@phdthesis{Jordan2021, author = {Jordan, Franziska}, title = {Systematische Bildanalyse des R{\"o}ntgen-Thorax bei Patienten mit akuter Herzinsuffizienz. Ergebnisse des AHF-Registers W{\"u}rzburg}, doi = {10.25972/OPUS-24332}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-243324}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Im Zuge der Erstdiagnostik einer Krankenhausaufnahme bei akuter Herzinsuffizienz ist die R{\"o}ntgen-Thorax-Untersuchung fester Bestandteil. Ziel dieser Arbeit war es, ihren klinischen Stellenwert und die Aufnahmequalit{\"a}t systematisch zu untersuchen. In der AHF-Registerstudie wurden alle am Universit{\"a}tsklinikum W{\"u}rzburg vorstelligen Patienten mit akuter Herzinsuffizienz konsekutiv registriert und umfassend ph{\"a}notypisiert. Die R{\"o}ntgen-Thorax-Befunde wurden systematisch informationsextrahiert, auf Konsistenz {\"u}berpr{\"u}ft, katalogisiert und klassifiziert.}, subject = {AHF}, language = {de} } @phdthesis{Schneider2021, author = {Schneider, Dominik}, title = {Systematische Videoanalyse von Verletzungen im Profibasketball der M{\"a}nner}, doi = {10.25972/OPUS-22268}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222681}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Bisher gibt es nur wenige Forschungsarbeiten, die sich mit der videogest{\"u}tzten Analyse von Basketballverletzungen besch{\"a}ftigen. In der vorliegenden Arbeit wurden Basketballverletzungen der ersten Basketballbundesliga und der zweiten Basketballbundesliga systematisch per Video analysiert, mit dem Ziel, Verletzungsmuster zu beschreiben und somit gegebenenfalls die Rate von Basketballverletzungen durch geeignete Pr{\"a}ventionsans{\"a}tze zu reduzieren. Hierbei wurden Daten hinsichtlich der Rahmenbedingungen, des Orts der Verletzung, der Spielsituation, der Ausl{\"o}ser und der Umst{\"a}nde der Verletzung an sich zu 215 Verletzungen mit Hilfe eines speziell f{\"u}r die videogest{\"u}tzte Analyse von Basketballverletzungen entwickelten Beobachtungsbogens erhoben. Es zeigte sich in 38\% der erhobenen F{\"a}lle das Bewegungsmuster Landung zum Verletzungszeitpunkt, was somit das h{\"a}ufigste zu Verletzungen f{\"u}hrende Bewegungsmuster war. Oft waren gerade die die athletische Spielweise des Basketballs charakterisierenden Spielaktionen (z. B. Korbleger bzw. Dunking und Shotblock) Ausl{\"o}ser von Verletzungen. Zudem ereigneten sich die Verletzungen im zweiten Viertel 2,1-fach h{\"a}ufiger und im vierten Viertel 1,9-fach h{\"a}ufiger im Vergleich zu den anderen beiden Vierteln. Ein weiteres wichtiges Resultat war, dass die Verletzungen in der Mehrzahl der F{\"a}lle (80\%) nicht auf ein Foulspiel zur{\"u}ckzuf{\"u}hren waren. Insgesamt ergibt sich aus den Erkenntnissen die Empfehlung der Implementierung von neuromuskul{\"a}ren Pr{\"a}ventionsprogrammen, welche die besonderen Verletzungsmechanismen des Basketballs miteinbeziehen. Bisherige Pr{\"a}ventionsprogramme k{\"o}nnen aufgrund dieser Datenlage bez{\"u}glich der Bewegungsmuster, der Spielposition, des Verletzungszeitpunkts und des Kontaktmechanismus sowie der individuellen Voraussetzungen des jeweiligen Spielers verwendet werden. Die Umsetzung sollte von Trainern/-innen mitgetragen und {\"u}berpr{\"u}ft werden. Foulregel{\"a}nderungen m{\"u}ssen gem{\"a}ß der vorliegenden Untersuchung - in Hinblick auf die Verletzungspr{\"a}vention nicht durchgef{\"u}hrt werden. Bez{\"u}glich der Resultate hinsichtlich des Verletzungszeitpunkts k{\"o}nnte nach Detektion der genauen Ursachen f{\"u}r eine geh{\"a}ufte Anzahl an Verletzungen in bestimmten Spielabschnitten durch weitere Studien eine Regel{\"a}nderung mit Verl{\"a}ngerung der Viertelpausen erwogen werden.}, subject = {Basketball}, language = {de} } @article{AdolphFleischhackGaabetal.2021, author = {Adolph, Jonas E. and Fleischhack, Gudrun and Gaab, Christine and Mikasch, Ruth and Mynarek, Martin and Rutkowski, Stefan and Sch{\"u}ller, Ulrich and Pfister, Stefan M. and Pajtler, Kristian W. and Milde, Till and Witt, Olaf and Bison, Brigitte and Warmuth-Metz, Monika and Kortmann, Rolf-Dieter and Dietzsch, Stefan and Pietsch, Torsten and Timmermann, Beate and Tippelt, Stephan}, title = {Systemic chemotherapy of pediatric recurrent ependymomas: results from the German HIT-REZ studies}, series = {Journal of Neuro-Oncology}, volume = {155}, journal = {Journal of Neuro-Oncology}, number = {2}, organization = {German GPOH HIT-Network}, issn = {0167-594X}, doi = {10.1007/s11060-021-03867-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308302}, pages = {193-202}, year = {2021}, abstract = {Purpose Survival in recurrent ependymoma (EPN) depends mainly on the extent of resection achieved. When complete resection is not feasible, chemotherapy is often used to extend progression-free and overall survival. However, no consistent effect of chemotherapy on survival has been found in patients with recurrent EPN. Methods Systemic chemotherapeutic treatment of 138 patients enrolled in the German HIT-REZ-studies was analyzed. Survival depending on the use of chemotherapy, disease-stabilization rates (RR), duration of response (DOR) and time to progression (TTP) were estimated. Results Median age at first recurrence was 7.6 years (IQR: 4.0-13.6). At first recurrence, median PFS and OS were 15.3 (CI 13.3-20.0) and 36.9 months (CI 29.7-53.4), respectively. The Hazard Ratio for the use of chemotherapy in local recurrences in a time-dependent Cox-regression analysis was 0.99 (CI 0.74-1.33). Evaluable responses for 140 applied chemotherapies were analyzed, of which sirolimus showed the best RR (50\%) and longest median TTP [11.51 (CI 3.98; 14.0) months] in nine patients, with the strongest impact found when sirolimus was used as a monotherapy. Seven patients with progression-free survival > 12 months after subtotal/no-resection facilitated by chemotherapy were found. No definitive survival advantage for any drug in a specific molecularly defined EPN type was found. Conclusion No survival advantage for the general use of chemotherapy in recurrent EPN was found. In cases with incomplete resection, chemotherapy was able to extend survival in individual cases. Sirolimus showed the best RR, DOR and TTP out of all drugs analyzed and may warrant further investigation.}, language = {en} } @phdthesis{HafergebZailer2021, author = {Hafer [geb. Zailer], Elina}, title = {Tagging - Development of new qNMR methods}, doi = {10.25972/OPUS-21958}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219583}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {High-resolution nuclear magnetic resonance (NMR) spectroscopy is used in structure elucidation and qualitative as well as quantitative examination of product components. Despite the worldwide development of numerous innovative NMR spectroscopic methods, several official methods that analyze specific substances and do not represent a holistic analysis, are still in use for the quality control of drugs, food and chemicals. Thus, counterfeit or contaminated products of inferior quality can be brought onto the market and distributed despite previous quality controls. To prevent this, three NMR spectroscopic methods have been developed within the scope of this work (1) to study the peroxide value in vegetable and animal oils, (2) for the qualitative and quantitative analysis of metal cations and (3) to determine the enantiomeric excess in chiral alcohols. In oil analysis, titration methods are used to determine the bulk quality parameters such as peroxide value, which represents the concentration of peroxides. Titrations show several drawbacks, such as the need of a large amount of sample and solvents, cross reactions and the low robustness. Thus, an alternative NMR spectroscopic method was developed to improve the peroxide analysis by using triphenylphosphine as a derivatization reagent, which reacts with peroxides in a stoichiometric ratio of 1:1 forming triphenylphosphine oxide. In the 1H-31P decoupled NMR spectrum, the signals of the unreacted triphenylphosphine and the reacted triphenylphosphine oxide are detected at 7.4 ppm and 7.8 ppm, respectively. The ratio of the two signals is used for the calculation of the peroxide concentration. 108 oil samples with a peroxide value between 1 meq/kg and 150 meq/kg were examined using the developed method. Oils with a very low peroxide value of less than 3 meq/kg showed a relative standard deviation of 4.9\%, highly oxidized oils with a peroxide value of 150 meq/kg of 0.2\%. The NMR method was demonstrated as a powerful technique for the analysis of vegetable and krill oils. Another 1H NMR spectroscopic method was developed for the qualitative determination of Be2+, Sr2+ and Cd2+, and for the qualitative and quantitative determination of Ca2+, Mg2+, Hg2+, Sn2+, Pb2+ and Zn2+ by using ethylenediamine tetraacetate (EDTA) as complexing agent. EDTA is a hexadentate ligand that forms stable chelate complexes with divalent cations. The known amount of added EDTA and the signal ratio of free and complexed EDTA are used to calculate the concentrations of the divalent cations, which makes the use of an internal standard obsolete. The use of EDTA with Be2+, Sr2+, Cd2+, Ca2+, Mg2+, Hg2+, Sn2+, Pb2+ and Zn2+ result in complexes whose signals are pH-independent, showing cation-specific chemical shifts and couplings in the 1H NMR spectrum that are used for identification and quantification. In the presented NMR method, the limit of quantification of the cations Ca2+, Mg2+, Hg2+, Sn2+, Pb2+, and Zn2+ was determined with 5-22 μg/mL. This method is applicable in the food and drug sectors. The third NMR spectroscopic method introduced an alternative determination of the enantiomer excess (ee) of the chiral alcohols menthol, borneol, 1-phenylethanol and linalool using phosgene as a derivatizing reagent. Phosgene reacts with a chiral alcohol to form carboxylic acid diesters, made of two identical (RR, SS) or two different enantiomers (RS, SR). These two different types of diastereomers can be examined by the difference of their chemical shifts. In the presented method, the integration values of the carbonyl signals in the 13C NMR spectrum are used for the determination of the enantiomer excess. The limit of quantification depends, among others, on the sample and on the non-labelled or 13C-labelled phosgene used for the analysis. In the case of menthol, a quantification limit of ee=99.1\% was determined using non-labelled phosgene and ee=99.9\% using 13C-labelled phosgene. The 13C NMR method was also applied for the quality control of the enantiomeric purity of borneol, 1-phenylethanol and linalool. The developed 13C NMR method represents a powerful alternative to Mosher's reagent for investigating the enantiomeric excess in chiral alcohols. This work demonstrates the variety of possibilities of applications for the quantitative nuclear magnetic resonance spectroscopy in the chemical analysis of drugs, food and chemicals using tagging reactions such as derivatizations and complexations. The nuclear resonance spectroscopic methods developed in this research work represent powerful alternatives to the previously used quality control techniques.}, subject = {NMR Spektroskopie}, language = {en} } @article{FranzsicoFantuzziCardozoetal.2021, author = {Franzsico, Marcos A. S. and Fantuzzi, Felipe and Cardozo, Thiago M. and Esteves, Pierre M. and Engels, Bernd and Oliveira, Ricardo R.}, title = {Taming the Antiferromagnetic Beast: Computational Design of Ultrashort Mn-Mn Bonds Stabilized by N-Heterocyclic Carbenes}, series = {Chemistry—A European Journal}, volume = {27}, journal = {Chemistry—A European Journal}, number = {47}, doi = {10.1002/chem.202101116}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-256874}, pages = {12126-12136}, year = {2021}, abstract = {The development of complexes featuring low-valent, multiply bonded metal centers is an exciting field with several potential applications. In this work, we describe the design principles and extensive computational investigation of new organometallic platforms featuring the elusive manganese-manganese bond stabilized by experimentally realized N-heterocyclic carbenes (NHCs). By using DFT computations benchmarked against multireference calculations, as well as MO- and VB-based bonding analyses, we could disentangle the various electronic and structural effects contributing to the thermodynamic and kinetic stability, as well as the experimental feasibility, of the systems. In particular, we explored the nature of the metal-carbene interaction and the role of the ancillary η\(^{6}\) coordination to the generation of Mn\(_{2}\) systems featuring ultrashort metal-metal bonds, closed-shell singlet multiplicities, and positive adiabatic singlet-triplet gaps. Our analysis identifies two distinct classes of viable synthetic targets, whose electrostructural properties are thoroughly investigated.}, language = {en} } @article{EiringMcLaughlinMatikondaetal.2021, author = {Eiring, Patrick and McLaughlin, Ryan and Matikonda, Siddharth S. and Han, Zhongying and Grabenhorst, Lennart and Helmerich, Dominic A. and Meub, Mara and Beliu, Gerti and Luciano, Michael and Bandi, Venu and Zijlstra, Niels and Shi, Zhen-Dan and Tarasov, Sergey G. and Swenson, Rolf and Tinnefeld, Philip and Glembockyte, Viktorija and Cordes, Thorben and Sauer, Markus and Schnermann, Martin J.}, title = {Targetable conformationally restricted cyanines enable photon-count-limited applications}, series = {Angewandte Chemie Internationale Edition}, volume = {60}, journal = {Angewandte Chemie Internationale Edition}, number = {51}, doi = {10.1002/anie.202109749}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-256559}, pages = {26685-26693}, year = {2021}, abstract = {Cyanine dyes are exceptionally useful probes for a range of fluorescence-based applications, but their photon output can be limited by trans-to-cis photoisomerization. We recently demonstrated that appending a ring system to the pentamethine cyanine ring system improves the quantum yield and extends the fluorescence lifetime. Here, we report an optimized synthesis of persulfonated variants that enable efficient labeling of nucleic acids and proteins. We demonstrate that a bifunctional sulfonated tertiary amide significantly improves the optical properties of the resulting bioconjugates. These new conformationally restricted cyanines are compared to the parent cyanine derivatives in a range of contexts. These include their use in the plasmonic hotspot of a DNA-nanoantenna, in single-molecule F{\"o}rster-resonance energy transfer (FRET) applications, far-red fluorescence-lifetime imaging microscopy (FLIM), and single-molecule localization microscopy (SMLM). These efforts define contexts in which eliminating cyanine isomerization provides meaningful benefits to imaging performance.}, language = {en} } @article{WobserRothAppenzelleretal.2021, author = {Wobser, Marion and Roth, Sabine and Appenzeller, Silke and Houben, Roland and Schrama, David and Goebeler, Matthias and Geissinger, Eva and Rosenwald, Andreas and Maurus, Katja}, title = {Targeted deep sequencing of mycosis fungoides reveals intracellular signaling pathways associated with aggressiveness and large cell transformation}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {21}, issn = {2072-6694}, doi = {10.3390/cancers13215512}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250094}, year = {2021}, abstract = {Introduction: Large-cell transformation (LCT) of mycosis fungoides (MF) has been associated with a higher risk of relapse and progression and, consequently, restricted prognosis. Its molecular pathogenesis has not been elucidated yet. Materials and Methods: In order to address molecular mechanisms of LCT, we performed hybrid capture panel-based sequencing of skin biopsies from 10 patients suffering from MF with LCT versus 17 patients without LCT including follow-up biopsies during clinical course, respectively (51 samples in total). The analyzed patients were attributed to three different groups based on the presence of LCT and clinical behavior. Results: While indolent MF cases without LCT did not show pathogenic driver mutations, a high rate of oncogenic alterations was detected in patients with LCT and aggressive clinical courses. Various genes of different oncogenic signaling pathways, including the MAPK and JAK-STAT signaling pathways, as well as epigenetic modifiers were affected. A high inter-individual and distinctive intra-individual mutation diversity was observed. Oncogenic RAS mutations were exclusively detected in patients with LCT. Conclusion: Our data demonstrate that LCT transition of MF is associated with increased frequency of somatic mutations in cancer-associated genes. In particular, the activation of RAS signaling — together with epigenetic dysregulation — may crucially contribute to the molecular pathogenesis of the LCT phenotype, thus conveying its adverse clinical behavior.}, language = {en} } @article{PauliPaulProppertetal.2021, author = {Pauli, Martin and Paul, Mila M. and Proppert, Sven and Mrestani, Achmed and Sharifi, Marzieh and Repp, Felix and K{\"u}rzinger, Lydia and Kollmannsberger, Philip and Sauer, Markus and Heckmann, Manfred and Sir{\´e}n, Anna-Leena}, title = {Targeted volumetric single-molecule localization microscopy of defined presynaptic structures in brain sections}, series = {Communications Biology}, volume = {4}, journal = {Communications Biology}, doi = {10.1038/s42003-021-01939-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259830}, pages = {407}, year = {2021}, abstract = {Revealing the molecular organization of anatomically precisely defined brain regions is necessary for refined understanding of synaptic plasticity. Although three-dimensional (3D) single-molecule localization microscopy can provide the required resolution, imaging more than a few micrometers deep into tissue remains challenging. To quantify presynaptic active zones (AZ) of entire, large, conditional detonator hippocampal mossy fiber (MF) boutons with diameters as large as 10 mu m, we developed a method for targeted volumetric direct stochastic optical reconstruction microscopy (dSTORM). An optimized protocol for fast repeated axial scanning and efficient sequential labeling of the AZ scaffold Bassoon and membrane bound GFP with Alexa Fluor 647 enabled 3D-dSTORM imaging of 25 mu m thick mouse brain sections and assignment of AZs to specific neuronal substructures. Quantitative data analysis revealed large differences in Bassoon cluster size and density for distinct hippocampal regions with largest clusters in MF boutons. Pauli et al. develop targeted volumetric dSTORM in order to image large hippocampal mossy fiber boutons (MFBs) in brain slices. They can identify synaptic targets of individual MFBs and measured size and density of Bassoon clusters within individual untruncated MFBs at nanoscopic resolution.}, language = {en} } @article{LinzBrandsKertelsetal.2021, author = {Linz, Christian and Brands, Roman C. and Kertels, Olivia and Dierks, Alexander and Brumberg, Joachim and Gerhard-Hartmann, Elena and Hartmann, Stefan and Schirbel, Andreas and Serfling, Sebastian and Zhi, Yingjun and Buck, Andreas K. and K{\"u}bler, Alexander and Hohm, Julian and Lapa, Constantin and Kircher, Malte}, title = {Targeting fibroblast activation protein in newly diagnosed squamous cell carcinoma of the oral cavity - initial experience and comparison to [\(^{18}\)F]FDG PET/CT and MRI}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {48}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {12}, issn = {1619-7070}, doi = {10.1007/s00259-021-05422-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307246}, pages = {3951-3960}, year = {2021}, abstract = {Purpose While [\(^{18}\)F]-fluorodeoxyglucose ([\(^{18}\)F]FDG) is the standard for positron emission tomography/computed tomography (PET/CT) imaging of oral squamous cell carcinoma (OSCC), diagnostic specificity is hampered by uptake in inflammatory cells such as neutrophils or macrophages. Recently, molecular imaging probes targeting fibroblast activation protein α (FAP), which is overexpressed in a variety of cancer-associated fibroblasts, have become available and might constitute a feasible alternative to FDG PET/CT. Methods Ten consecutive, treatment-na{\"i}ve patients (8 males, 2 females; mean age, 62 ± 9 years) with biopsy-proven OSCC underwent both whole-body [\(^{18}\)F]FDG and [\(^{68}\)Ga]FAPI-04 (FAP-directed) PET/CT for primary staging prior to tumor resection and cervical lymph node dissection. Detection of the primary tumor, as well as the presence and number of lymph node and distant metastases was analysed. Intensity of tracer accumulation was assessed by means of maximum (SUV\(_{max}\)) and peak (SUV\(_{peak}\) standardized uptake values. Histological work-up including immunohistochemical staining for FAP served as standard of reference. Results [\(^{18}\)F]FDG and FAP-directed PET/CT detected all primary tumors with a SUVmax of 25.5 ± 13.2 (FDG) and 20.5 ± 6.4 (FAP-directed) and a SUVpeak of 16.1 ± 10.3 ([\(^{18}\)F]FDG) and 13.8 ± 3.9 (FAP-directed), respectively. Regarding cervical lymph node metastases, FAP-directed PET/CT demonstrated comparable sensitivity (81.3\% vs. 87.5\%; P = 0.32) and specificity (93.3\% vs. 81.3\%; P = 0.16) to [\(^{18}\)F]FDG PET/CT. FAP expression on the cell surface of cancer-associated fibroblasts in both primary lesions as well as lymph nodes metastases was confirmed in all samples. Conclusion FAP-directed PET/CT in OSCC seems feasible. Future research to investigate its potential to improve patient staging is highly warranted.}, language = {en} } @article{DohrnIhneHegenbartetal.2021, author = {Dohrn, Maike F. and Ihne, Sandra and Hegenbart, Ute and Medina, Jessica and Z{\"u}chner, Stephan L. and Coelho, Teresa and Hahn, Katrin}, title = {Targeting transthyretin - Mechanism-based treatment approaches and future perspectives in hereditary amyloidosis}, series = {Journal of Neurochemistry}, volume = {156}, journal = {Journal of Neurochemistry}, number = {6}, doi = {10.1111/jnc.15233}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224481}, pages = {802 -- 818}, year = {2021}, abstract = {The liver-derived, circulating transport protein transthyretin (TTR) is the cause of systemic hereditary (ATTRv) and wild-type (ATTRwt) amyloidosis. TTR stabilization and knockdown are approved therapies to mitigate the otherwise lethal disease course. To date, the variety in phenotypic penetrance is not fully understood. This systematic review summarizes the current literature on TTR pathophysiology with its therapeutic implications. Tetramer dissociation is the rate-limiting step of amyloidogenesis. Besides destabilizing TTR mutations, other genetic (RBP4, APCS, AR, ATX2, C1q, C3) and external (extracellular matrix, Schwann cell interaction) factors influence the type of onset and organ tropism. The approved small molecule tafamidis stabilizes the tetramer and significantly decelerates the clinical course. By sequence-specific mRNA knockdown, the approved small interfering RNA (siRNA) patisiran and antisense oligonucleotide (ASO) inotersen both significantly reduce plasma TTR levels and improve neuropathy and quality of life compared to placebo. With enhanced hepatic targeting capabilities, GalNac-conjugated siRNA and ASOs have recently entered phase III clinical trials. Bivalent TTR stabilizers occupy both binding groves in vitro, but have not been tested in trials so far. Tolcapone is another stabilizer with the potential to cross the blood-brain barrier, but its half-life is short and liver failure a potential side effect. Amyloid-directed antibodies and substances like doxycycline aim at reducing the amyloid load, however, none of the yet developed antibodies has successfully passed clinical trials. ATTR-amyloidosis has become a model disease for pathophysiology-based treatment. Further understanding of disease mechanisms will help to overcome the remaining limitations, including application burden, side effects, and blood-brain barrier permeability.}, language = {en} } @article{ReifTesfaselassieWolters2021, author = {Reif, Magnus and Tesfaselassie, Mewael F. and Wolters, Maik H.}, title = {Technological Growth and Hours in the Long Run: Theory and Evidence}, series = {Economica}, volume = {88}, journal = {Economica}, number = {352}, doi = {10.1111/ecca.12385}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262801}, pages = {1016 -- 1053}, year = {2021}, abstract = {Over the last few decades, hours worked per capita have declined substantially in many OECD economies. Using the standard neoclassical growth model with endogenous work-leisure choice, we assess the role of trend growth slowdown in accounting for the decline in hours worked. In the model, a permanent reduction in technological growth decreases steady-state hours worked by increasing the consumption-output ratio. Our empirical analysis exploits cross-country variation in the timing and size of the decline in technological growth to show that technological growth has a highly significant positive effect on hours. A decline in the long-run trend of technological growth by 1 percentage point is associated with a decline in trend hours worked in the range of 1-3\%. This result is robust to controlling for taxes, which have been found in previous studies to be an important determinant of hours. Our empirical finding is quantitatively in line with the one implied by a calibrated version of the model, though evidence for the model's implication that the effect on hours works via changes in the consumption-output ratio is rather mixed.}, language = {en} } @article{BarlinnWinzerWorthmannetal.2021, author = {Barlinn, J. and Winzer, S. and Worthmann, H. and Urbanek, C. and H{\"a}usler, K. G. and G{\"u}nther, A. and Erdur, H. and G{\"o}rtler, M. and Busetto, L. and Wojciechowski, C. and Schmitt, J. and Shah, Y. and B{\"u}chele, B. and Sokolowski, P. and Kraya, T. and Merkelbach, S. and Rosengarten, B. and Stangenberg-Gliss, K. and Weber, J. and Schlachetzki, F. and Abu-Mugheisib, M. and Petersen, M. and Schwartz, A. and Palm, F. and Jowaed, A. and Volbers, B. and Zickler, P. and Remi, J. and Bardutzky, J. and B{\"o}sel, J. and Audebert, H. J. and Hubert, G. J. and Gumbinger, C.}, title = {Telemedizin in der Schlaganfallversorgung - versorgungsrelevant f{\"u}r Deutschland}, series = {Der Nervenarzt}, volume = {92}, journal = {Der Nervenarzt}, number = {6}, issn = {0028-2804}, doi = {10.1007/s00115-021-01137-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307752}, pages = {593-601}, year = {2021}, abstract = {Hintergrund und Ziel Telemedizinische Schlaganfall-Netzwerke tragen dazu bei, die Schlaganfallversorgung und insbesondere den Zugang zu zeitkritischen Schlaganfalltherapien in vorrangig strukturschwachen, l{\"a}ndlichen Regionen zu gew{\"a}hrleisten. Ziel ist eine Darstellung der Nutzungsfrequenz und regionalen Verteilung dieser Versorgungsstruktur. Methoden Die Kommission „Telemedizinische Schlaganfallversorgung" der Deutschen Schlaganfall-Gesellschaft f{\"u}hrte eine Umfragestudie in allen Schlaganfall-Netzwerken durch. Ergebnisse In Deutschland sind 22 telemedizinische Schlaganfall-Netzwerke aktiv, welche insgesamt 43 Zentren (pro Netzwerk: Median 1,5, Interquartilsabstand [IQA] 1-3) sowie 225 Kooperationskliniken (pro Netzwerk: Median 9, IQA 4-17) umfassen und an einem unmittelbaren Zugang zur Schlaganfallversorgung f{\"u}r 48 Mio. Menschen teilhaben. Im Jahr 2018 wurden 38.211 Telekonsile (pro Netzwerk: Median 1340, IQA 319-2758) durchgef{\"u}hrt. Die Thrombolyserate betrug 14,1 \% (95 \%-Konfidenzintervall 13,6-14,7 \%), eine Verlegung zur Thrombektomie wurde bei 7,9 \% (95 \%-Konfidenzintervall 7,5-8,4 \%) der isch{\"a}mischen Schlaganfallpatienten initiiert. Das Finanzierungssystem ist uneinheitlich mit einem Verg{\"u}tungssystem f{\"u}r die Zentrumsleistungen in nur drei Bundesl{\"a}ndern. Diskussion Etwa jeder 10. Schlaganfallpatient wird telemedizinisch behandelt. Die telemedizinischen Schlaganfall-Netzwerke erreichen vergleichbar hohe Lyseraten und Verlegungen zur Thrombektomie wie neurologische Stroke-Units und tragen zur Sicherstellung einer fl{\"a}chendeckenden Schlaganfallversorgung bei. Eine netzwerk{\"u}bergreifende Sicherstellung der Finanzierung und einheitliche Erhebung von Qualit{\"a}tssicherungsdaten haben das Potenzial diese Versorgungsstruktur zuk{\"u}nftig weiter zu st{\"a}rken.}, language = {de} } @article{ShanBoeckKelleretal.2021, author = {Shan, Junwen and B{\"o}ck, Thomas and Keller, Thorsten and Forster, Leonard and Blunk, Torsten and Groll, J{\"u}rgen and Teßmar, J{\"o}rg}, title = {TEMPO/TCC as a Chemo Selective Alternative for the Oxidation of Hyaluronic Acid}, series = {Molecules}, volume = {26}, journal = {Molecules}, number = {19}, issn = {1420-3049}, doi = {10.3390/molecules26195963}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248362}, year = {2021}, abstract = {Hyaluronic acid (HA)-based hydrogels are very commonly applied as cell carriers for different approaches in regenerative medicine. HA itself is a well-studied biomolecule that originates from the physiological extracellular matrix (ECM) of mammalians and, due to its acidic polysaccharide structure, offers many different possibilities for suitable chemical modifications which are necessary to control, for example, network formation. Most of these chemical modifications are performed using the free acid function of the polymer and, additionally, lead to an undesirable breakdown of the biopolymer's backbone. An alternative modification of the vicinal diol of the glucuronic acid is oxidation with sodium periodate to generate dialdehydes via a ring opening mechanism that can subsequently be further modified or crosslinked via Schiff base chemistry. Since this oxidation causes a structural destruction of the polysaccharide backbone, it was our intention to study a novel synthesis protocol frequently applied to selectively oxidize the C6 hydroxyl group of saccharides. On the basis of this TEMPO/TCC oxidation, we studied an alternative hydrogel platform based on oxidized HA crosslinked using adipic acid dihydrazide as the crosslinker.}, language = {en} } @article{KlaffehnSellmannKirschetal.2021, author = {Klaffehn, Annika L. and Sellmann, Florian B. and Kirsch, Wladimir and Kunde, Wilfried and Pfister, Roland}, title = {Temporal binding as multisensory integration: Manipulating perceptual certainty of actions and their effects}, series = {Attention, Perception \& Psychophysics}, volume = {83}, journal = {Attention, Perception \& Psychophysics}, number = {8}, issn = {1943-393X}, doi = {10.3758/s13414-021-02314-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-273195}, pages = {3135-3145}, year = {2021}, abstract = {It has been proposed that statistical integration of multisensory cues may be a suitable framework to explain temporal binding, that is, the finding that causally related events such as an action and its effect are perceived to be shifted towards each other in time. A multisensory approach to temporal binding construes actions and effects as individual sensory signals, which are each perceived with a specific temporal precision. When they are integrated into one multimodal event, like an action-effect chain, the extent to which they affect this event's perception depends on their relative reliability. We test whether this assumption holds true in a temporal binding task by manipulating certainty of actions and effects. Two experiments suggest that a relatively uncertain sensory signal in such action-effect sequences is shifted more towards its counterpart than a relatively certain one. This was especially pronounced for temporal binding of the action towards its effect but could also be shown for effect binding. Other conceptual approaches to temporal binding cannot easily explain these results, and the study therefore adds to the growing body of evidence endorsing a multisensory approach to temporal binding.}, language = {en} } @article{MuthWirthKunde2021, author = {Muth, Felicitas V. and Wirth, Robert and Kunde, Winfried}, title = {Temporal binding past the Libet clock: testing design factors for an auditory timer}, series = {Behavior Research Methods}, volume = {53}, journal = {Behavior Research Methods}, number = {3}, doi = {10.3758/s13428-020-01474-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234922}, pages = {1322-1341}, year = {2021}, abstract = {Voluntary actions and causally linked sensory stimuli are perceived to be shifted towards each other in time. This so-called temporal binding is commonly assessed in paradigms using the Libet Clock. In such experiments, participants have to estimate the timing of actions performed or ensuing sensory stimuli (usually tones) by means of a rotating clock hand presented on a screen. The aforementioned task setup is however ill-suited for many conceivable setups, especially when they involve visual effects. To address this shortcoming, the line of research presented here establishes an alternative measure for temporal binding by using a sequence of timed sounds. This method uses an auditory timer, a sequence of letters presented during task execution, which serve as anchors for temporal judgments. In four experiments, we manipulated four design factors of this auditory timer, namely interval length, interval filling, sequence predictability, and sequence length, to determine the most effective and economic method for measuring temporal binding with an auditory timer.}, language = {en} } @phdthesis{Roth2021, author = {Roth, Nicolas M{\´e}riadec Max Andr{\´e}}, title = {Temporal development of communities with a focus on insects, in time series of one to four decades}, doi = {10.25972/OPUS-23549}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235499}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Changes and development are fundamental principles in biocenoses and can affect a multitude of ecological processes. In insect communities phenological and density changes, changes in species richness and community composition, as well as interactions between those changes, are the most important macro processes. However, climate change and other factors like habitat degradation and loss alter these processes leading to shifts and general biodiversity declines. Even though knowledge about insect decline in central Europe increased during the last decades, there are significant knowledge gaps about the development of insect communities in certain habitats and taxa. For example, insect communities in small lentic as well as in forested habitats are under-sampled and reported to be less endangered than communities in other habitats. Furthermore, the changes within habitats and taxa are additionally influenced by certain traits, like host or feeding specialization. To disentangle these influences and to increase the knowledge about the general long-term development of insect communities, comprehensive long-term monitoring studies are needed. In addition, long-term effects of conservation strategies should also be evaluated on large time scales in order to be able to decide on a scientific base which strategies are effective in promoting possibly declining taxa. Hence, this thesis also tackles the effects of an integrative conservation strategy on wood dependent beetle and fungi, beside the development of water beetle and macro moth communities over multiple decades. In Chapter 2 I present a study on the development of water beetle communities (Dytiscidae, Haliplidae, Noteridae) in 33 water bodies in Southern Germany from 1991 to 2018. Time-standardized capture per waterbody was used during three periods: between 1991 and 1995, 2007 and 2008, and 2017 and 2018. Results showed annual declines in both species number (ca. -1\%) and abundance (ca. -2\%). In addition, community composition shifted over time in part due to changing pH values. Hence, the recorded changes during the 28-year study period partly reflect natural succession processes. However, since also moor-related beetle species decreased significantly, it is likely that water beetles in southern Germany are also threatened by non-successional factors, including desiccation, increased nitrogen input and/or mineralization, as well as the loss of specific habitats. The results suggest, that in small to midsize lentic waterbodies, current development should aim for constant creation of new water bodies and protection of moor waterbodies in order to protect water beetle communities on a landscape scale. In Chapter 3 I present an analysis of the development of nocturnal macro moth species richness, abundance and biomass over four decades in forests of southern Germany. Two local scale data sets featuring a coppiced oak forest as well as an oak high forest were analysed separately from a regional data set representing all forest types in the temperate zone of Central Europe. At the regional scale species richness, abundance and biomass showed annual declines of ca. 1 \%, 1.3 \% and 1.4 \%, respectively. These declines were more pronounced in plant host specialists and in dark coloured species. In contrast, species richness increased by ca. 1.5 \% annually in the coppiced forest, while no significant trends were found in the high forest. In contrast to past assumptions, insect decline apparently affects also hyper diverse insect groups in forests. Since host specialists and dark coloured species were affected more heavily by the decline than other groups, habitat loss and climate change seem to be potential drivers of the observed trends. However, the positive development of species richness in the coppiced oak forest indicates that maintaining complex and diverse forest ecosystems through active management might compensate for negative trends in biodiversity. Chapter 4 features a study specifically aiming to investigate the long-term effect of deadwood enrichment as an integrative conservation strategy on saproxylic beetles and fungi in a central European beech forest at a landscape scale. A before-after control-impact design, was used to compare assemblages and gamma diversities of saproxylic organisms (beetles and fungi) in strictly protected old-growth forest areas (reserves) and previously moderately and intensively managed forest areas. Forests were sampled one year before and a decade after starting a landscape-wide strategy of dead-wood enrichment. Ten years after the start of the dead-wood enrichment, neither gamma diversities of saproxylic organisms nor species composition of beetles did reflect the previous management types anymore. However, fungal species composition still mirrored the previous management gradient. The results demonstrated that intentional enrichment of dead wood at the landscape scale can effectively restore communities of saproxylic organisms and may thus be a suitable strategy in addition to permanent strict reserves in order to protect wood dependent organisms in Europe. In this thesis I showed, that in contrast to what was assumed and partly reported so far, also water beetles in lentic water bodies and macro moths in forests decreased in species richness, abundance and biomass during the last three to four decades. In line with earlier studies, especially dark coloured species and specialists decreased more than light-coloured species and generalists. The reasons for these declines could partly be attributed to natural processes and pollution and possibly to climate change. However, further studies, especially experimental ones, will be needed to achieve a better understanding of the reasons for insect decline. Furthermore, analyses of time series data should be interpreted cautiously especially if the number of sampling years is smaller than ten years. In addition, validation techniques such as left- and right- censoring and cross validation should be used in order to proof the robustness of the analyses. However, the lack of knowledge, we are still facing today, should not prevent scientists and practitioners from applying conservation measures. In order to prove the effectiveness of such measures, long-term monitoring is crucial. Such control of success is essential for evidence based and thus adapted conservation strategies of threatened organisms.}, subject = {climate change}, language = {en} } @article{LeidingerVedderCabral2021, author = {Leidinger, Ludwig and Vedder, Daniel and Cabral, Juliano Sarmento}, title = {Temporal environmental variation may impose differential selection on both genomic and ecological traits}, series = {Oikos}, volume = {130}, journal = {Oikos}, number = {7}, doi = {10.1111/oik.08172}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-238945}, pages = {1100 -- 1115}, year = {2021}, abstract = {The response of populations and species to changing conditions determines how community composition will change functionally, including via trait shifts. Selection from standing variation has been suggested to be more efficient than acquiring new mutations. Yet, studies on community trait composition and trait selection largely focus on phenotypic variation in ecological traits, whereas the underlying genomic traits remain understudied. Using a genome-explicit, niche- and individual-based model, we address the potential interactions between genomic and ecological traits shaping communities under an environmental selective forcing, namely temporal positively autocorrelated environmental fluctuation. In this model, all ecological traits are explicitly coded by the genome. For our experiments, we initialized 90 replicate communities, each with ca 350 initial species, characterized by random genomic and ecological trait combinations, on a 2D spatially explicit landscape with two orthogonal gradients (temperature and resource use). We exposed each community to two contrasting scenarios: without (i.e. static environments) and with temporal variation. We then analyzed emerging compositions of both genomic and ecological traits at the community, population and genomic levels. Communities in variable environments were species poorer than in static environments, and populations more abundant, whereas genomes had lower genetic linkage, mean genetic variation and a non-significant tendency towards higher numbers of genes. The surviving genomes (i.e. those selected by variable environments) coded for enhanced environmental tolerance and smaller biomass, which resulted in faster life cycles and thus also in increased potential for evolutionary rescue. Under temporal environmental variation, larger, less linked genomes retained more variation in mean dispersal ability at the population level than at genomic level, whereas the opposite trend emerged for biomass. Our results provide clues to how sexually-reproducing diploid plant communities might react to variable environments and highlights the importance of genomic traits and their interaction with ecological traits for eco-evolutionary responses to changing climates.}, language = {en} } @phdthesis{Pieper2021, author = {Pieper, Sabrina H.}, title = {Temporal information transfer by electrical stimulation in auditory implants}, doi = {10.25972/OPUS-22388}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223887}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {In deafness, which is caused by the malfunctioning of the inner ear, an implantation of a cochlear implant (CI) is able to restore hearing. The CI is a neural prosthesis that is located within the cochlea. It replaces the function of the inner hair cells by direct electrical stimulation of the auditory nerve fibers. The CI enables many deaf or severe hearing-impaired people to achieve a good speech perception. Nevertheless, there is a lot of potential for further improvements. Compared to normal-hearing listeners rate pitch discrimination is much worse. Rate pitch discrimination is the ability to distinguish the pitch of two stimuli with two different pulse rates. This ability is important for enjoying music as well as speech perception (in noise). Further, the small dynamic range in electrical hearing (compared to normal-hearing listeners) and therefore the small intensity resolution limits the performance of CI users. Both, rate pitch coding and dynamic range were investigated in this doctoral thesis. For the first issue, a pitch discrimination task was designed to determine the just-noticeable-difference (JND) in pitch with 200 and 400 pps as reference. Additionally to the default biphasic pulse (single pulse) the experiment was performed with double pulses. The double pulse consists out of two biphasic pulses directly after each other and a small interpulse interval (IPI) in between. Three different IPIs (15, 50, and 150 µs) were tested. The statistical analysis of JNDs revealed no significant effects between stimulation with single-pulse or double-pulse trains. A follow-up study investigated an alternating pulse train consisting of single and double pulses. To investigate if the 400 pps alternating pulse train is comparable in pitch with the 400 pps single-pulse train, a pairwise pitch comparison test was conducted. The alternating pulse train was compared with single-pulse trains at 200, 300 and 400 pps. The results showed that the alternating pulse train is for most subjects similar in pitch with the 200 pps single-pulse train. Therefore, pitch perception seemed to be dominated by the double pulses within the pulse train. Accordingly, double pulses with different amplitudes were tested. Based on the facilitation effect, a larger neuronal response was expected by stimulating with two pulses with a short IPI within the temporal facilitation range. In other studies, this effect was shown to be maximal in CIs of the manufacturer Cochlear, with first pulse amplitudes set at or slightly below the electrically evoked compound action potential (ECAP) threshold. The second pulse amplitude did not influence the facilitation effect and therefore could be choose at will. Similarly, this effect was tested in this thesis with CIs of the manufacturer MED-EL. Nevertheless, to achieve a proper signal-to-noise ratio, technical issues had to be addressed like a high noise floor, resulting in incorrect determination of the ECAP threshold. After solving this issues, the maximum facilitation effect was around the ECAP threshold as in the previous study with Cochlear. For future studies this effect could be used in a modified double pulse rate pitch experiment with the first pulse amplitude at ECAP threshold and the second pulse amplitude variable to set the most comfortable loudness level (MCL). The last study within this thesis investigated the loudness perception at two different loudness levels and the resulting dynamic range for different interphase-gaps (IPG). A larger IPG can reduce the amplitude at same loudness level to save battery power. However, it was unknown if the IPG has an influence on the dynamic range. Different IPGs (10 and 30 µs) were compared with the default IPG (2.1 µs) in a loudness matching experiment. The experiment was performed at the most comfortable loudness level (MCL) of the subject and the amplitude of half the dynamic range (50\%-ADR). An upper dynamic range was calculated from the results of MCL and 50\%-ADR (therefore not the whole dynamic range was covered). As expected from previous studies a larger IPG resulted in smaller amplitudes. However, the observed effect was larger at MCL than at 50\%-ADR which resulted in a smaller upper dynamic range. This is the first time a decrease of this dynamic range was shown.}, subject = {Cochlear-Implantat}, language = {en} } @article{NavarroStegnerNieswandtetal.2021, author = {Navarro, Stefano and Stegner, David and Nieswandt, Bernhard and Heemskerk, Johan W. M. and Kuijpers, Marijke J. E.}, title = {Temporal roles of platelet and coagulation pathways in collagen- and tissue factor-induced thrombus formation}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {1}, issn = {1422-0067}, doi = {10.3390/ijms23010358}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284219}, year = {2021}, abstract = {In hemostasis and thrombosis, the complex process of thrombus formation involves different molecular pathways of platelet and coagulation activation. These pathways are considered as operating together at the same time, but this has not been investigated. The objective of our study was to elucidate the time-dependency of key pathways of thrombus and clot formation, initiated by collagen and tissue factor surfaces, where coagulation is triggered via the extrinsic route. Therefore, we adapted a microfluidics whole-blood assay with the Maastricht flow chamber to acutely block molecular pathways by pharmacological intervention at desired time points. Application of the technique revealed crucial roles of glycoprotein VI (GPVI)-induced platelet signaling via Syk kinase as well as factor VIIa-induced thrombin generation, which were confined to the first minutes of thrombus buildup. A novel anti-GPVI Fab EMF-1 was used for this purpose. In addition, platelet activation with the protease-activating receptors 1/4 (PAR1/4) and integrin αIIbβ3 appeared to be prolongedly active and extended to later stages of thrombus and clot formation. This work thereby revealed a more persistent contribution of thrombin receptor-induced platelet activation than of collagen receptor-induced platelet activation to the thrombotic process.}, language = {en} } @article{DelgoboHeinrichsHapkeetal.2021, author = {Delgobo, Murilo and Heinrichs, Margarete and Hapke, Nils and Ashour, DiyaaElDin and Appel, Marc and Srivastava, Mugdha and Heckel, Tobias and Spyridopoulos, Ioakim and Hofmann, Ulrich and Frantz, Stefan and Ramos, Gustavo Campos}, title = {Terminally Differentiated CD4\(^+\) T Cells Promote Myocardial Inflammaging}, series = {Frontiers in Immunology}, volume = {12}, journal = {Frontiers in Immunology}, issn = {1664-3224}, doi = {10.3389/fimmu.2021.584538}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229612}, year = {2021}, abstract = {The cardiovascular and immune systems undergo profound and intertwined alterations with aging. Recent studies have reported that an accumulation of memory and terminally differentiated T cells in elderly subjects can fuel myocardial aging and boost the progression of heart diseases. Nevertheless, it remains unclear whether the immunological senescence profile is sufficient to cause age-related cardiac deterioration or merely acts as an amplifier of previous tissue-intrinsic damage. Herein, we sought to decompose the causality in this cardio-immune crosstalk by studying young mice harboring a senescent-like expanded CD4\(^+\) T cell compartment. Thus, immunodeficient NSG-DR1 mice expressing HLA-DRB1*01:01 were transplanted with human CD4\(^+\) T cells purified from matching donors that rapidly engrafted and expanded in the recipients without causing xenograft reactions. In the donor subjects, the CD4\(^+\) T cell compartment was primarily composed of na{\"i}ve cells defined as CCR7\(^+\)CD45RO\(^-\). However, when transplanted into young lymphocyte-deficient mice, CD4\(^+\) T cells underwent homeostatic expansion, upregulated expression of PD-1 receptor and strongly shifted towards effector/memory (CCR7\(^-\) CD45RO\(^+\)) and terminally-differentiated phenotypes (CCR7\(^-\)CD45RO\(^-\)), as typically seen in elderly. Differentiated CD4\(^+\) T cells also infiltrated the myocardium of recipient mice at comparable levels to what is observed during physiological aging. In addition, young mice harboring an expanded CD4\(^+\) T cell compartment showed increased numbers of infiltrating monocytes, macrophages and dendritic cells in the heart. Bulk mRNA sequencing analyses further confirmed that expanding T-cells promote myocardial inflammaging, marked by a distinct age-related transcriptomic signature. Altogether, these data indicate that exaggerated CD4\(^+\) T-cell expansion and differentiation, a hallmark of the aging immune system, is sufficient to promote myocardial alterations compatible with inflammaging in juvenile healthy mice.}, language = {en} }