@article{LuraghiIngleseKoelligan2021, author = {Luraghi, Silvia and Inglese, Guglielmo and K{\"o}lligan, Daniel}, title = {The passive voice in ancient Indo-European languages: inflection, derivation, periphrastic verb forms}, series = {Folia Linguistica}, volume = {55}, journal = {Folia Linguistica}, number = {s42-s2}, issn = {0165-4004}, doi = {10.1515/flin-2021-2033}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-247034}, pages = {339 -- 391}, year = {2021}, abstract = {The IE languages developed different strategies for the encoding of the passive function. In some language branches, the middle voice extended to the passive function to varying extents. In addition, dedicated derivational formations arose in a number of languages, such as the Greek -ē-/-thē- aorist and the Indo-Aryan -ya-presents. Periphrastic formations involving a verbal adjective or a participle are also widely attested, and played an important role in the building of the passive paradigm in e.g. Romance and Germanic languages. As the periphrastic passive is also attested in Hittite alongside passive use of the middle, both strategies seem to be equally ancient. Some minor strategies include lexical passives and the extensive lability of verbs. A survey of possible strategies provides evidence for the rise of a disparate number of morphemes and constructions, and for their ongoing incorporation into the inflectional paradigms (paradigmaticization) of given languages, thus adding to our knowledge about cross-linguistic sources of passive morphology and grammaticalization processes involved.}, language = {en} } @phdthesis{Hartmannsberger2021, author = {Hartmannsberger, Beate}, title = {The pathogenicity and origin of auto-antibodies in chronic inflammatory demyelinating polyradiculoneuropathy and the identification of cutaneous biomarkers in Charcot-Marie-Tooth 1A patients}, doi = {10.25972/OPUS-21145}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-211451}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Peripheral neuropathies can severely affect patients. Causes for the disease are diverse but can be classified into two main groups, acquired and hereditary. Examples for these two types are chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Charcot-Marie-Tooth disease type 1A (CMT1A). CIDP has an estimated prevalence of about 1-9:100 000. In this pathogenetically hetereo- geneous patient group about 5-10\% show auto-antibodies against the node of Ranvier and present with distinct symptoms. Treatment with rituximab - a monoclonal antibody that deletes CD20 + B cells - has been shown to be effective in a majority of auto-antibody as- sociated CIDP cases. This suggests that B cells and the produced auto-antibodies might be pathogenic. Previous studies delivered evidence that auto-antibodies alone can induce nerve damage. In this study, the aim was to investigate the pathomechanism of auto-antibodies in vivo and their exact origin: For the analysis of the pathogenicity of auto-antibodies, passive transfer experiments on Lewis rats were performed with whole IgG from a patient with anti-contactin-1 (CNTN1) IgG4 auto-antibodies. IgG was infused through an intrathe- cal catheter targeting the thoracic/lumbar region of the spine over a long-term, 3-week period. In a previous study of our group, the IgG from the same patient has been re- ported to have mild pathogenic effects when applied intraneurally into the sciatic nerve of Lewis rats. In this study however, binding of auto-antibodies to nerve roots could not be detected. Neither evaluation of electrophysiological properties after the injection period nor motor and sensory skills tested throughout the injection period showed differences when compared to animals infused with control IgG. This suggests that in the chronic intrathecal protocol anti-CNTN1 auto-antibodies did not have a pathogenic effect. In peripheral blood, four B cell subsets capable to produce antibodies were previously described: memory B cells, plasmablasts (PBs), B1 cells and CD20 + CD38 hi cells. For the identification of the B cell subsets that produce auto-antibodies, purification and sort protocols as well as an enzyme-linked immuno spot (ELISpot) assay for IgG and IgM were established successfully. Since unstimulated B cell subsets produced very small amounts of IgG and IgM, peripheral blood mononuclear cells (PBMCs) were stimulated with IL-2 and R848 for 72 h prior to sorting. While the memory B cell frequency decreased after stimulation, the frequency of CD20 + CD38 hi cells increased and the overall number of antibody-secreting cells was increased. When stimulating patient PBMCs for 10 days though, detection of anti-neurofascin-155 (NF155) auto-antibodies in supernatants by enzyme-linked immunosorbent assay (ELISA) was possible in two out of three patient samples. Even though cell sorting was feasible after 10 days of stimulation, detection of auto-antibodies could not be accomplished using antigen-specific ELISpot. Although the implementation of the cell sorting and purification protocol was successful, further adjustments of the antigen-specific ELISpot need to be performed. However, we could show that after 10 days of stimulation auto-antibody detection is possible by ELISA which helps to pre-screen if patient PBMC contain auto-reactive B cells. CMT1A has an estimated prevalence of 1:5000 and is caused by a duplication of the peripheral myelin protein 22 kDa (PMP22) gene. Patients suffer from distal weakness and muscle wasting leading even to wheelchair-dependency in some cases. Although different treatment options for CMT1A have been tested in previous clinical trials, none of them have been successful. In this study, the aim was to identify objective and reproducible outcome measures that assess the actual nerve damage in a large cohort of CMT1A patients by analyzing a series of parameters. Glabrous skin samples were collected from 48 CMT1A, 7 CIDP and 16 small fiber neuropathy patients and 45 healthy controls. 40-µm cryosections from the lateral part of the index finger were double-labeled using immunoflu- orescence to investigate cutaneous innervation. The disease severity which was assessed using the Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNSv2) and ranged between mild to severe (3-27) correlated with age in CMT1A patients. Furthermore, the intraepidermal nerve fiber density (IENFD) was reduced in CMT1A patients in comparison to controls and correlated negatively with the disease severity. In controls however, the IENFD correlated inversely with age. Meissner corpuscle density tended to be reduced and correlated inversely with age in CMT1A patients. This was not observed in healthy controls though. Compared to controls, Merkel cell density was also reduced in CMT1A, while the fraction of denervated Merkel cell was increased and correlated with age. Further differences were revealed concerning the node of Ranvier. Paranodes were shortened and the fraction of long nodes was decreased in CMT1A patients compared to controls. These data suggest that the IENFD, the Meissner corpuscle and Merkel cell densities are possible candidates for outcome measures as they are associated with disease severity or age of patients. However, a reliable statement about the suitability as a marker for disease progression can not be made in this study since only six CMT1A patients agreed to give a follow-up biopsy two years later.}, language = {en} } @phdthesis{Filin2021, author = {Filin, Daniel}, title = {The Princes' War in South Germany 1458-1463}, doi = {10.25972/OPUS-23123}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231236}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {The Princes' War in South Germany (1458-1463) was the biggest military collision in the German lands in the middle of the fifteenth century. The most prominent princes of southern Germany participated in this struggle. Due to its significant scope, this conflict provides a valuable case study for achieving a better understanding of the conditions at the heart of the Holy Roman Empire at the sunset of the Middle Ages. The purpose of this study was to fill an existing gap in the modern research literature and provide a comprehensive up-to date monograph on the subject. The study was realized mainly on the basis of archival work and primary sources. Thousands of letters and documents exchanged between the princes, their advisors and the city representatives were carefully studied and analysed. Extensive use of printed sources as well as scientific literature also greatly facilitated this research. The first part of the dissertation provides a detailed description of the war itself and the events that led to it. In the initial phase of the struggle, Albrecht Achilles used his position as the imperial captain to advance his own interests. His actions enraged both Duke Ludwig and Elector Friedrich and made the war unavoidable. For more than two years two major coalitions of princes exchanged blows but as the dust settled the status quo ante bellum was restored in the eastern theatre of actions, while at the western front Elector Friedrich forced each of his opponents to make serious concessions. The second part of the dissertation is devoted to honor and reputation. It explores how these two constituents affected the actions and decision-making of the princes. The lack of a powerful arbiter allowed each of the princes to interpret the meaning of "right" and "justice" as most suited him, although they hardly intentionally misused these terms. Thus, more often than not, the important actors seemed to believe in the appropriateness of their deeds. Nevertheless, despite frequent emotional response, in the competition between emotions and cold calculation the latter usually prevailed. The conflict showed the confines of each of its major participants and the modus operandi of the Empire that prevented change and was tuned to keep the old order of things.}, subject = {F{\"u}rstenkrieg <1458-1463>}, language = {en} } @article{KelmGermerSchlegeletal.2021, author = {Kelm, Matthias and Germer, Christoph-Thomas and Schlegel, Nicolas and Flemming, Sven}, title = {The revival of surgery in Crohn's disease — early intestinal resection as a reasonable alternative in localized ileitis}, series = {Biomedicines}, volume = {9}, journal = {Biomedicines}, number = {10}, issn = {2227-9059}, doi = {10.3390/biomedicines9101317}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246296}, year = {2021}, abstract = {Crohn's disease (CD) represents a heterogeneous and complex disease with no curative therapeutic option available to date. Current therapy is mainly antibody-based focusing on the immune system while other treatment alternatives such as surgery are considered to be "last options". However, medical therapy for CD results in mild to severe side effects in a relevant amount of patients and some patients do not respond to the medication. Following that, quality of life is often significantly reduced in this patient cohort, thus, therapeutic alternatives are urgently needed. Updated evidence has revealed that surgery such as ileocecal resection (ICR) might be a potential therapeutic option in case of localized terminal ileitis since resection at early time points improves quality of life and significantly reduces the postoperative need for immunosuppressive medication with low rates of morbidity. In addition, new surgical approaches such as Kono-S anastomosis or inclusion of the mesentery result in significantly reduced rates of disease recurrence and reoperation. Based on the new evidence, the goal of this review is to provide an update on the role of surgery as a reasonable alternative to medical therapy in the interdisciplinary treatment of patients with CD.}, language = {en} } @article{BrychMuraliHaendel2021, author = {Brych, Mareike and Murali, Supriya and H{\"a}ndel, Barbara}, title = {The Role of Blinks, Microsaccades and their Retinal Consequences in Bistable Motion Perception}, series = {Frontiers in Psychology}, volume = {12}, journal = {Frontiers in Psychology}, issn = {1664-1078}, doi = {10.3389/fpsyg.2021.647256}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235217}, year = {2021}, abstract = {Eye-related movements such as blinks and microsaccades are modulated during bistable perceptual tasks. However, if they play an active role during internal perceptual switches is not known. We conducted two experiments involving an ambiguous plaid stimulus, wherein participants were asked to continuously report their percept, which could consist of either unidirectional coherent or bidirectional component movement. Our main results show that blinks and microsaccades did not facilitate perceptual switches. On the contrary, a reduction in eye movements preceded the perceptual switch. Blanks, on the other hand, thought to mimic the retinal consequences of a blink, consistently led to a switch. Through the timing of the blank-introduced perceptual change, we were able to estimate the delay between the internal switch and the response. This delay further allowed us to evaluate that the reduction in blink probability co-occurred with the internal perceptual switch. Additionally, our results indicate that distinct internal processes underlie the switch to coherent vs. component percept. Blanks exclusively facilitated a switch to the coherent percept, and only the switch to coherent percept was followed by an increase in blink rate. In a second study, we largely replicated the findings and included a microsaccade analysis. Microsaccades only showed a weak relation with perceptual switches, but their direction was correlated with the perceived motion direction. Nevertheless, our data suggests an interaction between microsaccades and blinks by showing that microsaccades were differently modulated around blinks compared with blanks. This study shows that a reduction in eye movements precedes internal perceptual switches indicating that the rate of blinks can set the stage for a reinterpretation of sensory input. While a perceptual switch based on changed sensory input usually leads to an increase in blink rate, such an increase was only present after the perceptual switch to coherent motion but absent after the switch to component percept. This provides evidence of different underlying mechanism or internal consequence of the two perceptual switches and suggests that blinks can uncover differences in internal percept-related processes that are not evident from the percept itself.}, language = {en} } @phdthesis{Kalb2021, author = {Kalb, Jacqueline}, title = {The role of BRCA1 and DCP1A in the coordination of transcription and replication in neuroblastoma}, doi = {10.25972/OPUS-24871}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248711}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {The deregulation of the MYC oncoprotein family plays a major role in tumorigenesis and tumour maintenance of many human tumours. Because of their structure and nuclear localisation, they are defined as undruggable targets which makes it difficult to find direct therapeutic approaches. An alternative approach for targeting MYC-driven tumours is the identification and targeting of partner proteins which score as essential in a synthetic lethality screen. Neuroblastoma, an aggressive entity of MYCN-driven tumours coming along with a bad prognosis, are dependent on the tumour suppressor protein BRCA1 as synthetic lethal data showed. BRCA1 is recruited to promoter regions in a MYCN-dependent manner. The aim of this study was to characterise the role of BRCA1 in neuroblastoma with molecular biological methods. BRCA1 prevents the accumulation of RNA Polymerase II (RNAPII) at the promoter region. Its absence results in the formation of DNA/RNA-hybrids, so called R-loops, and DNA damage. To prevent the accumulation of RNAPII, the cell uses DCP1A, a decapping factor known for its cytoplasmatic and nuclear role in mRNA decay. It is the priming factor in the removal of the protective 5'CAP of mRNA, which leads to degradation by exonucleases. BRCA1 is necessary for the chromatin recruitment of DCP1A and its proximity to RNAPII. Cells showed upon acute activation of MYCN a higher dependency on DCP1A. Its activity prevents the deregulation of transcription and leads to proper coordination of transcription and replication. The deregulation of transcription in the absence of DCP1A results in replication fork stalling and leads to activation of the Ataxia telangiectasia and Rad3 related (ATR) kinase. The result is a disturbed cell proliferation to the point of increased apoptosis. The activation of the ATR kinase pathway in the situation where DCP1A is knocked down and MYCN is activated, makes those cells more vulnerable for the treatment with ATR inhibitors. In summary, the tumour suppressor protein BRCA1 and the decapping factor DCP1A, mainly known for its function in the cytoplasm, have a new nuclear role in a MYCN-dependent context. This study shows their essentiality in the coordination of transcription and replication which leads to an unrestrained growth of tumour cells if uncontrolled.}, subject = {Neuroblastom}, language = {en} } @phdthesis{RuedtvonCollenberg2021, author = {R{\"u}dt von Collenberg, Cora Freifrau}, title = {The role of Ciliary Neurotrophic Factor in hippocampal synaptic plasticity and learning}, doi = {10.25972/OPUS-20664}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206646}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Ciliary neurotrophic factor (Cntf) acts as a differentiation and survival factor for different types of neurons and glial cells. It is expressed by peripheral Schwann cells and astrocytes in the central nervous system and mediates its effects via a receptor complex involving CntfRα, LifRß and gp130, leading to downstream activation of Stat3. Recent studies by our group have shown that Cntf modulates neuronal microtubule dynamics via Stat3/stathmin interaction. In a mouse model for motor neuron disease, i.e. pmn, Cntf is able to rescue axonal degeneration through Stat3/stathmin signaling. While these findings suggest a role of Cntf in controlling axonal functions in the neuromuscular system, additional data indicate that Cntf might also play a role in synaptic plasticity in the hippocampus. Electrophysiological recordings in hippocampal organotypic cultures and acute slices revealed a deficit in long-term potentiation (LTP) in Cntf -/- mice. This deficit was rescued by 24 h stimulation with Cntf, combined with an acute application of Cntf during LTP-measurements indicating that Cntf is both necessary and sufficient for hippocampal LTP, and possibly synaptic plasticity. Therefore, Cntf knockout mice were investigated to elucidate this possible role of Cntf in hippocampal LTP and synaptic plasticity. First, we validated the presence of Cntf in the target tissue: in the hippocampus, Cntf was localized in Gfap-positive astrocytes surrounding small blood vessels in the fissure and in meningeal areas close to the dentate gyrus. Laser micro-dissection and qPCR analysis showed a similar distribution of Cntf-coding mRNA validating the obtained immunofluorescent results. Despite the strong LTP deficit in organotypic cultures, in vivo behavior of Cntf -/- mice regarding hippocampus-dependent learning and anxiety-related paradigms was largely inconspicuous. However, western blot analysis of hippocampal organotypic cultures revealed a significant reduction of pStat3 levels in Cntf -/- cultures under baseline conditions, which in turn were elevated upon Cntf stimulation. In order to resolve and examine synaptic structures we turned to in vitro analysis of cultured hippocampal neurons which indicated that pStat3 is predominantly located in the presynapse. In line with these findings, presynapses of Cntf -/- cultures were reduced in size and when in contact to astrocytes, contained less pStat3 immunoreactivity compared to presynapses in wildtype cultures. In conclusion, our findings hypothesize that despite of a largely inconspicuous behavioral phenotype of Cntf -/- mice, Cntf appears to have an influence on pStat3 levels at hippocampal synapses. In a next step these two key questions need to be addressed experimentally: 1) is there a compensatory mechanism by members of the Cntf family, possibly downstream of pStat3, which explains the in vivo behavioral results of Cntf -/- mice and can likewise account for the largely inconspicuous phenotype in CNTF-deficient humans? 2) How exactly does Cntf influence LTP through Stat3 signaling? To unravel the underlying mechanism further experiments should therefore investigate whether microtubule dynamics downstream of Stat3 and stathmin signaling are involved in the Cntf-induced modulation of hippocampal synaptic plasticity, similar to as it was shown in motoneurons.}, subject = {Hippocampus}, language = {en} } @phdthesis{Kumari2021, author = {Kumari, Khushbu}, title = {The role of lipid transfer proteins (LTPs) during the fertilization process in Arabidopsis thaliana}, doi = {10.25972/OPUS-19961}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-199613}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Double fertilization is a defining characteristic of flowering plants (angiosperms). As the sperm cells of higher plants are non-motile, they need to be transported to the female gametophyte via the growing pollen tube. The pollen-tube journey through the female tissues represents a highly complex process. To provide for successful reproduction it demands intricate communication between the cells of the two haploid gametophytes - the polar growing pollen tube (carrying the two non-motile sperm cells) and the ovule (hosting the egg cell/synergid cells). The polar growth of the pollen tube towards the female gamete is guided by different signaling molecules, including sugars, amino acids and peptides. Some of these belong to the family of lipid transfer proteins (LTPs), which are secreted cysteine-rich peptides. Depending on the plant species several lines of evidence have also suggested potential roles for LTPs during pollen germination or pollen-tube guidance. Although Arabidopsis thaliana has 49 annotated genes for LTPs, several of which are involved in plant immunity and cell-to-cell communication, the role of most members of this family during fertilization is unknown. The aim of this project was therefore to systematically identify LTPs which play a role in the fertilization process in A. thaliana, particularly during pollen tube guidance. To identify candidate proteins, the expression profile of LTPs in reproductive tissue was investigated. This was accomplished by in-silico bioinformatic analysis using different expression databases. Following confirmion of these results by qRT-PCR analysis, seven Type-I nsLTPs (LTP1, LTP2, LTP3, LTP4, LTP5, LTP6 and LTP12) were found to be exclusively expressed in pistils. Except for LTP12, all other pistil expressed LTPs were transcriptionally induced upon pollination. Using reporter-based transcriptional and translational fusions the temporal and spatial expression patterns together with protein localizations for LTP2, 3, 4, 5, 6, and 12 were determined in planta. Stable transgenic plants carrying PromLTP::GUS constructs of the six different LTP candidates showed that most of LTPs were expressed in the stigma/stylar region and were induced upon pollination. With respect to protein localization on the cellular level, they split into two categories: LTP2, LTP5 and LTP6 were localized in the cell wall, while LTP3, LTP4 and LTP12 were specifically targeted to the plasma membrane. For the functional characterization of the candidate LTPs, several T-DNA insertion mutant plant lines were investigated for phenotypes affecting the fertilization process. Pollen development and quality as well as their in-vitro germination rate did not differ between the different single ltp mutant lines and wildtype plants. Moreover, in-vivo cross pollination experiments revealed that tube growth and fertilization rate of the mutant plants were similar to wildtype plants. Altogether, no discernible phenotype was evident in other floral and vegetative parts between different single ltp mutant lines and wildtype plants. As there was no distinguishable phenotype observed for single ltp-ko plants, double knock out plants of the two highly homologous genes LTP2 (expressed in the female stigma, style and transmitting tract) and LTP5 (expressed in the stigma, style, pollen pollen-tube and transmitting tract) were generated using the EPCCRISPR-Cas9 genome editing technique. Two ltp2ltp5 mutant transgenic-lines (\#P31-P2 and \#P31-P3) with frameshift mutations in both the genes could be established. Further experiments showed, that the CRISPR/Cas9-mediated knock-out of LTP2/LTP5 resulted in significantly reduced fertilization success. Cell biological analyses revealed that the ltp2ltp5 double mutant was impaired in pollen tube guidance towards the ovules and that this phenotype correlated with aberrant callose depositions in the micropylar region during ovule development. Detailed analysis of in-vivo pollen-tube growth and reciprocal cross pollination assay suggested that, the severely compromised fertility was not caused by any defect in development of the pollen grains, but was due to the abnormal callose deposition in the embryo sac primarily concentrated at the synergid cell near the micropylar end. Aberrant callose deposition in ltp2ltp5 ovules pose a complete blockage for the growing pollen tube to change its polarity to enter the funiculus indicating funicular and micropylar defects in pollen tube guidance causing fertilization failure. Our finding suggests that female gametophyte expressed LTP2 and LTP5 play a crucial role in mediating pollen tube guidance process and ultimately having an effect on the fertilization success. In line with the existence of a N-terminal signal peptide, secreted LTPs might represent a well-suited mobile signal carrier in the plant's extracellular matrix. Previous reports suggested that, LTPs could act as chemoattractant peptide, imparting competence to the growing pollen tube, but the molecular mechanism is still obscure. The results obtained in this thesis further provide strong evidence, that LTP2/5 together regulate callose homeostasis and testable models are discussed. Future work is now required to elucidate the detailed molecular link between these LTPs and their potential interacting partners or receptors expressed in pollen and synergid cells, which should provide deeper insight into their functional role as regulatory molecules in the pollen tube guidance mechanism.}, subject = {Fertilization in angiosperm}, language = {en} } @phdthesis{Becker2021, author = {Becker, Isabelle Carlotta}, title = {The role of megakaryocytes and platelets in vascular and osteogenic development}, doi = {10.25972/OPUS-21024}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-210241}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Platelets, small anucleate cell fragments in the blood stream, derive from large precursor cells, so-called megakaryocytes (MK) residing in the bone marrow (BM). In addition to their role in wound healing, platelets have been shown to play a significant role during inflammatory bleeding. Above all, the immunoreceptor tyrosine-based activation motif (ITAM) receptors GPVI as well as CLEC-2 have been identified as main regulators of vascular integrity. In addition to ITAM-bearing receptors, our group identified GPV as another potent regulator of hemostasis and thrombosis. Surprisingly, concomitant lack of GPV and CLEC-2 deteriorated blood-lymphatic misconnections observed in Clec2-/- mice resulting in severe edema formation and intestinal inflammation. Analysis of lymphatic and vascular development in embryonic mesenteries revealed severely defective blood-lymph-vessel separation, which translated into thrombocytopenia and increased vascular permeability due to reduced tight junction density in mesenteric blood vessels and consequent leakage of blood into the peritoneal cavity. Recently, platelet granule release has been proposed to ameliorate the progression of retinopathy of prematurity (ROP), a fatal disease in newborns leading to retinal degradation. The mechanisms governing platelet activation in this process remained elusive nonetheless, which prompted us to investigate a possible role of ITAM signaling. In the second part of this thesis, granule release during ROP was shown to be GPVI- and partly CLEC-2-triggered since blockade or loss of these receptors markedly deteriorated ROP progression. Proplatelet formation from MKs is highly dependent on a functional microtubule and actin cytoskeleton, the latter of which is regulated by several actin-monomer binding proteins including Cofilin1 and Twinfilin1 that have been associated with actin-severing at pointed ends. In the present study, a redundancy between both proteins especially important for the guided release of proplatelets into the bloodstream was identified, since deficiency in both proteins markedly impaired MK functionality mainly due to altered actin-microtubule crosstalk. Besides ITAM-triggered activation, platelets and MKs are dependent on inhibitory receptors, which prevent overshooting activation. We here identified macrothrombocytopenic mice with a mutation within Mpig6b encoding the ITIM-bearing receptor G6b-B. G6b-B-mutant mice developed a severe myelofibrosis associated with sex-specific bone remodeling defects resulting in osteosclerosis and -porosis in female mice. Moreover, G6b-B was shown to be indispensable for MK maturation as verified by a significant reduction in MK-specific gene expression in G6b-B-mutant MKs due to reduced GATA-1 activity.}, subject = {Megakaryozyt}, language = {en} } @article{MeisterGarbeTrappeetal.2021, author = {Meister, Julia and Garbe, Philipp and Trappe, Julian and Ullmann, Tobias and Es-Senussi, Ashraf and Baumhauer, Roland and Lange-Athinodorou, Eva and El-Raouf, Amr Abd}, title = {The Sacred Waterscape of the Temple of Bastet at Ancient Bubastis, Nile Delta (Egypt)}, series = {Geosciences}, volume = {11}, journal = {Geosciences}, number = {9}, issn = {2076-3263}, doi = {10.3390/geosciences11090385}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246129}, year = {2021}, abstract = {Sacred water canals or lakes, which provided water for all kinds of purification rites and other activities, were very specific and important features of temples in ancient Egypt. In addition to the longer-known textual record, preliminary geoarchaeological surveys have recently provided evidence of a sacred canal at the Temple of Bastet at Bubastis. In order to further explore the location, shape, and course of this canal and to find evidence of the existence of a second waterway, also described by Herodotus, 34 drillings and five 2D geoelectrical measurements were carried out in 2019 and 2020 near the temple. The drillings and 2D ERT surveying revealed loamy to clayey deposits with a thickness of up to five meters, most likely deposited in a very low energy fluvial system (i.e., a canal), allowing the reconstruction of two separate sacred canals both north and south of the Temple of Bastet. In addition to the course of the canals, the width of about 30 m fits Herodotus' description of the sacred waterways. The presence of numerous artefacts proved the anthropogenic use of the ancient canals, which were presumably connected to the Nile via a tributary or canal located west or northwest of Bubastis.}, language = {en} } @article{ZimniakKirschnerHilpertetal.2021, author = {Zimniak, Melissa and Kirschner, Luisa and Hilpert, Helen and Geiger, Nina and Danov, Olga and Oberwinkler, Heike and Steinke, Maria and Sewald, Katherina and Seibel, J{\"u}rgen and Bodem, Jochen}, title = {The serotonin reuptake inhibitor Fluoxetine inhibits SARS-CoV-2 in human lung tissue}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, doi = {10.1038/s41598-021-85049-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259820}, pages = {5890}, year = {2021}, abstract = {To circumvent time-consuming clinical trials, testing whether existing drugs are effective inhibitors of SARS-CoV-2, has led to the discovery of Remdesivir. We decided to follow this path and screened approved medications "off-label" against SARS-CoV-2. Fluoxetine inhibited SARS-CoV-2 at a concentration of 0.8 mu g/ml significantly in these screenings, and the EC50 was determined with 387 ng/ml. Furthermore, Fluoxetine reduced viral infectivity in precision-cut human lung slices showing its activity in relevant human tissue targeted in severe infections. Fluoxetine treatment resulted in a decrease in viral protein expression. Fluoxetine is a racemate consisting of both stereoisomers, while the S-form is the dominant serotonin reuptake inhibitor. We found that both isomers show similar activity on the virus, indicating that the R-form might specifically be used for SARS-CoV-2 treatment. Fluoxetine inhibited neither Rabies virus, human respiratory syncytial virus replication nor the Human Herpesvirus 8 or Herpes simplex virus type 1 gene expression, indicating that it acts virus-specific. Moreover, since it is known that Fluoxetine inhibits cytokine release, we see the role of Fluoxetine in the treatment of SARS-CoV-2 infected patients of risk groups.}, language = {en} } @article{GeyerLanding2021, author = {Geyer, Gerd and Landing, Ed}, title = {The Souss lagerstatte of the Anti-Atlas, Morocco: discovery of the first Cambrian fossil lagerstatte from Africa}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-021-82546-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259236}, pages = {3107}, year = {2021}, abstract = {Episodic low oxygenated conditions on the sea-floor are likely responsible for exceptional preservation of animal remains in the upper Amouslek Formation (lower Cambrian, Stage 3) on the northern slope of the western Anti-Atlas, Morocco. This stratigraphic interval has yielded trilobite, brachiopod, and hyolith fossils with preserved soft parts, including some of the oldest known trilobite guts. The "Souss fossil lagerstatte" (newly proposed designation) represents the first Cambrian fossil lagerstatte in Cambrian strata known from Africa and is one of the oldest trilobite-bearing fossil lagerstatten on Earth. Inter-regional correlation of the Souss fossil lagerstatte in West Gondwana suggests its development during an interval of high eustatic levels recorded by dark shales that occur in informal upper Cambrian Series 2 in Siberia, South China, and East Gondwana.}, language = {en} } @article{Stawski2021, author = {Stawski, Theresa Paola}, title = {The state-regime-nexus: law and legal order}, series = {Zeitschrift f{\"u}r Vergleichende Politikwissenschaft}, volume = {15}, journal = {Zeitschrift f{\"u}r Vergleichende Politikwissenschaft}, number = {3}, issn = {1865-2654}, doi = {10.1007/s12286-021-00508-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270118}, pages = {357-373}, year = {2021}, abstract = {The aim of this paper is to illuminate the interdependent relation and connectivity between state and regime known as the state-regime-nexus. To conceptualize the reciprocal institutional relation between state and regime and to deepen the understanding of the state-regime-nexus, I focus on law and legal order as one mutual linkage between state and regime in both democratic and autocratic regimes. To do so, this conceptual paper addresses two points that are part of the same topic: the relation between state, regime and law and different variants of legal order in democratic and autocratic regimes. This creates a theoretical basis to gain more conceptual and analytical clarity in the complex realm of the state-regime-nexus.}, language = {en} } @phdthesis{Herrmann2021, author = {Herrmann, Marc}, title = {The Total Variation on Surfaces and of Surfaces}, doi = {10.25972/OPUS-24073}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240736}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {This thesis is concerned with applying the total variation (TV) regularizer to surfaces and different types of shape optimization problems. The resulting problems are challenging since they suffer from the non-differentiability of the TV-seminorm, but unlike most other priors it favors piecewise constant solutions, which results in piecewise flat geometries for shape optimization problems.The first part of this thesis deals with an analogue of the TV image reconstruction approach [Rudin, Osher, Fatemi (Physica D, 1992)] for images on smooth surfaces. A rigorous analytical framework is developed for this model and its Fenchel predual, which is a quadratic optimization problem with pointwise inequality constraints on the surface. A function space interior point method is proposed to solve it. Afterwards, a discrete variant (DTV) based on a nodal quadrature formula is defined for piecewise polynomial, globally discontinuous and continuous finite element functions on triangulated surface meshes. DTV has favorable properties, which include a convenient dual representation. Next, an analogue of the total variation prior for the normal vector field along the boundary of smooth shapes in 3D is introduced. Its analysis is based on a differential geometric setting in which the unit normal vector is viewed as an element of the two-dimensional sphere manifold. Shape calculus is used to characterize the relevant derivatives and an variant of the split Bregman method for manifold valued functions is proposed. This is followed by an extension of the total variation prior for the normal vector field for piecewise flat surfaces and the previous variant of split Bregman method is adapted. Numerical experiments confirm that the new prior favours polyhedral shapes.}, subject = {Gestaltoptimierung}, language = {en} } @article{HoeslFroehlichPoschetal.2021, author = {Hoesl, Christine and Fr{\"o}hlich, Thomas and Posch, Christian and Kneitz, Hermann and Goebeler, Matthias and Schneider, Marlon R. and Dahlhoff, Maik}, title = {The transmembrane protein LRIG1 triggers melanocytic tumor development following chemically induced skin carcinogenesis}, series = {Molecular Oncology}, volume = {15}, journal = {Molecular Oncology}, number = {8}, doi = {10.1002/1878-0261.12945}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-238925}, pages = {2140 -- 2155}, year = {2021}, abstract = {The incidence of melanoma and nonmelanoma skin cancer has increased tremendously in recent years. Although novel treatment options have significantly improved patient outcomes, the prognosis for most patients with an advanced disease remains dismal. It is, thus, imperative to understand the molecular mechanisms involved in skin carcinogenesis in order to develop new targeted treatment strategies. Receptor tyrosine kinases (RTK) like the ERBB receptor family, including EGFR/ERBB1, ERBB2/NEU, ERBB3, and ERBB4, are important regulators of skin homeostasis and their dysregulation often results in cancer, which makes them attractive therapeutic targets. Members of the leucine-rich repeats and immunoglobulin-like domains protein family (LRIG1-3) are ERBB regulators and thus potential therapeutic targets to manipulate ERBB receptors. Here, we analyzed the function of LRIG1 during chemically induced skin carcinogenesis in transgenic mice expressing LRIG1 in the skin under the control of the keratin 5 promoter (LRIG1-TG mice). We observed a significant induction of melanocytic tumor formation in LRIG1-TG mice and no difference in papilloma incidence between LRIG1-TG and control mice. Our findings also revealed that LRIG1 affects ERBB signaling via decreased phosphorylation of EGFR and increased activation of the oncoprotein ERBB2 during skin carcinogenesis. The epidermal proliferation rate was significantly decreased during epidermal tumorigenesis under LRIG1 overexpression, and the apoptosis marker cleaved caspase 3 was significantly activated in the epidermis of transgenic LRIG1 mice. Additionally, we detected LRIG1 expression in human cutaneous squamous cell carcinoma and melanoma samples. Therefore, we depleted LRIG1 in human melanoma cells (A375) by CRISPR/Cas9 technology and found that this caused EGFR and ERBB3 downregulation in A375 LRIG1 knockout cells 6 h following stimulation with EGF. In conclusion, our study demonstrated that LRIG1-TG mice develop melanocytic skin tumors during chemical skin carcinogenesis and a deletion of LRIG1 in human melanoma cells reduces EGFR and ERBB3 expression after EGF stimulation.}, language = {en} } @article{WienrichReitelbachCarolus2021, author = {Wienrich, Carolin and Reitelbach, Clemens and Carolus, Astrid}, title = {The Trustworthiness of Voice Assistants in the Context of Healthcare Investigating the Effect of Perceived Expertise on the Trustworthiness of Voice Assistants, Providers, Data Receivers, and Automatic Speech Recognition}, series = {Frontiers in Computer Science}, volume = {3}, journal = {Frontiers in Computer Science}, doi = {10.3389/fcomp.2021.685250}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260209}, year = {2021}, abstract = {As an emerging market for voice assistants (VA), the healthcare sector imposes increasing requirements on the users' trust in the technological system. To encourage patients to reveal sensitive data requires patients to trust in the technological counterpart. In an experimental laboratory study, participants were presented a VA, which was introduced as either a "specialist" or a "generalist" tool for sexual health. In both conditions, the VA asked the exact same health-related questions. Afterwards, participants assessed the trustworthiness of the tool and further source layers (provider, platform provider, automatic speech recognition in general, data receiver) and reported individual characteristics (disposition to trust and disclose sexual information). Results revealed that perceiving the VA as a specialist resulted in higher trustworthiness of the VA and of the provider, the platform provider and automatic speech recognition in general. Furthermore, the provider's trustworthiness affected the perceived trustworthiness of the VA. Presenting both a theoretical line of reasoning and empirical data, the study points out the importance of the users' perspective on the assistant. In sum, this paper argues for further analyses of trustworthiness in voice-based systems and its effects on the usage behavior as well as the impact on responsible design of future technology.}, language = {en} } @phdthesis{Blank2021, author = {Blank, Felix}, title = {The use of the Hypercube Queueing Model for the location optimization decision of Emergency Medical Service systems}, doi = {10.25972/OPUS-24909}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-249093}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Die strategische Planung von medizinischen Notfallsystemen steht in einem unmittelbaren Zusammenhang mit der {\"U}berlebenswahrscheinlichkeit von betroffenen Patienten. Die Forschung hat zahlreiche Kenngr{\"o}ßen und Evaluationsparameter entwickelt, die zur Bewertung verwendet werden k{\"o}nnen. Darunter fallen beispielsweise die Reaktionszeit, die Systemauslastung, diverse Wartezeitenparameter sowie der Anteil der Nachfrage, der nicht unmittelbar bedient werden kann. Dabei ist das Hypercube Queueing Modell eines der am h{\"a}ufigsten verwendeten Modelle. Aufgrund seines theoretischen Hintergrundes und der damit verbundenen hohen notwendigen Rechenzeiten wurde das Hypercube Queueing Modell erst in der j{\"u}ngeren Vergangenheit h{\"a}ufiger zur Optimierung von medizinischen Notfallsystemen verwendet. Gleichermaßen wurden nur wenige Systemparameter mit Hilfe des Modelles berechnet und das volle Potenzial demnach noch nicht ausgesch{\"o}pft. Die meisten der bereits vorhandenen Studien im Bereich der Optimierung unter Zuhilfenahme eines Hypercube Queueing Modells nutzen die zu erwartende Reaktionszeit des Systems als Zielparameter. Obwohl die Verwendung von diesem eine zumeist ausgeglichene Systemkonfiguration zur Folge hat, wurden andere Zielparameter identifziert. Die Verwendung des Hypercube Queueing Modells in den Modellen der robusten Optimierung sowie des robusten Goal Programmings haben versucht einen ganzheitlicheren Blick, durch die Verwendung von unterschiedlichen Tageszeiten, zu offerieren. Dabei hat sich gezeigt, dass das Verhalten von medizinischen Notfallsystemen sowie die Parameter stark von diesen abh{\"a}ngen. Daher sollte die Analyse und gegebenenfalls Optimierung dieser Systeme unterschiedliche Verteilungen der Nachfrage, in Abh{\"a}ngigkeit ihrer Menge und r{\"a}umlichen Verteilung, unbedingt ber{\"u}cksichtigen um eine m{\"o}glichst ganzheitliche Entscheidungsgrundlage zu garantieren.}, subject = {Warteschlangentheorie}, language = {en} } @article{TongsompornWananiyakulSteuding2021, author = {Tongsomporn, Janyarak and Wananiyakul, Saeree and Steuding, J{\"o}rn}, title = {The values of the periodic zeta-function at the nontrivial zeros of Riemann's zeta-function}, series = {Symmetry}, volume = {13}, journal = {Symmetry}, number = {12}, issn = {2073-8994}, doi = {10.3390/sym13122410}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252261}, year = {2021}, abstract = {In this paper, we prove an asymptotic formula for the sum of the values of the periodic zeta-function at the nontrivial zeros of the Riemann zeta-function (up to some height) which are symmetrical on the real line and the critical line. This is an extension of the previous results due to Garunkštis, Kalpokas, and, more recently, Sowa. Whereas Sowa's approach was assuming the yet unproved Riemann hypothesis, our result holds unconditionally.}, language = {en} } @phdthesis{Koeniger2021, author = {K{\"o}niger, Tobias}, title = {The Vessel Wall and Beyond: Characterization of Myeloid Progenitors in the Adult Mouse Brain}, doi = {10.25972/OPUS-18646}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186465}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {After almost two decades of extensive research, some controversy has remained regarding the self-renewal of resident macrophages of the central nervous system (CNS). Concurrently, the vessel wall has emerged as a potentially ubiquitous niche for stem and progenitor cells, including committed macrophage precursors. It is conceivable that their occurrence in the CNS might explain the brain-resident hematopoietic potential, which has repeatedly been observed but not yet characterized in detail. In this work, the presence of hematopoietic progenitors inside and outside the vessel wall was studied in the adult mouse brain, as well as their possible contribution to the resident macrophage pool. An immunohistological analysis did not corroborate CD45+ SCA-1+ macrophage progenitors, which have been characterized in peripheral arteries, in the circle of Willis. Accordingly, the ex vivo culture of CNS vessels did not provide evidence for de novo formation of macrophages, but for the extensive proliferative capacity of mature cells. However, when analyzing whole brain suspensions in colony-forming unit (CFU) assays, rare Iba1- Cx3cr1- (immature) clonogenic cells were detected, which were enriched at the cerebral surface/meninges and differentiated into macrophages in culture. Intravenous antibody injection and cell sorting confirmed their residence behind the blood-brain barrier. Intriguingly, brain-derived CFUs produced a unique pattern of colony types compared to cells from bone marrow (BM) or blood. Still they displayed the same immunophenotype as BM-resident myeloid progenitors (CD45lo, LIN-, SCA-1-, IL7Rα-, c-KIT+) and could be further stratified into a progenitor hierarchy giving rise to all erythro-myeloid cell types in vitro. This similarity was substantiated by labeling of their progeny in Flt3Cre x Rosa26mT/mG mice, which indicated a descendance from hematopoietic stem cells. While forced repopulation of brain macrophages using the CSF-1R inhibitor PLX5622 did not point to a role of progenitors in in vivo microglia/macrophage maintenance, recent advances in hematology imply that they might be involved in CNS immunosurveillance. In conclusion, though there was no evidence for adventitial macrophage precursors in the CNS, this study confirms the presence of myeloid progenitors in the adult brain and provides the anatomical and phenotypical details necessary to elucidate their relevance in neuroinflammation.}, subject = {Gehirn}, language = {en} } @article{MottolaRamirezZavalaHuenningeretal.2021, author = {Mottola, Austin and Ram{\´i}rez-Zavala, Bernardo and H{\"u}nninger, Kerstin and Kurzai, Oliver and Morschh{\"a}user, Joachim}, title = {The zinc cluster transcription factor Czf1 regulates cell wall architecture and integrity in Candida albicans}, series = {Molecular Microbiology}, volume = {116}, journal = {Molecular Microbiology}, number = {2}, doi = {10.1111/mmi.14727}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259583}, pages = {483-497}, year = {2021}, abstract = {The fungal cell wall is essential for the maintenance of cellular integrity and mediates interactions of the cells with the environment. It is a highly flexible organelle whose composition and organization is modulated in response to changing growth conditions. In the pathogenic yeast Candida albicans, a network of signaling pathways regulates the structure of the cell wall, and mutants with defects in these pathways are hypersensitive to cell wall stress. By harnessing a library of genetically activated forms of all C. albicans zinc cluster transcription factors, we found that a hyperactive Czf1 rescued the hypersensitivity to cell wall stress of different protein kinase deletion mutants. The hyperactive Czf1 induced the expression of many genes with cell wall-related functions and caused visible changes in the cell wall structure. C. albicans czf1Δ mutants were hypersensitive to the antifungal drug caspofungin, which inhibits cell wall biosynthesis. The changes in cell wall architecture caused by hyperactivity or absence of Czf1 resulted in an increased recognition of C. albicans by human neutrophils. Our results show that Czf1, which is known as a regulator of filamentous growth and white-opaque switching, controls the expression of cell wall genes and modulates the architecture of the cell wall.}, language = {en} } @phdthesis{Bartsch2021, author = {Bartsch, Jan}, title = {Theoretical and numerical investigation of optimal control problems governed by kinetic models}, doi = {10.25972/OPUS-24906}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-249066}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {This thesis is devoted to the numerical and theoretical analysis of ensemble optimal control problems governed by kinetic models. The formulation and study of these problems have been put forward in recent years by R.W. Brockett with the motivation that ensemble control may provide a more general and robust control framework for dynamical systems. Following this formulation, a Liouville (or continuity) equation with an unbounded drift function is considered together with a class of cost functionals that include tracking of ensembles of trajectories of dynamical systems and different control costs. Specifically, \$L^2\$, \$H^1\$ and \$L^1\$ control costs are taken into account which leads to non--smooth optimization problems. For the theoretical investigation of the resulting optimal control problems, a well--posedness theory in weighted Sobolev spaces is presented for Liouville and related transport equations. Specifically, existence and uniqueness results for these equations and energy estimates in suitable norms are provided; in particular norms in weighted Sobolev spaces. Then, non--smooth optimal control problems governed by the Liouville equation are formulated with a control mechanism in the drift function. Further, box--constraints on the control are imposed. The control--to--state map is introduced, that associates to any control the unique solution of the corresponding Liouville equation. Important properties of this map are investigated, specifically, that it is well--defined, continuous and Frechet differentiable. Using the first two properties, the existence of solutions to the optimal control problems is shown. While proving the differentiability, a loss of regularity is encountered, that is natural to hyperbolic equations. This leads to the need of the investigation of the control--to--state map in the topology of weighted Sobolev spaces. Exploiting the Frechet differentiability, it is possible to characterize solutions to the optimal control problem as solutions to an optimality system. This system consists of the Liouville equation, its optimization adjoint in the form of a transport equation, and a gradient inequality. Numerical methodologies for solving Liouville and transport equations are presented that are based on a non--smooth Lagrange optimization framework. For this purpose, approximation and solution schemes for such equations are developed and analyzed. For the approximation of the Liouville model and its optimization adjoint, a combination of a Kurganov--Tadmor method, a Runge--Kutta scheme, and a Strang splitting method are discussed. Stability and second--order accuracy of these resulting schemes are proven in the discrete \$L^1\$ norm. In addition, conservation of mass and positivity preservation are confirmed for the solution method of the Liouville model. As numerical optimization strategy, an adapted Krylow--Newton method is applied. Since the control is considered to be an element of \$H^1\$ and to obey certain box--constraints, a method for calculating a \$H^1\$ projection is presented. Since the optimal control problem is non-smooth, a semi-smooth adaption of Newton's method is taken into account. Results of numerical experiments are presented that successfully validate the proposed deterministic framework. After the discussion of deterministic schemes, the linear space--homogeneous Keilson--Storer master equation is investigated. This equation was originally developed for the modelling of Brownian motion of particles immersed in a fluid and is a representative model of the class of linear Boltzmann equations. The well--posedness of the Keilson--Storer master equation is investigated and energy estimates in different topologies are derived. To solve this equation numerically, Monte Carlo methods are considered. Such methods take advantage of the kinetic formulation of the Liouville equation and directly implement the behaviour of the system of particles under consideration. This includes the probabilistic behaviour of the collisions between particles. Optimal control problems are formulated with an objective that is constituted of certain expected values in velocity space and the \$L^2\$ and \$H^1\$ costs of the control. The problems are governed by the Keilson--Storer master equation and the control mechanism is considered to be within the collision kernel. The objective of the optimal control of this model is to drive an ensemble of particles to acquire a desired mean velocity and to achieve a desired final velocity configuration. Existence of solutions of the optimal control problem is proven and a Keilson--Storer optimality system characterizing the solution of the proposed optimal control problem is obtained. The optimality system is used to construct a gradient--based optimization strategy in the framework of Monte--Carlo methods. This task requires to accommodate the resulting adjoint Keilson--Storer model in a form that is consistent with the kinetic formulation. For this reason, we derive an adjoint Keilson--Storer collision kernel and an additional source term. A similar approach is presented in the case of a linear space--inhomogeneous kinetic model with external forces and with Keilson--Storer collision term. In this framework, a control mechanism in the form of an external space--dependent force is investigated. The purpose of this control is to steer the multi--particle system to follow a desired mean velocity and position and to reach a desired final configuration in phase space. An optimal control problem using the formulation of ensemble controls is stated with an objective that is constituted of expected values in phase space and \$H^1\$ costs of the control. For solving the optimal control problems, a gradient--based computational strategy in the framework of Monte Carlo methods is developed. Part of this is the denoising of the distribution functions calculated by Monte Carlo algorithms using methods of the realm of partial differential equations. A standalone C++ code is presented that implements the developed non--linear conjugated gradient strategy. Results of numerical experiments confirm the ability of the designed probabilistic control framework to operate as desired. An outlook section about optimal control problems governed by non--linear space--inhomogeneous kinetic models completes this thesis.}, subject = {Optimale Kontrolle}, language = {en} } @phdthesis{Suess2021, author = {S{\"u}ß, Jasmin}, title = {Theoretische Untersuchungen an molekularen Aggregaten: 2D-Spektroskopie und Exzitonendynamik}, doi = {10.25972/OPUS-24713}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-247136}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Diese Dissertation besch{\"a}ftigt sich mit der Exzitonendynamik molekularer Aggregate, die nach Mehrphotonen-Anregung auf ultrakurzer Zeitskala stattfindet. Hierbei liegt der Fokus auf der Charakterisierung der Exziton-Exziton-Annihilierung (EEA) mithilfe von zweidimensionaler optischer Spektroskopie f{\"u}nfter Ordnung. Dazu werden zwei verschiedene Modellsysteme implementiert: Das elektronische Homodimer und das elektronische Homotrimer-Modell, wobei Letzteres eine Erweiterung des Dimer-Modells darstellt. Die Kopplung des quantenmechanischen Systems an die Umgebung wird mithilfe des Quantum-Jump-Ansatzes umgesetzt. Besonderes Interesse kommt der Analyse des Signals f{\"u}nfter Ordnung in Abh{\"a}ngigkeit der Populationszeit T zu. Anhand des Dimer-Modells als kleinstm{\"o}gliches Aggregat lassen sich bereits gute Vorhersagen auch {\"u}ber das Verhalten gr{\"o}ßerer molekularer Aggregate treffen. Der Zerfall des oszillierenden Signals f{\"u}r lange Populationszeiten korreliert mit der EEA. Dies zeigt, dass die zweidimensionale optische Spektroskopie genutzt werden kann, um den Annihilierungsprozess zu charakterisieren. Innerhalb des Modells des Dimers wird weiterhin der Einfluss der Intraband-Relaxation untersucht. Zunehmende Intraband-Relaxation verhindert den Austausch zwischen den lokalen Zust{\"a}nden, der essentiell f{\"u}r den Annihilierungsprozess ist, und die EEA wird blockiert. Das elektronische Trimer-Modell erweitert das Dimer-Modell um eine Monomereinheit. Somit befinden sich die Exzitonen im Anschluss an die Anregung nicht mehr unvermeidlich nebeneinander. Es gibt somit eine Konfiguration, bei der sich die Exzitonen zun{\"a}chst zueinander bewegen m{\"u}ssen, bevor die Startbedingung des Annihilierungsprozesses gegeben ist. Dieser zus{\"a}tzliche Schritt wird auch Exzitonendiffusion genannt. Die Ergebnisse dieser Arbeit legen nahe, dass das erwartete Verhalten nur zu sehr kurzen Zeiten im Femtosekundenbereich auftritt und somit die Zeitskala der Exzitonendiffusion im Falle des Trimers nicht sichtbar wird. Es bedarf demnach eines gr{\"o}ßeren Modellsystems, bei dem sich der Effekt der zeitverz{\"o}gert eintretenden EEA deutlich in der Zerfallsdynamik manifestieren kann.}, subject = {Molekulardynamik}, language = {de} } @article{WernerHiguchiPomperetal.2021, author = {Werner, Rudolf A. and Higuchi, Takahiro and Pomper, Martin G. and Rowe, Steven P.}, title = {Theranostics in oncology — thriving, now more than ever}, series = {Diagnostics}, volume = {11}, journal = {Diagnostics}, number = {5}, issn = {2075-4418}, doi = {10.3390/diagnostics11050805}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236662}, year = {2021}, abstract = {Tracing its roots back to the 1940s, theranostics in nuclear oncology has proved successful mainly due to the beneficial effects of image-guided therapeutic concepts for patients afflicted with a variety of different cancers. The majority of these treatments are not only characterized by substantial prolongation of progression-free and overall survival, but are also generally safe, rendering theranostic agents as an attractive treatment option in various clinical scenarios in oncology. In this Special Issue Novel Theranostic Agents, nine original articles from around the globe provide further evidence on the use of the theranostic concept for neuroendocrine neoplasm (NEN), prostate cancer (PC), meningioma, and neuroblastoma. The investigated diagnostic and therapeutic radiotracers target not only established structures, such as somatostatin receptor, prostate-specific membrane antigen or norepinephrine transporter, but also recently emerging targets such as the C-X-C motif chemokine receptor 4. Moreover, the presented original articles also combine the concept of theranostics with in-depth read-out techniques such as radiomics or novel reconstruction algorithms on pretherapeutic scans, e.g., for outcome prediction. Even 80 years after its initial clinical introduction, theranostics in oncology continues to thrive, now more than ever.}, language = {en} } @article{StetterWeidnerLillaetal.2021, author = {Stetter, Christian and Weidner, Franziska and Lilla, Nadine and Weiland, Judith and Kunze, Ekkehard and Ernestus, Ralf-Ingo and Muellenbach, Ralf Michael and Westermaier, Thomas}, title = {Therapeutic hypercapnia for prevention of secondary ischemia after severe subarachnoid hemorrhage: physiological responses to continuous hypercapnia}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-021-91007-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260779}, pages = {11715}, year = {2021}, abstract = {Temporary hypercapnia has been shown to increase cerebral blood flow (CBF) and might be used as a therapeutical tool in patients with severe subarachnoid hemorrhage (SAH). It was the aim of this study was to investigate the optimum duration of hypercapnia. This point is assumed to be the time at which buffer systems become active, cause an adaptation to changes of the arterial partial pressure of carbon dioxide (PaCO2) and annihilate a possible therapeutic effect. In this prospective interventional study in a neurosurgical ICU the arterial partial pressure of carbon dioxide (PaCO\(_2\)) was increased to a target range of 55 mmHg for 120 min by modification of the respiratory minute volume (RMV) one time a day between day 4 and 14 in 12 mechanically ventilated poor-grade SAH-patients. Arterial blood gases were measured every 15 min. CBF and brain tissue oxygen saturation (StiO\(_2\)) were the primary and secondary end points. Intracranial pressure (ICP) was controlled by an external ventricular drainage. Under continuous hypercapnia (PaCO\(_2\) of 53.17 ± 5.07), CBF was significantly elevated between 15 and 120 min after the start of hypercapnia. During the course of the trial intervention, cardiac output also increased significantly. To assess the direct effect of hypercapnia on brain perfusion, the increase of CBF was corrected by the parallel increase of cardiac output. The maximum direct CBF enhancing effect of hypercapnia of 32\% was noted at 45 min after the start of hypercapnia. Thereafter, the CBF enhancing slowly declined. No relevant adverse effects were observed. CBF and StiO\(_2\) reproducibly increased by controlled hypercapnia in all patients. After 45 min, the curve of CBF enhancement showed an inflection point when corrected by cardiac output. It is concluded that 45 min might be the optimum duration for a therapeutic use and may provide an optimal balance between the benefits of hypercapnia and risks of a negative rebound effect after return to normal ventilation parameters.}, language = {en} } @phdthesis{Weidner2021, author = {Weidner, Franziska}, title = {Therapeutische Hyperkapnie bei aneurysmatischer Subarachnoidalblutung (SAB) : Evaluation der optimalen Hyperkapniedauer}, doi = {10.25972/OPUS-23869}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-238696}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {In einer vorangegangenen Phase-1-Studie wurde beobachtet, dass bei Patienten mit schwerer aneurysmatischer SAB, die CBF durch intermittierende kontrollierte Hyperkapnie erh{\"o}ht werden kann. Zudem zeigte sich in dieser vorherigen Studie nach dem Zur{\"u}cksetzen der mechanischen Beatmung auf die Ausgangsparameter eine langsame und asymptotische R{\"u}ckkehr der CBF zu den Ausgangsniveaus ohne einen negativen Rebound-Effekt. Diese Beobachtung legte nahe, dass eine l{\"a}ngere Dauer der Hyperkapnie den CBF-erh{\"o}henden Effekt verl{\"a}ngern kann. Die vorliegende Studie wurde als Dosisoptimierungsstudie geplant, um den Zeitpunkt zu bestimmen, zu dem der CBF ein Maximum erreicht, und unter der Annahme, dass nach diesem Maximum Puffermechanismen in Blut und Liquor zu Anpassungsmechanismen f{\"u}hren k{\"o}nnen, die nach dem Abbruch zu einem negativen Rebound-Effekt f{\"u}hren. Es ergab sich eine "Netto" - Optimaldauer der Hyperkapnieintervention von 45 Minuten.}, subject = {Hyperkapnie}, language = {de} } @article{NowotnyAhmedBensingetal.2021, author = {Nowotny, Hanna and Ahmed, S. Faisal and Bensing, Sophie and Beun, Johan G. and Br{\"o}samle, Manuela and Chifu, Irina and Claahsen van der Grinten, Hedi and Clemente, Maria and Falhammar, Henrik and Hahner, Stefanie and Husebye, Eystein and Kristensen, Jette and Loli, Paola and Lajic, Svetlana and Reisch, Nicole}, title = {Therapy options for adrenal insufficiency and recommendations for the management of adrenal crisis}, series = {Endocrine}, volume = {71}, journal = {Endocrine}, number = {3}, organization = {Endo ERN (MTG1)}, issn = {1355-008X}, doi = {10.1007/s12020-021-02649-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308769}, pages = {586-594}, year = {2021}, abstract = {Adrenal insufficiency (AI) is a life-threatening condition requiring life-long glucocorticoid (GC) substitution therapy, as well as stress adaptation to prevent adrenal crises. The number of individuals with primary and secondary adrenal insufficiency in Europe is estimated to be 20-50/100.000. A growing number of AI cases are due to side effects of GC treatment used in different treatment strategies for cancer and to immunotherapy in cancer treatment. The benefit of hormone replacement therapy is evident but long-term adverse effects may arise due to the non-physiological GC doses and treatment regimens used. Given multiple GC replacement formulations available comprising short-acting, intermediate, long-acting and novel modified-release hydrocortisone as well as subcutaneous formulations, this review offers a concise summary on the latest therapeutic improvements for treatment of AI and prevention of adrenal crises. As availability of various glucocorticoid formulations and access to expert centers across Europe varies widely, European Reference Networks on rare endocrine conditions aim at harmonizing treatment and ensure access to specialized patient care for individual case-by-case treatment decisions. To improve the availability across Europe to cost effective oral and parenteral formulations of hydrocortisone will save lives.}, language = {en} } @article{GromerKiserPauli2021, author = {Gromer, Daniel and Kiser, Dominik P. and Pauli, Paul}, title = {Thigmotaxis in a virtual human open field test}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, doi = {10.1038/s41598-021-85678-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259850}, pages = {6670}, year = {2021}, abstract = {Animal models are used to study neurobiological mechanisms in mental disorders. Although there has been significant progress in the understanding of neurobiological underpinnings of threat-related behaviors and anxiety, little progress was made with regard to new or improved treatments for mental disorders. A possible reason for this lack of success is the unknown predictive and cross-species translational validity of animal models used in preclinical studies. Re-translational approaches, therefore, seek to establish cross-species translational validity by identifying behavioral operations shared across species. To this end, we implemented a human open field test in virtual reality and measured behavioral indices derived from animal studies in three experiments (N=31, N=30, and N=80). In addition, we investigated the associations between anxious traits and such behaviors. Results indicated a strong similarity in behavior across species, i.e., participants in our study-like rodents in animal studies-preferred to stay in the outer region of the open field, as indexed by multiple behavioral parameters. However, correlational analyses did not clearly indicate that these behaviors were a function of anxious traits of participants. We conclude that the realized virtual open field test is able to elicit thigmotaxis and thus demonstrates cross-species validity of this aspect of the test. Modulatory effects of anxiety on human open field behavior should be examined further by incorporating possible threats in the virtual scenario and/or by examining participants with higher anxiety levels or anxiety disorder patients.}, language = {en} } @article{BuergerVloetHaberetal.2021, author = {Buerger, Arne and Vloet, Timo D. and Haber, Lisa and Geissler, Julia M.}, title = {Third-wave interventions for eating disorders in adolescence - systematic review with meta-analysis}, series = {Borderline Personality Disorder and Emotion Dysregulation}, volume = {8}, journal = {Borderline Personality Disorder and Emotion Dysregulation}, doi = {10.1186/s40479-021-00158-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260545}, year = {2021}, abstract = {Context: Third-wave therapies have demonstrated efficacy as a treatment option for EDs in adulthood. Data on the suitability for EDs in adolescence are lacking. Objective: To estimate the efficacy of third-wave interventions to reduce ED symptoms in adolescents in randomized controlled trials (RCTs) and uncontrolled studies. Data sources: We systematically reviewed the databases PubMed (1976-January 2021), PsycINFO (1943-January 2021), and the Cochrane database (1995-January 2021) for English-language articles on third-wave therapies. References were screened for further publications of interest. Study selection: RCTs and pre-post studies without control group, comprising patients aged 11-21 years (mean age = 15.6 years) with an ED diagnosis (anorexia nervosa, bulimia nervosa, binge eating disorder, eating disorder not otherwise specified) investigating the efficacy of third-wave psychological interventions were included. Efficacy had to be evaluated according to the Eating Disorder Examination or Eating Disorder Examination-Questionnaire, the Eating Disorder Inventory-2, the Eating Disorder Inventory-3, or the Structured Interview for Anorexic and Bulimic Disorders for DSM-IV and ICD-10. The outcome assessed in the meta-analysis was the EDE total score. Data extraction: Independent extraction of data by two authors according to a pre-specified data extraction sheet and quality indicators. Data synthesis: We identified 1000 studies after removal of duplicates, assessed the full texts of 48 articles for eligibility, and included 12 studies with a total of 487 participants (female 97.3\%/male 2.6\%) in the qualitative synthesis and seven studies in the meta-analysis. Articles predominantly reported uncontrolled pre-post trials of low quality, with only two published RCTs. Treatments focused strongly on dialectical behaviour therapy (n = 11). We found moderate effects of third-wave therapies on EDE total score interview/questionnaire for all EDs (d = - 0.67; z = - 5.53; CI95\% = - 0.83 to - 0.59). Descriptively, the effects appeared to be stronger in patients with BN and BED. Conclusion: At this stage, it is not feasible to draw conclusions regarding the efficacy of third-wave interventions for the treatment of EDs in adolescence due to the low quality of the empirical evidence. Since almost all of the identified studies used DBT, it is unfortunately not possible to assess other third-wave treatments' efficacy.}, language = {en} } @article{Solymosi2021, author = {Solymosi, L{\´a}szl{\´o}}, title = {Three Decades of Success for Clinical Neuroradiology}, series = {Clinical Neuroradiology}, volume = {31}, journal = {Clinical Neuroradiology}, number = {3}, doi = {10.1007/s00062-021-01090-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-264772}, pages = {543-544}, year = {2021}, abstract = {No abstract available.}, language = {en} } @phdthesis{Lauton2021, author = {Lauton, Felix}, title = {Three Essays on the Procurement of Essential Medicines in Developing Countries}, doi = {10.25972/OPUS-22063}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220631}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {The first problem is that of the optimal volume allocation in procurement. The choice of this problem was motivated by a study whose objective was to support decision-making at two procurement organizations for the procurement of Depot Medroxyprogesterone Acetate (DMPA), an injectable contraceptive. At the time of this study, only one supplier that had undergone the costly and lengthy process of WHO pre-qualification was available to these organizations. However, a new entrant supplier was expected to receive WHO qualification within the next year, thus becoming a viable second source for DMPA procurement. When deciding how to allocate the procurement volume between the two suppliers, the buyers had to consider the impact on price as well as risk. Higher allocations to one supplier yield lower prices but expose a buyer to higher supply risks, while an even allocation will result in lower supply risk but also reduce competitive pressure, resulting in higher prices. Our research investigates this single- versus dual-sourcing problem and quantifies in one model the impact of the procurement volume on competition and risk. To support decision-makers, we develop a mathematical framework that accounts for the characteristics of donor-funded global health markets and models the effects of an entrant on purchasing costs and supply risks. Our in-depth analysis provides insights into how the optimal allocation decision is affected by various parameters and explores the trade-off between competition and supply risk. For example, we find that, even if the entrant supplier introduces longer leads times and a higher default risk, the buyer still benefits from dual sourcing. However, these risk-diversification benefits depend heavily on the entrant's in-country registration: If the buyer can ship the entrant's product to only a selected number of countries, the buyer does not benefit from dual sourcing as much as it would if entrant's product could be shipped to all supplied countries. We show that the buyer should be interested in qualifying the entrant's product in countries with high demand first. In the second problem we explore a new tendering mechanism called the postponement tender, which can be useful when buyers in the global health industry want to contract new generics suppliers with uncertain product quality. The mechanism allows a buyer to postpone part of the procurement volume's allocation so the buyer can learn about the unknown quality before allocating the remaining volume to the best supplier in terms of both price and quality. We develop a mathematical model to capture the decision-maker's trade-offs in setting the right split between the initial volume and the postponed volume. Our analysis shows that a buyer can benefit from this mechanism more than it can from a single-sourcing format, as it can decrease the risk of receiving poor quality (in terms of product quality and logistics performance) and even increase competitive pressure between the suppliers, thereby lowering the purchasing costs. By considering market parameters like the buyer's size, the suppliers' value (difference between quality and cost), quality uncertainty, and minimum order volumes, we derive optimal sourcing strategies for various market structures and explore how competition is affected by the buyer's learning about the suppliers' quality through the initial volume. The third problem considers the repeated procurement problem of pharmacies in Kenya that have multi-product inventories. Coordinating orders allows pharmacies to achieve lower procurement prices by using the quantity discounts manufacturers offer and sharing fixed ordering costs, such as logistics costs. However, coordinating and optimizing orders for multiple products is complex and costly. To solve the coordinated procurement problem, also known as the Joint Replenishment Problem (JRP) with quantity discounts, a novel, data-driven inventory policy using sample-average approximation is proposed. The inventory policy is developed based on renewal theory and is evaluated using real-world sales data from Kenyan pharmacies. Multiple benchmarks are used to evaluate the performance of the approach. First, it is compared to the theoretically optimal policy --- that is, a dynamic-programming policy --- in the single-product setting without quantity discounts to show that the proposed policy results in comparable inventory costs. Second, the policy is evaluated for the original multi-product setting with quantity discounts and compared to ex-post optimal costs. The evaluation shows that the policy's performance in the multi-product setting is similar to its performance in the single-product setting (with respect to ex-post optimal costs), suggesting that the proposed policy offers a promising, data-driven solution to these types of multi-product inventory problems.}, subject = {Entwicklungsl{\"a}nder}, language = {en} } @article{DorjiSchuldtNeudametal.2021, author = {Dorji, Yonten and Schuldt, Bernhard and Neudam, Liane and Dorji, Rinzin and Middleby, Kali and Isasa, Emilie and K{\"o}rber, Klaus and Ammer, Christian and Annigh{\"o}fer, Peter and Seidel, Dominik}, title = {Three-dimensional quantification of tree architecture from mobile laser scanning and geometry analysis}, series = {Trees}, volume = {35}, journal = {Trees}, number = {4}, issn = {0931-1890}, doi = {10.1007/s00468-021-02124-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307501}, pages = {1385-1398}, year = {2021}, abstract = {Key message Mobile laser scanning and geometrical analysis revealed relationships between tree geometry and seed dispersal mechanism, latitude of origin, as well as growth. Abstract The structure and dynamics of a forest are defined by the architecture and growth patterns of its individual trees. In turn, tree architecture and growth result from the interplay between the genetic building plans and environmental factors. We set out to investigate whether (1) latitudinal adaptations of the crown shape occur due to characteristic solar elevation angles at a species' origin, (2) architectural differences in trees are related to seed dispersal strategies, and (3) tree architecture relates to tree growth performance. We used mobile laser scanning (MLS) to scan 473 trees and generated three-dimensional data of each tree. Tree architectural complexity was then characterized by fractal analysis using the box-dimension approach along with a topological measure of the top heaviness of a tree. The tree species studied originated from various latitudinal ranges, but were grown in the same environmental settings in the arboretum. We found that trees originating from higher latitudes had significantly less top-heavy geometries than those from lower latitudes. Therefore, to a certain degree, the crown shape of tree species seems to be determined by their original habitat. We also found that tree species with wind-dispersed seeds had a higher structural complexity than those with animal-dispersed seeds (p < 0.001). Furthermore, tree architectural complexity was positively related to the growth performance of the trees (p < 0.001). We conclude that the use of 3D data from MLS in combination with geometrical analysis, including fractal analysis, is a promising tool to investigate tree architecture.}, language = {en} } @article{KunzKneisel2021, author = {Kunz, Julius and Kneisel, Christof}, title = {Three-dimensional investigation of an open- and a closed-system Pingo in northwestern Canada}, series = {Permafrost and Periglacial Processes}, volume = {32}, journal = {Permafrost and Periglacial Processes}, number = {4}, doi = {10.1002/ppp.2115}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-257678}, pages = {541-557}, year = {2021}, abstract = {The present study presents three-dimensional investigations of a hydrostatic pingo in the Mackenzie Delta region and a hydraulic pingo in the Ogilvie Mountains and contributes to a better understanding about the internal structures of the two pingo types. A combined approach using quasi-three-dimensional electrical resistivity tomography, ground-penetrating radar and frost probing allowed a clear delineation of frozen and unfrozen areas in the subsurface. At the hydrostatic pingo a massive ice core as well as a surrounding talik could be detected, but the location of the ice core and the talik differs from previous published assumptions. In contrast to acknowledged theory, at our site the massive ice core is not located in the center of the pingo but at the western edge, whereas the eastern flank is underlain by a talik, which surrounds the massive ice core. At the hydraulic pingo, the expected internal structure could be confirmed and the pathway of upwelling water could also be detected. The combined approach of the applied methods represents the first known three-dimensional geoelectrical investigation of pingos and provides new insights into the internal structure and architecture of the two different pingo types. The chosen approach allows further conclusions on the formation of these permafrost-affected landforms.}, language = {en} } @article{PorubskyPopovicBadveetal.2021, author = {Porubsky, Stefan and Popovic, Zoran V. and Badve, Sunil and Banz, Yara and Berezowska, Sabina and Borchert, Dietmar and Br{\"u}ggemann, Monika and Gaiser, Timo and Graeter, Thomas and Hollaus, Peter and Huettl, Katrin S. and Kotrova, Michaela and Kreft, Andreas and Kugler, Christian and L{\"o}tscher, Fabian and M{\"o}ller, Burkhard and Ott, German and Preissler, Gerhard and Roessner, Eric and Rosenwald, Andreas and Str{\"o}bel, Philipp and Marx, Alexander}, title = {Thymic hyperplasia with lymphoepithelial sialadenitis (LESA)-like features: strong association with lymphomas and non-myasthenic autoimmune diseases}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {2}, issn = {2072-6694}, doi = {10.3390/cancers13020315}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223049}, year = {2021}, abstract = {Thymic hyperplasia (TH) with lymphoepithelial sialadenitis (LESA)-like features (LESA-like TH) has been described as a tumor-like, benign proliferation of thymic epithelial cells and lymphoid follicles. We aimed to determine the frequency of lymphoma and autoimmunity in LESA-like TH and performed retrospective analysis of cases with LESA-like TH and/or thymic MALT-lymphoma. Among 36 patients (21 males) with LESA-like TH (age 52 years, 32-80; lesion diameter 7.0 cm, 1-14.5; median, range), five (14\%) showed associated lymphomas, including four (11\%) thymic MALT lymphomas and one (3\%) diffuse large B-cell lymphoma. One additional case showed a clonal B-cell-receptor rearrangement without evidence of lymphoma. Twelve (33\%) patients (7 women) suffered from partially overlapping autoimmune diseases: systemic lupus erythematosus (n = 4, 11\%), rheumatoid arthritis (n = 3, 8\%), myasthenia gravis (n = 2, 6\%), asthma (n = 2, 6\%), scleroderma, Sj{\"o}gren syndrome, pure red cell aplasia, Grave's disease and anti-IgLON5 syndrome (each n = 1, 3\%). Among 11 primary thymic MALT lymphomas, remnants of LESA-like TH were found in two cases (18\%). In summary, LESA-like TH shows a striking association with autoimmunity and predisposes to lymphomas. Thus, a hematologic and rheumatologic workup should become standard in patients diagnosed with LESA-like TH. Radiologists and clinicians should be aware of LESA-like TH as a differential diagnosis for mediastinal mass lesions in patients with autoimmune diseases.}, language = {en} } @phdthesis{Ruecker2021, author = {R{\"u}cker, Viktoria}, title = {Time trends and determinants of stroke mortality in Germany}, doi = {10.25972/OPUS-23311}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233116}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {In several countries, a decline in mortality, case-fatality and recurrence rates of stroke was observed. However, studies investigating sex-specific and subtype-specific (pathological and etiological) time trends in stroke mortality, case-fatality and recurrence rates are scarce, especially in Germany. The decline in ischemic stroke mortality and case-fatality might be associated with the high quality of acute care of ischemic stroke, but the exact determinants of early outcome remains unknown for Germany. Therefore, as first step of this thesis, we investigated the time trends of subtype- and sex-specific age- standardized stroke mortality rates in Germany from 1998 to 2015, by applying joinpoint regression on official causes of death statistics, provided by the Federal Statistical Office. Furthermore, a regional comparison of the time trends in stroke mortality between East and West was conducted. In the second step, time trends in case-fatality and stroke recurrence rates were analyzed using data from a population- based stroke register in Germany between 1996 and 2015. The analysis was stratified by sex and etiological subtype of ischemic stroke. In the third step, quality of stroke care and the association between adherence to measures of quality of acute ischemic stroke care and in-hospital mortality was estimated based on data from nine regional hospital-based stroke registers in Germany from the years 2015 and 2016. We showed that in Germany, age-standardized stroke mortality declined by over 50\% from 1998 to 2015 both, in women and men. Stratified by the pathological subtypes of stroke, the decrease in mortality was larger in ischemic stroke compared to hemorrhagic stroke. Different patterns in the time trends of stroke were observed for stroke subtypes, regions in Germany (former Eastern part of Germany (EG), former Western part of Germany (WG)) and sex, but in all strata a decline was found. By applying joinpoint regression, the number of changes in time trend differed between the regions and up to three changes in the trend in ischemic stroke mortality were detected. Trends in hemorrhagic stroke were in parallel between the regions with up to one change (in women) in joinpoint regression. Comparing the regions, stroke mortality was higher in EG compared to WG throughout the whole observed time period, however the differences between the regions started to diminish from 2007 onwards. Further it was found that, based on the population-based Erlangen Stroke Project (ESPro), case-fatality and recurrence rates in ischemic stroke patients are still high in Germany. 46\% died and 20\% got a recurrent stroke within the first five years after stroke. Case-fatality rates declined statistically significant from 1996 to 2015 across all ischemic stroke patients and all etiological subtypes of ischemic stroke. Based on Cox regression no statistically significant decrease in stroke recurrence was observed. Based on the pooled data of nine regional hospital-based stroke registers from the years 2015 and 2016 covering about 80\% of all hospitalized stroke patients in Germany, a high quality of care of acute ischemic stroke patients, measured via 11 evidence-based quality indicators (QI) of process of care, was observed. Across all registers, most QI reached the predefined target values for good quality of stroke care. 9 out of 11 QI showed a significant association with 7-day in-hospital mortality. An inverse linear association between overall adherence to QI and 7-day in-hospital mortality was observed. In conclusion, stroke mortality and case-fatality showed a favorable development over time in Germany, which might partly be due to improvements in acute treatment. This is supported by the association between overall adherence to quality of care and in-hospital mortality. However, there might be room for improvements in long-term secondary prevention, as no clear reduction in recurrence rates was observed.}, subject = {Schlaganfall}, language = {en} } @phdthesis{LindenbergverhSchubert2021, author = {Lindenberg [verh. Schubert], Annekathrin}, title = {Timing of sensory preferences in \(Camponotus\) Ants}, doi = {10.25972/OPUS-16094}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-160948}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Ants belong to the most successful insects living on our planet earth. One criterion of their tremendous success is the division of labor among workers that can be related to age (age¬- or temporal polyethism) and/ or body size (size-related polymorphism). Young ants care for the queen and brood in the nest interior and switch to foraging tasks in the outside environment with ongoing age. This highly flexible interior-exterior transition probably allows the ant workers to properly match the colony needs and is one of the most impressive behaviors a single worker undergoes during its life. As environmental stimuli are changing with this transition, workers are required to perform a new behavioral repertoire. This requires significant adaptions in sensory and higher¬-order integration centers in the brain, like the mushroom bodies. Furthermore, foragers need proper time measuring mechanisms to cope with daily environmental changes and to adapt their own mode of life. Therefore, they possess a functional endogenous clock that generates rhythms with a period length of approximately 24 hours. The species-rich genus of Camponotus ants constitute a rewarding model to study how behavioral duties of division of labor were performed and modulated within the colony and how synaptic plasticity in the brain is processed, as they can divide their labor to both, age and body size, simultaneously. In my PhD thesis, I started to investigate the behavioral repertoire (like foraging and locomotor activity) of two sympatric Camponotus species, C. mus and C. rufipes workers under natural and under controlled conditions. Furthermore, I focused on the division of labor in C. rufipes workers and started to examine structural and ultrastructural changes of neuronal architectures in the brain that are accompanied by the interior-exterior transition of C. rufipes ants. In the first part of my thesis, I started to analyze the temporal organization of task allocation throughout the life of single C. rufipes workers. Constant video-tracking of individually labeled workers for up to 11 weeks, revealed an age-related division of labor of interior and exterior workers. After emergence, young individuals are tended to by older ones within the first 48 hours of their lives before they themselves start nurturing larvae and pupae. Around 52\% switch to foraging duties at an age of 14-20 days. The workers that switched to foraging tasks are mainly media-sized workers and seem to be more specialized than nurses. Variations in proportion and the age of switching workers between and within different subcolonies indicate how highly flexible and plastic the age-related division of labor occurs in this ant species. Most of the observed workers were engaged in foraging tasks exclusively during nighttime. As the experiments were conducted in the laboratory, they are completely lacking environmental stimuli of the ants´ natural habitat. I therefore asked in a second study, how workers of the two closely related Camponotus species, C. rufipes and C. mus, adapt their daily activity patterns (foraging and locomotor activity) under natural (in Uruguay, South America) and controlled (in the laboratory) conditions to changing thermal conditions. Monitoring the foraging activity of both Camponotus species in a field experiment revealed, that C. mus workers are exclusively diurnal, whereas C. rufipes foragers are predominantly nocturnal. However, some nests showed an elevated daytime activity, which could be an adaption to seasonally cold night temperatures. To further investigate the impact of temperature and light on the differing foraging activity patterns in the field, workers of both Camponotus species were artificially exposed to different thermal regimes in the laboratory, simulating local winter and summer conditions. Here again, C. mus workers display solely diurnal locomotor activity, whereas workers of C. rufipes shifted their locomotor activity from diurnal under thermal winter conditions to nocturnal under thermal summer conditions. Hence, the combination of both, field work and laboratory studies, shows that daily activity is mostly shaped by thermal conditions and that temperature cycles are not just limiting foraging activity but can be used as zeitgeber to schedule the outside activities of the nests. Once an individual worker switches from indoor duties to exterior foraging tasks, it is confronted with an entirely new set of sensory information. To cope with changes of the environmental conditions and to facilitate the behavioral switch, workers need a highly flexible and plastic neuronal system. Hence, my thesis further focuses on the underlying neuronal adaptations of the visual system, including the optic lobes as the primary visual neuropil and the mushroom bodies as secondary visual brain neuropil, that are accompanied with the behavioral switch from nursing to foraging. The optic lobes as well as the mushroom bodies of light-deprived workers show an `experience-independent´ volume increase during the first two weeks of adulthood. An additional light exposure for 4 days induces an `experience-dependent´ decrease of synaptic complexes in the mushroom body collar, followed by an increase after extended light exposure for 14 days. I therefore conclude, that the plasticity of the central visual system represents important components for the optimal timing of the interior-exterior transitions and flexibility of the age-related division of labor. These remarkable structural changes of synaptic complexes suggest an active involvement of the mushroom body neuropil in the lifetime plasticity that promotes the interior-exterior transition of Camponotus rufipes ants. Beside these investigations of neuronal plasticity of synaptic complexes in the mushroom bodies on a structural level, I further started to examine mushroom body synaptic structures at the ultrastructural level. Until recently, the detection of synaptic components in projection neuron axonal boutons were below resolution using classical Transmission Electron Microscopy. Therefore, I started to implement Electron Tomography to increase the synaptic resolution to understand architectural changes in neuronal plasticity process. By acquiring double tilt series and consecutive computation of the acquired tilt information, I am now able to resolve individual clear-core and dense-core vesicles within the projection neuron cytoplasm of C. rufipes ants. I additionally was able to reveal single postsynaptic Kenyon cell dendritic spines (~62) that surround one individual projection neuron bouton. With this, I could reveal first insights into the complex neuronal architecture of single projection neuron boutons in the olfactory mushroom body lip region. The high resolution images of synaptic architectures at the ultrastructural level, received with Electron Tomography would promote the understanding of architectural changes in neuronal plasticity. In my PhD thesis, I demonstrate that the temporal organization within Camponotus colonies involves the perfect timing of different tasks. Temperature seems to be the most scheduling abiotic factors of foraging and locomotor activity. The ants do not only need to adapt their behavioral repertoire in accordance to the interior-exterior switch, also the parts in the peripheral and central that process visual information need to adapt to the new sensory environment.}, subject = {Rossameise}, language = {en} } @phdthesis{Lodes2021, author = {Lodes, Nina Theresa}, title = {Tissue Engineering f{\"u}r seltene Erkrankungen mit St{\"o}rungen des mukozili{\"a}ren Transports}, doi = {10.25972/OPUS-20017}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200178}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Bei der zystischen Fibrose (CF) sowie der prim{\"a}ren Ziliendyskinesie (PCD) handelt es sich um zwei seltene Erkrankungen, die unter anderem den mukozili{\"a}ren Transport beeintr{\"a}chtigen. CF geh{\"o}rt hierbei zu den am h{\"a}ufigsten vorkommenden angeborenen Stoffwechselerkrankungen, wobei Betroffene unter einem Defekt des Cystic Fibrosis Transmembrane Conductor Regulator (CFTR)-Gens leiden, der durch die Produktion von hochviskosem Sekret in muzinproduzierenden Organen, wie dem gastrointestinalen Trakt und der Lunge, gekennzeichnet ist. Patienten, die an PCD leiden, weisen Defekte in, zum jetzigen Zeitpunkt, ca. 38 bekannten und PCD-assoziierten Genen auf, die in strukturellen Defekten des zili{\"a}ren Apparats und somit in dysfunktionalen Kinozilien resultieren. Da aktuell weder f{\"u}r die CF noch f{\"u}r die PCD eine Heilung m{\"o}glich ist, steht bei der Therapie vor allem die Linderung der Symptome im Fokus. Grundlegendes Ziel ist der langfristige Erhalt der Lungenfunktion sowie die Pr{\"a}vention bakterieller Infekte. Als bisherige Modellsysteme zur Erforschung m{\"o}glicher Therapeutika gelten Tiermodelle, die den humanen Ph{\"a}notyp aufgrund von Speziesdiversit{\"a}t nicht vollst{\"a}ndig abbilden k{\"o}nnen. Als vielversprechende Testsysteme f{\"u}r die zystische Fibrose gelten humane intestinale Organoidkulturen. Nachdem allerdings vorwiegend respiratorische Symptome f{\"u}r die Mortalit{\"a}t der Patienten verantwortlich sind, stellen CF-Atemwegsmodelle bessere Testsysteme f{\"u}r zuk{\"u}nftige Therapeutika dar. Atmungsorganoidkulturen wurden verwendet, um die CFTR-Funktionalit{\"a}t zu untersuchen, repr{\"a}sentieren aber nicht vollst{\"a}ndig die in vivo Situation. Deshalb werden zur Entwicklung neuer Therapiestrategien patientenspezifische 3D in vitro Testsysteme der humanen Atemwege ben{\"o}tigt, die insbesondere im Hinblick auf personalisierte Medizin ihren Einsatz finden. In der vorliegenden Arbeit wurde eine f{\"u}r den Lehrstuhl neue Methode zur Zellgewinnung aus nasalen Schleimhautabstrichen etabliert, die eine standardisierte Versorgung mit humanem Prim{\"a}rmaterial garantiert. Zur Generierung einer krankheitsspezifischen Zelllinie, wie beispielsweise einer PCD-Zelllinie mit Hilfe des CRISPR/Cas9-Systems, ist eine Atemwegszelllinie erforderlich, die die in vivo Situation vollst{\"a}ndig repr{\"a}sentiert. So wurden vier verschiedene respiratorische Epithelzelllinien (HBEC3-KT, Calu-3, VA10 und Cl-huAEC) auf ihren mukozili{\"a}ren Ph{\"a}notyp hin untersucht, wobei lediglich die Zelllinie HBEC3-KT in zilientragende Zellen differenzierte. Diese zeigten jedoch nur auf ca. 5 \% der Modelloberfl{\"a}che Kinozilien, wodurch die humane respiratorische Mukosa nicht komplett abgebildet werden konnte und die HBEC3-KT-Zelllinie keine geeignete Zelllinie zur Generierung einer PCD-Zelllinie darstellte. Mit Hilfe des Tissue Engineering war es m{\"o}glich, 3D in vitro Testsysteme basierend auf zwei unterschiedlichen Matrices, der biologischen SIS (small intestinal submucosa) und der synthetischen Polyethylenterephthalat (PET)-Membran, aufzubauen. Es wurden 3D Atemwegstestsysteme mit humanen prim{\"a}ren nasalen und tracheobronchialen Epithelzellen generiert. Erg{\"a}nzend zu histologischen Untersuchungen und zur Charakterisierung spezifischer Marker des respiratorischen Systems mittels Immunfluoreszenz, wurde die Ultrastruktur der Modelle, mit speziellem Fokus auf zili{\"a}re Strukturen, analysiert. Um R{\"u}ckschl{\"u}sse auf die zili{\"a}re Funktionalit{\"a}t ziehen zu k{\"o}nnen und somit eine hohe in vivo Korrelation zu best{\"a}tigen, wurde im Rahmen dieser Arbeit am Lehrstuhl f{\"u}r Tissue Engineering und Regenerative Medizin die Methode der Hochgeschwindigkeitsvideomikroskopie etabliert, welche die Analyse der Zilienschlagfrequenz sowie des mukozili{\"a}ren Transports erm{\"o}glicht. Ebenfalls wurde der Einfluss von isotoner Kochsalzl{\"o}sung und des � 2-adrenergen Agonisten Salbutamol, das vor allem als Bronchodilatator bei Asthmapatienten eingesetzt wird, auf die Zilienschlagfrequenz analysiert. Es konnte gezeigt werden, dass beide Substanzen den Zilienschlag im Atemwegsmodell erh{\"o}hen. Zur Generierung der Testsysteme der beiden seltenen Erkrankungen CF und PCD wurden Epithelzellen der betroffenen Patienten zun{\"a}chst mittels nicht-invasiver Raman-Spektroskopie auf einen potentiellen Biomarker untersucht, welcher Einsatz in der Diagnostik der beiden Krankheiten finden k{\"o}nnte. Es konnte jedoch weder f{\"u}r die CF noch f{\"u}r die PCD ein Biomarker aufgedeckt werden. Jedoch zeigten PCD-Zellen eine geringe Auftrennung gegen{\"u}ber nicht-PCD Zellen. Anschließend wurden 3D-Atemwegstestsysteme basierend auf Patientenzellen aufgebaut. Der Ph{\"a}notyp der CF-Modelle wurde mittels immunhistologischer F{\"a}rbung und der Analyse des gest{\"o}rten mukozili{\"a}ren Transports verifiziert. Strukturelle zili{\"a}re Defekte konnten durch die ultrastrukturelle Analyse von Zilienquerschnitten in drei donorspezifischen PCD-Modellen identifiziert werden. Dar{\"u}ber hinaus konnte die zili{\"a}re Funktionalit{\"a}t mit Hilfe der Hochgeschwindigkeitsvideomikroskopie nicht nachgewiesen werden. Zusammenfassend ist es in dieser Arbeit gelungen, eine neue Methode zur vollst{\"a}ndigen Charakterisierung von 3D-Atemwegstestsystemen zu etablieren, die die Analyse der Zilienschlagfrequenz sowie des mukozili{\"a}ren Transports erm{\"o}glicht. Es konnte erstmalig gezeigt werden, dass mit Hilfe des Tissue Engineering ein personalisiertes Krankheitsmodell f{\"u}r die PCD auf Segmenten eines dezellularisierten porzinen Jejunums generiert werden kann, das zuk{\"u}nftig ein Testsystem f{\"u}r potentielle Therapeutika darstellen kann.}, subject = {In-vitro-Kultur}, language = {de} } @article{GraserLiedtkeJakob2021, author = {Graser, Stephanie and Liedtke, Daniel and Jakob, Franz}, title = {TNAP as a new player in chronic inflammatory conditions and metabolism}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {2}, issn = {1422-0067}, doi = {10.3390/ijms22020919}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258888}, year = {2021}, abstract = {This review summarizes important information on the ectoenzyme tissue-nonspecific alkaline phosphatase (TNAP) and gives a brief insight into the symptoms, diagnostics, and treatment of the rare disease Hypophosphatasia (HPP), which is resulting from mutations in the TNAP encoding ALPL gene. We emphasize the role of TNAP beyond its well-known contribution to mineralization processes. Therefore, above all, the impact of the enzyme on central molecular processes in the nervous system and on inflammation is presented here.}, language = {en} } @article{LinkBorgesJonesetal.2021, author = {Link, Fabian and Borges, Alyssa R. and Jones, Nicola G. and Engstler, Markus}, title = {To the Surface and Back: Exo- and Endocytic Pathways in Trypanosoma brucei}, series = {Frontiers in Cell and Developmental Biology}, volume = {9}, journal = {Frontiers in Cell and Developmental Biology}, issn = {2296-634X}, doi = {10.3389/fcell.2021.720521}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-244682}, year = {2021}, abstract = {Trypanosoma brucei is one of only a few unicellular pathogens that thrives extracellularly in the vertebrate host. Consequently, the cell surface plays a critical role in both immune recognition and immune evasion. The variant surface glycoprotein (VSG) coats the entire surface of the parasite and acts as a flexible shield to protect invariant proteins against immune recognition. Antigenic variation of the VSG coat is the major virulence mechanism of trypanosomes. In addition, incessant motility of the parasite contributes to its immune evasion, as the resulting fluid flow on the cell surface drags immunocomplexes toward the flagellar pocket, where they are internalized. The flagellar pocket is the sole site of endo- and exocytosis in this organism. After internalization, VSG is rapidly recycled back to the surface, whereas host antibodies are thought to be transported to the lysosome for degradation. For this essential step to work, effective machineries for both sorting and recycling of VSGs must have evolved in trypanosomes. Our understanding of the mechanisms behind VSG recycling and VSG secretion, is by far not complete. This review provides an overview of the trypanosome secretory and endosomal pathways. Longstanding questions are pinpointed that, with the advent of novel technologies, might be answered in the near future.}, language = {en} } @article{HerbertWoeckelKreienbergetal.2021, author = {Herbert, S. L. and W{\"o}ckel, A. and Kreienberg, R. and K{\"u}hn, T. and Flock, F. and Felberbaum, R. and Janni, W. and Curtaz, C. and Kiesel, M. and St{\"u}ber, T. and Diessner, J. and Salmen, J. and Schwentner, L. and Fink, V. and Bekes, I. and Leinert, E. and Lato, K. and Polasik, A. and Schochter, F. and Singer, S.}, title = {To which extent do breast cancer survivors feel well informed about disease and treatment 5 years after diagnosis?}, series = {Breast Cancer Research and Treatment}, volume = {185}, journal = {Breast Cancer Research and Treatment}, organization = {BRENDA study group}, issn = {0167-6806}, doi = {10.1007/s10549-020-05974-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232356}, pages = {677-684}, year = {2021}, abstract = {Objective In this study, we investigated to which extent patients feel well informed about their disease and treatment, which areas they wish more or less information and which variables are associated with a need for information about the disease, medical tests and treatment. Methods In a German multi-centre prospective study, we enrolled 759 female breast cancer patients at the time of cancer diagnosis (baseline). Data on information were captured at 5 years after diagnosis with the European Organisation for Research and Treatment of Cancer (EORTC) Information Module (EORTC QLQ-INFO24). Good information predictors were analysed using linear regression models. Results There were 456 patients who participated at the 5-year follow-up. They reported to feel well informed about medical tests (mean score 78.5) and the disease itself (69.3) but relatively poorly about other services (44.3) and about different places of care (31.3). The survivors expressed a need for more information concerning: side effects and long-term consequences of therapy, more information in general, information about aftercare, prognosis, complementary medicine, disease and therapy. Patients with higher incomes were better informed about medical tests (β 0.26, p 0.04) and worse informed with increasing levels of fear of treatment (β - 0.11, p 0.02). Information about treatment was reported to be worse by survivors > 70 years old (β -0.34, p 0.03) and by immigrants (β -0.11, p 0.02). Survivors who had received additional written information felt better informed about disease, medical tests, treatment and other services (β 0.19/0.19/0.20/0.25; each p < 0.01). Conclusion Health care providers have to reconsider how and what kind of information they provide. Providing written information, in addition to oral information, may improve meeting those information needs.}, language = {en} } @article{OsmanogluKhaledAlSeiariAlKhoorietal.2021, author = {Osmanoglu, {\"O}zge and Khaled AlSeiari, Mariam and AlKhoori, Hasa Abduljaleel and Shams, Shabana and Bencurova, Elena and Dandekar, Thomas and Naseem, Muhammad}, title = {Topological Analysis of the Carbon-Concentrating CETCH Cycle and a Photorespiratory Bypass Reveals Boosted CO\(_2\)-Sequestration by Plants}, series = {Frontiers in Bioengineering and Biotechnology}, volume = {9}, journal = {Frontiers in Bioengineering and Biotechnology}, issn = {2296-4185}, doi = {10.3389/fbioe.2021.708417}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-249260}, year = {2021}, abstract = {Synthetically designed alternative photorespiratory pathways increase the biomass of tobacco and rice plants. Likewise, some in planta-tested synthetic carbon-concentrating cycles (CCCs) hold promise to increase plant biomass while diminishing atmospheric carbon dioxide burden. Taking these individual contributions into account, we hypothesize that the integration of bypasses and CCCs will further increase plant productivity. To test this in silico, we reconstructed a metabolic model by integrating photorespiration and photosynthesis with the synthetically designed alternative pathway 3 (AP3) enzymes and transporters. We calculated fluxes of the native plant system and those of AP3 combined with the inhibition of the glycolate/glycerate transporter by using the YANAsquare package. The activity values corresponding to each enzyme in photosynthesis, photorespiration, and for synthetically designed alternative pathways were estimated. Next, we modeled the effect of the crotonyl-CoA/ethylmalonyl-CoA/hydroxybutyryl-CoA cycle (CETCH), which is a set of natural and synthetically designed enzymes that fix CO₂ manifold more than the native Calvin-Benson-Bassham (CBB) cycle. We compared estimated fluxes across various pathways in the native model and under an introduced CETCH cycle. Moreover, we combined CETCH and AP3-w/plgg1RNAi, and calculated the fluxes. We anticipate higher carbon dioxide-harvesting potential in plants with an AP3 bypass and CETCH-AP3 combination. We discuss the in vivo implementation of these strategies for the improvement of C3 plants and in natural high carbon harvesters.}, language = {en} } @phdthesis{Shamburger2021, author = {Shamburger, William}, title = {Total Synthesis of Mono- and Dimeric Naphthylisoquinoline Alkaloids and Related Analogs}, doi = {10.25972/OPUS-25061}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250612}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Our research group focusses on the isolation, structural elucidation, and synthesis of bioactive natural products, among others, the naphthylisoquinoline alkaloids from tropical lianas. This intriguing class of compounds comprises representatives with activities against, e.g. P. falciparum, the cause of Malaria tropica, against the neglected disease leishmaniasis, and, as discovered more recently, against different types of cancer cells. Based on the high potency of theses extraordinary secondary metabolites, this thesis was devoted to the total synthesis of bioactive natural products and closely related analogs.}, subject = {Naphthylisochinolinalkaloide}, language = {en} } @article{DischingerHasingerKoenigsraineretal.2021, author = {Dischinger, Ulrich and Hasinger, Julia and K{\"o}nigsrainer, Malina and Corteville, Carolin and Otto, Christoph and Fassnacht, Martin and Hankir, Mohamed and Seyfried, Florian Johannes David}, title = {Toward a Medical Gastric Bypass: Chronic Feeding Studies With Liraglutide + PYY\(_{3-36}\) Combination Therapy in Diet-Induced Obese Rats}, series = {Frontiers in Endocrinology}, volume = {11}, journal = {Frontiers in Endocrinology}, issn = {1664-2392}, doi = {10.3389/fendo.2020.598843}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223113}, year = {2021}, abstract = {Background Combination therapies of anorectic gut hormones partially mimic the beneficial effects of bariatric surgery. Thus far, the effects of a combined chronic systemic administration of Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\)) have not been directly compared to Roux-en-Y gastric bypass (RYGB) in a standardized experimental setting. Methods High-fat diet (HFD)-induced obese male Wistar rats were randomized into six treatment groups: (1) RYGB, (2) sham-operation (shams), (3) liraglutide, (4) PYY\(_{3-36}\), (5) PYY\(_{3-36}\)+liraglutide (6), saline. Animals were kept on a free choice high- and low-fat diet. Food intake, preference, and body weight were measured daily for 4 weeks. Open field (OP) and elevated plus maze (EPM) tests were performed. Results RYGB reduced food intake and achieved sustained weight loss. Combined PYY\(_{3-36}\)+liraglutide treatment led to similar and plateaued weight loss compared to RYGB. Combined PYY\(_{3-36}\)+liraglutide treatment was superior to PYY\(_{3-36}\) (p ≤ 0.0001) and liraglutide (p ≤ 0.05 or p ≤ 0.01) mono-therapy. PYY\(_{3-36}\)+liraglutide treatment and RYGB also reduced overall food intake and (less pronounced) high-fat preference compared to controls. The animals showed no signs of abnormal behavior in OF or EPM. Conclusions Liraglutide and PYY\(_{3-36}\) combination therapy vastly mimics reduced food intake, food choice and weight reducing benefits of RYGB.}, language = {en} } @phdthesis{Schoenwetter2021, author = {Sch{\"o}nwetter, Elisabeth Sofie}, title = {Towards an understanding of the intricate interaction network of TFIIH}, doi = {10.25972/OPUS-16892}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-168926}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {The integrity of its DNA is fundamental for every living cell. However, DNA is constantly threatened by exogenous and endogenous damaging agents that can cause a variety of different DNA lesions. The severe consequences of an accumulation of DNA lesions are reflected in cancerogenesis and aging. Several DNA repair mechanisms ensure the repair of DNA lesions and thus maintain DNA integrity. One of these DNA repair mechanisms is nucleotide excision repair (NER), which is famous for its ability to address a large variety of structurally unrelated DNA lesions. A key component of eukaryotic NER is the transcription factor II H (TFIIH) complex, which is not only essential for DNA repair but also for transcription. The TFIIH complex is composed of ten subunits. How these subunits work together during NER to unwind the DNA around the lesion is, however, not yet fully understood. High-resolution structural data and biochemical insights into the function of every subunit are thus indispensable to understand the functional networks within TFIIH. The importance of an intact TFIIH complex is reflected in the severe consequences of patient mutations in the TFIIH subunits XPB, XPD or p8 leading to the hallmark diseases xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Defects in the NER pathway are further associated with several types of cancer including skin cancer. The herein described work focused on five TFIIH subunits derived from the thermophilic fungus Chaetomium thermophilum, the p34/p44 pair and the ternary XPB/p52/p8 complex. The interaction between p34 and p44 was characterized based on a high-resolution structure of the p34_vWA/p44_RING minimal complex. Biochemical studies of the p34/p44 interaction led to the disclosure of an additional interaction between the p34 and p44 subunits, which had not been characterized so far. The p34/p44 interaction was shown to be central to TFIIH, which justifies the presence of several redundant interfaces to safeguard the interaction between the two proteins and might explain why so far, no patient mutations in these subunits have been identified. The p52 subunit of TFIIH was known to be crucial to stimulate the ATPase activity of XPB, which is required during NER. This work presents the first entire atomic resolution structural characterization of p52, which was derived of several crystal structures of p52 variants and a p52/p8 variant thereby demonstrating the interaction between p52 and p8. The precise structural model of p52 offered the possibility to investigate interactions with other TFIIH subunits in more detail. The middle domain 2 of p52 and the N-terminal domain of XPB were shown to mediate the main interaction between the two subunits. An analysis of the p52 crystal structures within recently published cryo-electron microscopy structures of TFIIH provides a model of how p52 and p8 stimulate the ATPase activity of XPB, which is essential for NER and transcription. The structural and biochemical findings of this work provide an additional building block towards the uncovering of the architecture and function of this essential transcription factor.}, subject = {DNS-Reparatur}, language = {en} } @article{KraftReichertPryss2021, author = {Kraft, Robin and Reichert, Manfred and Pryss, R{\"u}diger}, title = {Towards the interpretation of sound measurements from smartphones collected with mobile crowdsensing in the healthcare domain: an experiment with Android devices}, series = {Sensors}, volume = {22}, journal = {Sensors}, number = {1}, issn = {1424-8220}, doi = {10.3390/s22010170}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252246}, year = {2021}, abstract = {The ubiquity of mobile devices fosters the combined use of ecological momentary assessments (EMA) and mobile crowdsensing (MCS) in the field of healthcare. This combination not only allows researchers to collect ecologically valid data, but also to use smartphone sensors to capture the context in which these data are collected. The TrackYourTinnitus (TYT) platform uses EMA to track users' individual subjective tinnitus perception and MCS to capture an objective environmental sound level while the EMA questionnaire is filled in. However, the sound level data cannot be used directly among the different smartphones used by TYT users, since uncalibrated raw values are stored. This work describes an approach towards making these values comparable. In the described setting, the evaluation of sensor measurements from different smartphone users becomes increasingly prevalent. Therefore, the shown approach can be also considered as a more general solution as it not only shows how it helped to interpret TYT sound level data, but may also stimulate other researchers, especially those who need to interpret sensor data in a similar setting. Altogether, the approach will show that measuring sound levels with mobile devices is possible in healthcare scenarios, but there are many challenges to ensuring that the measured values are interpretable.}, language = {en} } @phdthesis{Schortmann2021, author = {Schortmann, Max}, title = {Toxizit{\"a}t und klinische Ergebnisse der moderat hypofraktionierten und bildgef{\"u}hrten Teletherapie des lokalisierten Prostatakarzinoms an der Klinik und Poliklinik f{\"u}r Strahlentherapie des Universit{\"a}tsklinikums W{\"u}rzburg - Eine retrospektive Analyse -}, doi = {10.25972/OPUS-24948}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-249483}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Ziel der Arbeit war es, onkologische und toxizit{\"a}tsbezogene Langzeitdaten der moderat hypofraktionierten, Cone-beam-CT gef{\"u}hrten intensit{\"a}tsmodulierten Radiotherapie mit simultan integriertem Boost als prim{\"a}re Therapieform beim lokalisierten Prostatakarzinom zu generieren und mithin zur Diskussion um den Stellenwert dieser Therapieform beizutragen. Dazu wurden die Daten von 346 Patienten mit lokalisiertem Prostatakarzinom, welche im Zeitraum von 2005-2015 an der Klinik f{\"u}r Strahlentherapie des Uniklinikums W{\"u}rzburg bestrahlt wurden, ausgewertet. Die vorliegende Arbeit zeigt, dass die Bestrahlung mit 2 Gy {\"A}quivalenzdosen von 80,4 beziehungsweise 83 Gy eine Zeit- und kostensparende Alternative zu konventionellen Fraktionierungsregimen bei guten onkologischen Ergebnissen und vertretbarer Toxizit{\"a}t darstellt. Verglichen mit anderen Therapieprotokollen f{\"a}llt insbesondere die niedrige Rate an sp{\"a}ter gastrointestinaler Toxizit{\"a}t auf. Diese konnte durch strikte Rektumschonung erreicht werden. Die Applikation einer Antihormontherapie f{\"u}hrt bei Hochrisikopatienten zu signifikant besserer biochemischer Kontrolle. Dar{\"u}ber hinaus k{\"o}nnte auch die Bildf{\"u}hrung sowie die Applikation eines simultan integrierten Boosts das biochemisch rezidivfreie {\"U}berleben positiv beeinflusst haben. Das in W{\"u}rzburg entwickelte Zielvolumenkonzept mit simultan integriertem Boost scheint sich g{\"u}nstig bez{\"u}glich der Rektumtoxizit{\"a}t auszuwirken.}, subject = {Prostatakrebs}, language = {de} } @article{BechtSchollmayerMonakhovaetal.2021, author = {Becht, Alexander and Schollmayer, Curd and Monakhova, Yulia and Holzgrabe, Ulrike}, title = {Tracing the origin of paracetamol tablets by near-infrared, mid-infrared, and nuclear magnetic resonance spectroscopy using principal component analysis and linear discriminant analysis}, series = {Analytical and Bioanalytical Chemistry}, volume = {413}, journal = {Analytical and Bioanalytical Chemistry}, number = {11}, doi = {10.1007/s00216-021-03249-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265400}, pages = {3107-3118}, year = {2021}, abstract = {Most drugs are no longer produced in their own countries by the pharmaceutical companies, but by contract manufacturers or at manufacturing sites in countries that can produce more cheaply. This not only makes it difficult to trace them back but also leaves room for criminal organizations to fake them unnoticed. For these reasons, it is becoming increasingly difficult to determine the exact origin of drugs. The goal of this work was to investigate how exactly this is possible by using different spectroscopic methods like nuclear magnetic resonance and near- and mid-infrared spectroscopy in combination with multivariate data analysis. As an example, 56 out of 64 different paracetamol preparations, collected from 19 countries around the world, were chosen to investigate whether it is possible to determine the pharmaceutical company, manufacturing site, or country of origin. By means of suitable pre-processing of the spectra and the different information contained in each method, principal component analysis was able to evaluate manufacturing relationships between individual companies and to differentiate between production sites or formulations. Linear discriminant analysis showed different results depending on the spectral method and purpose. For all spectroscopic methods, it was found that the classification of the preparations to their manufacturer achieves better results than the classification to their pharmaceutical company. The best results were obtained with nuclear magnetic resonance and near-infrared data, with 94.6\%/99.6\% and 98.7/100\% of the spectra of the preparations correctly assigned to their pharmaceutical company or manufacturer.}, language = {en} } @article{AlbertLeziusStoerketal.2021, author = {Albert, Judith and Lezius, Susanne and St{\"o}rk, Stefan and Morbach, Caroline and G{\"u}der, G{\"u}lmisal and Frantz, Stefan and Wegscheider, Karl and Ertl, Georg and Angermann, Christiane E.}, title = {Trajectories of Left Ventricular Ejection Fraction After Acute Decompensation for Systolic Heart Failure: Concomitant Echocardiographic and Systemic Changes, Predictors, and Impact on Clinical Outcomes}, series = {Journal of the American Heart Association}, volume = {10}, journal = {Journal of the American Heart Association}, doi = {10.1161/JAHA.120.017822}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230210}, year = {2021}, abstract = {Prospective longitudinal follow-up of left ventricular ejection fraction (LVEF) trajectories after acute cardiac decompensation of heart failure is lacking. We investigated changes in LVEF and covariates at 6-months' follow-up in patients with a predischarge LVEF ≤40\%, and determined predictors and prognostic implications of LVEF changes through 18-months' follow-up. Methods and Results Interdisciplinary Network Heart Failure program participants (n=633) were categorized into subgroups based on LVEF at 6-months' follow-up: normalized LVEF (>50\%; heart failure with normalized ejection fraction, n=147); midrange LVEF (41\%-50\%; heart failure with midrange ejection fraction, n=195), or persistently reduced LVEF (≤40\%; heart failure with persistently reduced LVEF , n=291). All received guideline-directed medical therapies. At 6-months' follow-up, compared with patients with heart failure with persistently reduced LVEF, heart failure with normalized LVEF or heart failure with midrange LVEF subgroups showed greater reductions in LV end-diastolic/end-systolic diameters (both P<0.001), and left atrial systolic diameter (P=0.002), more increased septal/posterior end-diastolic wall-thickness (both P<0.001), and significantly greater improvement in diastolic function, biomarkers, symptoms, and health status. Heart failure duration <1 year, female sex, higher predischarge blood pressure, and baseline LVEF were independent predictors of LVEF improvement. Mortality and event-free survival rates were lower in patients with heart failure with normalized LVEF (P=0.002). Overall, LVEF increased further at 18-months' follow-up (P<0.001), while LV end-diastolic diameter decreased (P=0.048). However, LVEF worsened (P=0.002) and LV end-diastolic diameter increased (P=0.047) in patients with heart failure with normalized LVEF hospitalized between 6-months' follow-up and 18-months' follow-up. Conclusions Six-month survivors of acute cardiac decompensation for systolic heart failure showed variable LVEF trajectories, with >50\% showing improvements by ≥1 LVEF category. LVEF changes correlated with various parameters, suggesting multilevel reverse remodeling, were predictable from several baseline characteristics, and were associated with clinical outcomes at 18-months' follow-up. Repeat hospitalizations were associated with attenuation of reverse remodeling."}, language = {en} } @article{JordanJaeckleScheidtetal.2021, author = {Jordan, Martin C. and J{\"a}ckle, Veronika and Scheidt, Sebastian and Gilbert, Fabian and H{\"o}lscher-Doht, Stefanie and Erg{\"u}n, S{\"u}leyman and Meffert, Rainer H. and Heintel, Timo M.}, title = {Trans-obturator cable fixation of open book pelvic injuries}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-021-92755-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-261212}, year = {2021}, abstract = {Operative treatment of ruptured pubic symphysis by plating is often accompanied by complications. Trans-obturator cable fixation might be a more reliable technique; however, have not yet been tested for stabilization of ruptured pubic symphysis. This study compares symphyseal trans-obturator cable fixation versus plating through biomechanical testing and evaluates safety in a cadaver experiment. APC type II injuries were generated in synthetic pelvic models and subsequently separated into three different groups. The anterior pelvic ring was fixed using a four-hole steel plate in Group A, a stainless steel cable in Group B, and a titan band in Group C. Biomechanical testing was conducted by a single-leg-stance model using a material testing machine under physiological load levels. A cadaver study was carried out to analyze the trans-obturator surgical approach. Peak-to-peak displacement, total displacement, plastic deformation and stiffness revealed a tendency for higher stability for trans-obturator cable/band fixation but no statistical difference to plating was detected. The cadaver study revealed a safe zone for cable passage with sufficient distance to the obturator canal. Trans-obturator cable fixation has the potential to become an alternative for symphyseal fixation with less complications.}, language = {en} } @article{AbboudAsendorfHeinrichetal.2021, author = {Abboud, Tammam and Asendorf, Thomas and Heinrich, Jutta and Faust, Katharina and Krieg, Sandro M. and Seidel, Kathleen and Mielke, Dorothee and Matthies, Cordola and Ringel, Florian and Rohde, Veit and Szel{\´e}nyi, Andrea}, title = {Transcranial versus direct cortical stimulation for motor-evoked potentials during resection of supratentorial tumors under general anesthesia (the TRANSEKT-trial): study protocol for a randomized controlled trial}, series = {Biomedicines}, volume = {9}, journal = {Biomedicines}, number = {10}, issn = {2227-9059}, doi = {10.3390/biomedicines9101490}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248513}, year = {2021}, abstract = {Background: Monitoring of motor function during surgery for supratentorial tumors under general anesthesia applies either transcranial electrical stimulation (TES) or direct cortical stimulation (DCS) to elicit motor-evoked potentials. To date, there is no guideline that favor one method over the other. Therefore, we designed this randomized study to compare between both methods regarding the prediction of postoperative motor deficits and extent of tumor resection. Methods: This is a multicenter (six centers in Germany and one in Switzerland), double blind, parallel group, exploratory, randomized controlled clinical trial. Patients without or with mild paresis, who are scheduled for surgical resection of motor-eloquent brain tumors under general anesthesia will be randomized to surgical resection under TES or surgical resection under DCS. The primary endpoint is sensitivity and specificity in prognosis of motor function 7 days after surgery. The main secondary endpoint is the extent of tumor resection. The study is planned to include 120 patients within 2 years. Discussion: The present exploratory study should compare TES and DCS regarding sensitivity and specificity in predicting postoperative motor deficit and extent of tumor resection to calculate the required number of patients in a confirmatory trial to test the superiority of one method over the other.}, language = {en} } @article{BielmeierRothSchmittetal.2021, author = {Bielmeier, Christina B. and Roth, Saskia and Schmitt, Sabrina I. and Boneva, Stefaniya K. and Schlecht, Anja and Vallon, Mario and Tamm, Ernst R. and Erg{\"u}n, S{\"u}leyman and Neueder, Andreas and Braunger, Barbara M.}, title = {Transcriptional profiling identifies upregulation of neuroprotective pathways in retinitis pigmentosa}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {12}, issn = {1422-0067}, doi = {10.3390/ijms22126307}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260769}, year = {2021}, abstract = {Hereditary retinal degenerations like retinitis pigmentosa (RP) are among the leading causes of blindness in younger patients. To enable in vivo investigation of cellular and molecular mechanisms responsible for photoreceptor cell death and to allow testing of therapeutic strategies that could prevent retinal degeneration, animal models have been created. In this study, we deeply characterized the transcriptional profile of mice carrying the transgene rhodopsin V20G/P23H/P27L (VPP), which is a model for autosomal dominant RP. We examined the degree of photoreceptor degeneration and studied the impact of the VPP transgene-induced retinal degeneration on the transcriptome level of the retina using next generation RNA sequencing (RNASeq) analyses followed by weighted correlation network analysis (WGCNA). We furthermore identified cellular subpopulations responsible for some of the observed dysregulations using in situ hybridizations, immunofluorescence staining, and 3D reconstruction. Using RNASeq analysis, we identified 9256 dysregulated genes and six significantly associated gene modules in the subsequently performed WGCNA. Gene ontology enrichment showed, among others, dysregulation of genes involved in TGF-β regulated extracellular matrix organization, the (ocular) immune system/response, and cellular homeostasis. Moreover, heatmaps confirmed clustering of significantly dysregulated genes coding for components of the TGF-β, G-protein activated, and VEGF signaling pathway. 3D reconstructions of immunostained/in situ hybridized sections revealed retinal neurons and M{\"u}ller cells as the major cellular population expressing representative components of these signaling pathways. The predominant effect of VPP-induced photoreceptor degeneration pointed towards induction of neuroinflammation and the upregulation of neuroprotective pathways like TGF-β, G-protein activated, and VEGF signaling. Thus, modulation of these processes and signaling pathways might represent new therapeutic options to delay the degeneration of photoreceptors in diseases like RP.}, language = {en} } @article{HabensteinSchmittLiessemetal.2021, author = {Habenstein, Jens and Schmitt, Franziska and Liessem, Sander and Ly, Alice and Trede, Dennis and Wegener, Christian and Predel, Reinhard and R{\"o}ssler, Wolfgang and Neupert, Susanne}, title = {Transcriptomic, peptidomic, and mass spectrometry imaging analysis of the brain in the ant Cataglyphis nodus}, series = {Journal of Neurochemistry}, volume = {158}, journal = {Journal of Neurochemistry}, number = {2}, doi = {10.1111/jnc.15346}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239917}, pages = {391 -- 412}, year = {2021}, abstract = {Behavioral flexibility is an important cornerstone for the ecological success of animals. Social Cataglyphis nodus ants with their age-related polyethism characterized by age-related behavioral phenotypes represent a prime example for behavioral flexibility. We propose neuropeptides as powerful candidates for the flexible modulation of age-related behavioral transitions in individual ants. As the neuropeptidome of C. nodus was unknown, we collected a comprehensive peptidomic data set obtained by transcriptome analysis of the ants' central nervous system combined with brain extract analysis by Q-Exactive Orbitrap mass spectrometry (MS) and direct tissue profiling of different regions of the brain by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS. In total, we identified 71 peptides with likely bioactive function, encoded on 49 neuropeptide-, neuropeptide-like, and protein hormone prepropeptide genes, including a novel neuropeptide-like gene (fliktin). We next characterized the spatial distribution of a subset of peptides encoded on 16 precursor proteins with high resolution by MALDI MS imaging (MALDI MSI) on 14 µm brain sections. The accuracy of our MSI data were confirmed by matching the immunostaining patterns for tachykinins with MSI ion images from consecutive brain sections. Our data provide a solid framework for future research into spatially resolved qualitative and quantitative peptidomic changes associated with stage-specific behavioral transitions and the functional role of neuropeptides in Cataglyphis ants.}, language = {en} } @article{GeisingerRodriguezCasuriagaBenavente2021, author = {Geisinger, Adriana and Rodr{\´i}guez-Casuriaga, Rosana and Benavente, Ricardo}, title = {Transcriptomics of Meiosis in the Male Mouse}, series = {Frontiers in Cell and Developmental Biology}, volume = {9}, journal = {Frontiers in Cell and Developmental Biology}, issn = {2296-634X}, doi = {10.3389/fcell.2021.626020}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231032}, year = {2021}, abstract = {Molecular studies of meiosis in mammals have been long relegated due to some intrinsic obstacles, namely the impossibility to reproduce the process in vitro, and the difficulty to obtain highly pure isolated cells of the different meiotic stages. In the recent years, some technical advances, from the improvement of flow cytometry sorting protocols to single-cell RNAseq, are enabling to profile the transcriptome and its fluctuations along the meiotic process. In this mini-review we will outline the diverse methodological approaches that have been employed, and some of the main findings that have started to arise from these studies. As for practical reasons most studies have been carried out in males, and mostly using mouse as a model, our focus will be on murine male meiosis, although also including specific comments about humans. Particularly, we will center on the controversy about gene expression during early meiotic prophase; the widespread existing gap between transcription and translation in meiotic cells; the expression patterns and potential roles of meiotic long non-coding RNAs; and the visualization of meiotic sex chromosome inactivation from the RNAseq perspective.}, language = {en} } @article{LiuKoleBudimanetal.2021, author = {Liu, Zhiqiang and Kole, Goutam Kumar and Budiman, Yudha P. and Tian, Ya-Ming and Friedrich, Alexandra and Luo, Xiaoling and Westcott, Stephen A. and Radius, Udo and Marder, Todd B.}, title = {Transition metal catalyst-free, base-promoted 1,2-additions of polyfluorophenylboronates to aldehydes and ketones}, series = {Angewandte Chemie International Edition}, volume = {60}, journal = {Angewandte Chemie International Edition}, number = {30}, doi = {10.1002/anie.202103686}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-256487}, pages = {16529-16538}, year = {2021}, abstract = {A novel protocol for the transition metal-free 1,2-addition of polyfluoroaryl boronate esters to aldehydes and ketones is reported, which provides secondary alcohols, tertiary alcohols, and ketones. Control experiments and DFT calculations indicate that both the ortho-F substituents on the polyfluorophenyl boronates and the counterion K\(^+\) in the carbonate base are critical. The distinguishing features of this procedure include the employment of commercially available starting materials and the broad scope of the reaction with a wide variety of carbonyl compounds giving moderate to excellent yields. Intriguing structural features involving O-H⋅⋅⋅O and O-H⋅⋅⋅N hydrogen bonding, as well as arene-perfluoroarene interactions, in this series of racemic polyfluoroaryl carbinols have also been addressed.}, language = {en} } @article{RymaTylekLiebscheretal.2021, author = {Ryma, Matthias and Tylek, Tina and Liebscher, Julia and Blum, Carina and Fernandez, Robin and B{\"o}hm, Christoph and Kastenm{\"u}ller, Wolfgang and Gasteiger, Georg and Groll, J{\"u}rgen}, title = {Translation of collagen ultrastructure to biomaterial fabrication for material-independent but highly efficient topographic immunomodulation}, series = {Advanced materials}, volume = {33}, journal = {Advanced materials}, number = {33}, doi = {10.1002/adma.202101228}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-256381}, year = {2021}, abstract = {Supplement-free induction of cellular differentiation and polarization solely through the topography of materials is an auspicious strategy but has so far significantly lagged behind the efficiency and intensity of media-supplementation-based protocols. Consistent with the idea that 3D structural motifs in the extracellular matrix possess immunomodulatory capacity as part of the natural healing process, it is found in this study that human-monocyte-derived macrophages show a strong M2a-like prohealing polarization when cultured on type I rat-tail collagen fibers but not on collagen I films. Therefore, it is hypothesized that highly aligned nanofibrils also of synthetic polymers, if packed into larger bundles in 3D topographical biomimetic similarity to native collagen I, would induce a localized macrophage polarization. For the automated fabrication of such bundles in a 3D printing manner, the strategy of "melt electrofibrillation" is pioneered by the integration of flow-directed polymer phase separation into melt electrowriting and subsequent selective dissolution of the matrix polymer postprocessing. This process yields nanofiber bundles with a remarkable structural similarity to native collagen I fibers, particularly for medical-grade poly(ε-caprolactone). These biomimetic fibrillar structures indeed induce a pronounced elongation of human-monocyte-derived macrophages and unprecedentedly trigger their M2-like polarization similar in efficacy as interleukin-4 treatment.}, language = {en} } @phdthesis{Herter2021, author = {Herter, Daniel}, title = {Transmissionsgrad Lithium-Disilikat-verst{\"a}rkter Keramik f{\"u}r sichtbares blaues Licht in Abh{\"a}ngigkeit von Schichtst{\"a}rke und Farbe}, doi = {10.25972/OPUS-24897}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248977}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Diese Studie untersucht den Transmissionsgrad von sichtbarem blauem Licht durch Lithium-Disilikat-verst{\"a}rkte Keramik in Abh{\"a}ngigkeit von der Schichtst{\"a}rke, Farbe und Transluzenz. Weiterhin wurde der Einfluss der Oberfl{\"a}chenbehandlung sowie des Zwischenmediums zwischen Lichtleiter und Keramikoberfl{\"a}che untersucht. Dazu wurden plane Proben mit einer Schichtst{\"a}rke von 1,25 mm, 2,5 mm, 5 mm, 7,5 mm der Keramik IPS e.max CAD und mit einem S{\"a}gemikrotom ges{\"a}gt und anschließend kristallisiert. Die Messung des Transmissionsgrades des Lichtes eines LED-Lichtger{\"a}tes erfolgte mit einem faseroptischen Spektralfotometer. Je dicker, opaker und dunkler eine Keramikprobe ist, desto geringer ist ihr Transmissionsgrad. Die Abnahme des Transmissionsgrades konnte durch das Lambert-Beer'sche-Gesetz beschrieben werden. Der Einfluss der Reflexion und / oder Streuung an der Oberfl{\"a}che muss als Absorptionsgrad α miteinbezogen werden. Der Absorptionsgrad α ist von der Oberfl{\"a}chenbehandlung und dem Medium zwischen Lichtleiter und Keramikoberfl{\"a}che abh{\"a}ngig. Die Durchf{\"u}hrung einer multiplen linearen Regressionsanalyse zeigt, dass die Schichtst{\"a}rke, Transluzenz, Helligkeitsstufen und die Farben einen signifikanten Einfluss auf den Transmissionsgrad haben. Den st{\"a}rksten Einfluss hat die Keramikschichtst{\"a}rke. Der Transmissionsgrad der Farben B und D unterscheidet sich nicht signifikant vom Transmissionsgrad der Farbe A. Dagegen weist die Keramik der Farbe Bleach einen signifikant h{\"o}heren und die Keramik der Farbe C einen signifikant niedrigeren Transmissionsgrad auf. Der Absorptionsgrad der glasierten Oberfl{\"a}che und der Absorptionsgrad bei Belichtung durch die Zwischenmedien ist im Vergleich zum Absorptionsgrad einer ges{\"a}gten Oberfl{\"a}che, bzw. bei Belichtung ohne Zwischenmedium signifikant niedriger. Dagegen ist der Unterschied des Absorptionsgrades der polierten Oberfl{\"a}che zum Absorptionsgrad der ges{\"a}gten Oberfl{\"a}che bei Mittelung der Versuche ohne bzw. mit Zwischenmedien knapp nicht signifikant.}, subject = {Transmissionsgrad}, language = {de} } @phdthesis{Breunig2021, author = {Breunig, Daniel Manfred}, title = {Transport properties and proximity effect of topological hybrid structures}, doi = {10.25972/OPUS-25054}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250546}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Over the last two decades, accompanied by their prediction and ensuing realization, topological non-trivial materials like topological insulators, Dirac semimetals, and Weyl semimetals have been in the focus of mesoscopic condensed matter research. While hosting a plethora of intriguing physical phenomena all on their own, even more fascinating features emerge when superconducting order is included. Their intrinsically pronounced spin-orbit coupling leads to peculiar, time-reversal symmetry protected surface states, unconventional superconductivity, and even to the emergence of exotic bound states in appropriate setups. This Thesis explores various junctions built from - or incorporating - topological materials in contact with superconducting order, placing particular emphasis on the transport properties and the proximity effect. We begin with the analysis of Josephson junctions where planar samples of mercury telluride are sandwiched between conventional superconducting contacts. The surprising observation of pronounced excess currents in experiments, which can be well described by the Blonder-Tinkham-Klapwijk theory, has long been an ambiguous issue in this field, since the necessary presumptions are seemingly not met. We propose a resolution to this predicament by demonstrating that the interface properties in hybrid nanostructures of distinctly different materials yet corroborate these assumptions and explain the outcome. An experimental realization is feasible by gating the contacts. We then proceed with NSN junctions based on time-reversal symmetry broken Weyl semimetals and including superconducting order. Due to the anisotropy of the electron band structure, both the transport properties as well as the proximity effect depend substantially on the orientation of the interfaces between the materials. Moreover, an imbalance can be induced in the electron population between Weyl nodes of opposite chirality, resulting in a non-vanishing spin polarization of the Cooper pairs leaking into the normal contacts. We show that such a system features a tunable dipole character with possible applications in spintronics. Finally, we consider partially superconducting surface states of three-dimensional topological insulators. Tuning such a system into the so-called bipolar setup, this results in the formation of equal-spin Cooper pairs inside the superconductor, while simultaneously acting as a filter for non-local singlet pairing. The creation and manipulation of these spin-polarized Cooper pairs can be achieved by mere electronic switching processes and in the absence of any magnetic order, rendering such a nanostructure an interesting system for superconducting spintronics. The inherent spin-orbit coupling of the surface state is crucial for this observation, as is the bipolar setup which strongly promotes non-local Andreev processes.}, subject = {Supraleitung}, language = {en} } @article{BieberFoersterHaefelietal.2021, author = {Bieber, Michael and Foerster, Kathrin I. and Haefeli, Walter E. and Pham, Mirko and Schuhmann, Michael K. and Kraft, Peter}, title = {Treatment with edoxaban attenuates acute stroke severity in mice by reducing blood-brain barrier damage and inflammation}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {18}, issn = {1422-0067}, doi = {10.3390/ijms22189893}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284481}, year = {2021}, abstract = {Patients with atrial fibrillation and previous ischemic stroke (IS) are at increased risk of cerebrovascular events despite anticoagulation. In these patients, treatment with non-vitamin K oral anticoagulants (NOAC) such as edoxaban reduced the probability and severity of further IS without increasing the risk of major bleeding. However, the detailed protective mechanism of edoxaban has not yet been investigated in a model of ischemia/reperfusion injury. Therefore, in the current study we aimed to assess in a clinically relevant setting whether treatment with edoxaban attenuates stroke severity, and whether edoxaban has an impact on the local cerebral inflammatory response and blood-brain barrier (BBB) function after experimental IS in mice. Focal cerebral ischemia was induced by transient middle cerebral artery occlusion in male mice receiving edoxaban, phenprocoumon or vehicle. Infarct volumes, functional outcome and the occurrence of intracerebral hemorrhage were assessed. BBB damage and the extent of local inflammatory response were determined. Treatment with edoxaban significantly reduced infarct volumes and improved neurological outcome and BBB function on day 1 and attenuated brain tissue inflammation. In summary, our study provides evidence that edoxaban might exert its protective effect in human IS by modulating different key steps of IS pathophysiology, but further studies are warranted.}, language = {en} } @article{BaumKojKloetingetal.2021, author = {Baum, Petra and Koj, Severin and Kl{\"o}ting, Nora and Bl{\"u}her, Matthias and Classen, Joseph and Paeschke, Sabine and Gericke, Martin and Toyka, Klaus V. and Nowicki, Marcin and Kosacka, Joanna}, title = {Treatment-induced neuropathy in diabetes (TIND) — Developing a disease model in type 1 diabetic rats}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {4}, issn = {1422-0067}, doi = {10.3390/ijms22041571}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285793}, year = {2021}, abstract = {Treatment-induced neuropathy in diabetes (TIND) is defined by the occurrence of an acute neuropathy within 8 weeks of an abrupt decrease in glycated hemoglobin-A1c (HbA1c). The underlying pathogenic mechanisms are still incompletely understood with only one mouse model being explored to date. The aim of this study was to further explore the hypothesis that an abrupt insulin-induced fall in HbA1c may be the prime causal factor of developing TIND. BB/OKL (bio breeding/OKL, Ottawa Karlsburg Leipzig) diabetic rats were randomized in three groups, receiving insulin treatment by implanted subcutaneous osmotic insulin pumps for 3 months, as follows: Group one received 2 units per day; group two 1 unit per day: and group three 1 unit per day in the first month, followed by 2 units per day in the last two months. We serially examined blood glucose and HbA1c levels, motor- and sensory/mixed afferent conduction velocities (mNCV and csNCV) and peripheral nerve morphology, including intraepidermal nerve fiber density and numbers of Iba-1 (ionized calcium binding adaptor molecule 1) positive macrophages in the sciatic nerve. Only in BB/OKL rats of group three, with a rapid decrease in HbA1c of more than 2\%, did we find a significant decrease in mNCV in sciatic nerves (81\% of initial values) after three months of treatment as compared to those group three rats with a less marked decrease in HbA1c <2\% (mNCV 106\% of initial values, p ≤ 0.01). A similar trend was observed for sensory/mixed afferent nerve conduction velocities: csNCV were reduced in BB/OKL rats with a rapid decrease in HbA1c >2\% (csNCV 90\% of initial values), compared to those rats with a mild decrease <2\% (csNCV 112\% of initial values, p ≤ 0.01). Moreover, BB/OKL rats of group three with a decrease in HbA1c >2\% showed significantly greater infiltration of macrophages by about 50\% (p ≤ 0.01) and a decreased amount of calcitonin gene related peptide (CGRP) positive nerve fibers as compared to the animals with a milder decrease in HbA1c. We conclude that a mild acute neuropathy with inflammatory components was induced in BB/OKL rats as a consequence of an abrupt decrease in HbA1c caused by high-dose insulin treatment. This experimentally induced neuropathy shares some features with TIND in humans and may be further explored in studies into the pathogenesis and treatment of TIND.}, language = {en} } @article{PhilippDietzBucheltetal.2021, author = {Philipp, Marius and Dietz, Andreas and Buchelt, Sebastian and Kuenzer, Claudia}, title = {Trends in satellite earth observation for permafrost related analyses — A review}, series = {Remote Sensing}, volume = {13}, journal = {Remote Sensing}, number = {6}, doi = {10.3390/rs13061217}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234198}, year = {2021}, abstract = {Climate change and associated Arctic amplification cause a degradation of permafrost which in turn has major implications for the environment. The potential turnover of frozen ground from a carbon sink to a carbon source, eroding coastlines, landslides, amplified surface deformation and endangerment of human infrastructure are some of the consequences connected with thawing permafrost. Satellite remote sensing is hereby a powerful tool to identify and monitor these features and processes on a spatially explicit, cheap, operational, long-term basis and up to circum-Arctic scale. By filtering after a selection of relevant keywords, a total of 325 articles from 30 international journals published during the last two decades were analyzed based on study location, spatio- temporal resolution of applied remote sensing data, platform, sensor combination and studied environmental focus for a comprehensive overview of past achievements, current efforts, together with future challenges and opportunities. The temporal development of publication frequency, utilized platforms/sensors and the addressed environmental topic is thereby highlighted. The total number of publications more than doubled since 2015. Distinct geographical study hot spots were revealed, while at the same time large portions of the continuous permafrost zone are still only sparsely covered by satellite remote sensing investigations. Moreover, studies related to Arctic greenhouse gas emissions in the context of permafrost degradation appear heavily underrepresented. New tools (e.g., Google Earth Engine (GEE)), methodologies (e.g., deep learning or data fusion etc.)and satellite data (e.g., the Methane Remote Sensing LiDAR Mission (Merlin) and the Sentinel-fleet)will thereby enable future studies to further investigate the distribution of permafrost, its thermal state and its implications on the environment such as thermokarst features and greenhouse gas emission rates on increasingly larger spatial and temporal scales.}, language = {en} } @article{GesslerLehmannBoeseletal.2021, author = {Gessler, Florian and Lehmann, Felix and B{\"o}sel, Julian and Fuhrer, Hannah and Neugebauer, Hermann and Wartenberg, Katja E. and Wolf, Stefan and Bernstock, Joshua D. and Niesen, Wolf-Dirk and Schuss, Patrick}, title = {Triage and Allocation of Neurocritical Care Resources During the COVID 19 Pandemic - A National Survey}, series = {Frontiers in Neurology}, volume = {11}, journal = {Frontiers in Neurology}, issn = {1664-2295}, doi = {10.3389/fneur.2020.609227}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221593}, year = {2021}, abstract = {Objective: In light of the ongoing COVID-19 pandemic and the associated hospitalization of an overwhelming number of ventilator-dependent patients, medical and/or ethical patient triage paradigms have become essential. While guidelines on the allocation of scarce resources do exist, such work within the subdisciplines of intensive care (e.g., neurocritical care) remains limited. Methods: A 16-item questionnaire was developed that sought to explore/quantify the expert opinions of German neurointensivists with regard to triage decisions. The anonymous survey was conducted via a web-based platform and in total, 96 members of the Initiative of German Neurointensive Trial Engagement (IGNITE)-study group were contacted via e-mail. The IGNITE consortium consists of an interdisciplinary panel of specialists with expertise in neuro-critical care (i.e., anesthetists, neurologists and neurosurgeons). Results: Fifty members of the IGNITE consortium responded to the questionnaire; in total the respondents were in charge of more than 500 Neuro ICU beds throughout Germany. Common determinants reported which affected triage decisions included known patient wishes (98\%), the state of health before admission (96\%), SOFA-score (85\%) and patient age (69\%). Interestingly, other principles of allocation, such as a treatment of "youngest first" (61\%) and members of the healthcare sector (50\%) were also noted. While these were the most accepted parameters affecting the triage of patients, a "first-come, first-served" principle appeared to be more accepted than a lottery for the allocation of ICU beds which contradicts much of what has been reported within the literature. The respondents also felt that at least one neurointensivist should serve on any interdisciplinary triage team. Conclusions: The data gathered in the context of this survey reveal the estimation/perception of triage algorithms among neurointensive care specialists facing COVID-19. Further, it is apparent that German neurointensivists strongly feel that they should be involved in any triage decisions at an institutional level given the unique resources needed to treat patients within the Neuro ICU.}, language = {en} } @article{RiemerKrankeHelfetal.2021, author = {Riemer, Manuel and Kranke, Peter and Helf, Antonia and Mayer, Debora and Popp, Maria and Schlesinger, Tobias and Meybohm, Patrick and Weibel, Stephanie}, title = {Trial registration and selective outcome reporting in 585 clinical trials investigating drugs for prevention of postoperative nausea and vomiting}, series = {BMC Anesthesiology}, volume = {21}, journal = {BMC Anesthesiology}, doi = {10.1186/s12871-021-01464-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265518}, year = {2021}, abstract = {Background: Selective outcome reporting in clinical trials introduces bias in the body of evidence distorting clinical decision making. Trial registration aims to prevent this bias and is suggested by the International Committee of Medical Journal Editors (ICMJE) since 2004. Methods: The 585 randomized controlled trials (RCTs) published between 1965 and 2017 that were included in a recently published Cochrane review on antiemetic drugs for prevention of postoperative nausea and vomiting were selected. In a retrospective study, we assessed trial registration and selective outcome reporting by comparing study publications with their registered protocols according to the 'Cochrane Risk of bias' assessment tool 1.0. Results: In the Cochrane review, the first study which referred to a registered trial protocol was published in 2004. Of all 585 trials included in the Cochrane review, 334 RCTs were published in 2004 or later, of which only 22\% (75/334) were registered. Among the registered trials, 36\% (27/75) were pro- and 64\% (48/75) were retrospectively registered. 41\% (11/27) of the prospectively registered trials were free of selective outcome reporting bias, 22\% (6/27) were incompletely registered and assessed as unclear risk, and 37\% (10/27) were assessed as high risk. Major outcome discrepancies between registered and published high risk trials were a change from the registered primary to a published secondary outcome (32\%), a new primary outcome (26\%), and different outcome assessment times (26\%). Among trials with high risk of selective outcome reporting 80\% favoured at least one statistically significant result. Registered trials were assessed more often as 'overall low risk of bias' compared to non-registered trials (64\% vs 28\%). Conclusions: In 2017, 13 years after the ICMJE declared prospective protocol registration a necessity for reliable clinical studies, the frequency and quality of trial registration in the field of PONV is very poor. Selective outcome reporting reduces trustworthiness in findings of clinical trials. Investigators and clinicians should be aware that only following a properly registered protocol and transparently reporting of predefined outcomes, regardless of the direction and significance of the result, will ultimately strengthen the body of evidence in the field of PONV research in the future.}, language = {en} } @article{BanKaračićTomićetal.2021, author = {Ban, Željka and Karačić, Zrinka and Tomić, Sanja and Amini, Hashem and Marder, Todd B. and Piantanida, Ivo}, title = {Triarylborane dyes as a novel non-covalent and non-inhibitive fluorimetric markers for DPP III enzyme}, series = {Molecules}, volume = {26}, journal = {Molecules}, number = {16}, issn = {1420-3049}, doi = {10.3390/molecules26164816}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245046}, year = {2021}, abstract = {Novel dyes were prepared by simple "click CuAAC" attachment of a triarylborane-alkyne to the azide side chain of an amino acid yielding triarylborane dye 1 which was conjugated with pyrene (dye 2) forming a triarylborane-pyrene FRET pair. In contrast to previous cationic triarylboranes, the novel neutral dyes interact only with proteins, while their affinity to DNA/RNA is completely abolished. Both the reference triarylborane amino acid and triarylborane-pyrene conjugate bind to BSA and the hDPP III enzyme with high affinities, exhibiting a strong (up to 100-fold) fluorescence increase, whereby the triarylborane-pyrene conjugate additionally retained FRET upon binding to the protein. Furthermore, the triarylborane dyes, upon binding to the hDPP III enzyme, did not impair its enzymatic activity under a wide range of experimental conditions, thus being the first non-covalent fluorimetric markers for hDPP III, also applicable during enzymatic reactions with hDPP III substrates.}, language = {en} } @article{HeydarianSchweinlinSchwarzetal.2021, author = {Heydarian, Motaharehsadat and Schweinlin, Matthias and Schwarz, Thomas and Rawal, Ravisha and Walles, Heike and Metzger, Marco and Rudel, Thomas and Kozjak-Pavlovic, Vera}, title = {Triple co-culture and perfusion bioreactor for studying the interaction between Neisseria gonorrhoeae and neutrophils: A novel 3D tissue model for bacterial infection and immunity}, series = {Journal of Tissue Engineering}, volume = {12}, journal = {Journal of Tissue Engineering}, doi = {10.1177/2041731420988802}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259032}, pages = {2041731420988802}, year = {2021}, abstract = {Gonorrhea, a sexually transmitted disease caused by the bacteria Neisseria gonorrhoeae, is characterized by a large number of neutrophils recruited to the site of infection. Therefore, proper modeling of the N. gonorrhoeae interaction with neutrophils is very important for investigating and understanding the mechanisms that gonococci use to evade the immune response. We have used a combination of a unique human 3D tissue model together with a dynamic culture system to study neutrophil transmigration to the site of N. gonorrhoeae infection. The triple co-culture model consisted of epithelial cells (T84 human colorectal carcinoma cells), human primary dermal fibroblasts, and human umbilical vein endothelial cells on a biological scaffold (SIS). After the infection of the tissue model with N. gonorrhoeae, we introduced primary human neutrophils to the endothelial side of the model using a perfusion-based bioreactor system. By this approach, we were able to demonstrate the activation and transmigration of neutrophils across the 3D tissue model and their recruitment to the site of infection. In summary, the triple co-culture model supplemented by neutrophils represents a promising tool for investigating N. gonorrhoeae and other bacterial infections and interactions with the innate immunity cells under conditions closely resembling the native tissue environment.}, language = {en} } @article{FoehrenbacherZehKrahfussetal.2021, author = {F{\"o}hrenbacher, Steffen A. and Zeh, Vivien and Krahfuss, Mirjam J. and Ignat'ev, Nikolai V. and Finze, Maik and Radius, Udo}, title = {Tris(pentafluoroethyl)difluorophosphorane and N-Heterocyclic Carbenes: Adduct Formation and Frustrated Lewis Pair Reactivity}, series = {European Journal of Inorganic Chemistry}, volume = {2021}, journal = {European Journal of Inorganic Chemistry}, number = {20}, doi = {10.1002/ejic.202100183}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-257386}, pages = {1941-1960}, year = {2021}, abstract = {The synthesis and characterization of Lewis acid/base adducts between tris(pentafluoroethyl)difluorophosphorane PF\(_{2}\)(C\(_{2}\)F\(_{5}\))\(_{3}\) and selected N-heterocyclic carbenes (NHCs) R\(_{2}\)Im (1,3-di-organyl-imidazolin-2-ylidene) and phosphines are reported. For NHCs with small alkyl substituents at nitrogen (R=Me, nPr, iPr) the adducts NHC ⋅ PF\(_{2}\)(C\(_{2}\)F\(_{5}\))\(_{3}\) (2 a-h) were isolated. The reaction with the sterically more demanding NHCs Dipp\(_{2}\)Im (1,3-bis-(2,6-di-iso-propylphenyl)-imidazolin-2-ylidene) (1 i) and tBu\(_{2}\)Im (1,3-di-tert-butyl-imidazolin-2-ylidene) (1 j) afforded the aNHC adducts 3 i and 3 j (a denotes "abnormal" NHC coordination via a backbone carbon atom). The use of tBuMeIm (1-tert-butyl-3-methyl-imidazolin-2-ylidene) (1 m) led to partial decomposition of the NHC and formation of the salt [tBuMeIm-H][MeIm ⋅ PF\(_{2}\)(C\(_{2}\)F\(_{5}\))\(_{3}\)] (4 m). The phosphorane PF\(_{2}\)(C\(_{2}\)F\(_{5}\))\(_{3}\) forms adducts with PMe\(_{3}\) but does not react with PPh\(_{3}\) or PCy\(_{3}\). The mer-cis isomer of literature-known Me\(_{3}\)P ⋅ PF\(_{2}\)(C\(_{2}\)F\(_{5}\))\(_{3}\) (5 a) was structurally characterized. Mixtures of the phosphorane PF\(_{2}\)(C\(_{2}\)F\(_{5}\))\(_{3}\) and the sterically encumbered NHCs tBu\(_{2}\)Im, Dipp\(_{2}\)Im, and Dipp\(_{2}\)Im\(^{H2}\) (1,3-bis-(2,6-di-iso-propylphenyl)-imidazolidin-2-ylidene) (1 k) showed properties of FLPs (Frustrated Lewis Pairs) as these mixtures were able to open the ring of THF (tetrahydrofuran) to yield NHC-(CH\(_{2}\))\(_{4}\)O-PF\(_{2}\)(C\(_{2}\)F\(_{5}\))\(_{3}\) 6 i-k. Furthermore, the deprotonation of the weak C-H acids CH\(_{3}\)CN, acetone, and ethyl acetate was achieved, which led to the formation of the corresponding imidazolium salts and the phosphates [PF\(_{2}\)(C\(_{2}\)F\(_{5}\))\(_{3}\)(CH\(_{2}\)CN)]\(^{-}\) (7), [PF\(_{2}\)(C\(_{2}\)F\(_{5}\))\(_{3}\)(OC(=CH\(_{2}\))CH\(_{3}\))]\(^{-}\) (8) and [PF\(_{2}\)(C\(_{2}\)F\(_{5}\))\(_{3}\)(CH\(_{2}\)CO\(_{2}\)Et)]\(^{-}\) (9).}, language = {en} } @article{FoehrenbacherKrahfussZapfetal.2021, author = {F{\"o}hrenbacher, Steffen A. and Krahfuss, Mirjam J. and Zapf, Ludwig and Friedrich, Alexandra and Ignat'ev, Nikolai V. and Finze, Maik and Radius, Udo}, title = {Tris(pentafluoroethyl)difluorophosphorane: a versatile fluoride acceptor for transition metal chemistry}, series = {Chemistry Europe}, volume = {27}, journal = {Chemistry Europe}, number = {10}, doi = {10.1002/chem.202004885}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-256665}, pages = {3504-3516}, year = {2021}, abstract = {Fluoride abstraction from different types of transition metal fluoride complexes [L\(_n\)MF] (M=Ti, Ni, Cu) by the Lewis acid tris(pentafluoroethyl)difluorophosphorane (C\(_2\)F\(_5\))\(_3\)PF\(_2\) to yield cationic transition metal complexes with the tris(pentafluoroethyl)trifluorophosphate counterion (FAP anion, [(C\(_2\)F\(_5\))\(_3\)PF\(_3\)]\(^-\)) is reported. (C\(_2\)F\(_5\))\(_3\)PF\(_2\) reacted with trans-[Ni(iPr\(_2\)Im)\(_2\)(Ar\(^F\))F] (iPr2Im=1,3-diisopropylimidazolin-2-ylidene; Ar\(^F\)=C\(_6\)F\(_5\), 1 a; 4-CF\(_3\)-C\(_6\)F\(_4\), 1 b; 4-C\(_6\)F\(_5\)-C\(_6\)F\(_4\), 1 c) through fluoride transfer to form the complex salts trans-[Ni(iPr\(_2\)Im)\(_2\)(solv)(Ar\(^F\))]FAP (2 a-c[solv]; solv=Et\(_2\)O, CH\(_2\)Cl\(_2\), THF) depending on the reaction medium. In the presence of stronger Lewis bases such as carbenes or PPh\(_3\), solvent coordination was suppressed and the complexes trans-[Ni(iPr\(_2\)Im)\(_2\)(PPh\(_3\))(C\(_6\)F\(_5\))]FAP (trans-2 a[PPh\(_3\)]) and cis-[Ni(iPr\(_2\)Im)\(_2\)(Dipp\(_2\)Im)(C\(_6\)F\(_5\))]FAP (cis-2 a[Dipp\(_2\)Im]) (Dipp\(_2\)Im=1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene) were isolated. Fluoride abstraction from [(Dipp\(_2\)Im)CuF] (3) in CH\(_2\)Cl\(_2\) or 1,2-difluorobenzene led to the isolation of [{(Dipp\(_2\)Im)Cu}\(_2\)]\(^2\)\(^+\)2 FAP\(^-\) (4). Subsequent reaction of 4 with PPh\(_3\) and different carbenes resulted in the complexes [(Dipp\(_2\)Im)Cu(LB)]FAP (5 a-e, LB=Lewis base). In the presence of C6Me6, fluoride transfer afforded [(Dipp\(_2\)Im)Cu(C\(_6\)Me\(_6\))]FAP (5 f), which serves as a source of [(Dipp\(_2\)Im)Cu)]\(^+\). Fluoride abstraction of [Cp\(_2\)TiF\(_2\)] (7) resulted in the formation of dinuclear [FCp\(_2\)Ti(μ-F)TiCp\(_2\)F]FAP (8) (Cp=η\(^5\)-C\(_5\)H\(_5\)) with one terminal fluoride ligand at each titanium atom and an additional bridging fluoride ligand.}, language = {en} } @article{KalogirouSchwingerKocotetal.2021, author = {Kalogirou, Charis and Schwinger, Marcel and Kocot, Arkadius and Riedmiller, Hubertus}, title = {Troubleshooting of failed continence mechanisms in the ileocecal pouch: Operative technique and long-term results of the intussuscepted ileal nipple valve}, series = {International Journal of Urology}, volume = {28}, journal = {International Journal of Urology}, number = {11}, doi = {10.1111/iju.14654}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259431}, pages = {1105-1111}, year = {2021}, abstract = {Objectives To provide a detailed step-by-step operative technique, and to report on long-term functional and metabolic outcomes in secondary continence mechanisms in the form of secondary intussuscepted ileal nipple valves in revisional surgery of ileocecal pouches. Methods From May 1997 to May 2015, 18 female and 10 male patients suffering from dysfunctional primary continence mechanisms of their ileocecal pouch underwent revisonal surgery to create a secondary ileal nipple valve at our tertiary referral center. The average follow-up period was 65.4 months. Results After surgery, 24 patients were continent by day and night, and four patients showed minor incontinence with the use of a safety pad. The average frequency of clean intermittent catheterization decreased both during the day and at night. The diameter of the catheters used for clean intermittent catheterization increased significantly. No patient showed stomal stenosis, change of stool habits or metabolic situation in the follow-up period. Furthermore, the creation of the secondary ileal nipple valves did not affect the capacity of the reservoir. In the long-term follow up, two patients required the construction of a third continence mechanism, making for an overall success rate of 92\% in the study group. Conclusion To our knowledge, this is the first study of long-term results after the creation of secondary ileal nipple valves. We provide evidence that the creation of a secondary ileal nipple valve is a safe and reliable procedure for continence restoration in ileocecal pouches with excellent functional and metabolic long-term outcomes.}, language = {en} } @article{GehrkeHackenbergTecleetal.2021, author = {Gehrke, Thomas and Hackenberg, Stephan and Tecle, Nyat and Hagen, Rudolf and Scherzad, Agmal}, title = {Tuberculosis in the Head and Neck: Changing Trends and Age-Related Patterns}, series = {The Laryngoscope}, volume = {131}, journal = {The Laryngoscope}, number = {12}, doi = {10.1002/lary.29668}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-257524}, pages = {2701-2705}, year = {2021}, abstract = {Objective To evaluate changing trends in patient collectives, age-related patterns of manifestation, and diagnostic pathways of patients with extrapulmonary head and neck tuberculosis (TB), and to provide strategies to fasten diagnosis in these patients. Study design Case control study. Methods A 10-year retrospective analysis of 35 patients diagnosed with extrapulmonary TB in the head and neck at a tertiary university institution from 2009 to 2019, with special focus on the influence of the patient's age on consideration of TB and clinical patterns. Results The vast majority of patients younger than 40 years had their origin in countries with high TB burden (P = .0003), and TB was considered very early as a differential diagnosis (P = .0068), while most patients older than 40 years were domestic citizens initially suspected for a malignancy, who more often had an underlying immunosuppressive condition (0.0472). Most frequent manifestations in both groups were the lymph nodes, larynx, and oropharynx. Surprisingly, no differences in the rates of open TB or history of TB infection in the family anamnesis were found. Conclusion The two groups of patients found most often are younger patients migrating from regions with high TB burden and elderly domestic patients suffering from immunosuppressive conditions, with the latter often being misdiagnosed as malignancies. TB remains an important but difficult differential diagnosis, due to the initially unspecific symptoms and the great variety in the presentation of manifestations in the head and neck.}, language = {en} } @article{HaiderAhmadYangetal.2021, author = {Haider, Malik Salman and Ahmad, Taufiq and Yang, Mengshi and Hu, Chen and Hahn, Lukas and Stahlhut, Philipp and Groll, J{\"u}rgen and Luxenhofer, Robert}, title = {Tuning the thermogelation and rheology of poly(2-oxazoline)/poly(2-oxazine)s based thermosensitive hydrogels for 3D bioprinting}, series = {Gels}, volume = {7}, journal = {Gels}, number = {3}, issn = {2310-2861}, doi = {10.3390/gels7030078}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241781}, year = {2021}, abstract = {As one kind of "smart" material, thermogelling polymers find applications in biofabrication, drug delivery and regenerative medicine. In this work, we report a thermosensitive poly(2-oxazoline)/poly(2-oxazine) based diblock copolymer comprising thermosensitive/moderately hydrophobic poly(2-N-propyl-2-oxazine) (pPrOzi) and thermosensitive/moderately hydrophilic poly(2-ethyl-2-oxazoline) (pEtOx). Hydrogels were only formed when block length exceeded certain length (≈100 repeat units). The tube inversion and rheological tests showed that the material has then a reversible sol-gel transition above 25 wt.\% concentration. Rheological tests further revealed a gel strength around 3 kPa, high shear thinning property and rapid shear recovery after stress, which are highly desirable properties for extrusion based three-dimensional (3D) (bio) printing. Attributed to the rheology profile, well resolved printability and high stackability (with added laponite) was also possible. (Cryo) scanning electron microscopy exhibited a highly porous, interconnected, 3D network. The sol-state at lower temperatures (in ice bath) facilitated the homogeneous distribution of (fluorescently labelled) human adipose derived stem cells (hADSCs) in the hydrogel matrix. Post-printing live/dead assays revealed that the hADSCs encapsulated within the hydrogel remained viable (≈97\%). This thermoreversible and (bio) printable hydrogel demonstrated promising properties for use in tissue engineering applications.}, language = {en} } @article{GrunzPennigFieberetal.2021, author = {Grunz, Jan-Peter and Pennig, Lenhard and Fieber, Tabea and Gietzen, Carsten Herbert and Heidenreich, Julius Frederik and Huflage, Henner and Gruschwitz, Philipp and Kuhl, Philipp Josef and Petritsch, Bernhard and Kosmala, Aleksander and Bley, Thorsten Alexander and Gassenmaier, Tobias}, title = {Twin robotic x-ray system in small bone and joint trauma: Impact of cone-beam computed tomography on treatment decisions}, series = {European Radiology}, volume = {31}, journal = {European Radiology}, issn = {0938-7994}, doi = {10.1007/s00330-020-07563-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235233}, pages = {3600-3609}, year = {2021}, abstract = {Objectives Trauma evaluation of extremities can be challenging in conventional radiography. A multi-use x-ray system with cone-beam CT (CBCT) option facilitates ancillary 3-D imaging without repositioning. We assessed the clinical value of CBCT scans by analyzing the influence of additional findings on therapy. Methods Ninety-two patients underwent radiography and subsequent CBCT imaging with the twin robotic scanner (76 wrist/hand/finger and 16 ankle/foot/toe trauma scans). Reports by on-call radiologists before and after CBCT were compared regarding fracture detection, joint affliction, comminuted injuries, and diagnostic confidence. An orthopedic surgeon recommended therapy based on reported findings. Surgical reports (N = 52) and clinical follow-up (N = 85) were used as reference standard. Results CBCT detected more fractures (83/64 of 85), joint involvements (69/53 of 71), and multi-fragment situations (68/50 of 70) than radiography (all p < 0.001). Six fractures suspected in radiographs were ruled out by CBCT. Treatment changes based on additional information from CBCT were recommended in 29 patients (31.5\%). While agreement between advised therapy before CBCT and actual treatment was moderate (κ = 0.41 [95\% confidence interval 0.35-0.47]; p < 0.001), agreement after CBCT was almost perfect (κ = 0.88 [0.83-0.93]; p < 0.001). Diagnostic confidence increased considerably for CBCT studies (p < 0.001). Median effective dose for CBCT was 4.3 μSv [3.3-5.3 μSv] compared to 0.2 μSv [0.1-0.2 μSv] for radiography. Conclusions CBCT provides advantages for the evaluation of acute small bone and joint trauma by detecting and excluding extremity fractures and fracture-related findings more reliably than radiographs. Additional findings induced therapy change in one third of patients, suggesting substantial clinical impact.}, language = {en} } @article{SchmidtFantuzziKlopfetal.2021, author = {Schmidt, Paul and Fantuzzi, Felipe and Klopf, Jonas and Schr{\"o}der, Niklas B. and Dewhurst, Rian D. and Braunschweig, Holger and Engel, Volker and Engels, Bernd}, title = {Twisting versus delocalization in CAAC- and NHC-stabilized boron-based biradicals: the roles of sterics and electronics}, series = {Chemistry - A European Journal}, volume = {27}, journal = {Chemistry - A European Journal}, number = {16}, doi = {10.1002/chem.202004619}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-256636}, pages = {5160-5170}, year = {2021}, abstract = {Twisted boron-based biradicals featuring unsaturated C\(_2\)R\(_2\) (R=Et, Me) bridges and stabilization by cyclic (alkyl)(amino)carbenes (CAACs) were recently prepared. These species show remarkable geometrical and electronic differences with respect to their unbridged counterparts. Herein, a thorough computational investigation on the origin of their distinct electrostructural properties is performed. It is shown that steric effects are mostly responsible for the preference for twisted over planar structures. The ground-state multiplicity of the twisted structure is modulated by the σ framework of the bridge, and different R groups lead to distinct multiplicities. In line with the experimental data, a planar structure driven by delocalization effects is observed as global minimum for R=H. The synthetic elusiveness of C\(_2\)R\(_2\)-bridged systems featuring N-heterocyclic carbenes (NHCs) was also investigated. These results could contribute to the engineering of novel main group biradicals.}, language = {en} } @article{KiemLeischNeureiteretal.2021, author = {Kiem, Dominik and Leisch, Michael and Neureiter, Daniel and Haslauer, Theresa and Egle, Alexander and Melchardt, Thomas and Topp, Max S. and Greil, Richard}, title = {Two cases of pancytopenia with Coombs-negative hemolytic anemia after chimeric antigen receptor T-cell therapy}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {11}, issn = {1422-0067}, doi = {10.3390/ijms22115449}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284977}, year = {2021}, abstract = {Background: Chimeric antigen receptor (CAR) T-cells are changing the therapeutic landscape of hematologic malignancies. Severe side effects include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), but prolonged cytopenia has also been reported. The underlying mechanism for prolonged cytopenia is poorly understood so far. Cases: Severe pancytopenia with grade 2-3 anemia was marked 2-3 months after treatment. Laboratory evaluation revealed undetectable levels of haptoglobin with increased reticulocyte counts. Coomb's tests were negative, no schistocytes were detected on blood smear, and infectious causes were ruled out. Increased erythropoiesis without lymphoma infiltration was noted on bone marrow biopsy. A spontaneous increase in haptoglobin and hemoglobin levels was observed after several weeks. For one patient, peripheral CAR-T levels were monitored over time. We observed a decline at the same time as hemoglobin levels began to rise, implying a potential causality. Conclusion: To our knowledge, we describe the first two cases of Coombs-negative hemolytic anemia after CAR-T treatment for B-cell lymphoma. We encourage routine monitoring for hemolytic anemia after CAR-T treatment and also encourage further investigations on the underlying mechanism.}, language = {en} } @article{SchubertSchulzeProdromouetal.2021, author = {Schubert, Jonathan and Schulze, Andrea and Prodromou, Chrisostomos and Neuweiler, Hannes}, title = {Two-colour single-molecule photoinduced electron transfer fluorescence imaging microscopy of chaperone dynamics}, series = {Nature Communications}, volume = {12}, journal = {Nature Communications}, doi = {10.1038/s41467-021-27286-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265754}, year = {2021}, abstract = {Many proteins are molecular machines, whose function is dependent on multiple conformational changes that are initiated and tightly controlled through biochemical stimuli. Their mechanistic understanding calls for spectroscopy that can probe simultaneously such structural coordinates. Here we present two-colour fluorescence microscopy in combination with photoinduced electron transfer (PET) probes as a method that simultaneously detects two structural coordinates in single protein molecules, one colour per coordinate. This contrasts with the commonly applied resonance energy transfer (FRET) technique that requires two colours per coordinate. We demonstrate the technique by directly and simultaneously observing three critical structural changes within the Hsp90 molecular chaperone machinery. Our results reveal synchronicity of conformational motions at remote sites during ATPase-driven closure of the Hsp90 molecular clamp, providing evidence for a cooperativity mechanism in the chaperone's catalytic cycle. Single-molecule PET fluorescence microscopy opens up avenues in the multi-dimensional exploration of protein dynamics and allosteric mechanisms.}, language = {en} } @article{TamihardjaLutyjKraftetal.2021, author = {Tamihardja, J{\"o}rg and Lutyj, Paul and Kraft, Johannes and Lisowski, Dominik and Weick, Stefan and Flentje, Michael and Polat, B{\"u}lent}, title = {Two-Weekly High-Dose-Rate Brachytherapy Boost After External Beam Radiotherapy for Localized Prostate Cancer: Long-Term Outcome and Toxicity Analysis}, series = {Frontiers in Oncology}, volume = {11}, journal = {Frontiers in Oncology}, issn = {2234-943X}, doi = {10.3389/fonc.2021.764536}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250992}, year = {2021}, abstract = {Purpose Evaluation of clinical outcome of two-weekly high-dose-rate brachytherapy boost after external beam radiotherapy (EBRT) for localized prostate cancer. Methods 338 patients with localized prostate cancer receiving definitive EBRT followed by a two-weekly high-dose-rate brachytherapy boost (HDR-BT boost) in the period of 2002 to 2019 were analyzed. EBRT, delivered in 46 Gy (DMean) in conventional fractionation, was followed by two fractions HDR-BT boost with 9 Gy (D90\%) two and four weeks after EBRT. Androgen deprivation therapy (ADT) was added in 176 (52.1\%) patients. Genitourinary (GU)/gastrointestinal (GI) toxicity was evaluated utilizing the Common Toxicity Criteria for Adverse Events (version 5.0) and biochemical failure was defined according to the Phoenix definition. Results Median follow-up was 101.8 months. 15 (4.4\%)/115 (34.0\%)/208 (61.5\%) patients had low-/intermediate-/high-risk cancer according to the D`Amico risk classification. Estimated 5-year and 10-year biochemical relapse-free survival (bRFS) was 84.7\% and 75.9\% for all patients. The estimated 5-year bRFS was 93.3\%, 93.4\% and 79.5\% for low-, intermediate- and high-risk disease, respectively. The estimated 10-year freedom from distant metastasis (FFM) and overall survival (OS) rates were 86.5\% and 70.0\%. Cumulative 5-year late GU toxicity and late GI toxicity grade ≥ 2 was observed in 19.3\% and 5.0\% of the patients, respectively. Cumulative 5-year late grade 3 GU/GI toxicity occurred in 3.6\%/0.3\%. Conclusions Two-weekly HDR-BT boost after EBRT for localized prostate cancer showed an excellent toxicity profile with low GU/GI toxicity rates and effective long-term biochemical control.}, language = {en} } @misc{WinterFroemel2021, author = {Winter-Froemel, Esme}, title = {Ulrich Detges (2. April 1958-7. Februar 2021)}, series = {Zeitschrift f{\"u}r romanische Philologie}, volume = {137}, journal = {Zeitschrift f{\"u}r romanische Philologie}, number = {4}, issn = {1865-9063}, doi = {10.1515/zrp-2021-0071}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250801}, pages = {1299 -- 1302}, year = {2021}, abstract = {Kein Abstract verf{\"u}gbar.}, language = {de} } @phdthesis{RuckgebStelzl2021, author = {Ruck [geb. Stelzl], Claudia Michaela}, title = {Ultraschallgesteuerte Perikardpunktion unter Einsatz eines elektromagnetischen Ortungssystems - Entwicklung und experimentelle Validierung}, doi = {10.25972/OPUS-24754}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-247543}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Perikardpunktionen werden neben diagnostischen Anwendungen vor allem in Notfallsituationen, wie bei einer Perikardtamponade, eingesetzt und k{\"o}nnen dann lebensrettend sein. Unerfahrene Untersucher stellen hierbei aber einen wesent- lichen Faktor f{\"u}r Komplikationen oder den Behandlungserfolg dar. Um die Perikardpunktion zu optimieren, wurde im Rahmen einer experimentellen Untersuchung die neue Technik unter Verwendung eines elektromagnetischen Nadel Tracking Systems validiert. Hierzu wurde zun{\"a}chst ein Modell entwickelt um die Punktionsgenauigkeit des Systems abh{\"a}ngig von seinen Einflussgr{\"o}ßen m{\"o}glichst exakt beurteilen zu k{\"o}nnen. Es zeigte sich, dass das Punktionsergebnis von mehreren Faktoren wie Punktionswinkel, -seite, Ultraschallebene, Abstand zum Ziel und Vorhandensein von Metallgegenst{\"a}nden abh{\"a}ngt. Des Weiteren wurde ein realit{\"a}tsnahes Perikardpunktionsmodell verwendet. An diesem Modell wurden Perikarderg{\"u}sse unterschiedlicher Gr{\"o}ße simuliert und anschließend Punktionen mit der Nadel durchgef{\"u}hrt. Im BluePhantomTM Modell wurden mithilfe des Nadel Tracking Systems von unerfahrenen Untersuchern Trefferquoten zwischen 80 und 100\% erreicht, unabh{\"a}ngig von der Ergussgr{\"o}ße. Anatomisch orientierte Punktionen erreichten hingegen nur Trefferquoten zwischen 11 und 44\% bei einer Ergussmenge von 250 ml (bzw. 60-80\% bei 450 ml). Das getestete Nadel Tracking System k{\"o}nnte somit zur Verbesserung der Perikardpunktionen beitragen. F{\"u}r eine abschließende Bewertung ist eine Validierung der Methode unter klinischen Bedingungen m{\"o}glich.}, subject = {Perikard}, language = {de} } @article{KarimiFreundWageretal.2021, author = {Karimi, Sohail M. and Freund, Matthias and Wager, Brittney M. and Knoblauch, Michael and Fromm, J{\"o}rg and M. Mueller, Heike and Ache, Peter and Krischke, Markus and Mueller, Martin J. and M{\"u}ller, Tobias and Dittrich, Marcus and Geilfus, Christoph-Martin and Alfaran, Ahmed H. and Hedrich, Rainer and Deeken, Rosalia}, title = {Under salt stress guard cells rewire ion transport and abscisic acid signaling}, series = {New Phytologist}, volume = {231}, journal = {New Phytologist}, number = {3}, doi = {10.1111/nph.17376}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259635}, pages = {1040-1055}, year = {2021}, abstract = {Soil salinity is an increasingly global problem which hampers plant growth and crop yield. Plant productivity depends on optimal water-use efficiency and photosynthetic capacity balanced by stomatal conductance. Whether and how stomatal behavior contributes to salt sensitivity or tolerance is currently unknown. This work identifies guard cell-specific signaling networks exerted by a salt-sensitive and salt-tolerant plant under ionic and osmotic stress conditions accompanied by increasing NaCl loads. We challenged soil-grown Arabidopsis thaliana and Thellungiella salsuginea plants with short- and long-term salinity stress and monitored genome-wide gene expression and signals of guard cells that determine their function. Arabidopsis plants suffered from both salt regimes and showed reduced stomatal conductance while Thellungiella displayed no obvious stress symptoms. The salt-dependent gene expression changes of guard cells supported the ability of the halophyte to maintain high potassium to sodium ratios and to attenuate the abscisic acid (ABA) signaling pathway which the glycophyte kept activated despite fading ABA concentrations. Our study shows that salinity stress and even the different tolerances are manifested on a single cell level. Halophytic guard cells are less sensitive than glycophytic guard cells, providing opportunities to manipulate stomatal behavior and improve plant productivity.}, language = {en} } @phdthesis{LiessneeEller2021, author = {Liess [n{\´e}e Eller], Anna Katharina Luise}, title = {Understanding the regulation of the ubiquitin-conjugating enzyme UBE2S}, doi = {10.25972/OPUS-20419}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204190}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {The ubiquitination of proteins serves as molecular signal to control an enormous number of physiological processes and its dysregulation is connected to human diseases like cancer. The versatility of this signal stems from the diverse ways by which ubiquitin can be attached to its targets. Thus, specificity and tight regulation of the ubiquitination are pivotal requirements of ubiquitin signaling. Ubiquitin-conjugating enzymes (E2s) act at the heart of the ubiquitination cascade, transferring ubiquitin from a ubiquitin-activating enzyme (E1) to a ubiquitin ligase (E3) or substrate. When cooperating with a RING-type E3, ubiquitin-conjugating enzymes can determine linkage specificity in ubiquitin chain formation. Our understanding of the regulation of E2 activities is still limited at a structural level. The work described here identifies two regulation mechanisms in UBE2S, a cognate E2 of the human RING-type E3 anaphase-promoting complex/cyclosome (APC/C). UBE2S elongates ubiquitin chains on APC/C substrates in a Lys11 linkage-specific manner, thereby targeting these substrates for degradation and driving mitotic progression. In addition, UBE2S was found to have a role in DNA repair by enhancing non-homologous end-joining (NHEJ) and causing transcriptional arrest at DNA damage sites in homologous recombination (HR). Furthermore, UBE2S overexpression is a characteristic feature of many cancer types and is connected to poor prognosis and diminished response to therapy. The first regulatory mechanism uncovered in this thesis involves the intramolecular auto-ubiquitination of a particular lysine residue (Lys+5) close to the active site cysteine, presumably through conformational flexibility of the active site region. The Lys+5-linked ubiquitin molecule adopts a donor-like, 'closed' orientation towards UBE2S, thereby conferring auto-inhibition. Notably, Lys+5 is a major physiological ubiquitination site in ~25\% of the human E2 enzymes, thus providing regulatory opportunities beyond UBE2S. Besides the active, monomeric state and the auto-inhibited state caused by auto-ubiquitination, I discovered that UBE2S can adopt a dimeric state. The latter also provides an auto-inhibited state, in which ubiquitin transfer is blocked via the obstruction of donor binding. UBE2S dimerization is promoted by its unique C-terminal extension, suppresses auto-ubiquitination and thereby the proteasomal degradation of UBE2S. Taken together, the data provided in this thesis illustrate the intricate ways by which UBE2S activity is fine-tuned and the notion that structurally diverse mechanisms have evolved to restrict the first step in the catalytic cycle of E2 enzymes.}, subject = {E2}, language = {en} } @article{SchusterLisackSubotaetal.2021, author = {Schuster, Sarah and Lisack, Jaime and Subota, Ines and Zimmermann, Henriette and Reuter, Christian and Mueller, Tobias and Morriswood, Brooke and Engstler, Markus}, title = {Unexpected plasiticty in the life cycle of Trypanosoma brucei}, series = {eLife}, volume = {10}, journal = {eLife}, doi = {10.7554/eLife.66028.sa2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-261744}, year = {2021}, abstract = {African trypanosomes cause sleeping sickness in humans and nagana in cattle. These unicellular parasites are transmitted by the bloodsucking tsetse fly. In the mammalian host's circulation, proliferating slender stage cells differentiate into cell cycle-arrested stumpy stage cells when they reach high population densities. This stage transition is thought to fulfil two main functions: first, it auto-regulates the parasite load in the host; second, the stumpy stage is regarded as the only stage capable of successful vector transmission. Here, we show that proliferating slender stage trypanosomes express the mRNA and protein of a known stumpy stage marker, complete the complex life cycle in the fly as successfully as the stumpy stage, and require only a single parasite for productive infection. These findings suggest a reassessment of the traditional view of the trypanosome life cycle. They may also provide a solution to a long-lasting paradox, namely the successful transmission of parasites in chronic infections, despite low parasitemia.}, language = {en} } @article{AlmeidaHristovaDashkovskiy2021, author = {Almeida, R. and Hristova, S. and Dashkovskiy, S.}, title = {Uniform bounded input bounded output stability of fractional-order delay nonlinear systems with input}, series = {International Journal of Robust and Nonlinear Control}, volume = {31}, journal = {International Journal of Robust and Nonlinear Control}, number = {1}, doi = {10.1002/rnc.5273}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218554}, pages = {225 -- 249}, year = {2021}, abstract = {The bounded input bounded output (BIBO) stability for a nonlinear Caputo fractional system with time-varying bounded delay and nonlinear output is studied. Utilizing the Razumikhin method, Lyapunov functions and appropriate fractional derivatives of Lyapunov functions some new bounded input bounded output stability criteria are derived. Also, explicit and independent on the initial time bounds of the output are provided. Uniform BIBO stability and uniform BIBO stability with input threshold are studied. A numerical simulation is carried out to show the system's dynamic response, and demonstrate the effectiveness of our theoretical results.}, language = {en} } @phdthesis{Ross2021, author = {Ross, Veronique}, title = {Unterscheiden sich gesunde Neugeborene mit auff{\"a}lligem bzw. unauff{\"a}lligem H{\"o}rscreeningbefund in Eigenschaften der Grundfrequenzkontur ihrer spontanen Weinlaute?}, doi = {10.25972/OPUS-22487}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224875}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {In der vorliegenden Studie wurden gesunde Neugeborene mit unterschiedlichen H{\"o}rscreeningbefunden in den Eigenschaften der Grundfrequenzkontur ihrer spontanen Weinlaute untersucht. Ziel der vorliegenden Studie war es zu ermitteln, ob sich spontane Laut{\"a}ußerungen von gesunden Neugeborenen mit einem unauff{\"a}lligen Neugeborenenh{\"o}rscreening (NHS) im Vergleich zu einem auff{\"a}lligen NHS in den modellierten Grundfrequenzeigenschaften und der Melodiel{\"a}nge unterscheiden. Im Rahmen des Projektes wurden 82 gesunde Neugeborene (2.-4. Lebenstag) rekrutiert und je nach Ergebnis des routinem{\"a}ßig durchgef{\"u}hrten NHS in zwei Gruppen eingeteilt. Diese waren Neugeborene mit unauff{\"a}lligem NHS (Gruppe NHS_TU) und Neugeborene mit auff{\"a}lligem NHS (Gruppe NHS_TA). In einer Nachkontrolle nach 3 Monaten wurde {\"u}berpr{\"u}ft, ob die Neugeborene mit einem auff{\"a}lligem NHS auch alle h{\"o}rgesund waren. Es wurden insgesamt 2.330 spontane Laut{\"a}ußerungen aufgenommen und quantitativ analysiert. Hierbei wurden die Melodiel{\"a}nge, das Minimum, das Maximum, die mittlere Grundfrequenz und der Grundfrequenzhub f{\"u}r jede Laut{\"a}ußerung berechnet. F{\"u}r jedes Neugeborene wurde ein arithmetischer Mittelwert f{\"u}r die analysierten Variablen gebildet und anschließend zwischen beiden Gruppen verglichen. Die Ergebnisse der vorliegenden Studie belegen, dass sich gesunde Neugeborene mit unterschiedlichen H{\"o}rscreeningbefunden nicht signifikant in ihren Grundfrequenzeigenschaften unterscheiden. Somit konnte best{\"a}tigt werden, dass sich gesunde Neugeborene mit auff{\"a}lligem NHS, welche in der Nachuntersuchung h{\"o}rgesund sind (Falsch-Positiv-Getestete), die gleichen Lauteigenschaften wie Neugeborene mit unauff{\"a}lligem NHS aufweisen. Insgesamt konnte die vorliegende Studie erstmalig Eigenschaften der Grundfrequenzkontur spontaner Laut{\"a}ußerungen von Neugeborenen mit einem unauff{\"a}lligen NHS-Befund im Vergleich zu einem auff{\"a}lligen NHS-Befund objektiv analysieren und entsprechende Referenzwerte f{\"u}r gesunde Neugeborene liefern. Somit w{\"a}re eine wichtige Voraussetzung daf{\"u}r geschaffen, in nachfolgenden Studien zu untersuchen, ob die Melodiekontur ein potenzieller Fr{\"u}hindikator f{\"u}r eine sensorineurale H{\"o}rst{\"o}rung bei Neugeborenen sein k{\"o}nnte.}, subject = {Sprachentwicklung}, language = {de} } @phdthesis{GrafvonSodenFraunhofen2021, author = {Graf von Soden-Fraunhofen, Raban}, title = {Untersuchung der Begrenzung k{\"u}nstlicher Ern{\"a}hrung am Lebensende auf der Palliativstation der Universit{\"a}tsklinik W{\"u}rzburg}, doi = {10.25972/OPUS-23875}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-238755}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Untersuchung der Begrenzung k{\"u}nstlicher Ernährung am Lebensende auf der Palliativstation der Universitätsklinik W{\"u}rzburg Hintergrund: Leitlinien empfehlen die Beendigung lebensverlängernder Interventionen am Lebensende. Wir untersuchten die Relevanz von k{\"u}nstlicher Ernährung und Fl{\"u}ssigkeitszufuhr am Lebensende in einer spezialisierten Palliativstation (SPS) und die alltägliche Praxis einschränkender Entscheidungen. Methoden: Retrospektive Analysen der Akten der verstorbenen Patienten in den Jahren 2012-2014. Ergebnisse: 397/887 Patienten starben auf der Palliativstation (44,7\%). 65/397 Patienten erhielten in den letzten 11 Tagen ihres Lebens (16,3\%) entweder k{\"u}nstliche Ernährung (KE) oder therapeutische Fl{\"u}ssigkeitszufuhr (>1000 ml Fl{\"u}ssigkeit, FS). Bei 53/65 Patienten wurde die KE/FS mehr als 48 Stunden vor dem Tod (81,5\%) und bei 8/65 Patienten k{\"u}rzer als 48 Stunden vor dem Tod (12,3\%) beendet. 2/65 Patienten erhielten KE und FS bis zum Tod (3,0\%). Die Entscheidungsfindung bez{\"u}glich der Begrenzung von KE bzw. FS wurde in 44/65 Patientenakten (67,6\%) dokumentiert. Die Entscheidungen wurden 2-4 Tage vor dem Tod bei 25/44 Patienten (56,8\%), k{\"u}rzer als 2 Tage vor dem Tod bei 4/44 Patienten (9,0\%) und länger als 4 Tage vor dem Tod bei 15/44 Patienten (34,0\%) getroffe. Als Gr{\"u}nde wurden angegeben: Beginn der Sterbephase (33/44, 75,0 \%), Patientenwunsch (6/44, 13,6\%), Nebenwirkungen (3/44, 6,8\%) und andere (2/44, 4,5\%) ). Bei 43/63 Patienten wurden KE und FS auf einmal beendet (68,2\%) und bei 20/63 Patienten wurde es langsam {\"u}ber einen Zeitraum von etwa 48 Stunden beendet (31,7\%). 60/65 Patienten erhielten in den letzten 11 Lebenstagen auch potenziell lebensverlängernde Medikamente (60/65, 92,3\%). Bei 37/60 Patienten wurde die potenziell lebensverlängernde Medikation (LM) gleichzeitig mit der KE (61,6\%) beendet, bei 21/60 Patienten wurde die LM innerhalb von 48 Stunden nach Beendigung der KE (35,0\%) beendet und 2 / 65 Patienten erhielten LM bis zum Tod (3,0\%), einer von ihnen zusammen mit KE. Die beiden Patienten, die KE und FS bis zum Tod erhielten, blieben k{\"u}rzer als 48 Stunden auf der Palliativstation. Schlussfolgerung: Die Beendigung von KE und FS war ein relevantes Thema. Ebenso die Beendigung einer potentiell lebensverlängernden Medikation bei diesen Patienten. Auch in einem SPS-Setting ist die Sterbephase nicht leicht zu erkennen und die Entscheidungsfindung scheint Zeit zu brauchen. Ein rigoristischer Ansatz scheint nicht hilfreich zu sein.}, subject = {Begrenzung}, language = {de} } @phdthesis{Gurok2021, author = {Gurok, Anna}, title = {Untersuchung der postoperativen Ergebnisse nach Rekonstruktion des medialen-patellofemoralen Ligamentes (MPFL) nach 5 Jahren}, doi = {10.25972/OPUS-24058}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240585}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Patellaluxationen sind eine vor allem bei jungen, aktiven Patienten h{\"a}ufige Verletzung komplexer {\"A}tiologie. Die Rekonstruktion des medialen patellofemoralen Ligaments (MPFL) ist die aktuell etablierte Operationstechnik bei strecknaher patellofemoraler Instabilit{\"a}t, zu der in der Literatur eine Vielzahl an patellaren Fixationstechniken des autologen Sehnentransplantates beschrieben werden. In dieser Studie wurden 71 Patienten 5 Jahre nach Rekonstruktion des MPFLs mit patellarer Fixation in Weichteiltechnik nachuntersucht und die klinischen Ergebnisse der Operationsmethode und die Zufriedenheit der Patienten ermittelt. Daf{\"u}r wurde die Reluxationsrate ermittelt und die Funktion der Kniegelenke im Alltag mithilfe des Kujala- und des Lysholm-Fragebogens, das Aktivit{\"a}tsniveau der Patienten mit der Tegner-Aktivit{\"a}tsskala erfasst. Im Rahmen einer Nachuntersuchung wurden die Beweglichkeit des Kniegelenks und die Stabilit{\"a}t der Kniescheibe klinisch untersucht. Die Ergebnisse wurden unter Ber{\"u}cksichtigung klinischer und radiologischer Risikofaktoren ausgewertet. Die Studie ergab eine Reluxationsrate von 5,6\% und ist somit vergleichbar mit der Rate anderer in der Literatur beschriebener Techniken. Die Ergebnisse der klinischen Untersuchung ergaben eine stabile ligament{\"a}re F{\"u}hrung der Kniescheibe bei insgesamt guter Beweglichkeit der Kniegelenke, die Auswertung der Frageb{\"o}gen zeigten signifikante Verbesserungen der Funktion der operierten Kniegelenke im Alltag bei unver{\"a}ndertem Aktivit{\"a}tsniveau. Im Ergebnis kann durch die vorliegende Studie belegt werden, dass durch die Rekonstruktion des MPFL mit weichteiliger patellarer Fixation langfristig gute Ergebnisse bei einer niedrigen Komplikationsrate erzielt werden k{\"o}nnen. Allerdings erh{\"o}ht das Zusammentreffen verschiedener Pathologien wie eine Patella alta mit einer ausgepr{\"a}gten Dysplasie der Trochlea das Risiko f{\"u}r eine persistierende Instabilit{\"a}t und eine erneute Luxation.}, subject = {Patella}, language = {de} } @phdthesis{Traxler2021, author = {Traxler, Claudia}, title = {Untersuchung serumpiegelabh{\"a}ngiger unerw{\"u}nschter Arzneimittelwirkungen von selektiven Serotonin-R{\"u}ckaufnahme-Inhibitoren sowie Serotonin-Noradrenalin-R{\"u}ckaufnahme-Inhibitoren}, doi = {10.25972/OPUS-23594}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235946}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Hyponatri{\"a}mie, definiert als Serum-Natrium < 135 mmol/l, ist ein potentiell lebensbedrohender Zustand und wird h{\"a}ufig bei {\"a}lteren und psychiatrischen Patienten beobachtet. In den letzten Jahren wurden viele Case reports {\"u}ber SSRI- und SNRI- induzierte Hyponatri{\"a}mien publiziert. Kardiale Ver{\"a}nderungen, insbesondere eine verl{\"a}ngerte QT-Zeit oder erh{\"o}hte Herzfrequenz, werden auch als h{\"a}ufig beobachtete Nebenwirkungen unter Therapie mit Antidepressiva beschrieben. Dies konnte bislang insbesondere w{\"a}hrend der Einnahme von trizyklischen Antidepressiva beobachtet werden. Oft kann der beobachtete Effekt in Zusammenhang mit der verabreichten Dosis gebracht werden. Bei der SSRI- bzw. SNRI-induzierten Hyponatri{\"a}mie konnte dies bislang nicht gezeigt werden. In der Literatur lassen sich im Allgemeinen kaum Studien finden, die einen Zusammenhang der Serumkonzentration von SSRI und SNRI auf potentiell auftretende Nebenwirkungen untersucht haben. Ziel der vorliegenden Studie war zu zeigen, ob h{\"o}here Serumkonzentrationen von Citalopram, Escitalopram, Sertralin, Venlafaxin oder Duloxetin h{\"a}ufiger zu Hyponatri{\"a}mien bzw. Verl{\"a}ngerungen der QT-Zeit f{\"u}hren.}, subject = {Sertralin}, language = {de} } @phdthesis{Haschke2021, author = {Haschke, Sebastian}, title = {Untersuchung Thiol-En vernetzter Gelatine Hydrogele und Vergleich mit Alginat-Gelatine in Bezug auf das in vitro Zellverhalten von Fibroblasten}, doi = {10.25972/OPUS-24872}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248727}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Hydrogele stehen als Material f{\"u}r den 3D-Biodruck zunehmend im Fokus aktueller Forschung, da sie aufgrund ihrer wasserhaltigen Struktur optimale Voraussetzungen f{\"u}r Anwendungen der Zellkultur aufweisen. Durch die Verarbeitung solcher Biotinten mittels additiver Fertigungstechniken der Biofabrikation erhofft man sich besch{\"a}digtes oder krankes Gewebe zu heilen oder zu ersetzen. Allerdings wird der Fortschritt in diesem Bereich durch einen Mangel an geeigneten Materialien gebremst, weshalb die Entwicklung neuer Biotinten von zentraler Bedeutung ist. Das Polymer GelAGE ist ein am Lehrstuhl f{\"u}r Funktionswerkstoffe der Medizin und Zahnheilkunde der Universit{\"a}t W{\"u}rzburg synthetisiertes Hydrogelsystem. Zu diesem {\"u}ber eine Thiol-En Reaktion vernetzenden Material stehen systematische Untersuchungen der f{\"u}r die in vitro Zellkultur relevanten Eigenschaften noch aus. Das Ziel dieser Arbeit war daher die biologische Evaluation von GelAGE und der Vergleich mit der Biotinte Alginat-Gelatine. Zu diesem Zweck wurden L929-Zellen f{\"u}r 7 Tage in verschiedenen Hydrogelzusammensetzungen in vitro kultiviert. Um die zytokompatiblen Eigenschaften in den verschiedenen Versuchsgruppen zu untersuchen, wurden die Proben mittels der in vitro Testverfahren Live/Dead F{\"a}rbung, DNA-Assay, CCK-8-Assay und Phalloidin-F{\"a}rbung analysiert. Im Rahmen dieser Arbeit konnte ein Herstellungsprotokoll f{\"u}r das Material GelAGE etabliert werden, welches eine Grundlage f{\"u}r die Durchf{\"u}hrung weiterer biologischer Experimente bietet. Das Resultat der biologischen Untersuchungen war, dass das Polymer GelAGE als zytokompatibel bewertet werden kann, es jedoch nicht die Qualit{\"a}t des Alginat-Gelatine Hydrogelsystems aufweist. Allerdings konnten die Eigenschaften der GelAGE Proben teilweise durch eine Modifikation mit Humanem Pl{\"a}ttchenlysat verbessert werden. Des Weiteren konnten deutliche Unterschiede in der Zell-Material- Interaktion zwischen den verschiedenen GelAGE Varianten nachgewiesen werden.}, subject = {Hydrogel}, language = {de} } @phdthesis{Hermann2021, author = {Hermann, Alexander}, title = {Untersuchung von B-B-Doppelbindungen als Bestandteil konjugierter p-Systeme}, doi = {10.25972/OPUS-20459}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204592}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Der erste Teil dieser Arbeit besch{\"a}ftigt sich mit der "Synthese und Reaktivit{\"a}t sterisch anspruchsvoller Iminoborane". Dabei war es m{\"o}glich, ausgehend von einem Terphenylamin geeignete Aminoborane zu synthetisieren, welche anschließend mit starken, nicht-nukleophilen Basen umgesetzt wurden. Mittels formaler HCl-Eliminierung mit LiTmp gelang auf diese Weise die Darstellung sterisch anspruchsvoller Iminoborane. Der zweite Teil dieser Arbeit befasst sich mit der "Untersuchung von B-B-Doppelbindungen als Bestandteil konjugierter p-Systeme". Durch die Verwendung von sterisch wenig anspruchsvollen Liganden oder Boryl-Substituenten war es m{\"o}glich planare Diboren-Systeme zu generieren und dar{\"u}berhinaus Divinyldiborene darzustellen.}, subject = {Konjugation}, language = {de} } @phdthesis{Kreutzmann2021, author = {Kreutzmann, Moritz Paul}, title = {Untersuchung von Markern f{\"u}r oxidativen Stress und DNA-Sch{\"a}den bei arterieller Hypertonie}, doi = {10.25972/OPUS-24338}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-243380}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Patienten mit arterieller Hypertonie haben ein erh{\"o}htes Risiko eine Tumorerkrankung, insbesondere Nierenzellkarzinome, zu entwickeln. Die arterielle Hypertonie ist {\"u}ber die Entstehung von oxidativem Stress mit der Entwicklung von DNA-Sch{\"a}den verkn{\"u}pft, wobei ein hochreguliertes Renin-Angiotensin-Aldosteron-System (RAAS) eine entscheidende Rolle einnimmt. Das Ziel dieser Arbeit war es zum einen Hypertoniker (HypAll) und gesunde Kontrollen und zum anderen gut (HypGut) und schlecht (HypSch) eingestellte Hypertoniker unter Ber{\"u}cksichtigung der eingenommenen Antihypertensiva bez{\"u}glich ihrer Level an oxidativem Stress und DNA-Sch{\"a}den zu vergleichen. Zus{\"a}tzlich erfolgte im Rahmen einer L{\"a}ngsschnittanalyse der intraindividuelle Vergleich unter den Hypertonikern. Hierf{\"u}r erfolgte die Bestimmung von SHp, D-ROM und 3-Nitrotyrosin als Marker f{\"u}r oxidativen Stress im Plasma, von 8-oxodG, 15-F2t-Isoprostan und Malondialdehyd als Marker f{\"u}r oxidativen Stress im Urin und von γ-H2AX und Mikrokernen als Marker f{\"u}r DNA-Sch{\"a}den in Lymphozyten. Dabei konnte ein erh{\"o}hter oxidativer Stress in der HypAll-Gruppe verglichen zu den Kontrollen anhand aller Marker f{\"u}r oxidativen Stress mit Ausnahme von Malondialdehyd festgestellt werden. Nach Altersadjustierung zeigte sich dieser Gruppenunterschied nur noch f{\"u}r die Proteinstressmarker SHp und 3-Nitrotyrosin signifikant. Bez{\"u}glich der Marker f{\"u}r DNA-Sch{\"a}den ergab sich kein Unterschied zwischen HypAll und Kontrollen. Ebenso zeigte sich kein signifikanter Unterschied in den Leveln f{\"u}r oxidativen Stress und DNA-Sch{\"a}den zwischen der HypGut- und HypSch-Gruppe. Zuletzt konnte im Rahmen der L{\"a}ngsschnittstudie ein positiver Zusammenhang zwischen der Entwicklung des Blutdrucks und des oxidativen Stresses anhand der Ver{\"a}nderung von D-ROM und des systolischen Blutdrucks beobachtet werden. Die teils nicht-signifikanten und teils mangelnden Unterschiede zwischen HypAll und Kontrollen sowie zwischen HypGut und HypSch sind am ehesten durch das besondere Patientengut, welches sich auch grundlegend von dem anderer vergleichbarer Studien unterscheidet, erkl{\"a}rbar. Die Patienten mit therapieresistenter Hypertonie (TRH) zeichnen sich durch eine langj{\"a}hrige Einnahme zahlreicher Antihypertensiva aus. Diese, insbesondere die RAAS-wirksamen, besitzen eine {\"u}ber die reine Blutdrucksenkung hinausgehende antioxidative und antigenotoxische Wirkung, welche vermutlich zu einer Angleichung der Level f{\"u}r oxidativen Stress und DNA-Sch{\"a}den gef{\"u}hrt hat. Um die Dynamik der Biomarker und den Einfluss der Antihypertensiva auf oxidativen Stress und DNA-Sch{\"a}den besser zu verstehen, sind weitere Studien {\"u}ber einen l{\"a}ngeren Beobachtungszeitraum sowie mit zus{\"a}tzlich therapienaiven Hypertonikern sinnvoll. Die weitere Erforschung von Biomarkern, um sie im klinischen Alltag zur Verbesserung der Patientenbehandlung einsetzen zu k{\"o}nnen, ist notwendig.}, subject = {Oxidativer Stress}, language = {de} } @phdthesis{Rajab2021, author = {Rajab, Suhaila}, title = {Untersuchung von Sub-Millisekunden Dynamiken und allosterischer Kommunikation in Ligandenbindedom{\"a}nen ionotroper Glutamatrezeptoren}, doi = {10.25972/OPUS-24494}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-244946}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Ionotrope Glutamatrezeptoren (iGluRs) sind ligandengesteuerte Ionenkan{\"a}le und vermitteln den Großteil der exzitatorischen Signalweiterleitung im gesamten zentralen Nervensystem. Dar{\"u}ber hinaus spielen iGluRs eine entscheidende Rolle bei der neuronalen Entwicklung und Funktion, einschließlich Lernprozessen und Ged{\"a}chtnisbildung. Da eine Fehlfunktion dieser Rezeptoren mit zahlreichen neurodegenerativen Erkrankungen verbunden ist, stellen iGluRs zudem wichtige Zielproteine f{\"u}r die pharmakologische Wirkstoffentwicklung dar. Im Allgemeinen wird zwischen drei Untergruppen ionotroper Glutamatrezeptoren unterschieden, welche aufgrund ihrer Selektivit{\"a}t f{\"u}r einen bestimmten Liganden benannt sind: AMPA-, Kainate-, und NMDA-Rezeptoren. Die iGluRs jeder dieser Untergruppen bestehen in der Regel aus vier Untereinheiten, welche wiederum aus vier semiautonomen Dom{\"a}nen aufgebaut sind: (i) die aminoterminale Dom{\"a}ne (ATD), (ii) die Ligandenbindedom{\"a}ne (LBD), (iii) die Transmembrandom{\"a}ne (TMD) und (iv) die carboxyterminale Dom{\"a}ne (CTD). Die Ligandenbindedom{\"a}ne, welche wiederum aus zwei Lobes (D1 und D2) besteht und in ihrer Struktur einer Muschelschale {\"a}hnelt, vollzieht bei Bindung eines Neurotransmitters eine Konformations{\"a}nderung, wobei sie sich um den gebundenen Agonisten herumschließt. Diese Konformations{\"a}nderung der LBD wird auf die Transmembrandom{\"a}ne, welche den membran{\"u}berspannenden Ionenkanal ausbildet, {\"u}bertragen, was in einer Umlagerung der Transmembranhelices und infolgedessen der {\"O}ffnung des Ionenkanals resultiert. Die Konformations{\"a}nderung der LBD ist demnach die treibende Kraft, welche dem {\"O}ffnen und Schließen des Ionenkanals zugrunde liegt. Aus diesem Grund stellt die isolierte Ligandenbindedom{\"a}ne, welche als l{\"o}sliches Protein hergestellt werden kann, ein etabliertes Modellsystem zur Untersuchung der strukturellen und funktionellen Zusammenh{\"a}nge innerhalb des Funktionsmechanismus ionotroper Glutamatrezeptoren dar. Im Rahmen dieser Arbeit wurden die Konformationsdynamiken der in Escherichia coli-Bakterien exprimierten isolierten Ligandenbindedom{\"a}nen der drei homologen Untergruppen - AMPA-, Kainate- und NMDA-Rezeptoren - sowohl als Monomer als auch als Dimer untersucht. Hierbei wurden im ungebundenen Apo-Zustand der Proteine signifikante Kinetiken im Bereich von Nanosekunden bis Mikrosekunden festgestellt, welche bei Bindung eines Agonisten sowie bei Dimerisierung erheblichen Ver{\"a}nderungen zeigen. Dar{\"u}ber hinaus wurde allosterische Kommunikation zwischen den LBDs der NMDA-Untergruppe untersucht, wobei in der Tat ein deutlicher allosterischer Effekt in Bezug auf die Konformationsdynamiken der Proteine gemessen werden konnte. Weiterhin wurde ein PET-FCS-basiertes Verfahren zur Messung der Dissoziationskonstante der Bindung eines Liganden an die LBD eines AMPA-Rezeptors entwickelt. Zuletzt wurde außerdem ermittelt, ob ein Unterschied zwischen vollen und partiellen Agonisten hinsichtlich ihres Einflusses auf die Konformationsdynamiken einer AMPA-Rezeptor LBD besteht, was nachgewiesenermaßen nicht der Fall ist. Alle Messungen wurden auf Einzelmolek{\"u}lebene auf Zeitskalen von Nanosekunden bis Millisekunden basierend auf Fluoreszenzfluktuationen unter Verwendung des photoinduzierten Elektronentransfers (PET) in Kombination mit Korrelationsspektroskopie (PET-FCS) durchgef{\"u}hrt. Zu diesem Zweck wurden PET-basierte Fluoreszenzsonden entwickelt, um Konformations{\"a}nderungen auf einer r{\"a}umlichen Skala von einem Nanometer zu detektieren. Durch die Experimente innerhalb dieser Arbeit konnte gezeigt werden, dass die PET-FCS-Methode eine vielversprechende Erg{\"a}nzung zu allen bisher bestehenden Methoden zur Untersuchung der Konformationsdynamiken der Ligandenbindedom{\"a}ne ionotroper Glutamatrezeptoren darstellt und daher eine aussichtsreiche M{\"o}glichkeit zur Erweiterung des zuk{\"u}nftigen Verst{\"a}ndnisses der Funktionsweise von iGluRs bietet.}, subject = {Fluoreszenzkorrelationsspektroskopie}, language = {de} } @article{KleinsasserWiestScherzadetal.2021, author = {Kleinsasser, N. and Wiest, F. and Scherzad, A. and Ickrath, P. and Poier, N. and Hackenberg, S.}, title = {Untersuchungen zum Sch{\"a}digungspotenzial durch den Konsum von E-Zigaretten: In-vitro-Exposition von humanen Nasenschleimhautzellen mit Propylenglykol im Air-Liquid-Interface}, series = {HNO}, volume = {69}, journal = {HNO}, doi = {10.1007/s00106-021-00998-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-280329}, pages = {952-960}, year = {2021}, abstract = {Hintergrund Die E‑Zigarette erfreut sich in den letzten Jahren zunehmender Beliebtheit. Die Frage nach der Toxizit{\"a}t ist jedoch noch nicht eindeutig gekl{\"a}rt, und es herrscht global Unsicherheit im Umgang mit der E‑Zigarette. Ziel Ziel der vorliegenden Arbeit war es, Propylenglykol, ein Hauptbestandteil der Liquide, in Bezug auf m{\"o}gliche akute Entz{\"u}ndungsreaktionen, zyto- und genotoxische Auswirkungen auf humane Nasenschleimhautzellen zu untersuchen. Material und Methoden Die Nasenschleimhautzellen wurden von zehn Probanden im Air-Liquid-Interface kultiviert und anschließend mit unterschiedlichen Konzentrationen des Propylenglykols bedampft. Die Analyse erfolgte mittels Trypanblau-Test, Comet-Assay, Mikrokerntest und IL-6- und IL-8-Sandwich-ELISA. Ergebnis Der Trypanblau-Test zeigte keine Reduktion der Vitalit{\"a}t. Im Sandwich-ELISA konnte kein Anstieg der IL-6- und IL-8-Konzentrationen nachgewiesen werden. Im Comet-Assay zeigte das Olive Tail Moment eine Sch{\"a}digung im Vergleich zur Negativkontrolle in allen untersuchten Konzentrationen. Zudem zeigte sich eine dosisabh{\"a}ngige Sch{\"a}digung. Im Mikrokerntest konnte ein Unterschied zwischen dem Reinstoff und der Negativkontrolle gefunden werden. Schlussfolgerung Es zeigten sich m{\"o}glicherweise reparable DNS-Sch{\"a}digungen im Comet-Assay. Im Mikrokerntest konnten diese nur in der Reinstoffkonzentration best{\"a}tigt werden. Es sollte ein restriktiver Umgang mit der E‑Zigarette erfolgen, bis insbesondere Langzeitstudien vorliegen. Zudem ist eine eindeutige Deklaration der Inhaltsstoffe der Liquide durch die Hersteller zu fordern, um weitergehende Sch{\"a}digungspotenziale untersuchen zu k{\"o}nnen.}, language = {de} } @phdthesis{Buchner2021, author = {Buchner, Kim}, title = {Untersuchungen zur Assoziation von Schlafbruxismus und psychischer Belastung bei Kindern}, doi = {10.25972/OPUS-22563}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225639}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Bruxismus bezeichnet eine sich wiederholende Kaumuskelaktivit{\"a}t mit Knirschen oder Aufeinanderpressen der Z{\"a}hne. W{\"a}hrend bei Erwachsenen die Ursachen und die Pathophysiologie schon weitreichend erforscht wurden, gab es bei Kindern bislang keine systematische Untersuchung hinsichtlich des Zusammenhangs mit psychopathologischen Faktoren. Deshalb wurde unsere Studie nun erstmals mit Bruxismusmessung nach Goldstandard sowie mit normierten und validierten Frageb{\"o}gen zu verschiedenen psychosozialen Dimensionen als Querschnittsuntersuchung bei 53 acht- bis zw{\"o}lfj{\"a}hrigen Kindern durchgef{\"u}hrt. Besonderes Augenmerk wurde dabei auf den hypothetisierten Zusammenhang zwischen Schlafbruxismus und Angstsensitivit{\"a}t sowie Angstintensit{\"a}t gelegt. Außerdem wurde der Einfluss weiterer psychosozialer Faktoren (wie Lebensqualit{\"a}t, Anzahl negativer Lebensereignisse, Verhaltensauff{\"a}lligkeiten, ADHS-Symptomatik, depressive Symptomatik, Zwangssymptomatik, Ticsymptomatik, Alter und Geschlecht) auf die o.g. Pr{\"a}diktoren per multipler Regressionsanalyse gepr{\"u}ft. Auf Basis der durchgef{\"u}hrten Untersuchung ergaben sich keine Hinweise auf eine Assoziation von Bruxismus zu psychosozialen Dimensionen. Die vorbeschriebenen Zusammenh{\"a}nge erwiesen sich als statistisch nicht signifikant. Dies mag zum einen der Stichprobenauswahl von gesunden Kindern geschuldet sein, die weder von Bruxismus noch von anderen Faktoren vorbekannt klinisch beeintr{\"a}chtigt waren. Andererseits k{\"o}nnen aber auch fehlerhafte Ausgangs{\"u}berlegungen durch nicht dem Goldstandard entsprechenden Messungen der Vorstudien zu diesem Ergebnis gef{\"u}hrt haben. Dar{\"u}ber hinaus verl{\"a}uft die Kindesentwicklung interindividuell sehr variabel und tempor{\"a}re myofunktionelle Beeintr{\"a}chtigungen k{\"o}nnen ohne Bezug zu psychischer Belastung auftreten.}, subject = {Bruxismus}, language = {de} } @phdthesis{Scholl2021, author = {Scholl, Eva Elena}, title = {Untersuchungen zur Informationsweitergabe in Familien mit erblichem Brust- und Eierstockkrebs}, doi = {10.25972/OPUS-24325}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-243253}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {F{\"u}r die hier beschriebene Studie wurde ein Fragebogen erstellt, welcher von 80 Tr{\"a}gerinnen und Tr{\"a}gern einer pathogenen Mutation in den Genen BRCA1 oder BRCA2 ausgef{\"u}llt wurde. Die Befragung sollte untersuchen, ob den Befragten das Risiko ihrer Verwandten, ebenso Mutationstr{\"a}ger zu sein, bewusst war. Weiterhin sollte ermittelt werden, ob sie die jeweiligen Risikopersonen dar{\"u}ber informierten. Es zeigte sich, dass den meisten Befragten dieses Risiko bekannt war. Einigen Personen schienen jedoch nicht genau zu wissen, welche Verwandten als „Risikopersonen" z{\"a}hlen. Insbesondere war nicht allen Befragten die M{\"o}glichkeit bewusst, dass auch M{\"a}nner die Mutation tragen und an ihre Kinder weitergeben sowie selbst an Brustkrebs erkranken k{\"o}nnen. Weiterhin gaben mehr als ein Viertel der Befragten an, dass sie mindestens ein Familienmitglied, obwohl es ihnen als Risikoperson bekannt war, nicht informierten. Als h{\"a}ufigste Grund hierf{\"u}r wurde mangelnder Kontakt genannt. Vor dem Hintergrund der Angaben der Befragten sowie der aktuellen Forschungslage werden in der vorliegenden Arbeit M{\"o}glichkeiten diskutiert, wie die Anzahl der informierten Angeh{\"o}rigen verbessert werden k{\"o}nnte.}, subject = {Brustkrebs}, language = {de} } @phdthesis{Huehne2021, author = {H{\"u}hne, Tom}, title = {Untersuchungen zur selektiven Induktion von Zelltod in CD4+ Foxp3- konventionellen T-Zellen der Maus durch Hemmung der sauren Sphingomyelinase \(in\) \(vitro\)}, doi = {10.25972/OPUS-24835}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248351}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Die saure Sphingomyelinase (Asm) ist ein lysosomales Enzym, das sezerniert werden kann und die Reaktion von Sphingomyelin zu Ceramid und Phosphocholin katalysiert. Seine Funktion ist bedeutsam f{\"u}r die Aufrechterhaltung des zellul{\"a}ren Lipidstoffwechsels und f{\"u}r die Integrit{\"a}t der Plasmamembran. Enzymdefekte sind an der Pathogenese von Infektionen und zahlreichen Stoffwechselerkrankungen wie z.B. der Niemann-Pick-Krankheit, Diabetes mellitus Typ II und auch an der Entstehung psychischer Erkrankungen beteiligt. Immunologisch bedeutsam ist, dass durch Hemmung der Asm mit trizyklischen Antidepressiva (TZA) oder Serotonin-Wiederaufnahme-Inhibitoren (SSRI) die Frequenz CD4+ CD25+ Foxp3+ regulatorischer T-Zellen (Treg) der Maus erh{\"o}ht wird. Grund f{\"u}r die Frequenzerh{\"o}hung ist jedoch nicht die Erh{\"o}hung der absoluten Treg-Zellzahl, sondern das selektive Sterben CD4+ CD25- Foxp3- konventioneller T-Zellen (Tconv). Erstaunlicherweise f{\"u}hrt die Behandlung mit dem kompetitiven Asm-Inhibitor ARC39, einem Bisphosphonat, nicht zu diesem Effekt. Es konnte gezeigt werden, dass IL-2 die regulatorischen T-Zellen vor dem durch Asm-Hemmung induziertem Zelltod sch{\"u}tzt. In Abwesenheit von IL-2 gehen auch Treg-Zellen durch die Asm-Inhibition zugrunde. Treg-Zellen exprimieren konstitutiv CD25, den IL-2-Rezeptor, dessen α-Kette die Bindungsstelle von Interleukin-2 bildet. Die β- und γ-Kette des Rezeptors sind an der Bindung des Transkriptionsfaktors STAT5 beteiligt, das wiederum die Gentranskription von antiapoptotischen Proteinen wie bcl-2 und bcl-x sowie CD25 f{\"o}rdert. Dahingehend wurde versucht, den verantwortlichen Faktor f{\"u}r den Schutz von Treg-Zellen vor dem Zelltod in der IL-2-Signaltransduktion zu identifizieren. Der Transkriptionsfaktor STAT5 konnte hierbei ausgeschlossen werden. Weder die genetische {\"U}berexpression noch die Defizienz von STAT5 hatten Einfluss auf das T-Zell-Gleichgewicht. Die genauen molekularen Mechanismen der Treg-spezifischen IL-2-Protektion bleiben daher ungekl{\"a}rt. Zu diskutieren sind der Einfluss von Zn2+-Ionen, Januskinasen und Mitgliedern der FoxO-Familie. Die zugrundeliegende Hypothese, dass das spezifische Sterben konventioneller T-Zellen auf einer Erh{\"o}hung der lysosomalen Membranpermeabilit{\"a}t (LMP) besteht, woraufhin proapoptotisch wirksame Cathepsine ins Zytosol freigesetzt werden und Caspasen zur Ausl{\"o}sung von Apoptose f{\"u}hren, konnte nicht abschließend best{\"a}tigt werden. Jedoch wurde nachgewiesen, dass durch Inhibition von Cathepsinen das Sterben konventioneller T-Zellen in Abwesenheit von IL-2 verlangsamt wird. Eine Protektion der Tconv-Zellen durch Caspase-Inhibitoren kann nur bei hohen 60 Konzentrationen des Inhibitors ZVAD bei gleichzeitig geringer Asm-Inhibitor-Konzentration erreicht werden. In Zusammenschau der Ergebnisse m{\"u}ssen weitere Formen des Zelltods neben der Apoptose, etwa eine durch Asm-Inhibition induzierte Ferroptose, in Erw{\"a}gung gezogen werden. Neben dem durch Asm-Inhibition erzeugten Lipidstress beg{\"u}nstigt das Vorliegen von hypoxischen Bedingungen die Induktion von Zelltod. Schon das alleinige Auftreten von Hypoxie ohne den Einfluss von Asm-Inhibitoren f{\"u}hrt zu einer Treg-Frequenzerh{\"o}hung. Der Hypoxie-induzierte Faktor HIF-1α induziert die Expression von Foxp3, wodurch die Differenzierung und Suppressivit{\"a}t von CD4+ CD25+ Foxp3+ Treg-Zellen gef{\"o}rdert wird. Der Einfluss von Hypoxie spielt wom{\"o}glich vor allem in der Tumortherapie eine entscheidende Rolle. HIF-1α regt hypoxische, nicht-vaskularisierte Tumorareale zur Neovaskularisation an und bremst durch die Frequenzerh{\"o}hung regulatorischer T-Zellen die eigene Immunabwehr. Ein Abbau des Transkriptionsfaktors HIF-1α stellt somit eine therapeutische Option in der Therapie solider Tumoren dar. Abschließend l{\"a}sst sich also festhalten, dass die relative Frequenzerh{\"o}hung regulatorischer T-Zellen durch Asm-Inhibition nicht durch Apoptose erkl{\"a}rt werden kann, sondern alternative Erkl{\"a}rungsmodelle wie z.B. die Ferroptose in Betracht gezogen werden m{\"u}ssen. Die Protektion CD25+ regulatorischer T-Zellen beruht auf der Wirkung von IL-2 und wird durch Hypoxie positiv beeinflusst. Eine genaue Identifizierung der f{\"u}r den Zelltod relevanten Mechanismen ist erforderlich, um sichere therapeutische Maßnahmen im Rahmen von Infektionen und Autoimmunkrankheiten zu etablieren.}, subject = {Sphingomyelinphosphodiesterase}, language = {de} } @phdthesis{Schug2021, author = {Schug, Benedikt}, title = {Untersuchungen zur Ursache und Beeinflussung des Kriechverhaltens von Gips}, doi = {10.25972/OPUS-24650}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246503}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {In dieser Arbeit konnte ein weiterer und m{\"o}glicherweise entscheidender Schritt zur Aufkl{\"a}rung des Kriechmechanismus von Gips gemacht und darauf aufbauend Kriterien, Wege und Strategien aufgezeigt werden, um neue Antikriechmittelsubstanzen zu identifizieren oder vorhandene Kriechmittel gezielt zu verbessern. Die G{\"u}ltigkeit und Praxistauglichkeit der Kriterien wurde exemplarisch nachgewiesen. Die Basis der Untersuchungen wurde gelegt mit der Errichtung standardisierter Messaufbauten und Verfahren sowie Parameterauswahl f{\"u}r eine beschleunigte und reproduzierbare Darstellung des Kriechph{\"a}nomens, wobei zun{\"a}chst im Abgleich sichergestellt wurde, dass das beschleunigte Ph{\"a}nomen mit dem langsam {\"u}ber einen Zeitraum von Jahren erzeugten Ph{\"a}nomen deckungsgleich ist. Darauf aufbauend wurden innovative Untersuchungsmethoden entwickelt, um das Kriechverhalten zu charakterisieren und qualitativ sowie quantitativ zu analysieren. Hierzu wurde zun{\"a}chst ein Aufbau und eine Messroutine entwickelt und eingef{\"u}hrt, um morphologische Ver{\"a}nderungen w{\"a}hrend des Kriechvorgangs im Rasterelektronenmikroskop nachzuverfolgen. Im Weiteren wurden Versuchsaufbauten f{\"u}r statische 3-Punkt-Biegeversuche in verschiedenen L{\"o}sungen realisiert und diese ergebnisabh{\"a}ngig optimiert. Hierdurch konnte der Einfluss der L{\"o}slichkeit von Gips in den entsprechenden Medien auf das Kriechverhalten untersuchen werden. Mittels Laserscanning-Mikroskop wurden wiederum diese Ergebnisse untermauert. Als vorherrschender Kriechmechanismus von Gips wurde damit das Abgleiten einzelner Gipskristalle bedingt durch einen L{\"o}sungs-Abscheide-Mechanismus an Orten hoher mechanischer Belastung identifiziert und best{\"a}tigt.}, subject = {Rauchgasgips}, language = {de} } @article{HeimbergKnop2021, author = {Heimberg, Linda and Knop, Stefan}, title = {Updated Perspectives on the Management of Relapsed and Refractory Multiple Myeloma}, series = {Oncology Research and Treatment}, volume = {44}, journal = {Oncology Research and Treatment}, number = {12}, issn = {2296-5270}, doi = {10.1159/000520364}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-249773}, pages = {682-689}, year = {2021}, abstract = {Background: With the availability of T-cell-directed therapy and next-generation compounds of established classes of drugs, the treatment of relapsed/refractory (r/r) myeloma is getting more complex. However, treatment options in practice are limited by availability, approval, and patient comorbidity. The aim of this article is to provide a practical approach toward the choice of treatment for r/r myeloma patients. Summary: Regarding market authorization and current guidelines, at least in Germany, most patients nowadays will have received a doublet or triplet combination as first-line therapy containing a proteasome inhibitor and an immunomodulatory drug, mostly lenalidomide. We focus on the treatment options for patients that are ineligible for (another) stem cell transplantation. We will review treatment options for relapse after first- or second-line therapy and beyond third-line. Key Messages: There is promising data supporting the efficacy and safety of triplet combinations containing anti-CD38-monoclonal antibodies (anti-CD38 mAbs) at first or second relapse in combination with next-generation compounds. For the treatment beyond third-line, comparative studies are scarce but some promising compounds are available via conditional authorization, and there is more to come in the future. We will present some early phase trials featuring promising results.}, language = {en} } @article{LohPoigneeWamseretal.2021, author = {Loh, Frank and Poign{\´e}e, Fabian and Wamser, Florian and Leidinger, Ferdinand and Hoßfeld, Tobias}, title = {Uplink vs. Downlink: Machine Learning-Based Quality Prediction for HTTP Adaptive Video Streaming}, series = {Sensors}, volume = {21}, journal = {Sensors}, number = {12}, issn = {1424-8220}, doi = {10.3390/s21124172}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241121}, year = {2021}, abstract = {Streaming video is responsible for the bulk of Internet traffic these days. For this reason, Internet providers and network operators try to make predictions and assessments about the streaming quality for an end user. Current monitoring solutions are based on a variety of different machine learning approaches. The challenge for providers and operators nowadays is that existing approaches require large amounts of data. In this work, the most relevant quality of experience metrics, i.e., the initial playback delay, the video streaming quality, video quality changes, and video rebuffering events, are examined using a voluminous data set of more than 13,000 YouTube video streaming runs that were collected with the native YouTube mobile app. Three Machine Learning models are developed and compared to estimate playback behavior based on uplink request information. The main focus has been on developing a lightweight approach using as few features and as little data as possible, while maintaining state-of-the-art performance.}, language = {en} } @article{AtiyasDoganogluInceoglu2021, author = {Atiyas, Izak and Doganoglu, Toker and Inceoglu, Firat}, title = {Upstream Competition with Complex and Unobservable Contracts}, series = {Review of Industrial Organization}, volume = {58}, journal = {Review of Industrial Organization}, doi = {10.1007/s11151-020-09766-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241161}, pages = {399-429}, year = {2021}, abstract = {This paper examines situations where two vertically integrated firms consider supplying an input to an independent downstream competitor via privately observed contracts. We identify equilibria where competition in the upstream market emerges—the downstream competitor gets supplied—as well as when the downstream firm does not receive the input and is excluded from the market. The likelihood of the outcome in which the downstream firm does not get supplied depends not only on demand parameters, but also on contractual flexibility and observability. We show that when contracts are unobservable, downstream entry will occur less often. Furthermore, our results suggest that permitting contracts that enable the contracting parties to coordinate their behavior in the downstream market may improve welfare by increasing the likelihood that the downstream firm is supplied.}, language = {en} } @phdthesis{Stratmann2021, author = {Stratmann, Robert Henrik}, title = {Ursachen und Therapie duodenaler Obstruktion im Kindesalter am Universit{\"a}tsklinikum W{\"u}rzburg - Analyse von Genese, assoziierten Fehlbildungen, Therapie und Outcome}, doi = {10.25972/OPUS-25055}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250552}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Eine retrospektive Analyse von kindlichen Patienten mit duodenaler Obstruktion, welche zwischen dem 01.01.2005 und dem 30.06.2020 im Universit{\"a}tsklinikum W{\"u}rzburg in der Abteilung f{\"u}r Kinderchirurgie operativ behandelt wurden. Analyse von Ursachen, Gestationsalter, Geburtsgewicht, Geburtsmodus, Begleitfehlbildungen, Diagnosestellung, operativer Versorgung und aufgetretener Komplikationen. Duodenale Obstruktion wird meist von duodenalen Atresien und Stenosen verursacht. Es besteht eine H{\"a}ufung von begleitenden Fehlbildungen wie z.B. einer Trisomie 21, urogenitalen- oder Herzfehlbildungen. Eine Mehrheit der Patienten ist fr{\"u}hgeboren, extreme Unreife ist jedoch selten. Es besteht eine leichte Linksverschiebung des Geburtsgewichtes zur Hypotrophie. Bei korrekter chirurgischer Therapie haben Duodenalatresien und -stenosen eine gute Prognose, welche zumeist von den Begleiterkrankungen limitiert wird.}, subject = {Atresie}, language = {de} } @phdthesis{Schleier2021, author = {Schleier, Domenik}, title = {Using Photoionization to Investigate Reactive Boron Species and the Kinetics of Hydrocarbon Radicals}, doi = {10.25972/OPUS-24213}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242137}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {This thesis highlights the importance of isomer-selective approaches for the complete analysis of chemical processes. The method of choice is photoelectron/photoion coincidence spectroscopy, which allows simultaneous detection of electrons and ions coming from a single ionization event. Ionization techniques are sensitive and can record multiple species simultaneously, rendering them ideal tools to probe molecular transformations. Coupling these setups to synchrotron radiation allows one to analyze complex mixtures with isomer selectivity, based on ionization energies and vibrational structure in the cation, without any prior separation steps. Only few setups exist that can be used to gather these data, although their impact and applicability is growing steadily in various fields. For closed-shell species an easier and more widely used method is gas-chromatography, but most open shell species would not survive the separation process. Due to the reactivity of radicals they have to be created by selectively converting stable precursor molecules. Depending on the radical generation method different properties can be investigated ranging from thermodynamic data, over concentrations in high temperature environments, to chemical kinetics. The first part of this thesis deals with the determination of bimolecular rate constants. Isomeric hydrocarbon radicals were generated by a high intense UV light pulses and their kinetics with oxygen was measured. The pressure dependence of different isomers in the falloff region was compared to theoretical models, and their reactivity could be explained. The second part deals with boron containing compounds in various electronic situations. The corresponding precursors were successfully synthesized or could be bought. They were subjected to fluorine atoms in chemical reactors or destroyed pyrolytically at high temperatures. Most investigated species exhibited vibronic effects that could be elucidated using high level computations.}, subject = {Biradikal}, language = {en} } @article{PrietoGarciaTomaškovićShahetal.2021, author = {Prieto-Garcia, Cristian and Tomašković, Ines and Shah, Varun Jayeshkumar and Dikic, Ivan and Diefenbacher, Markus}, title = {USP28: oncogene or tumor suppressor? a unifying paradigm for squamous cell carcinoma}, series = {Cells}, volume = {10}, journal = {Cells}, number = {10}, issn = {2073-4409}, doi = {10.3390/cells10102652}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248409}, year = {2021}, abstract = {Squamous cell carcinomas are therapeutically challenging tumor entities. Low response rates to radiotherapy and chemotherapy are commonly observed in squamous patients and, accordingly, the mortality rate is relatively high compared to other tumor entities. Recently, targeting USP28 has been emerged as a potential alternative to improve the therapeutic response and clinical outcomes of squamous patients. USP28 is a catalytically active deubiquitinase that governs a plethora of biological processes, including cellular proliferation, DNA damage repair, apoptosis and oncogenesis. In squamous cell carcinoma, USP28 is strongly expressed and stabilizes the essential squamous transcription factor ΔNp63, together with important oncogenic factors, such as NOTCH1, c-MYC and c-JUN. It is presumed that USP28 is an oncoprotein; however, recent data suggest that the deubiquitinase also has an antineoplastic effect regulating important tumor suppressor proteins, such as p53 and CHK2. In this review, we discuss: (1) The emerging role of USP28 in cancer. (2) The complexity and mutational landscape of squamous tumors. (3) The genetic alterations and cellular pathways that determine the function of USP28 in squamous cancer. (4) The development and current state of novel USP28 inhibitors.}, language = {en} } @article{MaasMischingerComperatetal.2021, author = {Maas, Moritz and Mischinger, Johannes and Comp{\´e}rat, Eva and Scharpf, Marcus and Fend, Falko and Todenh{\"o}fer, Timlan and Stenzl, Arnulf and Gakis, Georgios and Rausch, Steffen}, title = {Utility of pT3 substaging in lymph node-negative urothelial carcinoma of the bladder: do pathologic parameters add to prognostic sub-stratification?}, series = {World Journal of Urology}, volume = {39}, journal = {World Journal of Urology}, number = {11}, issn = {1433-8726}, doi = {10.1007/s00345-021-03697-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266535}, pages = {4021-4027}, year = {2021}, abstract = {Purpose The value of bladder cancer (BC) substaging into macroscopic (pT3b) and microscopic (pT3a) perivesical fat extension in lymph node (Ln)-negative patients is controversially discussed and limited evidence for prognostic relevance of additional histopathological factors in pT3 BC exists. We evaluated the prognostic value of pT3 substaging and established pathological and clinical parameters with focus on tumor invasive front (TIF) and tumor size. Methods Specimens of 52 patients treated with radical cystectomy (RC) for pT3 a/b muscle-invasive BC were reviewed and re-evaluated by a pathologist specialized in uropathology. Clinical variables and standard histopathologic characteristics were assessed including TIF and tumor size. Their value as prognosticators for overall survival (OS) and recurrence-free survival (RFS) was evaluated. Results Mean age of patients was 67.55 years. Tumors were staged pT3a in 28 patients (53.8\%) and pT3b in 24 (46.8\%). Median OS was 34.51 months. Median tumor size was 3.2 cm, median TIF was 11.0 mm. Differences in OS between pT3a and pT3b were not significant (p = 0.45). Carcinoma in situ (CIS) and lymphovascular invasion (LVI) were significantly associated with pT3b tumors. Univariate analysis could not identify pathological prognosticators like TIF or tumor size for OS and RFS (p for all > 0.05). Conclusion No significant differences in OS or RFS were observed comparing Ln-negative pT3 BC following radical cystectomy. Additional pathologic variables like TIF could not be identified as prognosticator. Relevance of pT3 BC substaging needs reevaluation in larger prospective cohorts.}, language = {en} } @misc{Kraft2021, author = {Kraft, Isabel}, title = {Valerie Lukassen: Die einstimmigen Lieder Oswalds von Wolkenstein, 2., verb. u. korr. Auflage, Wiesbaden: Reichert 2020, 302 S., 5 Abb. (Imagines Medii Aevi 46)}, series = {Beitr{\"a}ge zur Geschichte der deutschen Sprache und Literatur}, volume = {143}, journal = {Beitr{\"a}ge zur Geschichte der deutschen Sprache und Literatur}, number = {4}, publisher = {De Gruyter}, issn = {1865-9373}, doi = {10.1515/bgsl-2021-0050}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250920}, pages = {653 -- 669}, year = {2021}, abstract = {Kein Abstract verf{\"u}gbar.}, language = {de} }