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OPEN FAU

Online publication system of Friedrich-Alexander-Universität Erlangen-Nürnberg

The online publication system OPEN FAU is the central publication platform for Open Access publishing for all members of Friedrich-Alexander-Universität. Qualified works from research and teaching may be published here free of charge, either as a primary or secondary publication. The full texts are permanently available worldwide and are findable and citable via catalogues and search engines.


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Recent Submissions

Doctoral thesis
Open Access
Highly Reactive Aluminyl Anions and Monomeric Alumoxanes
(2024) Grams, Samuel; Harder, Sjoerd
Dissertationsschrift zur Erlangung des Doktorgrades Dr. rer. nat.
Doctoral thesis
Open Access
CHEMO-SENSORY CHARACTERIZATION OF ODOR-ACTIVE CONSTITUENTS IN NATIVE WOODS AND THEIR STRUCTURE-ODOR RELATIONSHIPS
(2024) Ghadiriasli, Rahil; Büttner, Andrea
The living tree and its obtained wood have played a prominent role in human everyday life in the form of building material and furniture, or in products of daily use. The aroma components emanating from wood-based products have a powerful influence on human Psychophysiological activity and have been used for mental, spiritual and physical healing. The wood aroma can be used in the indoor environment to foster relaxation and stress release effects. The current study was conducted to determine the individual wood odor and its constituents in two diverse types of woods, namely Oak wood and cembran pine wood. Oak wood has been used since long during the maturation and aging process imparting aroma and flavor in alcoholic beverages and vinegar as by-products that have been either fermented or aged in oak barrels. Several investigations targeted the aroma composition of modified and heat-treated oak wood, but only little information about aroma-active compounds constituting the native and raw oak wood is available. The Cembran pine wood (Pinus cembra L.), also known as Arolla pine, Swiss pine, or Stone pine, has a prominent and long-lasting aroma that has been reported to relieve stress and that is widely used in aromatherapy. However, the odorants responsible for this distinctive aroma are not yet comprehensively revealed. Therefore, the main objective of this thesis was to characterize the impacting odorants and to deepen the knowledge about native oak wood and unique Cembran pine wood odor by applying a combinatory chemo-analytical approach based on human-sensory evaluations and multi-dimensional gas chromatographic and mass spectrometric techniques. Furthermore, it was tried in this thesis to gain deeper insights into formation pathways and odor sources in these two types of wood and their applications. Most of these odorants comprised aldehydes, acids, lactones, a series of terpenes, mostly mono- and sesquiterpenes, and several odor-active compounds containing a phenolic core moiety. The odor profiles of all wood samples were compared, the potent odorants were determined, and selected odorants of both types of wood samples (oak and Cembran wood samples) were quantified by application of stable isotope dilution assays (SIDA). Odor activity values (OAVs) were calculated based on the odor threshold (OTs) determined in water. The second part of this thesis dealt with the investigation of the effects of different geographical regions and pedoclimatic conditions on the odor of different wood samples. This study focused on elucidating the smell profiles of several natural oak samples from Germany, Austria, and Hungary. Particular consideration is given to view the current challenges associated with climate change on the forestry sector, and thus concerning the respective regional conditions, and underwent statistical interpretation. In the case of Cembran wood, the influence of different geographical forest regions in Austria and Italy was determined and evaluated by means of principal component analysis (PCA) and statistical interpretation of obtained data. Recombination experiments by mixing the dominant odor-active compounds in their naturally occurring concentrations revealed a good agreement of the model mixtures with the overall smell of the respective native wood samples. In addition, the structure odor relationships in representative substance classes of wood were elucidated. Specifically, the smell impressions of guaiacol and selected structurally related odorants such as alkylated, alkenylated, methoxylated and halogenated guaiacol derivatives were studied. All investigated compounds elicited characteristic smoky, vanilla-like, and /or clove-like smell impressions. Smoky smells, primarily comprising guaiacols, phenols and cresols, are enjoyed in diverse foods and beverages such as wine, whiskey, smoked ham, cheese, or baked goods such as pizza. Furthermore, the studies indicated that the odor properties of alkylated and halogenated guaiacols and phenols demonstrated the smoky smells are not the same for everyone and can be differently perceived in individual humans. Overall, the odor threshold investigation of guaiacol and its alkylated, alkenylated, and methoxylated derivatives showed that no specific substituent caused a significant and universal effect on OT. However, the positioning of the substituents to the hydroxyl function seems to have an impact on OT. Obtained data could be used to identification and analysis of the investigated compounds. Furthermore, the results can also be avail in understanding the structure and the odor correlation of compounds, which is still not fully resolved. Finally, to investigate the wine off-odors, barrel-aged wine samples were analyzed by gas chromatography-olfactometry (GC-O), with regards to the presence of the typical earthy-smelling off-odor. The 2-methylisoborneol (2-MIB) was detected in these wines, although the wine samples were seven years old and all the previous studies showed that this substance is unstable in wine and must. Degradation products of 2-MIB were synthesised, and with regard to their odor, these dehydration products were found to be odorless. To investigate this paradoxical situation, 2-MIB stability was analyzed in wine and model solutions, starting with an elevated initial concentration. Therefore it was concluded that although 2-MIB concentration greatly decreased with time it still can be detected in old wines and can induce the earthy off-odor.
Doctoral thesis
Open Access
With all, for all: From context-sensitive physical activity assessment to population-based physical activity promotion with a focus on health equity
(2024) Kohler, Simone; Pfeifer, Klaus
For decades, the epidemiology of physical activity (PA) and PA-related health promotion has been concerned with the problem of physical inactivity and has pursued a common goal: a healthier population through more PA. While epidemiology focuses on risk and protective factors for diseases, health promotion focuses on health promoting factors, health resources, and health equity. The latter is so important because non-communicable diseases (NCDs) follow a social gradient, affecting people with social disadvantages more than advantaged ones. One of the main risk factors for NCDs is physical inactivity. Between 2020 and 2030, nearly 500 million people will suffer from NCDs due to physical inactivity. Addressing this issue urgently remains a major challenge for all stakeholders involved in reducing health inequities through PArelated health promotion, whether they are researchers, policy-makers or local authorities. The first part of this dissertation is located in the field of epidemiology of PA. The development and evaluation of a computer based PA recall (cpar24) for recording PA and its meaning for the epidemiology of physical activity, as well as the relevance of context-sensitive data, are the focus. The evaluation results of cpar24 showed that it is a user-friendly, practical, valid, and reliable method for assessing activity data of German adults. The cpar24 is not only suitable for monitoring PA but also for assessing contextual determinants (type and domain), which enables a better understanding of health effects. Furthermore, insights can be derived from the cpar24 data, which serve as a basis for the development of specific recommendations for promoting PA. If it is possible to measure the PA behavior of population groups with different social status in representative cohort studies, this can also provide urgently needed information for improving health equity. The second part of this work deals with PA-related health promotion. One of the primary objectives was to create an umbrella review of successful population-based approaches to promoting PA, with a particular focus on health equity, to update the National Recommendations for PA and PA Promotion in Germany published in 2016. A total of six review articles were identified between January 2015 and December 2021, which represents an increase in scientific publications in this field compared to previous years, which included only two review articles. However, the state of research and thus the availability of scientific evidence on the effectiveness of population-based measures to promote PA with a focus on health equity is limited. In addition to the complexity of these approaches in complex systems such as communities, challenges for evaluation such as inadequate theoretical foundation and missing quality criteria are also discussed. In another study, the question of how to sustainably implement structure-building community-based PA-related health promotion with a focus on health equity in Germany was investigated. After several iterations and collaboration processes, a sixstage action model for successful and sustainable implementation of PA-related health promotion with a focus on health equity in the community was adopted in collaboration with stakeholders from science, politics, and local practice. Furthermore, this approach was systematically analyzed and theoretically reflected on the basis of a “conceptual model of the transdisciplinary research process”. Overall, it was confirmed that new knowledge could be generated for both practice and science by taking into account scientific and societal knowledge through several reflection loops. The subtitle of this work, “with all, for all”, emphasizes with “for all” the need to reach all people in future public health efforts, especially those population groups whose chances are limited by social disadvantage. “With all” emphasizes that “all stakeholders”, i.e. from science (epidemiology together with health promotion), politics, and practice, must be involved and work together to achieve sustainable effects on public health. In summary, the results presented here from two different research perspectives provide a deeper insight into existing challenges and show equitable solutions for reducing physical inactivity. The discussed interconnections between the epidemiology of PA and PA-related health promotion illustrate the importance of their collaboration, especially when epidemiological findings are (or can be) used in health promotion practice in such a way that sustainable interventions reach all population groups and contribute to improving the health of the population in an equitable manner.
Doctoral thesis
Open Access
β2-Mikroglobulin induziert die NLRP3-Inflammasom-Aktivierung in Myelom-assoziierten Makrophagen und fördert das Zellwachstum beim Multiplen Myelom
(2024) Hofbauer-Stache, Daniel; Burkovski, Andreas
Das MM (Multiples Myelom, Multiple myeloma) ist eine bisher unheilbare hämatologische B-Zellerkrankung, die durch die monoklonale Proliferation und Akkumulation maligner Plasma-zellen im KM (Knochenmark) gekennzeichnet ist. Hierbei stellt die inflammatorische Tumor-mikroumgebung, die mit den malignen Plasmazellen wechselwirkt, eine Schlüsselkomponente des MM dar. Diese trägt zur Aufrechterhaltung des Wachstums maligner MM-Zellen bei und wirkt sich sowohl auf die Bildung osteolytischer Läsionen als auch auf das gesamte Immun-system aus. Zwar ist bisher unklar, welchem physiologischen Ursprung das inflammatorische Tumormikromilieu bei MM-Patient:innen zugrunde liegt. Dennoch wir vermutet, dass proin-flammatorische MAMs (Myelom-assoziierte Makrophagen, Myeloma-associated macropha-ges) das KM-Tumorstroma infiltrieren und durch die Freisetzung von Wachstumsfaktoren und den proinflammatorischen Zytokinen IL-(Interleukin, Interleukin)-1β und IL-18 eine inflammato-rische Tumormikroumgebung induzieren. Diese stellen einen ungünstigen prognostischen Faktor dar und begünstigen die MM-Pathogenese. Aus diesem Grund wurde in der vorliegen-den Arbeit geklärt, welcher Zusammenhang zwischen einem in MAMs aktiven NLRP-(Nucleotide-binding oligomerization, leucine-rich repeat and pyrin domain-containing)-3-Inflammasom, das zelluläre Entzündungsreaktionen reguliert, der Entstehung einer inflamma-torischen Tumormikroumgebung und dem MM-Zellwachstum besteht. Zahlreiche Ergebnisse sprechen dafür, dass das aktive NLRP3-Inflammasom die MM-Pathogenese im KM von MM-Patient:innen maßgeblich beeinflusst. Dies wurde unter Verwendung des spezifischen NLRP3-Inflammasom-Inhibitors MCC950 bestätigt, der NLRP3-assoziierte Effekte signifikant reduzierte. Darüber hinaus wurde neben IL-1β insbesondere IL-18 als Wachstumsfaktor identi-fiziert, der den Rezeptor IL-18Rα auf der MM-Zelloberfläche stimuliert und somit eine ent-scheidende Rolle für das MM-Zellwachstum spielt. Hierbei wurde geklärt, welche Bedeutung β2m (β2-Mikroglobulin, β2-microglobulin), einer Komponente des MHC-(Haupthistokompatibilitätskomplex, Major histocompatibility complex)-I-Komplexes, zukommt. Frühere Studien sprechen dafür, dass eine hohe β2m-Konzentration mit der MM-Tumorlast, einer schlechten Prognose und dem Nichtansprechen von MM-Patient:innen auf eine Therapie korreliert. Außerdem synthetisieren MM-Zellen größere β2m-Mengen und setzen diese frei. Bisher ist jedoch wenig über die biologische Wirkung und das immunregulatorische Potential von β2m bekannt. Eine frühere Studie deutet darauf hin, dass β2m eine proinflammatorische Immunantwort in myeloischen Zellen induziert. Aus diesem Grund wurde weiterhin geklärt, ob β2m die Entstehung eines inflammatorischen Tumormikromilieus beeinflusst und das MM-Zellwachstum fördert. Zahlreiche Ergebnisse der vorliegenden Arbeit identifizierten β2m als endogenes DAMP (Schaden-assoziiertes molekulares Muster, Damage-associated molecular pattern), das das aktive NLRP3-Inflammasom in humanen Makrophagen induzierte und die Sekretion der proinflammatorischen Zytokine IL-1β und IL-18 begünstigte. Nachdem humane Makrophagen β2m phagozytierten, befand sich β2m im reifen Lysosom, das einen niedrigen pH-(Potentia hydrogenii)-Wert zwischen 4,5 und 5 aufweist. Da freies β2m die einzigartige Eigenschaft besitzt, unter einem in den Lysosomen vorherrschenden pH-Wert zu aggregieren, bildeten sich Amyloidfibrillen. Die Akkumulation der Amyloidfibrillen rief eine lysosomale Schädigung hervor, wodurch lysosomale Proteasen freigesetzt wurden, die das aktive NLRP3-Inflammasom und die daraus resultierende IL-1β- und IL-18-Sekretion induzierten. Hierbei stellen die β2m-Phagozytose sowie die lysosomale β2m-Aggregation die zellulären und molekularen Schlüsselereignisse dar. Diese Ergebnisse konnten unter Verwendung der β2m-Mutation W60G bestätigt werden. W60G weist im Vergleich zu β2m eine niedrigere Ag-gregationstendenz auf und war daher nicht in der Lage, ein aktives NLRP3-Inflammasom zu induzieren. Darüber hinaus lassen zahlreiche Ergebnisse vermuten, dass β2m das aktive NLRP3-Inflammasom in MAMs induzierte. Dadurch konnte das inflammatorische Tumormik-romilieu aufrechterhalten und sowohl das MM-Zellwachstum als auch die MM-Pathogenese entscheidend beeinflusst werden. Der Fokus richtete sich insbesondere auf das proinflamma-torische Zytokin IL-18, das das MM-Zellwachstum entscheidend begünstigte. Zukünftige präk-linische und klinische Studien sollten jedoch klären, ob IL-18 als universeller Wachstumsfaktor fungiert. Die Ergebnisse der vorliegenden Arbeit könnten den Weg für die Entwicklung neuar-tiger Wirkstoffe ebnen, sodass zukünftige therapeutische Ansätze optimiert und individuelle Behandlungen dieser schweren Erkrankung ermöglicht werden (Abbildung 2-1).
Doctoral thesis
Open Access
Role of HCMV in neurological decline of glioma patients during radiochemotherapy - Detection of HCMV in myelomonocytic cells from the peripheral blood of glioma patients
(2024) Neiswirth, Monika; Gaipl, Udo
Background The human cytomegalovirus (HCMV), also called human herpesvirus 5, belongs to the Herpesviridae and can cause the so-called cytomegaly. As with all Herpesviridae, the HCM virus persists in the human organism for a lifetime. This leads to lifelong seropositivity, which can be detected by laboratory chemistry. With increasing age, up to 90 % of the population have had contact with HCMV and are thus carriers of a latent infection. In the event of reactivation, healthy individuals usually do not experience symptoms. However, in immunocompromised individuals such as fetuses, AIDS or transplant patients, severe courses may occur with the risk of HCMV retinitis, which can lead to blindness, or life-threatening HCMV pneumonia. In addition, HCMV can affect the immune response and is associated with higher expression of inflammatory markers. In cancer patients with latent HCMV infection, nucleic acids and proteins of the virus have been detected in tissues of brain metastases from primary breast and colon cancer and in tissues of glioblastoma. Glioblastoma is the most aggressive and most commonly diagnosed primary brain tumor in adults. Over the past decade, the median survival time has been approximately 10 to 15 months, even with therapy. The current standard therapy is to first remove the tumor surgically, if possible. This is followed by radiotherapy in combination with the chemotherapeutic agent temozolomide. During and after radiotherapy of patients with brain tumors, sudden onset of severe neurological deficits was observed, which also led to a worsening of overall survival. Interestingly, these patients simultaneously showed reactivation of HCMV in serological tests. Therefore, immediate treatment with antiviral drugs was given, which improved the condition and also the survival of these patients within a short period of time. These findings suggest a relationship between HCMV infection/reactivation and the resulting encephalopathy. In which compartment this reactivation takes place and what triggers the neurological symptoms is not known. On the one hand, the virus may reactivate in the glioma tissue itself; on the other hand, immune cells may also be involved. HCMV persists mainly in myelomonocytic cells and their differentiation into macrophages or dendritic cells, triggered by inflammatory mediators, can provoke viral reactivation. In addition, irradiation of the brain makes the blood-brain barrier more permeable, allowing immune cells to migrate in greater numbers and also thus further promoting reactivation. This occurs particularly in an immunosuppressive environment generated during glioma therapy. Furthermore, it is important to further investigate whether there are specific risk factors for the development of HCMV-associated encephalopathy. It has been shown that patients who had significantly lower blood basophil counts pretherapeutically, had a higher risk of developing HCMV-associated encephalopathy. In addition, seropositive patients had a higher proportion of CD8+ T cells and a lower proportion of CD4+ T cells, resulting in an inverted CD4:CD8 ratio and reduced resistance to infection. Whether the timing of HCMV infection and the total number of reactivations a person undergoes over a lifetime have an impact on these factors is unclear. Material and Methods For the detection of even low levels of HCMV, a suitable digital droplet PCR (ddPCR) protocol was established. Various positive controls and primer/probe constellations were tested. Serum and peripheral blood mononuclear cells (PBMCs) from patients with intracranial malignancies were used for analysis. PBMCs were sorted into three major subclasses of monocytes: classical (CD14+ / CD16-), intermediate (CD14+ / CD16+), and nonclassical monocytes (CD14- / CD16+). In addition, CD14- / CD16- cells were defined as a fourth subgroup. The determination of viral load from whole blood was performed by the central laboratories of the University Hospital Erlangen. The ratio of CD4+ and CD8+ T cells in donors with different HCMV status was determined by flow cytometry. Results A suitable protocol for ddPCR for the detection of HCMV could be established. Despite cell sorting into three major myelomonocytic subclasses in which HCMV mainly persists, detection was not successful in seropositive healthy volunteers. Detection was also unsuccessful in asymptomatic healthy volunteers who showed serological reactivation of the virus. In contrast, analysis of blood samples from glioblastoma patients detected single virus-infected cells. It was shown that HCMV can first be detected in whole blood during the course of therapy and only later in serum. Conclusion and discussion Because HCMV is present at an extremely low copy number in the latent stage, the probability of detecting an HCMV-infected cell is low. Moreover, in healthy subjects, a rapid immune response may prevent the onset of symptoms. Since the symptoms of encephalopathy appear at the onset of radiotherapy, it can be assumed that reactivation in the cellular compartment, rather than spread of the virus and infection of other cell types, is primarily responsible for the neurological symptoms. However, no monocytic cell series has been identified that is primarily involved in HCMV reactivation. In the future, it will be necessary to further develop the detection method of HCMV in order to also identify latently infected cells in seropositive patients. In patients who developed HCMV-associated encephalopathy during brain irradiation, HCMV could be detected in monocytes. However, no cell population could be defined that seems to play a predominant role in this. Therefore, in further studies with a larger number of patients, additional cell types need to be analysed to further elucidate the genesis of HCMV-associated encephalopathy. In addition, seropositive patients should be clinically examined, and blood samples obtained at closer intervals during therapy to determine the time of highest risk for HCMV-associated encephalopathy and to identify possible promoting influences.