DUDE conducted by trained clinical psychologists; N = 800; 4 schools) and treatment group 2 (DUDE conducted by trained teachers; N = 800; 4 schools). The active control group (N = 1600; 8 schools) will only receive the mental health literacy prevention. Besides baseline assessment (T0), measurements will occur at the end of the treatment (T1) and at 6- (T2) and 12-month (T3) follow-up evaluations. The main outcome is the occurrence of NSSI within the last 6 months assessed by a short version of the Deliberate Self-Harm Inventory (DSHI-9) at the 1-year follow-up (primary endpoint; T3). Secondary outcomes are emotion regulation, suicidality, health-related quality of life, self-esteem, and comorbid psychopathology and willingness to change. Discussion DUDE is tailored to diminish the incidence of NSSI and to prevent its possible long-term consequences (e.g., suicidality) in adolescents. It is easy to access in the school environment. Furthermore, DUDE is a comprehensive approach to improve mental health via improved emotion regulation.}, language = {en} } @article{BumillerBiniHochKohlerAugustoetal.2022, author = {Bumiller-Bini Hoch, Val{\´e}ria and Kohler, Ana Fl{\´a}via and Augusto, Danillo G. and Lobo-Alves, Sara Cristina and Malheiros, Danielle and Cipolla, Gabriel Adelman and Winter Boldt, Angelica Beate and Braun-Prado, Karin and Wittig, Michael and Franke, Andre and Pf{\"o}hler, Claudia and Worm, Margitta and van Beek, Nina and Goebeler, Matthias and S{\´a}rdy, Mikl{\´o}s and Ibrahim, Saleh and Busch, Hauke and Schmidt, Enno and Hundt, Jennifer Elisabeth and Araujo-Souza, Patr{\´i}cia Savio de and Petzl-Erler, Maria Luiza}, title = {Genetic associations and differential mRNA expression levels of host genes suggest a viral trigger for endemic pemphigus foliaceus}, series = {Viruses}, volume = {14}, journal = {Viruses}, number = {5}, issn = {1999-4915}, doi = {10.3390/v14050879}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270572}, year = {2022}, abstract = {The long search for the environmental trigger of the endemic pemphigus foliaceus (EPF, fogo selvagem) has not yet resulted in any tangible findings. Here, we searched for genetic associations and the differential expression of host genes involved in early viral infections and innate antiviral defense. Genetic variants could alter the structure, expression sites, or levels of the gene products, impacting their functions. By analyzing 3063 variants of 166 candidate genes in 227 EPF patients and 194 controls, we found 12 variants within 11 genes associated with differential susceptibility (p < 0.005) to EPF. The products of genes TRIM5, TPCN2, EIF4E, EIF4E3, NUP37, NUP50, NUP88, TPR, USP15, IRF8, and JAK1 are involved in different mechanisms of viral control, for example, the regulation of viral entry into the host cell or recognition of viral nucleic acids and proteins. Only two of nine variants were also associated in an independent German cohort of sporadic PF (75 patients, 150 controls), aligning with our hypothesis that antiviral host genes play a major role in EPF due to a specific virus-human interaction in the endemic region. Moreover, CCL5, P4HB, and APOBEC3G mRNA levels were increased (p < 0.001) in CD4+ T lymphocytes of EPF patients. Because there is limited or no evidence that these genes are involved in autoimmunity, their crucial role in antiviral responses and the associations that we observed support the hypothesis of a viral trigger for EPF, presumably a still unnoticed flavivirus. This work opens new frontiers in searching for the trigger of EPF, with the potential to advance translational research that aims for disease prevention and treatment.}, language = {en} } @phdthesis{Burd2022, author = {Burd, Paul Ray}, title = {Multiwavelength Probes of Physical Conditions in the Blazar Zone of AGN jets}, doi = {10.25972/OPUS-29700}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297001}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Context. In active galaxies, matter is accreted onto super massive black holes (SMBH). This accretion process causes a region roughly the size of our solar system to outshine the entire host galaxy, forming an active galactic nucleus (AGN). In some of these active galaxies, highly relativistic particle jets are formed parallel to the rotation axis of the super massive black hole. A fraction of these sources is observed under a small inclination angle between the pointing direction of the jet and the observing line of sight. These sources are called blazars. Due to the small inclination angle and the highly relativistic speeds of the particles in the jet, beaming effects occur in the radiation of these particles. Blazars can be subdivided into the high luminosity flat spectrum radio quasars (FSRQs) and the low luminosity BL Lacertae objects (BL Lacs). As all AGN, blazars are broadband emitters and therefore observable from the longest wavelengths in the radio regime to the shortest wavelengths in the gamma-ray regime. In this thesis I will analyze blazars at these two extremes with respect to their parsec-scale properties in the radio and their time evolution properties in gamma-ray flux. Method. In the radio regime the technique of very long baseline interferometry (VLBI) can be used in order to spatially resolve the synchrotron radiation coming from those objects down to sub-parsec scales. This information can be used to observe the time evolution of the structure of such sources. This is done in large monitoring programs such as the MOJAVE (15 GHz) and the Boston University blazar monitoring program (43 GHz). In this thesis I utilize data of 28 sources from these monitoring programs spanning 10 years of observation from 2003 to 2013, resulting in over 1800 observed epochs, to study the brightness temperature and diameter gradients of these jets. I conduct a search for systematic geometry transitions in the radio jets. The synchrotron cooling time in the radio core of the jets is used to determine the magnetic field strength in the radio core. Considering the jet geometry, these magnetic field strengths are scaled to the ergosphere of the SMBH in order to obtain the distance of the radio core to the SMBH. In the gamma-regime these blazars cannot be spatially resolved. Due to this, it is hard to put strong constrains onto where the gamma-ray emitting region is. Blazars have shown to be variable at high energies on time scales down to minutes. The nature of this variability can be studied in order to put constrains on the particle acceleration mechanism and possibly the region and size of the gamma-ray emitting region. The variability of blazars in the energy range between 0.1 GeV and 1 GeV can for example be observed with the pair-conversion telescope on board the Fermi satellite. I use 10 years of data from the Fermi-LAT (LAT: Large Area Telescope) satellite in order to study the variability of a large sample of blazars (300-800, depending on the used significance filters for data points). I quantify this variability with the Ornstein-Uhlenbeck (OU) parameters and the power spectral density (PSD) slopes. The same procedure is applied to 20 light curves available for the radio sample. Results. The diameter evolution along the jet axis of the radio sources suggests, that FSRQs feature flatter gradients than BL Lacs. Fitting these gradients, it is revealed that BL Lacs are systematically better described by a simple single power law than FSRQs. I found 9 sources with a strongly constrained geometry transition. The sources are 0219+421, 0336-019, 0415+379, 0528+134, 0836+710, 1101+384, 1156+295, 1253-055 and 2200+420. In all of these sources, the geometry transition regions are further out in the jet than the Bondi sphere. The magnetic field strengths of BL Lacs is systematically larger than that of FSRQs. However the scaling of these fields suggest that the radio cores of BL Lac objects are closer to the SMBHs than the radio cores of FSRQs. Analyzing the variability of Fermi-LAT light curves yields consistent results for all samples. FSRQs show systematically steeper PSD slopes and feature OU parameters more favorable to strong variability than BL Lacs. The Fermi-LAT light curves of the sub-sample of radio jets, suggest an anticorrelation between the jet complexity from the radio observations and the OU-parameters as well as the PSD slopes from the gamma-ray observations. Conclusion. The flatter diameter gradients of FSRQs suggest that these sources are more collimated further down the jet than BL Lacs. The systematically better description of the diameter and brightness temperature gradient by a single power law of BL Lacs, suggest that FSRQs are more complex with respect to the diameter evolution along the jet and the surface brightness distribution than BL Lac objects. FSRQs often feature regions where recollimation can occur in distinct knots within the jets. For the sources where a geometry transition could be constrained, the Bondi radius, being systematically smaller than the position of the transition region along the jet axis, suggest that changing pressure gradients are not the sole cause for these systematic geometry transitions. Nevertheless they may be responsible for recollimation regions, found typically downstream the jet, beyond the Bondi radius and the transition zone. The difference in the distance of the radio cores between FSRQs and BL Lacs is most likely due to the combination of differences in SMBH masses and systematically smaller jet powers in BL Lacs. The variability in energy ranges above 100 MeV and above 1 GeV-regime suggest that many light curves of BL Lac objects are more likely to be white noise while the PSD slopes and the OU parameters of FSRQ gamma-ray light curves favor stronger variability on larger time scales with respect to the time binning of the analyzed light curve. Although the anticorrelation of the jet complexity acquired from the radio observations and the PSD slopes and OU parameters from the gamma-observations suggest that more complex sources favor OU parameters and PSD slopes resulting in more variability (not white noise) it is beyond the scope of this thesis to pinpoint whether this correlation results from causation. The question whether a complex jet causes more gamma-ray variability or more gamma-ray variability causes more complex jets cannot be answered at this point. Nevertheless the computed correlation measures suggest that this dependence is most likely not linear and therefore an indication that these effects might even interact.}, language = {en} } @masterthesis{Busch2022, type = {Bachelor Thesis}, author = {Busch, Marlene Corinna}, title = {Developing a virtual Control Room for future satellite missions}, doi = {10.25972/OPUS-25826}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258261}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {This thesis deals with the first part of a larger project that follows the ultimate goal of implementing a software tool that creates a Mission Control Room in Virtual Reality. The software is to be used for the operation of spacecrafts and is specially developed for the unique real-time requirements of unmanned satellite missions. Beginning from launch, throughout the whole mission up to the recovery or disposal of the satellite, all systems need to be monitored and controlled in continuous intervals, to ensure the mission's success. Mission Operation is an essential part of every space mission and has been undertaken for decades. Recent technological advancements in the realm of immersive technologies pave the way for innovative methods to operate spacecrafts. Virtual Reality has the capability to resolve the physical constraints set by traditional Mission Control Rooms and thereby delivers novel opportunities. The paper highlights underlying theoretical aspects of Virtual Reality, Mission Control and IP Communication. However, the focus lies upon the practical part of this thesis which revolves around the first steps of the implementation of the virtual Mission Control Room in the Unity Game Engine. Overall, this paper serves as a demonstration of Virtual Reality technology and shows its possibilities with respect to the operation of spacecrafts.}, subject = {Control room}, language = {en} }