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The impact of the Covid-19 pandemic called for rapid responses in face of unprecedented challenges. In this context, earning more about the causative agent SARS-CoV-2 becomes imperative. Therefore, clinical virus isolates were studied with focus on infectivity, replication kinetic, and caspase activity.
Firstly, clinical specimens collected from patients were tested for infectivity in cell culture. Combined with polymerase chain reaction results, a formula predicting infectivity in cell culture based on abundance of viral RNA was developed. Additionally, analysis of different specimen types, sources, and material, elucidate the question of infectivity. Here, infectivity was demonstrated in specimens derived from different parts of the respiratory tract, including specimens collected from deceased persons. A protocol for virus isolation on human airway epithelium in air-liquid interface culture was established.
Secondly, replication kinetics of 20 clinical isolates were compared, including a subset of seven sequenced isolates. All isolates replicated in the colon epithelial cell culture model. Within the subset, differences between isolates carrying the D614G amino acid exchange and with original spike protein were observed.
Lastly, elevated caspase activity was demonstrated in two cell culture models including human airway epithelium in air-liquid interface culture.
Subsequently, caspase inhibition by small-molecule compound Emricasan and its effects on the cytopathic effect observed in cell culture were studied. Here, increased cell survival in a colon epithelial cell line was shown with unimpaired virus replication. Elevated caspase activity was identified as early marker of infection and validated by testing across 20 clinical virus isolates.
This study offers information on infectivity that can help shape the understanding of transmission risk. As such, parts of the data collected here were used for validation of rapid antigen tests. The insights gained by studying caspase activity contributed in part to the development of a drug screening method by Bojkova et al.,41 thus aiding routine laboratory workflow. It was demonstrated that Emricasan exhibits no antiviral effect, while the finding of increased cell survival in cell culture could give rise to further research on prevention of tissue damage.
Um sich an ändernde Umwelteinflüsse und metabolische Bedürfnisse anpassen zu können, ist es für Zellen essenziell, dass Boten-RNA (engl. messenger RNA, mRNA) stetig und schnell nach der Translation abgebaut wird. In Prokaryoten ist dafür der Proteinkomplex Degradosom verantwortlich, in dem Endo- und Exoribonukleasen RNase E und PNPase das RNA-Transkript in kleinere Fragmente und schließlich einzelne Nukleotide spalten. Die DEAD-Box Helikase RhlB im Komplex dient zusätzlich dazu, mögliche Sekundärstrukturen in der RNA zu entfalten, welche sonst die weitere Degradation behindern würden. Es konnte gezeigt werden, dass RhlB’s sehr geringe katalytische Aktivität – gemessen durch ATP-Verbrauch und Rate an entwundener RNA – signifikant durch die allosterische Bindung an Komplexpartner RNase E erhöht wird. Gleichzeitig deuten andere Studien darauf hin, dass RhlB eine mögliche Selektivität für doppelsträngige RNA-Substrate mit 5‘-Einzelstrang-Überhängen aufweist.
Diese Arbeit liefert neue Erkenntnisse in Bezug auf die Kommunikation zwischen den Degradosom-Komponenten RhlB und RNase E aus E. coli, indem das potenzielle Wechselspiel zwischen RhlBs RNA-Selektivität und der allosterischen Aktivierung durch RNase E untersucht wurde. Der vielseitige Einsatz NMR-spektroskopischer Techniken sowie die Verwendung kurzer RNA-Substrate mit spezifischen Strang-Eigenschaften ermöglicht es, mit einen ungewöhnlichen, RNA-zentrierten Ansatz an diese unzureichend verstandene Protein-Interaktion heranzugehen.
Zunächst wurden hierzu eine Reihe kurzer doppelsträngiger RNA-Konstrukte hergestellt, die sich nicht nur in ihren Einzelstrang-Merkmalen unterscheiden, sondern auch die thermodynamischen Anforderungen eines DEAD-Box Helikase Substrats erfüllen, und gleichzeitig eine ausreichende NMR-spektroskopische Signal-Zuordnung erlauben. Die thermale Stabilität, das Faltungsverhalten sowie die 1H Imino-protonen- und 13C HSQC-Zuordnungen aller geeigneten Konstrukte wurden erfolgreich bestimmt.
Um den Einfluss spezifischer RNA-Substrate sowie die Bindung zweier verschiedener RNase E Fragmente auf RhlBs ATP-Umsatzrate zu untersuchen, wurde sich zunächst eines photometrischen Phosphat-Assays bedient. Damit konnte deutlich gezeigt werden, dass RhlB in Abwesenheit des Komplex-Partners nicht in der Lage ist, signifikante Mengen an ATP umzusetzen, unabhängig davon, welches RNA-Konstrukt eingesetzt wird. Die Bindung der RNase E Fragmente erhöhte signifikant die ATP-Hydrolyse-Rate der Helikase, wobei die größte Aktivierung für den RNA-Duplex mit 5‘-Einzelstrang sowie ein einzelsträngiges Substrat zu beobachten ist. Da diese Ergebnisse deutlich eine RNA-Abhängigkeit beim ATP-Umsatz der Helikase zeigen, wurde untersucht, ob diese Unterschiede ihren Ursprung bereits in der Bindung der spezifischen RNA-Substrate haben. Mittels einer Mischapparatur, die es erlaubt die enzymatische Reaktion direkt im Spektrometer zu initiieren sowie zeitaufgelöster 31P NMR-Experimente konnte die allosterische Aktivierung der ATP-Hydrolyse-Rate von RhlB auch unter NMR-spektroskopischen Messbedingungen nachgewiesen werden.
Da die Ergebnisse des ATPase Assays deutlich eine RNA-Abhängigkeit bei der ATP-Umsatz-Rate der Helikase zeigen, wurde zusätzlich untersucht, ob diese Unterschiede ihren Ursprung in den Affinitäten für die verschiedenen RNA-Substrate haben und ob diese durch die Bindung von RNase E and RhlB beeinflusst werden. Um im gleichen Zuge zu überprüfen, ob die Bindung der RNA an RhlB die RNA-Konformation oder Basenpaarung ändert, werden 1H NMR-Titrationsexperimente durchgeführt. Es konnte erstmals gezeigt werden, dass RhlB eine inhärente Präferenz für Duplexe mit 5‘-Überhang gegenüber Konstrukten mit 3‘-Überhang oder stumpfen Enden besitzt, was sich in einer erhöhten Affinität zeigt. Zusätzlich offenbaren die Messungen, dass RNase Es allosterische Bindung selektiv die Affinität gegenüber Konstrukten mit Einzelstrang-Überhang erhöht, während die Affinität zu RNA Duplexen ohne Überhang sogar verringert wird. Diese Ergebnisse liefern erstmals einen Nachweis, dass RNase E aktiv Einfluss auf RhlBs RNA-Bindung nimmt. Weder die Bindung der RNA and RhlB noch an den RhlB/RNase E Komplex scheint die Basenpaarung oder Konformation der RNA-Substrate zu beeinflussen, da lediglich eine homogene Peak-Verbreitung aller Imino-Protonen-Signale im 1H NMR-Spektrum beobachtet werden konnte.
Chapter I of this work addressed the piggyBac (PB) transposon system, a non-viral genome engineering tool that is capable of efficiently performing stable integration of DNA sequences into a target cells genome and has already been used in clinical trials. However, the PB transposase has the problematic property of preferentially integrating transposons near transcriptional start sites (TSSs). This increases the likelihood of causing genotoxic effects, limiting its potential use as a tool in clinical applications. It has been shown in the past that the PB transposase shows physical interactions with BET proteins (e.g. BRD4) through Co-IP experiments. Representatives of these proteins are part of the transcriptional activation complex and are abundant at TSSs. Accordingly, it was previously proposed that this interaction is the underlying cause for the biased integration preference. For the first chapter of this thesis, the goal was to disrupt this interaction potentially modifying said integration preference. A secondary structure hypothesized to be mainly responsible for said interaction was extensively mutated resulting in several PB variants that were analyzed for their interaction capacity through a series of Co-IP experiments with BRD4. In total, seven substitutions were identified (E380F, V390K, T392Y, M394R, K407C, K407Q, and K407V) which exhibited reduced interaction capacity with BRD4. Each of the aforementioned mutants were used to generate integration libraries and, through NGS, it was determined if the integration preferences of the respective mutants had changed. In the immediate range 200 base pairs up- and downstream from known TSSs all mutants used exhibited a reduced integration bias. At a wider observation window 3 kbp up- and downstream from TSSs, further mutants with the substitutions M394R, T392Y and V390K showed a reduction in integration frequency of 17.3%, 1.5% and 5.4%, respectively, compared to the wildtype. Of particular note was the M394R mutant, which showed a reduction in all window sizes analyzed with a maximum of 65% less integration preference in the immediate vicinity of TSSs, theoretically generating a safety advantage over the wildtype transposase.
Chapter II was dedicated to the overall safety improvement for transposon-based gene modification and addresses the time point after the transgene has already been integrated and serious side effects may not be preventable. With this in mind, the aim was to develop a novel suicide-switch that can be stably introduced into cells via transposition, and reliably leads to cell death of the modified cells once activated. A system based on CRISPR/Cas9 was developed, where single guide RNAs were used to guide the Cas9 nuclease to Alu elements. These are short, repetitive sequences, which are distributed over the human genome in more than one million copies. Inducing double strand breaks within these elements would lead to genomic fragmentation and cell death. To be inducible, a transcriptional as well as post- translational control mechanism was added. Transcription of the Cas9 nuclease was regulated using a tet-on system, making expression dependent on doxycycline (DOX) supplementation. Furthermore, a version of the Cas9 nuclease called arC9 was used that allows double strand break generation only in the presence of 4-Hydroxytamoxifen (4-HT). Together with an expression cassette for the Alu-specific guide RNA and an expression cassette for the reverse tetracycline controlled transactivator all components were arranged between transposase-specific recognition sequences on a plasmid to allow transposon-system based gene transfer. The system was tested in HeLa cells. First, conditional expression of the arC9 nuclease was confirmed by addition of 1 μg/ml DOX. Second, the suicide-switch was further induced by adding 200 nM 4-HT and protein extracts were assayed for the KAP1 phosphorylation. Only upon induction with DOX and 4-HT phosphorylated KAP1 was detected, indicating DNA damage. Further, extensive growth and survival experiments were conducted to determine the effect of suicide-switch induction on cell proliferation and survival. Between 24 and 48 hours after induction, a halt in cell division was detected, after which extensive cell death was observed. Within 5 days post induction, >99% of all cells were eliminated. In the absence of both inducers, no significant differences in survival were observed compared to control cells line lacking Alu-specific guide RNAs. Microscopic examinations of the <1% surviving cell fraction revealed a senescence-associated phenotype and showed no signs of resumption of the cell division process. Accordingly, the second chapter of this thesis also achieved its goal in developing a functional suicide-switch that can be inserted into human cells via transposition, is highly dependent on the necessary induction signals, and exhibits excellent elimination capabilities in the context tested.
Langzeitüberleben und Mortalitätsprädiktoren nach perkutanem
kathetergestütztem Aortenklappenersatz
(2022)
Ziel dieser Studie war die Evaluation von Patienten, die eine transfemorale oder eine transapikale TAVI erhalten haben, in Bezug auf ihre Mortalitätsprädiktoren und ihre Langzeit-Mortalität.
Methoden: Untersucht wurden Patienten mit einer minimalen FU-Zeit von sechs Jahren, welche im Zeitraum von 2006 – 2014 eine TAVI im Herzkatheterlabor des Universitätsklinikums in Frankfurt erhalten haben. Das Patientenkollektiv wurde basierend auf dem Zugangsweg (transfemoral oder transapikal) analysiert.
Ergebnisse: Insgesamt wurden 679 Patienten in die Studie eingeschlossen. 408 Patienten (59,82 %) bekamen eine transfemorale TAVI und 271 Patienten (39,74 %) bekamen eine transapikale TAVI. Der durchschnittliche STS-Score betrug in der transfemoralen Gruppe 4,21 ± 2,4 % und in der transapikalen Gruppe 4,19 ± 2,7 %. Die Mortalität war nach 30 Tagen (15,8 % transapikal versus 8,2 % transfemoral, p = 0,00) sowie im Langzeit-FU (79,5 % transapikal versus 68,3 % transfemoral, p = 0,00) signifikant höher in der transapikalen Gruppe. Viele postinterventionelle Komplikationen waren häufiger in der transfemoralen Gruppe. Postinterventionelle Schrittmacherimplantationen (15,7 % versus 4,1 %, p = 0,00), große und kleine vaskuläre Komplikationen (5,1 % versus 1,1 %, p = 0,01) sowie große und kleine zerebrovaskuläre Insulte (31,8 % versus 9,1 %, p = 0,00) kamen in der transfemoralen Gruppe signifikant häufiger vor. Allerdings war der transfemorale Zugangsweg mit einer besseren Überlebensrate assoziiert (Log Rank Test p = 0,01 und HR 1,33 (1,04 – 1,71), p = 0,03). Patienten mit einem hohen STS-Score (HR 1,09 (1,03 – 1,15), p = 0,00), einem vorbestehenden Diabetes Mellitus (HR 0,75 (0,58 – 0,97), p = 0,03) sowie großen Gefäßkomplikationen (HR 0,60 (0,37 – 0,99), p = 0,04) korrelieren mit einem schlechteren Langzeit-Überleben.
Zusammenfassung: Für den kathetergestützten Aortenklappenersatz weisen beide Zugangswege spezifische Risiken auf, daher sollte die individuell beste Variante für jeden Patienten ausgewählt werden.
This study investigates a historical event that occurred during the Indonesian Revolution as depicted in Indonesian historical films and argues that these films not only attempt to depict the past but also use the past as a means of social commentary, teaching moral insight, and historical reinforcement. The historical films selected are The Long March (Darah dan Do’a) (1950) and Mereka Kembali (1972). Both films deal with the Long March event experienced by the troops of the Siliwangi Division in 1948. These troops were previously assigned to infiltrate Yogyakarta and its surrounding areas. They were instructed to march back to their original base in West Java as a part of the military strategies to confront the Dutch during the Indonesian Revolution, also known as the Indonesian War of Independence. This event became known as the Long March of the Siliwangi Division. This study examines not only the representation of the past or the texts of the films but also the production process, which includes the motivations of the filmmakers and the public reception when the films were screened for the public at the time—in 1950 and 1972, respectively. This approach provides a broader and richer dimension, valuable insights into the behind-the-scenes process of making the selected historical films, and essential information about the public reception of the films. From the production point of view, there are two main reasons for making these historical films: personal reason and social engagement. Further, the military also plays a vital role in these historical film productions. From the historical representation aspect, these two films depict the events of the Long March of the Siliwangi Division as a journey full of various obstacles and difficulties, such as harsh terrain, lack of food, battles against the Dutch, and internal disputes with fellow Indonesians: Darul Islam. From the reception aspect, the audience’s point of view, these films provide several representations that meet their expectations about the Long March of the Siliwangi Division. However, the audience disagrees with some of the other representations. Finally, the study revealed that historical films are potential vehicles for telling, interpreting, entertaining, legitimating and preserving the past. In addition, this study has a vital implication for reopening the tradition of Indonesian film studies and reigniting attention to old films.
Untersuchung zur Sicherheit bei der simultan bilateralen Cochlea-Implantation bei Erwachsenen
(2023)
Schwerhörigkeit ist sowohl für die betroffenen Patienten als auch sozioökonomisch eine relevante Erkrankung. Sie stellt ein Hindernis für die soziale Teilhabe dar, reduziert die Lebensqualität und führt zu direkten und indirekten Gesundheitskosten.
Cochlea-Implantate sind vielkanalige Neuroprothesen, die über einen chirurgisch in die Hörschnecke eingebrachten Elektrodenträger das erste Neuron der Hörbahn direkt elektrisch stimulieren und so eine Hörwahrnehmung induzieren.
Dadurch kann ein Funktionsverlust der Haarzellen, welcher die häufigste Ursache für eine Schwerhörigkeit ist, ersetzt werden. Cochlea-Implantate stellen den Goldstandard der Hörrehabilitation bei hochgradig schwerhörigen oder postlingual ertaubten erwachsenen Patienten sowie in der Versorgung prälingual ertaubter Kinder dar.
Bei vielen schwerhörigen Patienten besteht die Indikation zur beidseitigen Versorgung mit einem Cochlea-Implantat. Prinzipiell besteht die Möglichkeit, diese chirurgische Versorgung beidseits einzeitig (simultan) oder zweizeitig (sequenziell) durchzuführen. Während die Sicherheit der bilateral-simultanen Operation für Kinder durch mehrere Studien belegt wurde, liegen für Erwachsene erst wenige Daten vor.
Die vorliegende Studie untersucht, ob die bilaterale simultane Implantation mit höheren Komplikationsraten als die sequenzielle Operation assoziiert ist und leistet damit einen Beitrag zur Entscheidungsfindung von Patienten und Behandlern.
Es konnten 169 zwischen 2008 und 2017 bilateral implantierte Patienten eingeschlossen werden. Davon wurden 34 simultan (Gruppe 1) und 135 (Gruppe 2) sequenziell versorgt. Es wurde die Dauer der Operation, das Auftreten von Minor- und Major-Komplikationen sowie die Dauer des stationären Aufenthalts erfasst und zwischen beiden Gruppen verglichen.
Die Ergebnisse zeigten, dass die Gesamtzeit der Patienten im Operationssaal in der simultan implantierten Gruppe deutlich kürzer war. Die Häufigkeit chirurgischer Major- und Minor-Komplikationen unterschied sich hingegen nicht signifikant. Bezüglich einer letalen nicht-chirurgischen Komplikation in der simultan implantierten Gruppe erfolgte eine umfangreiche Aufarbeitung, ohne dass ein kausaler Zusammenhang mit der gewählten Behandlungsmethode nachgewiesen werden konnte. Die Dauer des Krankenhausaufenthalts war in der simultanen Gruppe 0,7 Tage länger als bei unilateraler Implantation, aber 2,8 Tage kürzer als bei beiden sequenziellen Operation zusammen.
In der Zusammenschau aller berücksichtigten Komplikationen und der komplikationsrelevanten Faktoren ist die Sicherheit der simultan bilateralen Operation gegenüber dem sequenziellen Vorgehen als gleichwertig zu bewerten.
Jedoch muss individuell auf mögliche Risikokonstellationen des Patienten eingegangen werden, die bei der längeren Operationszeit der simultanen Implantation relevant sein kann. Daher ist eine sorgfältige Auswahl der Patienten
unter besonderer Berücksichtigung bestehender Komorbiditäten unerlässlich.
Global analysis of halogenated trace gases in the UTLS: from long-lived to short-lived substances
(2023)
In this dissertation, the distribution of chlorinated and brominated substances in the upper troposphere and lower stratosphere is investigated. These substances contribute significantly to the catalytic decomposition of ozone and are involved in the recurrent formation of the polar ozone hole in the Antarctic winter and spring. The Montreal Protocol, a multilateral environmental treaty to protect the ozone layer, has successfully reduced emissions of long-lived chlorine- and bromine-containing substances. Short-lived chlorinated and brominated substances, some of which are natural and anthropogenic in origin, are not regulated by the Montreal Protocol and it can be assumed that their relative contribution to the stratospheric halogen budget will increase, while the contribution of long-lived compounds will steadily decrease. The distribution of long- and short-lived halogenated substances are part of current research. For the upper troposphere and lower stratosphere, the very short-lived substances are particularly important. The lower stratosphere needs special investigation in this respect, since its composition is influenced by different transport processes. The influences on ozone trends in the lower stratosphere are subject to great uncertainties. Especially in the Southern Hemisphere, the number of observations is very limited.
In this work, the GhOST (Gas chromatograph for Observational Studies using Tracers) instrument was used during the SouthTRAC measurement campaign on the German HALO (High Altitude and LOng range) research aircraft, providing observations of halogenated hydrocarbons in Antarctic late winter to early spring 2019, a generally poorly sampled region. The polar vortex was, compared to previous years, significantly weaker and shifted towards the eastern South Pacific and South America. From the airborne measurements of chlorinated source gases, inorganic chlorine (the sum of active chlorine and reservoir gases; Cly) could be inferred with the result that Cly within the vortex increased up to 1687 ± 19 ppt at 385 K potential temperature, accounting for about 50 % of the total chlorine within the vortex and only 15 % of the total chlorine in the southern mid-latitudes. A comparison with the Northern Hemisphere could be made using the PGS measurement campaign in the Arctic winter 2015/2016. Under comparable conditions (season and distance from the tropopause), only 40 % of the total chlorine was in the inorganic form within the Arctic polar vortex and about 20 % was found in the mid-latitudes of the Northern Hemisphere. In addition, about 540 ppt more Cly was present in the Antarctic vortex than in the Arctic vortex, exceeding the annual variations previously reported for Antarctica.
The mean age of air plays an essential role in the derivation of Cly via the organic source gases, as was done in this work. A new method for determining the mean age of air from observational data has been introduced that accounts for extra-tropical input to the stratosphere in addition to tropical input. This new method was compared with the previously used method, which considered only the tropical input. The new method shows more realistic values especially near the tropopause. On average, the air of the lower stratosphere in the Northern Hemisphere was older than in the Southern Hemisphere by about 0.5 ± 0.3 years. About 65 K above the tropopause, the pattern changed with older air in the mid-latitudes of the Northern Hemisphere, but older air in high latitudes of the Southern Hemisphere, which implies differences in the strength and isolation of the respective polar vortex as well as the wave forcing in the shallow branch of the Brewer-Dobson circulation of the respective hemisphere. This is in good agreement with the distribution of Cly. The difference in the lower stratosphere was not clearly evident with the old method and it can be assumed that investigations of the differences in Cly of Northern and Southern Hemisphere will benefit from the new method.
Finally, the global and seasonal distribution of the two most important representatives of the short-lived brominated substances, CH2Br2 and CHBr3, was investigated. For this purpose, two additional HALO measurement campaigns have been used, the 2012 TACTS measurement campaign and the 2017 WISE measurement campaign, as well as the HIAPER Pole-to-Pole Observations (HIPPO) and Atmospheric Tomography (ATom) measurement campaigns. Observations of CH2Br2 show a pronounced seasonality in the free and upper troposphere of both hemispheres with slightly larger values in the Northern Hemisphere. CHBr3, on the other hand, shows a generally higher variability and lower seasonality with larger mixing ratios at mid and high latitudes in the northern hemispheric winter and autumn. A comparison of the lower stratosphere is limited to autumn and spring of both hemispheres due to the limited data basis of the observations. The distributions in each spring are similar (less than 0.1 ppt differences for e.g., CH2Br2). In hemispheric autumn, larger differences are evident with substantially smaller mixing ratios in the southern hemispheric lower stratosphere. This suggests that the transport processes of the two hemispheres may be different and implies that the input of tropospheric air (flushing) to the Northern Hemisphere lowest stratosphere is more efficient than in the Southern Hemisphere. Vertical profiles of CH2Br2 and CHBr3 in the mid-latitudes of both hemispheres and resulting vertical gradients support this conjecture. However, the Southern Hemisphere data set is insufficient to quantify this difference and further measurements are needed.
With the rise of digitalization and ubiquity of media use, both opportunities and challenges emerge for academic learning. One prevalent challenge is media multitasking, which can become distracting and hinder learning success. This thesis investigates two facets of this issue: the enhancement of data tracking, and the exploration of digital interventions that support self-control.
The first paper focuses on digital tracking of media use, as a comprehensive understanding of digital distractions requires careful data collection to avoid misinterpretations. The paper presents a tracking system where media use is linked to learning activities. An annotation dashboard enabled the enrichment of the log data with self-reports. The efficacy of this system was evaluated in a 14-day online course taken by 177 students, with results confirming the initial assumptions about media tracking.
The second paper tackles the recognition of whether a text was thoroughly read, an issue brought on by the tendency of students to skip lengthy and demanding texts. A method utilizing scroll data and time series classification algorithms is presented and tested, showing promising results for early recognition and intervention.
The third paper presents the results of a systematic literature review on the effectiveness of digital self-control tools in academic learning. The paper identifies gaps in existing research and outlines a roadmap for further research on self-control tools.
The fourth paper shares findings from a survey of 273 students, exploring the practical use and perceived helpfulness of DSCTs. The study highlights the challenge of balancing between too restrictive and too lenient DSCTs, particularly for platforms offering both learning content and entertainment. The results also show a special role of media use that is highly habitual.
The fifth paper of this work investigates facets of app-based habit building. In a study over 27 days, 106 school-aged children used the specially developed PROMPT-app. The children carried out one of three digital activities each day, each of which was supposed to promote a deeper or more superficial processing of plans. Significant differences regarding the processing of plans emerged between the three activities, and the results suggest that a child-friendly planning application needs to be personalized to be effective.
Overall, this work offers a comprehensive insight into the complexity and potentials of dealing with distracting media usage and shows ways for future research and interventions in this fascinating and ever more important field.
Synaptic transmission is a fundamental process that involves the transfer of information from a presynaptic neuron to a target cell through the release of neurotransmitters. The SV cycle is a complex series of events that enables the recycling of SVs, allowing for the sustained release of neurotransmitters. This process is mediated by a variety of proteins and enzymes, and its regulation is critical for maintaining proper synaptic function. Despite extensive research efforts, many aspects of the SV cycle and the underlying synaptic proteins remain poorly understood, highlighting the need for continued investigation into this important process. During this work, multiple aspects of synaptic transmission were studied by performing
behavioural, pharmacological, optogenetic, electrophysiological and ultrastructural assays on Caenorhabditis elegans. First, the role of two proteins (ERP-1 and RIMB-1) were analysed in the synaptic vesicle cycle. Second, a new optogenetic tool, the pOpsicle assay was described, which enables the direct visualization of synaptic vesicle (SV) release.
Activity-dependent bulk endocytosis (ADBE) enables the endocytosis of SV membrane and proteins in a fast manner during intense stimulation, resulting in bulk endosomes (also so-called large vesicles, LVs). Recycling proteins can be characterized by its site of action, whether they act at the plasma membrane (participating at the LV formation), or at the LV membrane (participating at the SV formation). ERP-1 (the C. elegans ortholog of Endophilin B) was recently identified as a possible SV recycling factor, its contribution to synaptic transmission has not been analysed before. During this project the function and possible cooperation of three proteins, ERP-1, UNC-57 (the C. elegans ortholog of Endophilin A) and CHC-1 (the C. elegans ortholog clathrin heavy chain) were studied, with a special emphasis of the site of action. It has been confirmed that these proteins participate together in synaptic vesicle recycling. Endophilins (ERP-1 and UNC-57) act both at the PM and the LV level, but while UNC-57 has been identified as the main player, ERP-1 rather has a minor role and acts as a back-up protein. CHC-1 functions the LV level in the first place, but it can compensate for the loss of UNC-57 and acts as a back-up protein at the PM.
RIM-binding protein is an evolutionarily conserved active zone protein, which interacts directly with RIM and N, P/Q, as well as L-type Ca2+ channels. RIM-BP and RIM have redundant functions in different model organisms including C. elegans, however, while the loss of UNC-10 (the C. elegans ortholog of RIM) led to drastic behavioural defects, the loss of RIMB-1 (the C. elegans ortholog of RIM-BP) led only to mild phenotypes. During this work the synaptic function of RIMB-1 and its interaction with UNC-10 and UNC-2 (C. elegans ortholog of the CaV2 1 subunit) were extensively investigated. It has been shown that RIMB-1 contributes to the precise localization of VGCCs in cooperation with UNC-10. Furthermore, it has been demonstrated, that RIMB-1 plays different roles in cholinergic and GABAergic neurons, thus it contributes to maintain a proper excitation/inhibition balance.
There are numerous available assays, which enable the indirect analysis of synaptic transmission, however, a tool, that enables the direct visualization of SV release, is highly desired. pOpsicle is a method which combines the optogenetic stimulation of cholinergic neurons with real-time visualization of SV release. A pH-sensitive fluorescence protein, pHuji, was inserted into the second intravesicular loop of the synaptic vesicle membrane protein, synaptogyrin (SNG-1). The fluorescence of pHuji is quenched inside the vesicles, but once they are released, the pH increases and pHuji can be detected. pOpsicle enables not only the direct visualization of SV exo-, and endocytosis events, but also the identification of putative SV recycling proteins.
Semi-arid African ecosystems influence trends and variability in global terrestrial carbon dynamics. However, there are uncertainties in potential effects of future climates for semi-arid ecosystems, especially for niche ecosystems. At the same time, African ecosystems provide the livelihoods and ecosystem services for around 1.4 billion people. Future population growth and associated changes in land use pose a challenge for the protection of African biodiversity. Therefore, this work focussed on future impacts of climate change on African ecosystems and carbon dynamics and also for African protected areas (PAs), where they may cooccur with other global change factors. Another focus was on uncertainties associated with future projections and with modelling the Nama Karoo, as an example of a semi-arid niche ecosystem. Dynamic vegetation models (DVMs) were the main research tool.
In Chapter 2, we analysed climate change impacts on African ecosystems and carbon pools until the end of the 21st century and associated uncertainties based on an ensemble of vegetation simulations with the DVM adaptive dynamic vegetation model (aDGVM). We investigated the impact of increased atmospheric CO2 concentrations and two climate change scenarios (medium (RCP4.5) and high emissions (RCP8.5); RCP - representative concentration pathway) on vegetation changes. Differences in the simulated vegetation were primarily driven by assumptions about the influence of CO2 on plants. Elevated CO2 concentrations led to increased total aboveground vegetation biomass and shrub encroachment into grasslands and savannas for both climate scenarios. In simulations without the direct influence of CO2 on plants, there was hardly any shrub encroachment and vegetation biomass decreased or varied between a slight decrease in some cases and a slight increase in others. Based on these results, biome changes due to climate change are likely in Africa in the future. Due to the large uncertainties in future projections, strategies to adapt to climate change must be flexible.
The simulated vegetation in Chapter 2 represented potential, natural vegetation and is particularly suitable to investigate PAs. However, PAs do not exist isolated from their environment and social developments. In Chapter 3, the vegetation projections with CO2 effect from Chapter 2 were combined with projections for population density and land use. Except for many PAs in North Africa, most PAs were adversely affected by at least one of the three drivers by the end of the 21st century in both investigated scenarios ("middle-of-the-road" and "fossil-fuelled development"). Cooccurrence of the drivers varied by region and scenario for PAs. Both scenarios implied increasing challenges for the conservation of African biodiversity in PAs. The impact of climate change on vegetation is likely to be exacerbated by socio-economic change for most African PAs. Strong mitigation of future climate change together with equitable societal development may facilitate successful ecosystem conservation.
The simulations in Chapters 2 and 3 showed large-scale patterns of vegetation change, but their low resolution makes them unsuitable for local analyses. In Chapter 4, the challenges of simulating smaller scale, semi-arid ecosystems and their carbon cycle were analysed for the Nama Karoo with the aDGVM2 and its shrub module. The aDGVM2 is based on the aDGVM, but represents plants more flexibly. In all tested aDGVM2 configurations, the carbon fluxes improved compared to initial simulations but still overestimated them. The measured morphology of the dwarf shrubs and soil water dynamics were not reproduced in aDGVM2. Semi-arid soil water dynamics and coping strategies of semi-arid dwarf shrubs under drought stress are not adequately implemented in the aDGVM2. Further field research on semi-arid water and carbon dynamics of vegetation is necessary to parameterise the aDGVM2 for dwarf shrubs. If these challenges are overcome, DVMs can be a powerful tool for much-needed research on the impacts of climate change on the Nama Karoo.
The analyses have shown that climate change under medium to high emission scenarios is likely to lead to large-scale changes in ecosystems and the carbon balance in Africa. Because lower emissions scenarios come with less uncertainty, climate change adaptation strategies likely need to be less complex or extensive if climate change is minimised. For African PAs, the challenges of climate change may be exacerbated by socio-economic factors to a regionally varying extent. This research suggests that successful ecosystem conservation depends on climate change mitigation measures and ensuring equitable, sustainable development. The shown uncertainties, e.g., in the implementation of the CO2 effect on plants or vegetation dynamics in more niche ecosystems, help to focus future research efforts and increase our understanding of the range of plausible futures we may need to adapt to.
This dissertation is about case competition in headless relatives. Case competition is a situation in which two cases are assigned but only one of them surfaces. One of the constructions in which case competition takes place is in headless relatives, i.e. relative clauses that lack a head. This dissertation has two goals: (i) to give an overview of the data, and (ii) to provide an account for the observed data.
The grammaticality of a headless relative is determined by two aspects. The first aspect concerns which case wins the case competition. In all languages with case competition that I am aware of, this is determined by the case scale in NOM < ACC < DAT. A case more to the right on the scale wins over a case more to the left on the scale. This scale is not specific to case competition in headless relatives, but it can also be observed in syncretism patterns and morphological case containment. I show that that the case scale can be derived from assuming the cumulative case decomposition (cf. Caha 2009). A case wins over another case when it contains all features that the other case contains.
The second aspect of case competition in headless relatives concerns whether the winner of the case competition is allowed to surface when it wins the case competition. The winning case can be either the internal case required by the predicate in the relative clause, or the external case required by the predicate in the main clause. It differs from language to language whether they allow the internal and the external case to surface.
All language types I discuss allow for a headless relative when the internal and the external case match. The unrestricted type of language allows both the internal case and the external case to surface when either of them wins the case competition. Examples of this language type are Old High German, Gothic and Ancient Greek. The internal-only type of language allows only the internal case to surface when it wins the case competition, and it does not allow the external case to do so. An example of this language type is Modern German. The external-only type of language allows only the external case to surface when it wins the case competition, and it does not allow the internal case to do so. To my knowledge, there is no language that behaves like this. The matching type of language allows neither the internal nor the external case to surface when either of them wins the case competition. An example of this language type is Polish.
To account for the data, I set up a proposal that generates the attested patterns and excludes the non-attested ones. I let the variation between languages follow from properties of languages that can be independently observed. By investigating the morphology of the languages, I suggest differences between the lexical entries in the different languages. These different lexical entries ultimately lead languages to be of different types. In my proposal, I assume that headless relatives are derived from light-headed relatives. Light-headed relatives contain a light head and a relative pronoun. In a headless relative either the light head or the relative pronoun is deleted. The necessary requirement for deletion is that the deleted element (either the light head or relative pronoun) is structurally or formally contained in the other element.
I motivate the analysis for the internal-only type of language for Modern German, for the matching type of language for Polish and for the unrestricted type of language for Old High German. I first identify the morphemes that the light heads and relative pronouns in the languages consist of, and then I show to which features each of the morphemes correspond. The crucial difference between the internal-only type of language Modern German and the matching type of language Polish is how the phi and case features are spelled out. In Modern German they are spelled out by a phi and case feature portmanteau, and, in Polish, the same features are spelled out by a phi feature morpheme and a case feature morpheme. Old High German differs from the other two languages in that it has light heads and relative pronouns that are syncretic. I show how these differences in the morphology of the languages ultimately leads to different grammaticality patterns in headless relatives.
Comparing my account to others shows that all proposals account for the case facts using some kind of case hierarchy. The proposals differ in how they model the variation, both in the technical details of the proposal, but more importantly, also in empirical scope and predictions they make.
Experiments on Vibrational Energy Transfer (VET) in proteins contribute to our understanding of fundamental biological processes such as allostery, dissipation of excess energy, and possibly enzymatic catalysis. While these processes have been studied for a long time, many questions remain unanswered. The aim of this work was to expand the application of existing spectroscopic techniques to investigate VET, seeking tailored solutions for the diversity of proteins and amino acid environments. Additionally, new target proteins were to be established to broaden the spectrum of VET experiments towards the role of VET and low-frequency protein modes (LFMs).
To test their suitability as VET sensors, the non-canonical amino acids (ncAAs) Azidoalanine (N3Ala), azido-L-Homoalanine (Aha), p-azido-Phenylalanine (N3Phe), p-cyano-Phenylalanine (CNPhe), and 4-cyano-Tryptophan (CNTrp) were coupled to the VET donor β-(1-azulenyl)-L-Alanine (AzAla) in dipeptides. Their spectral properties were compared using FTIR and VET spectra in H2O, dimethyl sulfoxide, and tetrahydrofuran.
The solvent strongly influences the measured VET signals, which can be explained by the direct interaction of the solvent with the dipeptides. Additionally, the peak time within the subgroups of azide and nitrile sensors increased with the size of the side chain, indicating the dependence between peak time and the distance between VET donor and sensor. When incorporated into a protein, solvent interactions are less dominant. Therefore, Aha, N3Phe, and CNPhe were additionally incorporated at two different positions in the PDZ protein domain and investigated. Due to Fermi resonances, signals from azide sensors are challenging to predict, unlike those of the nitrile sensors.
Overall, the experiments showed that nitrile groups can serve well as VET sensors, as their lower extinction coefficient is compensated for by a narrower bandwidth. This expands the number of potential target proteins, and sensor incorporation can be less disruptive at various protein locations.
Since the VET donor AzAla can inject the energy of a photon into a protein as vibrational energy at a specific location, it can also be used for the targeted excitation of LFMs. If these modes are involved in an enzymatic reaction, a direct influence on activity is expected. This hypothesis has long existed but has not been definitively verified. Some studies have found evidence for the involvement of LFMs in formate dehydrogenase (FDH) catalysis. Therefore, FDH was chosen for the investigation of LFMs in enzymes. This specific system additionally allows the use of a natural VET sensor: it forms a stable complex with NAD+ and N3-, an excellent IR marker. Thus, it provided the opportunity to test low-molecular-weight non-covalent ligands as VET sensors.
After ensuring sufficient AzAla supply through the internal establishment of an enzymatic synthesis, AzAla could be incorporated at various positions in FDH. Despite spectral overlap between free and bound N3-, the latter could be identified by its narrower FWHM. For some variants, no binding could be observed. Circular dichroism spectra showed that these variants structurally deviate slightly from other variants and the wild type (WT). VET could be observed over 22 Å from two regions of the protein to the N3- bound in the active center, at protein concentrations of below 2 mM. Unbound N3- did not generate signals, allowing it to be added in excess ensuring the saturation of the protein in VET experiments.
The activity of FDH WT and four AzAla mutants was investigated under substrate saturation without and with AzAla excitation. In these experiments, a slight reduction in activity under illumination was observed, even for the WT, who is not expected to interact with the excitation light. So far, a difference in sample temperature cannot be excluded as the cause for this decline.
The presented experiments with FDH illustrate the potential of low-molecular-weight ligands as VET sensors, with N3- being particularly attractive due to its simple structure (preventing Fermi resonances) and its high extinction coefficient. Its use can add many metalloproteins as potential targets for VET experiments and allows investigation without a VET sensor ncAA. Additionally, initial experiments were conducted to measure light-dependent FDH activity. By specifically exciting protein LFMs, this project could contribute in the future to answering longstanding questions about the extraordinary catalytic efficiency of enzymes.
In the past decade, the optogenetic toolbox for the manipulation of ion currents and cNMP levels in Caenorhabditis elegans (C. elegans) expanded. However, the implemented tools for cAMP generation were soluble enzymes (euPAC, bPAC, IlaC22 k27 and PaaC) and thus they do not precisely mimic physiological cAMP signalling occurring in microdomains in close proximity to the plasma membrane. Here, cAMP is predominantly generated by membrane-bound adenylyl cyclases, that are located in microdomains together with G protein-coupled receptors (GPCRs), protein kinase A (PKA) and their targets, enabling spatially and temporal regulation of cAMP signalling. For this reason, one aim of this study was to develop and implement membrane bound photoactivatable adenylyl cyclases for the manipulation of cAMP mediated signalling in close proximity to the plasma membrane. For this purpose, the guanylyl cyclase domains of the Blastocladiella and Catenaria Cyclase Opsins (CyclOps) were mutated to adenylyl cyclases either by introducing the mutations E497K and C566D (abbreviated as (A-2x)) or by the mutations E497K, H564D, and C566T (abbreviated as (A-3x)).
To determine the nucleotide specificity switch from GTP to ATP and the extent of light-dependent cAMP generation, the engineered enzymes were expressed in body wall muscle cells of C. elegans and in vitro cNMP measurements using C. elegans extracts were performed. Here, the highest levels of light induced cAMP generation during sustained stimulation (0.5 mW/mm2; 470 nm, 15 min) were detected for the variants BeCyclOp(A-2x), YFP-BeCyclOp(A-2x), and YFP-CaCyclOp(A-2x) (39, 57, 40 nM, respectively), though they did not reach the extent produced by the soluble bPAC (142 nM). In contrast, low magnitudes of generated cAMP were measured for the versions BeCyclOp(A-3x) and CaCyclOp(A-2x) (8 and 7 nM, respectively). Importantly, no obvious residual cGMP and basal activity was ascertained for any of the engineered enzymes.
To assess their potential to trigger and modulate cAMP mediated cholinergic neurotransmission, and to evaluate the influence of cytosolic and membrane proximal optogenetic cAMP generation, the enzymes were expressed in cholinergic motor neurons and compared to the implemented soluble bPAC via locomotion behaviour analysis on solid and in liquid media. Photoactivation of BeCyclOp(A-2x), YFP-BeCyclOp(A-2x), and YFP-CaCyclOp(A-2x) caused similarly enhanced or even more potent behavioural changes (swimming and crawling) as bPAC, whereas a more rapidly decaying response was observed for the bPAC evoked effects. Moreover, an increased diversity of the behavioural output was detected for cytosolic cAMP production by bPAC, i.e. increased bending angles and a decreased body length.
Confocal fluorescence microscopy was performed to examine the expression levels of YFP-tagged enzymes in cholinergic neurons, whereas both YFP-CyclOp(A-2x)s were expressed at similar levels, but 1.4-fold lower relative to the soluble bPAC-YFP. To compare the amount of light-dependent cAMP generation bPAC and BeCyclOp(A-2x) at light conditions that match the conditions of the behavioural experiments (30 s), cAMP measurements using C. elegans extracts were performed, whereas BeCyclOp(A-2x) depicted a 4-fold lower amount of optogenetic cAMP production than the soluble bPAC.
In sum, local (membrane proximal) cAMP generation by the membrane-bound photoactivatable adenylyl cyclases may more specifically activate cAMP dependent neurotransmission of cholinergic motor neurons than cytosolic cAMP generation, i.e. an increased mobilization and priming/docking of synaptic vesicles and an increased filling of the synaptic vesicles with the neurotransmitter acetylcholine and thus an increase in locomotion behaviour.
The optogenetic toolbox for the manipulation of cGMP mediated signalling in C. elegans consisted of the natural membrane-bound BeCyclOp and the artificial soluble bPGC. The latter generates cGMP with low efficiency and slow kinetics (~0.2 cGMP s-1), whereas BeCyclOp enables the production of much larger amounts of cGMP (L/D = 5000) at a high turnover rate (~17 cGMP s-1). Thus, one aim of this thesis was to implement a tool with features in between those of BeCyclOp and bPGC. Several orthologous CyclOps were assessed by Gao et al., 2015 for light-regulated cGMP production by in vitro assays based on the measurement of the cNMP content from CyclOp containing oocyte membranes. Here, CaCyclOp showed the highest ratio of light versus dark activity (L/D = 230) after BeCyclOp, and thus was selected for characterization in C. elegans...
First-principles modeling techniques offer the ability to simulate a wide range of systems under different physical conditions, such as temperature, pressure, and composition, without relying on empirical knowledge. Density functional theory (DFT), a quantum mechanical method, has become an exceptionally successful framework for materials science modeling. Employing DFT makes it possible to gain valuable insights into the fundamental state of a system, enabling the reliable determination of equilibrium crystal structures. Over time, DFT has become an essential tool that can be incorporated into various schemes for predicting the properties of a material related to its structure, insulating/metallic behavior, magnetism, and optics. DFT is regularly applied in numerous fields, spanning from fundamental subjects in condensed matter physics to the study of large-scale phenomena in geosciences. In the latter, the effectiveness of DFT stems from its ability to simulate the properties found on the Earth, other planets, and meteorites, which may pose challenges for their direct study or laboratory investigation.
In this thesis, a comprehensive examination of a family of monosulfides and a perovskite heterostructure was conducted. These materials are relevant for their potential applications in technology, energy harvesting, and in the case of monosulfides, their speculated abundance on the planet Mercury.
Firstly, a DFT approach was used to analyze two non-magnetic monosulfides, CaS and MgS. We determined their structural properties and then focused on the modeling of their reflectivity in the infrared region. The calculation of the reflectivity considered both harmonic and anharmonic contributions. In the harmonic limit, the non-analytic correction was employed to accurately determine the LO/TO splitting, which is necessary to delimit the retstrahlend band, that is, the maximum of the reflectivity. The anharmonic effects given by up to three-phonon and isotopic scatterings, which were included using perturbation theory, primarily smeared the reflectivity spectra edges in the high-wave region.
Secondly, four polymorphs of MnS were studied using a combination of first-principles methods to simulate their antiferromagnetic (AFM) and paramagnetic (PM) states. The integration of DFT+$U$ with special quasirandom structures (SQS) supercells, and occupation matrix control techniques was crucial for achieving convergence, structural optimization accuracy, and obtaining finite energy band gaps and local magnetic moments in the PM phases. The addition of the Hubbard $U$ correction was necessary to treat the highly-correlated Mn $d$-electrons. The success of our approach was clear based on our electronic structure predictions for the PM rock-salt B1-MnS polymorph. Experimentally this phase has been observed to be an insulator, but multiple \emph{ab initio} works resulted previously in metallic behavior. Our computations, on the other hand, predicted insulating and magnetic properties that compare well with available measurements. Additionally, the pressure-field stability of the four MnS polymorphs was studied. In the case of the PM phases, B1-MnS was identified to be the most stable up to about 21 GPa, then transforming into the B31-MnS polymorph. This finding was in close agreement with high-pressure experiments reporting a similar phase transformation. The optical properties of B1-, B4-, and B31-MnS were also simulated. The SQS technique was used to obtain soft-mode-free phonon band structures within the harmonic approximation. Then, the anharmonic effects were included, and the reflectivity was calculated for B1-MnS and B4-MnS. In both cases, a good agreement for the LO/TO splitting was achieved in comparison to experimental results.
Lastly, the oxygen-deficient heterostructure of LaAlO$_{3-\delta}$ /SrTiO$_{3-\delta}$ was investigated also employing DFT+$U$, with a particular emphasis on the potential impact of vacancy clustering at the interface. Six distinct configurations of pairs of vacancies were studied and their energies were compared to find the most stable one. The orbital reconstruction of Ti orbitals was also examined based on their location with respect to the vacancies and the local magnetic moments were calculated. The final results showed that linearly arranged vacancies located opposite to Ti ions give the most energetically stable configuration.
Menschen mit Epilepsie (engl. PWE) haben im Vergleich zur Allgemeinbevölkerung ein erhöhtes Risiko, vorzeitig zu versterben. Der plötzliche, unerwartete Tod bei Epilepsie (engl. Sudden Unexpected Death in Epilepsy, kurz SUDEP) stellt die häufigste epilepsiebedingte Todesursache dar. Obwohl das Thema in Fachkreisen zunehmende Aufmerksamkeit erfährt, die Empfehlung zur SUDEP Aufklärung zunehmend in nationalen Leitlinien aufgenommen wird, und der Patientenwunsch nach einer generellen SUDEP Aufklärung in verschiedenen Studien gezeigt werden konnte, besteht weiterhin ein Informationsdefizit unter PWE. Ursache hierfür scheint insbesondere die Sorge der behandelnden Neurolog*innen zu sein, Menschen mit Epilepsie übermäßig emotional zu belasten und ihre Lebensqualität zu mindern. Diese Studie untersucht sowohl das Vorwissen über SUDEP als auch unmittelbare sowie langfristige Auswirkungen einer SUDEP Aufklärung auf Erwachsene mit Epilepsie. Ziel ist mögliche negative Auswirkungen der Aufklärung sowie Auswirkungen auf das Verhalten aufzudecken. Aus diesem Zweck wählten wir ein prospektives, multizentrisches, longitudinales Studiendesign. Die Daten wurden in halbquantitativen Interviews vor (vor der Aufklärung), unmittelbar nach (nach der Aufklärung) und drei Monate nach (3-Monats Follow-up) der SUDEP Aufklärung erhoben. Um die direkte Vergleichbarkeit zwischen den Zeitpunkten zu ermöglichen wurden folgende validierte Instrumente verwendet: das Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) zur Erfassung depressiver Symptome, der EuroQoL (EQ-5D) zur Erfassung der gesundheitsbezogenen Lebensqualität (HRQoL), eine visuelle Analogskala (VAS) zur Erfassung des allgemeinen Gesundheitszustandes, die revised Epilepsy Stigma Scale (rESS) zur Erfassung der wahrgenommenen Stigmatisierung und die Seizure Worry Scale zur Erfassung anfallsbezogener Sorgen. Insgesamt wurden 236 Teilnehmende (Durchschnittsalter: 39,3 Jahre, Spannweite: 18-77 Jahre, 51,7 % Frauen) in die Studie eingeschlossen. 205 (86,9 %) der Teilnehmenden konnten erneut im Langzeit Follow-up nach drei Monaten befragt werden. Eine der Teilnehmenden verstarb im Zeitraum des Follow-ups an SUDEP. Keines der validierten Instrumente zeigte zwischen den Zeitpunkten vor der Aufklärung und dem 3-Monats Follow-up eine Verschlechterung. Vor der Aufklärung hatten nur 27,5 % der Teilnehmenden von SUDEP gehört, und nur 9,3 % gaben an, diese Informationen von ihrer bzw. ihrem Neurolog*in erhalten zu haben. Nach der Aufklärung gaben mehr als 85 % der Teilnehmenden an, mit der SUDEP Aufklärung zufrieden oder sehr zufrieden zu sein. Drei Viertel der Teilnehmenden gaben an, durch die Aufklärung nicht oder überhaupt nicht belastet zu sein. Mehr als 80 % der Teilnehmenden befürworteten eine generelle SUDEP Aufklärung für alle Menschen mit Epilepsie. Bei dem 3-Monats Follow-up gab die Mehrheit der Teilnehmenden an, keine Verhaltensänderung vorgenommen zu haben, 24,8 % berichteten jedoch von starken Verhaltensänderungen.
Unsere Studie zeigt, dass eine SUDEP Aufklärung keine negativen Auswirkungen auf den allgemeinen Gesundheitszustand, die HRQoL, depressive Symptome, krankheitsbezogene Stigmatisierung oder Sorgen vor Anfällen hat. Insgesamt zeigte sich eine hohe Zustimmung zur SUDEP Aufklärung. Eine generelle SUDEP Aufklärung könnte sich zudem positiv auf die Compliance auswirken und das Mortalitätsrisiko senken. Eine SUDEP Aufklärung bietet allerdings keinen sicheren Schutz vor SUDEP.
Identifizierung und funktionelle Analyse von Pathogenitätsfaktoren in Bartonella bacilliformis
(2023)
Die Carrión-Krankheit ist eine durch Vektoren übertragene vernachlässigte Tropenkrankheit (neglected tropical disease), die in den südamerikanischen Andentälern auf einer Höhe von 600 3.200 m über dem Meeresspiegel vor allem in Peru, aber auch in Ecuador und Kolumbien endemisch ist. Der Erreger dieser Infektionskrankheit ist Bartonella bacilliformis, ein strikt humanpathogenes, Gram-negatives, fakultativ intrazelluläres Stäbchen der Klasse der Alphaproteobakterien. In der akuten Krankheitsphase, die als "Oroya-Fieber" bezeichnet wird, infizieren die Erreger Erythrozyten und verursachen eine schwere akute hämolytische Anämie, hohes Fieber sowie eine ausgeprägte Immunsuppression. Für diese Phase wurden Sterblichkeitsraten von bis zu 88% beschrieben. Dem Oroya-Fieber folgt meist eine chronische Infektion der vaskulären Endothelzellen, bei der durch vaskulo-endotheliale Proliferationen noduläre, Hämangiom-ähnliche, kutane Gefäßläsionen, die als "Verruga peruana" bezeichnet werden, entstehen. Diese beiden Phasen treten in der Regel nacheinander, manchmal aber auch unabhängig voneinander auf. Die Übertragung auf dem Menschen erfolgt durch den Biss infizierter Sandmücken (Lutzomyia spp.), die in den hochgelegenen Regionen der Anden vorkommen. Klimatische Veränderungen führen jedoch zur Expansion des Vektors auf angrenzende Regionen und begünstigen damit die Ausbreitung von B. bacilliformis-Infektionen.
In der Erforschung der Carrión-Krankheit besteht ein erheblicher Wissensmangel zu zahlreichen Aspekten (z. B. Epidemiologie, Infektionsbiologie, Diagnostik, Therapie), wodurch die Entwicklung von potenziellen Diagnostika, Therapeutika oder Vakzinen verhindert wird. Auch wenn frühere Studien zum Ziel hatten, immundominante Proteine für die Entwicklung serodiagnostischer Verfahren und Impfstoffe zu identifizieren, ist bislang kein validierter serologischer Test bzw. ein Impfstoff verfügbar. Daher sollte im ersten Teil dieser Arbeit ein serologischer Test zum Nachweis von anti-B. bacilliformis-Antikörpern entwickelt werden. Hierzu wurde ein Ansatz aus reverser Vakzinologie in Kombination mit einer Analyse heterologer genomischer Expressionsbibliotheken verfolgt, um geeignete immundominante Proteine zu identifizieren. Insgesamt wurden 21 potenziell immundominante Proteine identifiziert, rekombinant produziert, und auf ihre Reaktivität mit B. bacilliformis Patientenseren mittels Immunoblotting analysiert. Von den 21 Antigenkandidaten erwiesen sich 14 als immunreaktiv, die anschließend in einer Lineblot-Analyse mit 26 Serumproben von peruanischen B. bacilliformis Patienten und 96 Serumproben von gesunden deutschen Blutspendern ohne Reisevorgeschichte in Südamerika auf ihren potenziellen Nutzen für serologische Test untersucht wurden. Drei Antigene (Porin-B, Autotransporter-E und hypothetisches Protein-B) erwiesen sich für die Entwicklung eines diagnostischen ELISA als geeignet und wurden in zwei verschiedenen Antigenkombinationen (ELISA 1: Porin-B, Autotransporter-E, ELISA 2: Porin-B, Autotransporter-E, hypothetisches Protein B) verwendet. Um die Leistungsfähigkeit des B. bacilliformis ELISA zu bewerten, wurde eine Receiver-Operating-Characteristic-Analyse durchgeführt. Für die Kombination aus Porin-B und Autotransporter-E lag die Sensitivität des Tests bei 80,8% und die Spezifität bei 94,8%, wohingegen die Kombination aus Porin-B, Autotransporter-E und dem hypothetischem Protein-B in einer Sensitivität von 76,9% und einer Spezifität von 93,8% resultierte. Dieser neu entwickelte ELISA könnte ein nützliches serodiagnostisches Instrument für künftige epidemiologische Studien über B. bacilliformis in endemischen Gebieten darstellen. Darüber hinaus könnten die hier identifizierten immundominanten Antigene eine erste Grundlage für die zukünftige Entwicklung von Impfstoffen für die Prävention Carrión-Krankheit bilden.
Erythrozyten-Invasion und Hämolyse sind wahrscheinlich die wichtigsten Schritte in der Pathogenese der Carrión-Krankheit und verantwortlich für die hohe Sterblichkeitsrate beim Menschen. Genaue mechanistische Kenntnis dieses Prozesses sind entscheidend für die Entwicklung therapeutischer Arzneimittel. Im zweiten Teil dieser Arbeit sollten die in der Hämolyse involvierten Pathogenitätsfaktoren von B. bacilliformis identifiziert werden. Hierzu wurde eine Tn5-Transposonmutagenese in den beiden B. bacilliformis Stämmen KC583 und KC584 durchgeführt. Ein screening nach Hämolyse-defizienten Mutanten führte zur Identifizierung von zwei Pathogenitätsfaktoren: einem Porin (Porin-A) und einer α/β-Hydrolase. Ihre vermutete Funktion im Prozess der Hämolyse wurde durch eine zielgerichtete markerlose Deletion sowie durch genetische Komplementationen in vitro funktionell bestätigt. Dabei zeigte sich, dass Porin-A und die α/β Hydrolase jeweils essenzielle Faktoren für die Hämolyse darstellen. Durch eine in silico-Charakterisierung konnte konservierte biologische Funktionen identifiziert sowie die dreidimensionale Struktur der Proteine vorhergesagt werden. Diese Versuche bilden eine experimentelle Basis, um die Rolle von Porin-A und der α/β-Hydrolase näher untersuchen zu können und um potenzielle (Porin-A und α/β-Hydrolase) Inhibitoren mit anti-hämolytischer und damit therapeutische Wirkung testen zu können.
mRNS ist einer der wichtigsten Informationsträger in lebenden Zellen. Mit ihr wird die in der DNS gespeicherte Information zu aktiven Zellprozessen umgesetzt. Dabei finden erste regulatorische Prozesse, die den Phänotyp eines Organismus bestimmen können, bereits über Strukturelemente auf der mRNS statt. Diese, als Riboschalter bezeichneten Strukturen, können spezifisch, kleine Moleküle binden und dadurch ihre Struktur ändern. Durch diese dynamische Änderung der Struktur, in An- oder Abwesenheit des Liganden, wird reguliert, ob nachfolgende Gene vom Ribosom abgelesen werden können. Der Cd1-Riboschalter aus Clostridium Difficile ist schon während der Transkription aktiv und ein Teil des regulatorischen Netzwerkes, das bestimmt, ob das Bakterium einen mobilen oder stationären Lebensstil einnimmt. Das zentrale Signalmolekül in diesem Netzwerk ist der sekundäre Botenstoff c-di-GMP, der gleichzeitig auch der Ligand des Cd1-Riboschalters ist. In der folgenden Arbeit wurde der zeitliche und strukturelle Ablauf des Cd1 Regulationsmechanismus und die Bindung von c-di-GMP untersucht. Auch ohne einen Riboschalter in der Sequenz ist strukturierte mRNS ein interessanter Forschungsgegenstand. Wie die Covid-19 Pandemie und die Forschungen, mRNS Abschnitte als Krebsmedikamente zu gebrauchen, zeigen, gewinnt RNS immer mehr an Bedeutung für die medizinische Forschung und Anwendung. Mit dieser Motivation im Hintergrund wurden drei weitere RNS Projekte bearbeitet. Im ersten wurde ein 19F-Screening für die Erkennung von RNS bindenden Fragmenten etabliert. Im zweiten wurde ein RNS Doppelstrang untersucht, der mit Hilfe verschiedener, kovalent gebundener Spiropyrane reversibel gefaltet und entfaltet werden sollte. Im abschließenden Projekt wurden im Rahmen der COVID-19-NMR Initiative zwei Sekundärstrukturelemente der Covid-19 RNS untersucht.
Bei der Untersuchung des Cd1-Riboschalters konnten folgende Ergebnisse erzielt werden. Es wird gezeigt, dass die Bindung von c-di-GMP an das Cd1-Aptamer ein konzentrationsabhängiges Magnesiumverhältnis braucht. Dieses Verhältnis wurde ausgehend von initialen Messungen als 1/40 (RNS/Ligand) bestimmt. Spätere ITC Messungen geben aber Hinweise darauf, dass dieses Verhältnis bei niedrigen RNS Konzentrationen höher liegt und bei größeren RNS Konzentrationen niedriger. Die Bestimmung des Start- und Endpunktes der c-di-GMP Bindung wird in Unterkapitel 3.1.2 behandelt. Es wurde ermittelt, dass Cd1 bei 83 Nukleotiden eine alternative schwach Ligand bindende Konformation einnimmt, die wahrscheinlich durch eine P1 Helix bis zum Erreichen von Cd1-87 stabilisiert wird. Ab Cd1-87 bildet sich die reguläre von der Literatur vorhergesagte Bindetasche. Das Ende der c-di-GMP Bindung wird mit Cd1-148 erreicht, auch wenn hier noch Reste der Reportersignale für Bindung zu sehen sind. Diese Reste werden aber aller Wahrscheinlichkeit nach durch eine Cd1-83 entsprechende Konformation der Bindetasche erzeugt. In Kapitel 3.2 wird gezeigt, wie durch NMR Messungen die Zuordnung der Sekundärstruktur des Cd1-Riboschalters vollzogen wurde. Durch diese Messungen konnte bestätigt werden, dass in allen Längen eine P2 und P3 Helix vorhanden ist. Im Aptamer wird die Ligandbindung durch zwei Interaktionen zwischen P2 und P3 stark stabilisiert und der untere Abschnitt der P3 erst dann nicht mehr dynamisch, wenn c-di-GMP gebunden wird. Durch x-filter Experimente und Mutationen konnte nachgewiesen werden, dass C87 das basenpaarende Nukleotid an einem G des Liganden ist. Die Anwesenheit des HP1 Stamms konnte in den Längen 147, 148 und 160 nachgewiesen werden, wobei besonders der Vergleich der NOESY Spektren von Cd1-147 und Cd1-148 die Änderung der Sekundärstruktur hin zum Antiterminator zeigen. Der Verlauf der Bindungsaffinitäten wurde auch durch ITC Messungen an Cd1-83, 86, 87, 88, 135 und 146 bestätigt. Für die volle Länge (Cd1-160) des Riboschalters konnte gezeigt werden, dass der Terminatorstamm ausgeformt ist. Die erreichten Ergebnisse wurden in einem Modell zusammengefasst und der zeitliche Verlauf der Cd1 Regulation simuliert. Aus der Simulation ist zu erkennen, dass Cd1, wie erwartet, Ligand abhängig schaltet. Dabei ist der Aus-Zustand bei hoher Ligandkonzentration zu 90% populiert und der An-Zustand zu 100% bei niedriger Konzentration. Des Weiteren konnte gezeigt werden, dass die Transkriptionsgeschwindigkeit bei hohen Ligandkonzentrationen einen starken Einfluss auf die Regulationseffizienz des Riboschalters hat. So ist bei einer Transkriptionsgeschwindigkeit von 100 nt/s nach 1 s eine Gleichverteilung von An- und Aus-Zustand zu erkennen. Dieses Verhalten kann durch einen Stopp der Transkription an der potentiellen Pausierstelle U141-145 aufgehoben werden. Unter den Rahmenbedingungen des Modells erwiesen sich Transkriptionsgeschwindkeiten von um die 20 nt/s als optimal und bei niedrigen Ligandkonzentrationen hatte die Transkriptionsgeschwindigkeit faktisch keine Auswirkungen auf die Regulation. Ein interessantes Ergebniss der Modellierung ergab sich aus der Notwendigkeit der Verwendung einer Rate für konkurrenzlose Basenpaarschließungen. Hier konnte gezeigt werden, dass eine Rate von 400 nt/s ausreicht um einen voll funktionsfähigen Riboschalter zu beschreiben.
Beim 19F Bindungsscreenings von 101 Fragmenten, die alle ein oder mehrere 19F Atome besaßen, an Cd1-98 wurden 9 Fragmente gefunden die an Cd1-98 binden. Diese sind größtenteils planar mit Ausnahme von 2 Fragmenten bei denen die eine Hälfte des Moleküls nicht aromatisch ist. Des Weiteren besitzen alle Fragmente, außer einem, mindestens eine Aminogruppe im Molekül. Die daraus resultierende Vermutung, dass die Fragmente in die RNS interkalieren, konnte durch RNS beobachtende NMR Messungen nicht überprüft werden, da keine Signaländerung im Imino-Bereich zu erkennen war. Durch Verdrängungsexperimente konnte gezeigt werden, dass die Fragmente, nicht wie c-di-GMP, die RNS Faltung homogenisieren und auch nicht in der Bindetasche gebunden werden.
Our mind has the function of representing the physical and social world we are in, so that we can efficiently interact with it. This results in a constant and dynamic interaction between mind and world that produces a balance when representations are at the same time accurate with respect to what the world is communicating to our organism, but also compatible with how our mind works.
A paradigmatic case of this interaction is offered by perception, which is the mental function that represents contingent aspects of the world built from what is captured by our senses. Indeed, the dominant philosophical view in cognitive science is that our perceptual states are representations of the world and not direct access to that world. These representational perceptual states therefor include the aspects of the world they represent and that initiate the perception by stimulating our sensory organs.
Perceptual representations are built using information from the sensory system, i.e., bottom-up information, but are also integrated with information previously acquired, i.e., top-down information, so that perception interacts with memory through language and other mental functions. Such organization is believed to reflect a general mechanism of our mind/brain, which is to acquire and use information to make efficient predictions about the future, continuously updating older information with present information.
This predictive processing works because the world is not random, but shows a regular structure from which reliable expectations can be built. One way that our minds make these predictions is by adapting to the structure of the world in an implicit, automatic and unconscious way, a process that has been called Implicit Statistical Learning (ISL). ISL is a learning process that does not require awareness and happens in an incidental and spontaneous way, with mere exposure to statistical regularities of the world. It is what happens when we learn a language during early childhood, and that allows us to be implicitly sensitive to the phonological structure of speech, or to associate speech patterns with objects and events to learn word meaning.
A specific case of ISL is the learning of spatial configuration in the visual world, which we apply to abstract arrays of items, but most importantly, also to more ecological settings such as the visual scenes we are immersed in during our everyday life. The knowledge we acquire about the structure of visual scenes has been called “Scene Grammar”, because it informs about presence and position of objects in a similar way to what linguistic grammar tells us about the presence and position of words. So, we implicitly acquire the semantics of scenes, learning which objects are consistent with a certain scene, as well as the syntax of scenes, learning where objects are positioned in a consistent way within a certain scene.
More recent developments have proposed that scene grammar knowledge might be organized based on a hierarchical system: objects are arranged in the scene, which offers the more general context, but within a scene we can identify different spatial and functional clusters of objects, called “phrases”, that offer a second level of context; within every phrase, then, objects have different status, with usually one object (“anchor object”) offering strong prediction of where and which are the other objects within the phrase (“local objects”). However, these further aspects of the organization of objects In scenes remain poorly understood.
Another problem relates to the way we measure the structure of scenes to compare the organization of the visual world with the organization in the mind. Typically, to decide if an object appears or not in a certain scene, and whether or not it appears in a certain position within a scene, researchers based their decision on intuition and common-sense, maybe validating those decisions with independent raters. But it has been shown that often these decisions can be limited and more complex information about objects’ arrangement in scenes can be lost.
A potential solution to this problem might be using large set of real-world images, that have annotations and segmentations of objects, to measures statistics about how objects are arranged in the environment. This idea exploits the nowadays larger availability of this kind of datasets due to increasing developments of computer vision algorithms, and also parallels with the established usage of large text corpora in language research.
The goals of the current investigation were to extract object statistics from this image datasets and test if they reliably predict behavioural responses during object processing, as well as to use these statistics to investigate more complex aspects of scene grammar, such as its hierarchical organization, to see if this organization is reflected in the organization of objects in our mind.
Climatology of morphology and cloud-radiative properties of marine low-level mixed-phase clouds
(2023)
Marine stratocumuli cover about 40 - 60% of the ocean surface. They self-organize into different morphological regimes. The two organized cellular regimes are called open and closed mesoscale-cellular convective (MCC) clouds. In mid-to-high latitudes, open and closed cells are the two most frequent types of MCC clouds. In particular, many MCC clouds consist of a mixture of vapor, liquid droplets, and ice particles, referred to as mixed-phase clouds (MPCs). Even for the same cloud fraction, the albedo of open cells is, on average, lower than that of closed MCC clouds. Cloud phase and morphology individually influence the cloud radiative effect. Thus, this thesis investigates the relationships between the cloud phase, MCC organization, cell size, and differences regarding the cloud-radiative effect.
This thesis focuses on space-borne retrievals to achieve extensive temporal and spatial coverage. The liDAR-raDAR (DARDAR) version 2 product collocates two active and one passive satellite: CloudSat, Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO), and Moderate Resolution Imaging Spectroradiometer (MODIS). The cloud phase of DARDAR is vertically integrated to establish a single cloud phase at each data point. The MCC classification data set based on the liquid water path (LWP) of MODIS scenes is collocated with the DARDAR product to determine the MCC organization. Cell-size statistics of both MCC clouds are obtained using a marker-based image segmentation method on MODIS reflectance scenes. In addition, based on MODIS reflectance scenes, a convolutional neural network (CNN) is developed to classify open and closed MCC scenes to avoid missing mature MPCs with a low LWP.
The first part of this thesis explores the relationships between cloud phase, morphology, and cloud albedo in the Southern Ocean (SO). At a given cloud-top temperature (CTT), seasonal changes in the mixed-phase fraction, defined as the number of MPCs divided by the sum of MPC and supercooled liquid cloud (SLC) pixels, are stronger than the morphological changes. Therefore, external factors seem to influence these changes instead of morphology. The dependence of cloud phase on cloud-top height (CTH) is more substantial than on CTT in clouds with CTHs below 2.5 km. The previously observed acceleration of closed-to-open transition in MPCs, known as preconditioning, is not the primary driver of climatological cloud morphology statistics in the SO. The morphological differences in cloud albedo are more pronounced in SLCs than in MPCs. This change in albedo alters the cloud radiative effect in the SO by 21Wm−2 to 39Wm−2 depending onseason and cloud phase.
Open and closed MCC clouds exhibit larger equivalent cell diameters in the MPCs than in SLCs in austral summer, whereas, in austral winter, the SLCs are larger. The cell’s aspect ratio accounts for varying CTHs. Closed cells have smaller aspect ratios than open cells, so their cell diameter is smaller, independent of CTH. While the seasonal differences in closed cells are due to changes in CTH, the seasonal aspect ratio differences in open cells are mainly caused by MPCs. With increasing aspect ratios, the cloud albedo decreases in both open and closed MCC clouds, with the most substantial decrease in open MPCs clouds. This leads to cloud-radiative changes of 60 - 75Wm−2 in the SO, depending on cloud phase and aspect ratio.
The established CNN exhibits a good accuracy of 80.6%, with even higher accuracies in the Open (85.5%) and Closed (87.3%) categories. The global MCC climatology based on the CNN generally agrees well with previous MCC distributions. The most notable difference occurs in the Northern Hemisphere (NH) in boreal winter, with a higher occurrence frequency of closed and open MCC clouds. This might indicate missing MPCs in previous studies based on the LWP and some restricted to warm cloud scenes. Thus, the developed CNN seems to better represent the different morphologies in MPCs than in previous classifications.
In conclusion, this thesis shows that understanding the dependencies of cloud phase, cloud morphology, and cell size is important to enhance predictions of the cloud-radiative effect and thus, it is important to evaluate how cloud phase, cloud morphology, and cellsize change in a warming climate.
This study examines the political contestation among Malay Professional Satirists (MPS) through their selected political satire works between 2011-2018. Political satire challenges those in power and is often regarded as fake news and libel. Therefore, political satirists tend to be frequently subject to legal action and are accused of disrupting national harmony. However, there is another group within the social and cultural community, which I call Social and Cultural Professionals (SCP), who also use satire but are supported by the government. This group frequently received financial benefits from the state and are at lower risk of suffering legal consequences. These contrasting conditions raise several important questions: who are the Malaysian Professional Satirists? Who are the targets of MPS in their satirical work? Why do MPS satirise them? And why do the MPS still produce political satire despite the potential legal consequences? Therefore, this study attempts to identify the characters, themes, and issues the MPS highlight; it also considers the reasons and motivations that political satirists have for creating such allegedly controversial works. Malaysia’s Reformasi movement and the booming use of the internet in 1998 mobilised multiple alternative social movements, mainly through art-related activities. Art workers, NGOs, as well as musical and cultural groups, protested creatively against the UMNO-BN ruling regime. Creative protests that employed satire and humour somehow succeeded in attracting a significant proportion of the public to follow political and current issues, especially youths in universities who had been depoliticised with the inception of the University and University College Act (AUKU 1979). This study establishes a point of view that political satire is a fun, loose, free form of resistance, contrasting with formal procedural democracy. The previous literature proposes that the study of Malaysia’s political system should focus on formal political procedures, especially election and representation. However, the study of political satire vis-à-vis democratisation is often neglected and thus such studies are scarce, which might have resulted from how satire is strictly discussed in terms of language and media. There has been a growing interest in how satirist and satirical works are regarded; hence, this study attempts to fill a gap in research on political satire in Malaysia. In contrast, democratisation is often discussed in terms of history, politics, anthropology, sociology, and economics. This qualitative study presents a comprehensive account of interviews with four (4) art workers identified as MPS, as based on appropriate criteria. Each informant had either partaken in alternative social movements or faced legal action from authorities or, indeed, both. In this study, the Theory of Contestation and Two-Social Reality serves as a primary framework to lead to an understanding of the contestation of power in Malaysia through political satire. This study further intends to broaden the knowledge of political satire and humour in the study of democratisation, adding to the existing literature, particularly outside formal political procedures.
IL-38 is the latest discovered cytokine of the IL-1 family and has been added to the IL-36 subfamily. Since its discovery in 2001, increasing evidence suggests predominantly anti-inflammatory properties of IL-38, which are most likely exerted through three potential receptors, the IL-1 Receptor 1 (IL-1R1), IL-36 Receptor (IL-36R) and the IL-1 Receptor Accessory Protein Like 1 (IL-1RAPL1). However, to this date detailed knowledge of IL-38 functioning remains to be examined. Importantly, how IL-38 is processed, secreted from cells and the exact mechanisms of target receptor binding and intracellular signaling are not fully understood. Further, IL-38 has been associated with regulatory functions in autoimmune diseases like systemic lupus erythematosus (SLE) and psoriasis. At the same time however, connections between B cells as indispensable part of immunity and IL-38 remain rare.
In this study we examined the influence of IL-38 in peripheral human blood B cells differentiating into antibody secreting cells using a three-step in vitro differentiation process. We first show that all potential IL-38 binding receptors are present on peripheral blood B cells on a gene expression level and remain detectable throughout B cell differentiation. Next, while B cells treated with exogenous IL-38 depict no differences in early B cell activation markers, the process of B cell differentiation revealed significant alterations in B cell phenotype created by IL-38 treatment. Predominantly on day 7 of the differentiation process, IL-38 treated B cells showed significantly reduced CD38 expression which depicts an important step in development towards plasma cells. We hypothesize that IL-38 acts antagonistically on the IL-1R1 pathway reducing Nuclear factor kappa B (NFκB) expression and consequently decreasing CD38 expression. Further IL-38 reduced early antibody production while increasing IgM secretion at the end stages of differentiation. Next, we repeated the differentiation assays under the influence of additional IL-21 stimulation to further enhance plasma cell development. In these experiments, the impact of IL-38 on B cell differentiation and immunoglobulin production were reduced, indicating a comparatively moderate relevance of IL-38 for B cell differentiation. We then examined how proliferation and cell death were impacted by exogenous IL-38 during B cell differentiation. IL-38 treatment alone significantly reduced B cell survival which was further augmented by IL-21 stimulation. We conclude that IL-38 and IL-21 act synergistically in promoting B cell apoptosis, also depicting an anti-inflammatory property of IL-38. Finally, using a siRNA we successfully performed an IL-38 knockdown experiment of human blood B cells reducing IL-38 expression to 44% measured on day 4 of B cell differentiation. In these experiments we observed reversed tendencies of CD38 expression compared to exogenous IL-38 treatment. Here, IL-38 knockdown cells showed increased CD38 expression indicating endogenous regulatory properties of IL-38 in B cell differentiation.
Our project, for the first time proves direct effects of IL-38 on human B cells. The results support previous research of IL-38 to act anti-inflammatory as it seems to modulate B cell differentiation, survival, and immunoglobulin production in a down-regulatory manner. These findings pave way for more detailed research on the connection between B cell homoeostasis and IL-38 function.
In this thesis, the focus is on the actions of primary school children using digital and analogue materials in comparable mathematical situations. To emphasise actions on different materials in the mathematical learning process, a semiotic perspective according to C. S. Peirce (CP 1931-35) on mathematics learning is adopted. This theoretical research perspective highlights the activity itself on diagrams as a mathematical activity and brings actions to the forefront of interest. The actions on comparable digital and analogue diagrams are the basis for the reconstruction of mathematical interpretations of learners in 3rd and 4th grade.
The research questions investigate to what extent possible differences between the reconstructed interpretations of the learners can be attributed to the different materials and what influence the material has on the mathematical relationships that the learners take into account in their actions to manipulate the diagram.
For the reconstruction of the diagram interpretations based on the learners' actions on the material, a semiotic specification of Vogel's (2017) adaptation of Mayring's (2014) context analysis is used. This specification is based on Peirce's triadic theory of signs (Billion, 2023). The reconstructed interpretations of the analogue and digital diagrams are compared in a second step to identify possible differences and similarities.
The results of the qualitative analyses show, among other things, that despite the different actions of the learners on the digital and analogue diagrams, it is possible to reconstruct the same diagram interpretations if the learners establish the same mathematical relationships between the parts of the diagrams in their actions. There are also passages in the analyses where the same diagram interpretations cannot be reconstructed based on the actions on the digital and analogue materials. If the digital material acts as a tool and automatically creates several relationships between the parts of the diagram triggered by an action, then the reconstruction of the learners' diagram interpretations based on the analysis of their actions is partially possible. If the tool automatically establishes relationships, these must then be interpreted by the learners using gestures and phonetic utterances to understand the newly created diagram. Thus, a tool changes how mathematical relationships are expressed, because learners no longer have to interpret the relationships before their actions to manipulate the diagram itself, but afterwards through gestures and phonetic utterances. Regarding diagrammatic reasoning according to Peirce (NEM IV), this means that with analogue material the focus is on the construction and manipulation of diagrams through rule-guided actions, whereas with digital material, which functions as a tool, there is more emphasis on observing the results of the manipulations on the diagram.
At the end of the thesis, a recommendation for teachers on how to design mathematics lessons for primary school children using digital and analogue materials will be derived from the results.
The literature cited in this summary can be found in the references of the presented thesis.
Anthropogenic interventions have altered all ecosystems around the world. One of those ecosystems are forests, the main resource for timber. They have been strongly transformed in their structure with large consequences on forest biodiversity. Especially the decrease in dead-wood volume due to the timber extraction and alternation of natural forest structures with even-aged stands of less diverse tree species composition has put especially saproxylic, i.e., dead-wood dependent species, under threat, which comprise about 20% of all forest species. Beetles, fungi and bacteria are three functional important groups for decomposition processes but we still lack much information about their sampling and the drivers of their diversity, thus it is difficult to comprehensively protect their diversity. Saproxylic fungi are a highly diverse species group and the main drivers of dead-wood decomposition; hence they play a major role in the global carbon cycle. Due to their cryptic lifestyle, many species are still unknown, but the recent advances in environmental DNA barcoding methods (metabarcoding) shed light on the formerly underestimated diversity. Yet, this method's accuracy and suitability in detecting specific species have not been assessed so far, limiting its current usefulness for species conservation. On the other hand, these methods are a convenient tool to study highly diverse areas with high numbers of unknown species, enabling the study of global diversity and its drivers, which are unknown for saproxylic fungi, but important to assess to predict the future impacts of global change. Since nature conservation concepts are usually not applied on a global scale, the drivers of diversity must also be assessed on smaller scales. Besides understanding the drivers of diversity, to identify focus scales to create comprehensive, evidence-based conservation concepts must utilize multi-taxonomic studies since saproxylic species are differently sensitive towards environmental variables and closely interact with each other. Filling these knowledge gaps is utterly needed to protect the high saproxylic diversity and ensure the functional continuity of decomposition processes, especially regarding the global change.
To address the usefulness of metabarcoding for fungal species conservation, I compared the traditional method of fruit body sampling with metabarcoding and their efficiency in detecting threatened fungal species in the first chapter of this thesis. Both methods have advantages and disadvantages. Their ability to detect threatened saproxylic fungal species and their dependencies on detecting specific fungal groups have not been compared, albeit they are important to inform species conservation like Red Lists properly. I found metabarcoding to generally detect more threatened fungal species than fruit body sampling with a higher frequency than fruit body sampling. Moreover, fruit body sampling detected a unique set of species, while fruit body sampling missed large parts of fungal diversity due to species-specific fruiting characteristics. Metabarcoding with high sampling intensity is thus a viable method to assess threatened saproxylic fungal diversity and inform nature conservation like Red Lists about distribution and abundances. Nevertheless, a complementary approach with fruit body sampling is indispensable for assessing all threatened fungal species.
In order to analyse the global diversity of saproxylic fungi and its drivers, I examined whether fungal species richness increases from the poles towards the equator and thus follows the latitudinal diversity gradient already found in many other species groups. I further investigated whether such an increase is caused by increasing ecological specialisation, i.e., niche partitioning, or local tree diversity, i.e., niche space. Gamma diversity per biome increased from the boreal, over the temperate to the tropics and thus confirmed the latitudinal diversity for saproxylic fungi. Contrastingly, alpha diversity at the log level did not significantly increase towards the tropics, suggesting a grain size dependency of the observed pattern and an equal niche space within dead-wood across latitudes. Ecological specialisation on the plot level was globally on a high level but did not increase significantly towards the equator. Additionally, I found local tree species richness to drive plot-based fungal diversity. Further analysis of gamma diversity against the total number of sampled tree species strengthened the assumption that tree species diversity and not increased ecological specialisation was the main driver of the latitudinal diversity gradient, as there was no significant difference between the gamma diversity of the temperate and tropical biome. Nonetheless, as the gamma diversity of the boreal biome was still significantly smaller, my results do not allow a complete neglection of the ecological specialisation hypothesis. The overall results indicate a strong dependency of saproxylic fungi diversity with host tree species diversity and that the global loss of tree species threatens saproxylic fungi with an unpredictable impact on carbon and nutrient cycling.
To support saproxylic conservation, I conducted two analyses. First, I compared the beta diversity of the three main decomposer groups (beetles, fungal fruit bodies, mycelial fungi (metabarcoding), and bacteria (metabarcoding)) across different scales to assess the impact of different environmental variables on their overall diversity. I used an experimental design to disentangle two different spatial scales, influenced by differences in macroclimate, forest microclimate and spatial distance, and two host scales, driven by differences between tree lineages and tree species. I set these beta diversities in relation to the gamma diversity of the three main decomposer groups to identify whether a unified conservation concept could be applied to one scale to optimally protect the diversity of all three species groups. Second, I identified whether diversity and community composition of fungi and bacteria differed among climate and land use gradients. Further I explored whether specialisation and niche packing could explain the expected pattern. To do so I used an experimental design disentangling climate and land use across a large gradient in Germany. The results differed among the species groups, denying a unified conservation concept focusing on one scale. Saproxylic beetle and fruit body beta diversity was equally high on each scale, as they are more sensitive towards environmental factors like macro- and microclimate. On the other hand, mycelial fungi and bacteria beta diversity was highest on the host scale, especially the host tree scale, indicating a high host specificity of the two groups. The second study also identified tree species as the main driver of diversity and community composition of these two study groups. Specialisation of fungi was not influenced by land use or climate. Bacterial specialisation and diversity were under a strong influence of mean precipitation. Comprehensive conservation of multi-taxonomic diversity across regions thus requires the integration of several scales. Within different macroclimatic regions, forests of varying microclimates, i.e., forest management, must be implemented. In these forests, dead-wood of different tree lineages, i.e., angio- and gymnosperms and tree species, must be provided.
Taken together, I could demonstrate that metabarcoding is an efficient method to sample threatened fungal species and identify differing drivers of fungal diversity present as fruit bodies or mycelium. Its usefulness will further increase due to the ongoing improvement of sequencing databases and thus better inform conservation concepts. Using metabarcoding, I could demonstrate that high host specialisation of saproxylic fungi is not a European but a global phenomenon and identify tree species loss under global change as one major concern for saproxylic diversity. My dissertation further highlighted the importance of multi-taxonomic studies for evidence-based nature conservation, as different species groups require varying concepts. These results were especially important for saproxylic bacteria as the drivers of their diversity are still largely unknown. Howbeit, large research gaps still exist regarding the impacts of global change on species and processes. Moreover, the spatial coverage of studies is needed to confirm or neglect the generality of current research especially concerning the highly diverse tropical areas. An increased focus on the drivers of diversity in these areas is crucial to ensure a globally comprehensive saproxylic conservation and the various ecosystem functions they control.
Die Kernspinresonanz(NMR)-Spektroskopie ist ein leistungsstarkes analytisches Werkzeug. Allerdings ist ihre Empfindlichkeit aufgrund geringer Wechselwirkungs-energie zwischen den Kernspins und dem externen Magnetfeld begrenzt. Die dynamische Kernpolarisation (DNP) erhöht DNP die Empfindlichkeit der NMR, indem sie die Polarisation von ungepaarten Elektronenspins auf die benachbarten Kernspins überträgt. In den letzten Jahrzehnten hat die DNP bei hohen Magnetfeldern erneut an Aufmerksamkeit gewonnen, bedingt durch die Verfügbarkeit leistungsstarker Gyrotron-Mikrowellen(mw)-Quellen. Jedoch wurde die Anwendung von DNP für Flüssigkeiten im Vergleich zu Festkörperproben bei niedrigen Temperaturen (≈100 K) weit weniger erforscht. Zwei Gründe können dafür hauptsächlich benennt werden. Bei hohen Magnetfeldern (entsprechend hohen mw-Frequenzen) wird die mw-Strahlung sehr stark von Flüssigkeiten absorbiert, was zu einer starken Erwärmung führt. Darüber hinaus sind die Translations- und Rotationsdynamik der Radikale und Target-Molekülen nicht schnell genug, um Spectraldichten bei den hohen mw-Frequenzen zu erzeugen, die für eine Overhauser-Effekt (OE) DNP Verstärkung benötigt werden. In dieser Arbeit wird gezeigt, Flüssigzustands-DNP bei hohen Magnetfeldern, insbesondere bei 9,4 T, mit hocheffizienten DNP-Probenköpfen möglich ist.
Der von skalaren Hyperfein-Wechselwirkung (hfWW) angetriebene OE ist für Flüssigzustands-DNP-Forschungen von besonderem Interesse, da der von der Theorie vorhergesagte Mechanismus auch bei hohen Magnetfeldern noch effizient ist. In der vorliegenden Arbeit wurde eine Methode zur Vorabprüfung potenzieller DNP-Kandidaten durch Messungen ihrer paramagnetischen NMR-Verschiebungen vorgeschlagen und untersucht. Wir beobachtete signifikante 13C-skalare OE DNP-Verstärkungen bis zu 50 bei den ausgewählten kleinen Biomolekülen, einschließlich Imidazol, Indol, verschiedene Aminosäuren und Kohlenhydraten. Das Lösungssystem wurde auch von organischen Lösungsmitteln auf Wasser erweitert.
Im Kontext von dipolarer OE DNP haben wir den Beitrag der Rotation des Radikals neben der Translationsbewegung zwischen Radikal und Target-Molekül zur OE DNP-Effizienz systematisch untersucht, indem wir verschiedene Nitroxidderivate mit unterschiedlichen Ringgeometrien und Substituenten verwendet haben. Mithilfe eines Models, das eine 'out-sphere' Translationsbewegung und eine 'inner-sphere' Rotationsbewegung des Radikal-Lösungsmittel-Komplexes enthält, konnte unsere Beobachtungen quantitativ simuliert werden. Außerdem wurde ein anderes Model untersucht, das eine Translationsbewegung mit der Rotation von Radikalen, bei denen das ungepaarte Elektron nicht im Zentrum sitzt, kombiniert.
Eine weitere neue Entdeckung in der DNP bei hohen Magnetfeldern waren der beobachtete SE (Solid-Effekt) an Lipidmolekülen mit BDPA-Radikal oberhalb der Lipidphasen-übergangstemperatur. Die neue Anwendung von SE DNP bietet einen alternativen Mechanismus zur OE DNP in Flüssigkeiten bei hohen Magnetfeldern und könnte möglicherweise auf Makromoleküle mit relativ langsamer Rotationsbewegung angewendet werden.
Wir haben zusätzliche Untersuchungen an den Lipiddoppelschichten mit Nitroxid-radikale durchgeführt, basierend auf dem beobachteten 1H DNP-Verstärkungen in einer viskosen Lipidumgebung bei 9,4 T . Durch Messung des Feldprofils wurden DNP-Verstärkungen durch OE und SE in Abhängigkeit ihrer relativen Verschiebungen von der Elektronen-Larmor-Frequenz bestimmt. Die individuelle OE DNP-Effizienzen für Protonen des Wassers, der Lipid-Cholin-Kopfgruppen oder der Lipid-Acylketten wurde bestimmt. Dadurch wird ein quantitativer Vergleich mit MD-Simulationen ermöglicht. Obwohl die von der MD-Simulationen vorhergesagten DNP Kopplungsfaktoren noch deutliche Abweichungen von den experimentellen Beobachtungen aufweisen, wird die schnelle Dynamik nahe der Elektronen-Larmor-Frequenz, die für einen erfolgreichen OE DNP Transfer erforderlich ist, von den MD-Simulationen gut erfasst.
In der Arbeit wurden auch zwei unterschiedliche Dreifachresonanz-DNP-Experimente durchgeführt. Zum einen wurde 13C OE DNP unter 1H-Entkopplung in wässriger Natriumpyruvatlösung, und zum anderen 13C-NMR von Glycin, verstärkt durch SE DNP an 1H zusammen mit einem 1H-13C INEPT-Polarisationstransfer, im Rahmen dieser Doktorarbeit durchgeführt.
The role of lncRNAs in the CVS and the endothelium is highly diverse and has been subject to a substantial amount of research over the last decade. The identification of lncRNAs as clinically relevant biomarkers and as co-regulatory molecules let to the appreciation of the functional relevance of lncRNAs.
In the present study, LINC00607 was identified as an endothelial-enriched, human-specific lncRNA. With its distinct functions, LINC00607 maintains and supports the endothelial homeostasis especially in response to VEGF-A signalling.
In the first part of this study, LINC00607 was functionally characterized in human endothelial cells. LINC00607 is highly and specifically expressed in endothelial cells and is differentially regulated in CVDs. Depletion of LINC00607 resulted in decreased angiogenic sprouting, reduced integration of ECs in a newly formed vascular network in vivo, enhanced endothelial migration and differential expression of many important genes for endothelial cell homeostasis. Functionally, LINC00607 maintains ERG-driven endothelial gene expression programs through BRG1. BRG1 secures stably accessible enhancer regions as well as TSS of ERG target genes, thus enabling transcription of endothelial gene programs.
The second part of this study proposes an additional mode of action for LINC00607. The strongly impaired response to VEGF-A after LINC00607 KO can only be partially explained by its’ expression control of ERG target genes. It rather appears that LINC00607 is involved in the control of alternative splicing of VEGF receptor FLT1. The differential splicing of FLT1 produces the anti-angiogenic soluble isoform of FLT1. Even though further validation is needed to uncover the underlying mechanism, there is the potential of a more general role of LINC00607 in splicing control through BRG1. As AS of FLT1 is a clinical marker in preeclampsia, LINC00607 might qualify to be an additional marker for the onset and manifestation of the pregnancy disorder.
Taken together, LINC00607 is a target in future for molecular therapy in CVD to restore a healthy endothelial phenotype and has the potential to serve as a biomarker in preeclampsia.
Binary neutron star mergers represent unique observational phenomena because all four fundamental interactions play an important role at various stages of their evolution by leaving imprints in astronomical observables. This makes their accurate numerical modeling a challenging multiphysics problem that promises to increase our understanding of the high-energy astrophysics at play, thereby providing constraints for the underlying fundamental theories such as the gravitational interaction or the strong interaction of dense matter. For example, the first and so far only multi-messenger observation of the binary neutron star merger GW170817 resulted in numerous bounds on the parameters of isolated non-rotating neutron stars, e.g., their maximum mass or their distribution in radii, which can be directly used to constrain the equation of state of cold nuclear matter. While many of these results stem from the observation of the inspiral gravitational-wave signal, the postmerger phase of binary neutron star mergers encodes even more details about the extreme physics of hot and dense neutron star matter. In this Thesis we focus on the exploration of dissipative and shearing effects in binary neutron star mergers in order to identify novel approaches to constrain hot and dense neutron star matter.
The first effect is the well-motivated dissipation of energy due to the bulk viscosity which arises from violations of weak chemical equilibrium. We start by exploring the impact of bulk viscosity on black-hole accretion. This simplified problem gives us the opportunity to develop a test case for future codes taking into account the effects of dissipation in a fully general-relativistic setup and build intuition in the physics of relativistic dissipation. Next, we move on to isolated neutron stars and binary neutron star mergers by developing a robust implementation of bulk-viscous dissipation for numerical relativity simulations. We test our implementation by calculating the damping of eigenmodes of isolated neutron stars and the violent migration scenario. Finally, we present the first results on the impact of bulk viscosity on binary neutron star mergers. We identify a number of ways how bulk viscosity impacts the postmerger phase, out of which the suppression of gravitational-wave emission and dynamical mass ejection are the most notable ones.
In the last part of this Thesis we investigate how the shearing dynamics at the beginning of the merger affects the amplification of different initial magnetic-field topologies. We explore the hypothesis that magnetic fields which are located only in a small region near the stellar surface prior to merger lead to a weaker magnetic-field amplification. We show first evidence which confirms this hypothesis and discuss possible implications for constraining the physics of superconduction in cold neutron stars.
Die nachfolgende Dissertation wurde an der Goethe-Universität Frankfurt am Institut für Geowissenschaften (FB 11) in der Arbeitsgruppe Kristallographie und Mineralogie (AG Winkler) verfasst. Die Betreuung der hier durchgeführten Arbeiten erfolgte hauptsächlich durch Prof. B. Winkler in Zusammenarbeit mit Dr. L. Bayarjargal, PD Dr. E. Haussühl und PD Dr. V. Vinograd. Bei dem vorliegenden Manuskript handelt es sich um eine kumulative bzw. publikationsbasierte Dissertation, welche die Forschungsergebnisse verschiedener bereits veröffentlichter wissenschaftlicher Fachartikel zusammenfasst.
Die Arbeit beschreibt verschiedene Synthesen und Untersuchungen an Carbonaten und teilt sich im Wesentlichen in zwei Abschnitte. Zum einen wurden Experimente mit Carbonaten bei Extrembedingungen bzw. unter hohen Drücken und hohen Temperaturen durchgeführt, wie sie auch im Inneren der Erde zu finden sind. Im zweiten Teil wurden Carbonate bei Raumbedingungen synthetisiert und der Einbau von Seltenerdelementen untersucht. Grundsätzlich werden jedoch in beiden Teilen dieser Arbeit die Strukturen und Eigenschaften verschiedener Carbonate und eine mögliche Kationensubstitution bzw. die Synthese isostruktureller Verbindungen erforscht.
Die rechtsmedizinische Begutachtung von Knochenfunden : eine hessenweite retrospektive Studie
(2023)
Einleitung: Zufällige Funde von Knochen(fragmenten) können von großem Interesse für z. B. Strafverfolgungs- und Denkmalbehörden oder Bauträger sein. Zur Beurteilung einer etwaigen strafrechtlichen oder historischen Relevanz tragen forensisch-osteologische Untersuchungen in einem hohen Maße bei. Die vorliegende Arbeit soll einen Überblick über die forensisch-osteologische Arbeit der beiden hessischen Institute für Rechtsmedizin geben und durch die Interpretation der Ergebnisse im (inter-)nationalen Vergleich regionale Besonderheiten und die Rolle der Rechtsmedizin bei der Begutachtung aufzeigen. Der daraus entstandene Erkenntnisgewinn soll ein Problembewusstsein schaffen sowie Fallarbeit und Lehre verbessern.
Material und Methoden: Zunächst wurden für den Zeitraum von 2005 bis 2019 die im Institut für Rechtsmedizin Gießen archivierten osteologischen Gutachten deskriptiv statistisch ausgewertet. Es wurden Daten zu Fundort, -umständen, Humanspezifität, postmortalem Intervall, Spuren von Gewalt und die Ergebnisse weiterführender Untersuchungen erhoben.
In einer zweiten Studie wurde die Auswertung auf archivierte forensisch- osteologische Gutachten des Instituts für Rechtsmedizin Frankfurt am Main ausgeweitet und der Auswertungszeitraum auf die Jahre 2011 bis einschließlich 2020 angepasst, um eine hessenweite Datengrundlage zu generieren.
Ergebnisse: In der ersten Studie wurden von den in dem 15-Jahres-Zeitraum begutachteten 172 Knochenfunden aus dem Institut für Rechtsmedizin Gießen 40 % in Wald- und Wiesengebieten aufgefunden. In 58 % enthielten die Funde menschliche Knochen, davon wurde in 32 % eine forensisch relevante Liegezeit von 50 Jahren oder weniger nicht ausgeschlossen, und 6% wiesen Zeichen perimortaler Gewalteinwirkung auf. Bei den Fällen, in denen eine Humanspezifität ausgeschlossen wurde, handelte es sich am häufigsten um Knochen von Hirsch bzw. Reh (32 %), Schwein (29 %) und Rind (14 %). In 20 % aller Fälle wurden
ergänzende DNA-Untersuchungen durchgeführt; in 62 % verlief die Typisierung humaner STR-Systeme erfolgreich und davon gelang in 41 % die Zuordnung zu einem antemortalen Profil einer vermissten Person.
In der zweiten, hessenweiten Studie, wurden 288 Knochenfunde eines 10-Jahres-Zeitraums ausgewertet. Mit 38,2 % wurden die meisten Funde in Wäldern, Wiesen und großen Parks getätigt. In 50,7 % der Fälle enthielten die Funde menschliche Knochen, davon wurde in 37,0 % eine forensisch relevante Liegezeit angenommen. Zeichen einer Gewalteinwirkung wurden in 77,4 % der Fälle mit menschlichen Knochen beschrieben, dabei handelte es sich mit 78,8 % am häufigsten um postmortale Beschädigungen, in 9,7 % um perimortale und in 11,5 % um antemortale Verletzungen. In 40,4 % der als human klassifizierten Knochenfunde wurden DNA-Untersuchungen durchgeführt. Dabei konnte in 81,3 % ein STR-Profil erstellt werden, das in 35,4% zu einer sicheren Identifizierung führte. Bei den zur Untersuchung überstellten nicht-menschlichen Knochen handelte es sich am häufigsten um Knochen vom Schwein (23,4 %), Hirsch (18,1 %), Rind (16,4 %), Reh (11,7 %) und Schaf (11,7 %).
Diskussion: Die Begutachtung von Knochen und Knochenfragmenten ist ein fester Bestandteil der rechtsmedizinischen Fallarbeit und zwingend erforderlich, um Fälle von forensischem Interesse zu identifizieren. Die makroskopische Befundung durch einen geschulten Untersucher erlaubt in der Regel bereits, Aussagen über die forensische Relevanz eines Fundes zu treffen und so die Weichen für das weitere Vorgehen zu stellen. Hilfreich bei der makroskopischen Beurteilung ist eine gute Kenntnis der regionalen Besonderheiten in dem Gebiet, in dem die Knochen gefunden wurden. Die makroskopische forensisch-osteologische Begutachtung stellt trotz der sich ständig weiterentwickelnden technischen Möglichkeiten ein unverzichtbares Werkzeug in der Bearbeitung von Knochenfunden dar. In Deutschland ist es Aufgabe der Rechtsmedizin, diese Expertise zu pflegen und vorzuhalten, mit dem Ziel, zur Aufklärung von Vermisstenfällen beizutragen und unentdeckte nichtnatürliche Todesfälle aufzuklären.
This work focuses on the investigation of K+, K- and ϕ-meson production in Ag(1.58 A GeV)+Ag collisions. The energetically cheapest channel for direct K+ production in binary NN-collisions NN→NΛK+ lies at exactly this energy. For the remaining K- and ϕ-mesons, an excess energy of 0.31 GeV and 0.34 GeV in the centre of mass system has to be provided by the system. This makes these particles an excellent probe for effects inside the medium.
K+ and K- mesons can be reconstructed directly as they possess a cτ of approximately 3.7 m. Using the approximately 3 billion recorded Ag(1.58 A GeV)+Ag 0-30% most central collision events, all reconstructed K+ and K- within the detector acceptance are investigated for their kinematic properties and their particle production rates compared to a selection of existing models.
Einleitung: Die Bronchiolitis obliterans ist eine seltene Lungenerkrankung unterschiedlicher Ätiologie, die mit einer chronischen Entzündung der kleinen Atemwege einhergeht. Mit der Identifizierung von Kandidaten-miRNA sollen Biomarker evaluiert werden, die in der Diagnostik der postinfektiösen Bronchiolitis obliterans (PIBO) herangezogen werden sowie in Zukunft eine mögliche Therapieoption darstellen können.
Material und Methoden: 19 Patientinnen und Patienten mit PIBO sowie 18 gesunde Kontrollen wurden in die Studie eingeschlossen. Nach Komplettsequenzierung wurden die miRNA-Profile der Patienten mit den Profilen der alters- und geschlechtsadaptierten gesunden Kontrollgruppe verglichen. Als Nebenzielgrößen wurden die Lungenfunktion und Sputum-Biomarker erfasst.
Ergebnisse: Die Patientenkohorte wies signifikant niedrigere Werte in der Lungenfunktionsdiagnostik (Patienten, Median: FVC (%) 76,3***, FEV1 (%) 59,8***, FEV1/FVC 0,68***, FEF75 (%) 25,1***, *p<0,05, **p<0,01, ***p<0,001) sowie eine signifikante Erhöhung der neutrophilen Granulozyten und der proinflammatorischen Zytokine IL-1β, IL-6 und IL-8 in der Sputumanalyse auf (Patienten, Median: Neutrophile (%) 82,5***, IL-1β (pg/ml) 1453,0**, IL-6 (pg/ml) 825,6**, IL-8 (pg/ml) 35368,0***). Die Analyse der miRNA-Expression ergab insgesamt 40 unterschiedlich regulierte miRNAs (padj ≤ 0,05). 22 miRNAs waren in der Patientenkohorte vermehrt exprimiert, 18 miRNAs waren vermindert exprimiert. Die vier miRNAs mit pbonf < 0,05 wurden in der weiteren Analyse berücksichtigt. Die miRNAs hsa-let-7b-3p und hsa-miR-146a-3p waren signifikant vermehrt exprimiert, wohingegen die miRNAs hsa-miR-1287-5p und hsa-miR-27b-3p signifikant vermindert exprimiert waren. Die identifizierten miRNAs spielen unter anderem eine Rolle im TGF-β- und Hippo-Signalweg.
Schlussfolgerung: Die Ergebnisse zeigen, dass das miRNA-Expressionsmuster bei Patienten, die an postinfektiöser Bronchiolitis obliterans erkrankt sind, alteriert ist. Die identifizierten miRNAs sind relevante Biomarker und können als potentielle Ziele von miRNA-Therapeutika in Betracht gezogen werden.
Einleitung: Im Jahr 2016 wurde eine neue, individuelle Lehrform, das „Lernzentrum für ein individualisiertes medizinisches Tätigkeitstraining und Entwicklung“ („Limette“), an der Westfälischen Wilhelms-Universität Münster entwickelt. Das Ziel dieser Lernform ist und war es, nicht nur die theoretische Lehre, sondern vor allem die praktische Lehre und praktische Szenarien in einem geschütztem Lernumfeld in der medizinischen Lehrdidaktik in den Vordergrund zu stellen.
Die Studierenden nehmen an verschiedenen Fächern der Limette teil. In dieser Promotionsarbeit liegt der Fokus auf der Limette Patient Blood Management (PBM) und Transfusionsmedizin.
Vor Kursbeginn wird den Studierenden Zugang zu verschiedenen Vorbereitungsvideos sowie weiteren theoretischen Materialien über PBM und Transfusionsmedizin zur Verfügung gestellt. Bei der Limette durchläuft jeder Studierende sechs verschiedene Stationen. Hierbei beobachten Dozenten die Fertigkeiten und die Umsetzung der Aufgabenlösung durch halbverspiegelte Scheiben, im Umgang mit echten Blutprodukten oder die Kommunikation mit Patienten, die von Schauspielern dargestellt werden. Die Beobachtungen werden den Dozenten des Seminars, welches im Anschluss zur Nachbesprechung stattfindet, mitgeteilt. Hier teilen die Studierenden untereinander ihr Wissen, können den Dozenten Fragen stellen und werden ihnen weitere theoretisch-praktische Kenntnisse vermittelt.
Ziel der Arbeit: Die Promotionsarbeit hat die Auswertung der Selbsteinschätzungsbögen vor und nach der Limette mit anschließender Interpretation der Ergebnisse zum Ziel. Es soll eruiert werden, ob diese neue Lehrmethodik effektiv in der Umsetzung des Lehrerfolgs ist.
Methodik: Die Selbsteinschätzungsbögen hinsichtlich medizinischer Fertigkeiten und Tätigkeiten werden vor und nach der Limette von den Studierenden ausgefüllt. Die Aufgabenstellungen fokussieren sich jeweils auf medizinische Tätigkeiten, bei denen aus 13 verschiedenen Entrustable Professional Activities (EPAs) diejenigen hinterlegt werden, die bei dieser Aufgabe gelehrt werden. Die Differenz von post- zu prä- Selbsteinschätzung zeigt den Lehrerfolg. Die EPAs werden alle analysiert und mit Hilfe der sogenannten Cohen-Zahl interpretiert. Die Cohen Zahl ist definiert als die Differenz zwischen den Mittelwerten zweier Gruppen dividiert durch die gemeinsame Standardabweichung der beiden Populationen. Nach dem Autor Hattie wurde die Skalierung von Cohen für die Lehre angepasst und dabei folgende Einteilung definiert: d = 0,2 (klein), d = 0,4 (mittel) und d = 0,6 (groß). Alle Methoden mit d > 0,4 wurden als „Zone der gewünschten Effekte“ eingestuft.
Ergebnisse: Im Wintersemester 2021/2022 nahmen n=122 Studierende teil, von welchen n=50 beide Fragebögen komplettierten. Eine signifikante Zahl der dargestellten EPAs (50%) hat gute Ergebnisse erzielt, weist mithin einen Cohen´s Wert von d > 0,40 auf. Im Sommersemester 2022 nahmen n=99 Studierende teil, wobei nur n=29 beide Selbsterhebungsbögen komplettierten. Aufgrund des niedrigen Rücklaufs war die Zahl der ausgefüllten Selbsteinschätzungsbögen deutlich geringer und zugleich die Ergebnisse geringer ausgeprägt. In jenem Semester weist die Mehrheit der Ergebnisse einen Cohen´s d-Wert zwischen 0,15 und 0,4 auf, was als durchschnittlicher Lehrerfolg beurteilt wird.
Schlussfolgerung: Die Lehrform der Limette ist eine neue Form der praktischen Lehrvermittlung, die kontinuierlichen Anpassungen unterliegt. Eine hohe Zahl an ausgefüllten Selbsteinschätzungsbögen ist erstrebenswert, um den Lehrerfolg positiv und statistisch signifikant interpretieren zu können. Hierbei ist es nötig, die Lehre in der Limette auszuwerten und gegebenenfalls weitere Anpassungen durchzuführen.
Die Limette ist eine neue Lehrmethode mit einem guten Lehrerfolg hinsichtlich der Vermittlung praktischer Fähigkeiten und sozialer Kompetenz, welche auch an anderen Institutionen angewandt und umgesetzt werden könnte.
Bislang sind die strukturellen Voraussetzungen für die Selektivität von Agonisten an den Retinoid Rezeptor Subtypen RXRα, RXRβ und RXRγ kaum erforscht, obwohl RXR-Modulatoren, die eine Subtypen-Präferenz aufweisen, aufgrund der unterschiedlichen Expressionsmuster der Subtypen Gewebe-spezifische Effekte vermitteln und somit Nebenwirkungen verringern könnten. Der Grund dieser Forschungslücke liegt teilweise darin, dass die Entwicklung Subtypen-selektiver RXR-Agonisten aufgrund der enormen strukturellen Ähnlichkeit der Ligandbindestellen in den RXR-Subtypen - alle Aminosäuren, die die Bindungsstellen bilden sind identisch - als unerreichbar angesehen wurde. Die Entdeckung des Naturstoffs Valerensäure als RXR-Agonist mit ausgeprägter Präferenz für den RXRβ-Subtyp hat jedoch gezeigt, dass Subtypen-selektive RXR-Modulation möglich ist249 und SAR-Studien an unterschiedlichen RXR-Ligand-Chemotypen haben in der Folge bestätigt, dass die Entwicklung von RXR-Liganden mit Subtypen-Präferenz erreicht werden kann.
Auf der Basis von Valerensäure und der in früheren Arbeiten entwickelten RXR-Agonisten wurden in dieser Arbeit Strukturmodifikationen identifiziert, die zu einer RXR-Subtypen-Präferenz beitragen. Durch die Verschmelzung dieser Strukturelemente ist es gelungen, einen neuen RXR-Agonist-Chemotyp (A) zu entwerfen, der durch strategische Methylierung und weitere Strukturmodifikationen zur Präferenz für jeden Subtyp optimiert werden konnte.
In einem Adipozyten-Differenzierungsexperiment konnte gezeigt werden, dass RXRα der wichtigste Heterodimer-Partner von PPARγ während der Adipogenese ist. Ferner unterstrich diese biologische Untersuchung das Potenzial von 99, 103 und 105 als Subtyp-präferentielle RXR-Agonisten in vitro Experimenten zu dienen.
Auf der Grundlage dieser Ergebnisse wurde eine mögliche Rolle von Acrylsäurepartialstrukturen natürlicher RXR-Liganden basierend auf dem zuvor entwickelten Chemotyp untersucht. Hierzu wurden das α-Methylacrylsäuremotiv des Naturstoffs Valerensäure (18) und das β-Methylacrylsäuremotiv des endogenen RXR-Agonisten 9-cis-Retinsäure in den Chemotyp A integriert (Chemotyp B), um die Rolle dieser Acrylsäuregruppen bei der Vermittlung der RXR-Subtypen-Selektivität zu untersuchen. Die Strukturmodifikationen an B zeigten, dass nur die α-Methyl-substituierte Acrylsäurekette toleriert bzw. von RXRβ präferiert wurde, was die RXR-Präferenz der Valerensäure (18) unterstützte.
In dieser Arbeit konnte gezeigt werden, dass RXR-Liganden mit Subtypen-Präferenz realisierbar sind und durch gezielte Strukturmodifikationen in ihrer Präferenz gesteuert werden können. Die Erkenntnisse zu den Struktur-Wirkungs-Beziehungen der neuen RXR-Agonist-Chemotypen A und B erweitern den Wissenstand über die strukturellen Voraussetzungen von RXR-Liganden für die Subtypen-Präferenz deutlich.
This cumulative dissertation examines learning in chemistry laboratories, focusing on the challenges and benefits of problem-based learning (PBL) for novices in the lab. It addresses the lack of consistent understanding about what should be learned in labs and why it's important. The research aims to understand what students learn, how they learn, and how lab learning can be improved.
A central concept in PBL labs is Information Literacy, defined as a sociocultural practice enabling learners to identify and use information sources within a specific context as legitimized by the practice community.
The first publication, Wellhöfer and Lühken (2022a), investigates the relationship between PBL and learner motivation. It identifies factors that can foster students' intrinsic motivation in a PBL lab. Autonomy is found to be a key factor, increasing student motivation and presenting a model of the autonomous scientific process. This model involves four steps: information acquisition, designing and applying experimental procedures, experimental feedback, and autonomous process optimization. The results suggest that intrinsic motivation in PBL labs can be enhanced by enabling students to independently execute these steps.
The second publication, Wellhöfer and Lühken (2022b), examines the information process students undergo during their first PBL lab. Using a sociocultural framework, it explores Information Literacy to understand students' handling of information and their perceptions of the information process. The findings reveal that in PBL labs, developing a practical, applicable experimental procedure is crucial for problem-solving and significantly shapes the information-acquisition process. This process is iterative, influenced by new information, leading to more precise information needs. Students assess information quality based on its usefulness for their problem, implementability (considering cognitive understanding, available equipment, and psychomotor skills), and safety.
Furthermore, the role of privileged knowledge forms in evaluating the quality of text sources is explored. Students viewed non-scientific sources as "poor" and scientific sources as "good," yet used both for information gathering. There were discrepancies between their assessment of source quality and actual use, indicating that perception of source quality doesn't always affect their practical decisions.
The third publication, Wellhöfer, Machleid, and Lühken (2023), investigates students' information practices in the lab, focusing on discourse between novice learners and experienced assistants. It shows that theoretical knowledge isn't sufficient for independent practical action, and students need actionable social information from experienced community members. The results highlight that information literacy in the lab for newcomers to a community of practice has distinctive features, and physical experience and tacit knowledge are crucial for learning the methods and group-specific knowledge of the practice community. The article demonstrates how learning information literacy in a practice community requires a social and physical experience and provides insights on how educators can support this process.
The Compressed Baryonic Matter (CBM) is one of the core experiments at the future Facility for Anti-proton and Ion Research (FAIR), Darmstadt, Germany. Its goal is to investigate nuclear matter characteristics at high net-baryon densities and moderate temperatures. The Silicon Tracking System (STS) is a central detector system of CBM.
It is placed inside a 1Tm magnet and operated at a temperature of about −10 °C to keep radiation-induced bulk current in the 300μm double-sided microstrip silicon sensors low. The design of the STS aims to minimize the material budget in the detector acceptance (2.5° < θ < 25°). In order to do so, the readout electronics is placed outside the active area, and the analog signals are transported via ultra-thin micro-cables. The STS comprises eight tracking stations with 876 modules. Each module is assembled on a carbon fiber ladder, which is subsequently mounted in the C-shaped aluminum frame.
The scope of the thesis focused on developing a modular control system framework that can be implemented for different sizes of experimental setups. The developed framework was used for setups that required a remote operation, like the irradiation of the powering modules for the front-end electronics (FEE), but also in laboratory-based setups where the automation and archiving were needed (thermal cycling of the STS electronics).
The low voltage powering modules will be placed in the vicinity of the experiment, therefore they will experience a total dose of up to 40mGy over the 10 years of STS lifetime.
To estimate the effects of the radiation on the low-voltage module performance, a dedicated irradiation campaign took place. It aimed at estimating the rate of radiation induced soft errors, that lead to the switch off of the FEE.
Regular power cycles of multiple front-end boards (FEBs) pose a risk to the experiment operation. Firstly, such behavior could negatively influence the physics performance but also have deteriorating effects on the hardware. It was further assessed what are the limitations of the FEBs with respect to the thermal cycling and the mechanical stress. The results served as an indication of possible failure modes of the FEB at the end of STS lifetime. Failure modes after repeated cycles and potential reasons were determined (e.g., Coefficient of Thermal Expansion (CTE) difference between the materials).
Due to the conditions inside the STS efficient temperature and humidity monitoring and control are required to avoid icing or water condensation on the electronics or silicon sensors. The most important properties of a suitable sensor candidate are resilience to the magnetic field, ionizing radiation tolerance, and fairly small size.
A general strategy for ambient parameters monitoring inside the STS was developed, and potential sensor candidates were chosen. To characterize the chosen relative humidity sensors the developed control framework was introduced. A sampling system with a ceramic sensor and Fiber Optic Sensors (FOS) were identified as reliable solutions for the distributed sensing system. Additionally, the industrial capacitive sensors will be used as a reference during the commissioning.
Two different designs of FOS were tested: a hygrometer and 5 sensors multiplexed in an array. The FOS hygrometer turned out to be a more reliable solution. One of the possible reasons for a worse performance is a relatively low distance between the subsequent sensors (15 cm) and a thicker coating. The results obtained from the time response study pointed out that the thinner coating of about 15μm should be a good compromise between the humidity sensitivity and the time response.
The implementation of the containerized-based control system framework for the mSTS is described in detail. The deployed EPICS-based framework proved to be a reliable solution and ensured the safety of the detector for almost 1.5 years. Moreover, the data related to the performance of the detector modules were analyzed and significant progress in the quality of modules was noted. Obtained data was also used to estimate the total fluence, which was based on the leakage current changes.
The developed framework provided a unique opportunity to automate and control different experimental setups which provided crucial data for the STS. Furthermore, the work underlines the importance of such a system and outlines the next steps toward the realization of a reliable Detector Control System for STS.
In the last twenty years, a variety of unexpected resonances had been observed within the charmonium mass region. Although the existence of unconventional states has been predicted by the quantum chromodynamics (QCD), a quantum field theory describing the strong force, a clear evidence was missing. The Y(4260) is such an unexpected and supernummerary state, first observed at BaBar in 2005, and aroused great interest, because it couples much stronger to hidden charm decays (charm-anticharm states like J/Psi or h_c) instead of open charm decays (D meson pairs). This is unusual for states with masses above the D anti-D threshold. Furthermore, it decays into a charged exotic state Y(4260)->Z_c(3900)^+- pi^-+. The charge of the Z_c(3900)^+- is an indication that it comprises of two more quarks than the charm-anticharm pair, and could therefore be assumed to be a four-quark state. Due to these still not understood properties of these QCD-allowed states, they are referred to as exotic XYZ states to emphasize their particularity.
In 2017, the collaboration of the Beijing Spectrometer III (BESIII) investigated the production reaction of the Y(4260) resonance based on a high-luminosity data set. This significantly improved precision of the measurement of the cross-section sigma(e+e- -> J/Psi pi^+ pi^-) permitted a resolution into two resonances, the Y(4230) and the Y(4360). The Z_c(3900)^+- had been discovered by the BESIII collaboration in 2013, thus this experiment at the Beijing Electron-Positron Collider II (BEPCII) is a top-performing facililty to study exotic charmonium-like states.
In this work, an inclusive reconstruction of the strange hyperon Lambda in the charmonium mass region is performed to study possible decays of Y states in order to provide further insight into their nature. Finding more states or new decay channels may provide crucial hints to understand the strong interaction beyond nonperturbative approaches.
Three resonances are observed in the energy dependent cross-section: the first with a mass of (4222.01 +- 5.68) MeV and a width of (154.26 +- 28.16) MeV, the second with a mass of (4358.88 +- 4.97) MeV and a width of (49.58 +- 13.54) MeV and the third with a mass of (4416.41 +- 2.37) MeV and a width of (23.88 +- 7.18) MeV. These resonances, with a statistical significance Z > 5sigma, can be interpreted as the states Y(4230), Y(4360) and psi(4415).
Additionally, a proton momentum-dependent analysis strategy has been used in terms of the inclusiveness of the reconstruction and to address the momentum discrepancies between generic MC and measured data.
"Autonomy is the condition under which what one does reflects who one is" (Weinrib, 2019, p.8). This quote encapsulates the core idea of autonomy, namely the correspondence of one’s inner values with one’s actions. This is a beautiful idea. After all, who wants their actions to be determined or controlled from the outside?
The classical definition of autonomy is precisely about this independence from external circumstances, which Murray (1938) primarily coined. Among other things, Murray characterizes autonomy as resistance to influence and defiance of authority. Similarly, Piaget (1983) describes individuals as autonomous, independent of external influences, in their thinking and actions, and foremost, adult authority. Subsequent work criticized this equation of autonomy with separation or independence (Bekker, 1993; Chirkov et al., 2003; Hmel & Pincus, 2002). In lieu thereof, autonomy is defined as an ability (Chirkov, 2011; Rössler, 2017) and as an essential human need (Ryan & Deci, 2006). Focus is now
on self-governing while relying on rationally determined values to pursue a happy life (Chirkov, 2011). According to Social Determination Theory (SDT), autonomy is about a sense of initiative and responsibility for one’s own actions. The experience of interest and appreciation can strengthen autonomy, whereas experiences of external control, e.g., through rewards or punishments, limit autonomy (Ryan & Deci, 2020). In the psychological discourse of autonomy, SDT is strongly represented (Chirkov et al., 2003; Koestner & Losier, 1996; Weinstein et al., 2012). Notably, SDT distinguishes between autonomy and independence as follows. While a person can autonomously ask for help or rely on others, a person can also be involuntarily alone and independent. Interestingly, these definitions are again closer to its etymological meaning as self-governing, originating from Greek αυτòνoμζ (autonomous).
The two strands of autonomy as independence and autonomy as self-determination are also reflected in the vital differentiation into reactive and reflective autonomy by Koestner and Losier (1996). Resisting external influence, particularly interpersonal in fluence, is what reactive autonomy entails. This interpretation is closely related to the classical concept of autonomy as separation and independence from others (Murray, 1938). On the other hand, reflective autonomy concerns intrapersonal processes, such as self-governing or self-regulation, as defined in Self-Determination Theory (Ryan et al., 2021). In this dissertation, we investigated the concept in three different approaches while focusing on its assessment and operationalization: To begin, in Article 1, we compared the layperson’s and the scientific perspective to each other to gain insight into the characteristics of autonomy. Then, in Articles 2 and 3, we experimentally tested behavioral autonomy as resistance to external influences. Simultaneously, we investigated the link between various autonomy trait measures and autonomous behavior. As a result, in Article 2, we looked at how people reacted to the effects of message framing and sender authority on social distancing behavior during the early COVID-19 pandemic. Finally, in Article 3 we investigated the resistance to a descriptive norm in answering factual questions, in the context of autonomous personality. In our first article, we used a semi-qualitative bottom-up approach to gain insights into the laypersons’ perspective on autonomy and compare it to the scientific notion. We followed a design proposed by Kraft-Todd and Rand (2019) on the term heroism. We derived five components from philosophical and psychological literature: dignity, independence from others, morality, self-awareness, and unconventionality. In three preregistered online studies, we compared these scientific components to the laypersons’ understanding of autonomy. In Study 1, participants (N = 222) listed at least three and up to ten examples of autonomous (self-determined) behaviors. Here, the participants named 807 meaningful examples, which we systematically categorized into 34 representative items for Study 2. Next, new participants (N = 114) rated these regarding their autonomy. Finally, we transferred the five highest-rated autonomy and the five lowest-rated autonomy items to Study 3 (N = 175). We asked participants to rate how strongly the items represented dignity, independence from others, morality, self-awareness, and unconventionality. We found all components to distinguish between high and low autonomy items but not for unconventionality. Thus, we conclude that laypersons’ view corresponds with the scientific characteristics of dignity, independence from others, self-awareness, and morality. A qualitative analysis of the examples also showed that both reactive and reflective definitions of autonomy are prevalent.
This Ph. D. thesis with the title "Characterisation of laser-driven radiation beams: Gamma-ray dosimetry and Monte Carlo simulations of optimised target geometry for record-breaking efficiency of MeV gamma-sources" is dedicated to the study of the acceleration of electrons by intense sub-picosecond laser pulses propagating in a sub-millimeter plasma with near-critical electron density (NCD) and resulting generation of the gamma bremsstrahlung and positrons in the targets of different materials and thickness.
Laser-driven particle acceleration is an area of increasing scientific interest since the recent development of short pulse, high-intensity laser systems. The interaction of intense high-energy, short-pulse lasers with solid targets leads to the production of high-energy electrons in the relativistic laser intensity regime of more than 1018 W /cm2. These electrons play the leading role in the first stage of the interaction of laser with matter, which leads to the creation of laser sources of particles and radiation. Therefore, the optimisation of the electron beam parameters in the direction of increasing the effective temperature and beam charge, together with a slight divergence, plays a decisive role, especially for further detection and characterisation of laser-driven photon and positron beams.
In the context of this work, experiments were carried out at the PHELIX laser system (Petawatt High-Energy Laser for Heavy Ion eXperiments) at GSI Helmholtz Center for Heavy-Ion Research GmbH in Darmstadt, Germany. This thesis presents a thermoluminescence dosimetry (TLD) based method for the measurement of bremsstrahlung spectra in the energy range from 30 keV to 100 MeV. The results of the TLD measurements reinforced the observed tendency towards the strong increase of the mean electron energy and number of super-ponderomotive electrons. In the case of laser interaction with long-scale NCD-plasmas, the dose caused by the gamma-radiation measured in the direction of the laser pulse propagation showed a 1000-fold increase compared to the high contrast shots onto plane foils and doses measured perpendicular to the laser propagation direction for all used combinations of targets and laser parameters.
In this thesis I present novel characterisation method using a combination of TLD measurements and Monte Carlo FLUKA simulations applicable to laser-driven beams. The thermoluminescence detector-based spectrometry method for simultaneous detection of electrons and photons from relativistic laser-induced plasmas initially developed by Behrens et al. (Behrens et al., 2003) and further applied in experiments at PHELIX laser (Horst et al., 2015) delivered good spectral information from keV energies up to some MeV, but as it was presented in (Horst et al., 2015) this method was not really suitable to resolve the content of photon spectra above 10 MeV because of the dominant presence of electrons. Therefore, I created new evaluation method of the incident electron spectra from the readings of TLDs. For this purpose, by means of MatLab programming language an unfolding algorithm was written. It was based on a sequential enumeration of matching data series of the dose values measured by the dosimeters and calculated with of FLUKA-simulations. The significant advantage of this method is the ability to obtain the spectrum of incident electrons in the low energy range from 1 keV, which is very difficult to measure reliably using traditional electron spectrometers.
The results of the evaluation of the effective temperature of super-ponderomotive electrons retrieved from the measured TLD-doses by means of the Monte-Carlo simulations demonstrated, that application of low density polymer foam layers irradiated by the relativistic sub-ps laser pulse provided a strong increase of the electron effective temperature from 1.5 - 2 MeV in the case of the relativistic laser interaction with a metallic foil up to 13 MeV for the laser shots onto the pre-ionized foam and more than 10 times higher charge carried by relativistic electrons.
The progressive simulation method of whole electron spectra described with two -temperatures Maxwellian distribution function has been developed and the results of dose simulations were compared with the acquired experimental data. The advanced feature of this method, which distinguishes it from the results of the simulation of the photon spectrum using the interaction with the target of mono-energetic electron beams (Nilgün Demir, 2013; Nilgün Demir, 2019) or the initial electron spectrum expressed as a function of one electron temperature (Fiorini, 2012), is the ability to simulate the initial electron spectrum described by the Maxwellian distribution function with two temperatures.
The important objective of this thesis was dedicated to the study and characterisation of laser-driven photon beams. In addition to this, the positron beams were evaluated. The investigation of bremsstrahlung photons and positrons spectra from high Z targets by varying the target thickness from 10 µm to 4 mm in simulated models of the interactions of electron spectra with Maxwellian distribution functions allowed to define an optimal thickness when the fluences of photons and positrons are maximal. Furthermore based on the results of FLUKA simulations the gold material was found to be the most suitable for the future experiments as e − γ target because of its highest bremsstrahlung yield.
Additionally Monte Carlo simulations were performed applying the obtained electron beam parameters from the electron acceleration process in laser-plasma interactions simulated with particle-in-cell (PIC) code for two laser energies of 20 J and 200 J. The corresponding electron spectra were imported into a Monte Carlo code FLUKA to simulate the production process of bremsstrahlung photons and positrons in Au converter. FLUKA simulations showed the record conversion of efficiency in MeV gammas can reach 10%, which reinforces the generation of positrons. The obtained results demonstrate the advantages of long-scale plasmas of near critical density (NCD) to increase the parameters of MeV particles and photon beams generated in relativistic laser-plasma interaction. The efficiency of the laser-driven generation of MeV electrons and photons by application of low-density polymer foams is essentially enhanced.
Herzkreislauferkrankungen führen weltweit weiterhin die Liste der häufigsten Todesursachen an. Dem frühzeitigen Erkennen kardialer Veränderungen kommt daher eine besondere Bedeutung zu. Das Erkennen subklinischer Veränderungen des Myokards mit Hilfe des myokardialen T1 Mappings und der Strain Analyse in der kardialen MRT mit der Bestimmung der Korrelation von T1 Mapping und Veränderung des myokardialen Strains war das primäre Ziel der vorliegenden Arbeit. Das native T1 Mapping sollte dabei diffuse kardiale Fibrose erkennen, während die Strainparameter zur Analyse der subtilen kardialen Funktion dienten. Wenn eine vermehrte diffuse Fibrose eine Einschränkung der myokardialen Funktion bedeutet, so müssten sich das native T1 Mapping und die Strainparameter gleichsinnig verändern.
Eingeschlossen in die Untersuchung wurden Patienten, die im Rahmen ihres Klinikaufenthaltes an der Kerckhoff-Klinik Bad Nauheim ein kardiales MRT erhielten und ihre Zustimmung zur Aufnahme in das geführte Register gaben. Alle durchgeführten MRT-Untersuchungen besaßen dabei eine medizinische Indikation. Die Untersuchung umfasste eine Blutentnahme sowie die Bildakquisition und das Ausfüllen eines Fragebogens. In der anschließenden Bildauswertung wurden das native T1 Mapping, eine Featuretrackinganalyse, sowie die reguläre diagnostische Beurteilung durch einen Facharzt durchgeführt. Die Patienten wurden anschließend nach ihren Diagnosen in Gruppen eingeteilt. Ein Jahr nach ihrer Untersuchung wurden die Patienten kontaktiert und erneut befragt, um den Anteil an „major adverse cerebro- and cardiovasculare events“ (MACCE) und der Gesamtsterblichkeit am Gesamtkollektiv festzustellen.
Es zeigten sich signifikante Zusammenhänge zwischen nativem T1 Mapping und den Strainparametern, ebenso wie signifikante Zusammenhänge von schwächerer Effektstärke zwischen ECV und den Strainparametern. Das erhöhte native T1 Mapping ging mit verringerten Strainparametern einher, was auf eine vermehrte Fibrose schließen lässt. In der Überlebensanalyse bezüglich des allgemeinen Überlebens zeigte sich nur das native T1 Mapping als unabhängiger Prädiktor, während bei den MACCE zusätzlich auch die Anzahl der betroffenen Segmente im „late gardolinium enhancement“ (LGE) einen unabhängigen Prädiktor darstellten. Der globale longitudinale Strain (GLS) verfehlte bezüglich der MACCE knapp das Signifikanzniveau, zeigte aber eine Tendenz zur Signifikanz.
Natives T1 Mapping und, in begrenztem Maße, möglicherweise auch der Strain haben eine besondere Rolle in der Diagnostik und können bereits früh kardiale Veränderungen detektieren. Da die erhöhten T1 Zeiten als Marker für morphologische Veränderungen mit den Strains als funktionelle Parameter korrelierten, lässt sich spekulieren, dass Fibrose eine Einschränkung der Funktion bedingt.
Diese Arbeit beschäftigt sich mit der türkischen Musikpolitik in der Zeit von Atatürk und seinem Auftrag insbesondere an den Komponisten, Ahmed Adnan Saygun, im Rahmen der vielfältigen Reformen in der jungen türkischen Republik, eine zeitgenössische türkische Kunstmusik zu schaffen. Mit dem Begriff des Kulturtransfers wird die Umsetzung von Atatürks Musikpolitik beschrieben, der auf die Entwicklung der Musik im 19. Jahrhundert, dem Zeitalter des sogenannten Nationalismus, zurückgreift und mit dem Kulturtransfer anderer Nationen verglichen wurde. Neben Saygun wurde auch das Wirken von vier anderen türkischen Komponisten, die mit Saygun die sogenannten ‚Türkischen Fünf‘ bildeten, erwähnt, die diesen Auftrag Atatürks sehr unterschiedlich umsetzten in einer Zeit der gesellschaftlichen Veränderungen und des ‚Kulturkampfs‘. In diesem Zusammenhang wurden die fünf Sinfonien von Saygun analysiert, der als ein Vorbild und Pionier fast aller Arten türkisch-klassischer Musik im Rahmen dieser musikalischen Revolution angesehen werden kann.
Saygun hat in Zusammenarbeit mit Béla Bartók türkische Volkslieder aufgenommen, verschriftlicht und systematisiert. In dieser Arbeit wurde daher untersucht, wie Saygun, der die türkische Kunst- und Volksmusik sowie in Paris die westeuropäische klassische Musik studiert hat, diese mit Mitteln klassischer Musikformen verbindet. Anhand der fünf Sinfonien von Ahmed Adnan Saygun wird gezeigt, dass er nicht nur als Komponist, sondern auch als Musikethnologe eine führende Rolle in der zeitgenössischen türkischen Kunstmusik übernahm und über den Kulturtransfer hinaus eine eigene ‚musikalische Sprache‘ entwickelte.
Eine der wichtigsten Quellen dieser Arbeit sind die handschriftlichen Partituren der Sinfonien und die Originalartikel von Ahmed Adnan Saygun, insbesondere Sayguns handgeschriebene Artikel ‚Orkestra‘ (dt.: Orchester) und die Artikelsammlung ‚Yalan‘ (dt.: Lüge), die in die deutsche Sprache übersetzt wurden. Als Ergebnisse der Analyse und Interpretation dieser und anderer Quellen, konnten Methoden aufgezeigt werden, die in Sayguns Werke und insbesondere in seinen Sinfonien in rhythmischen, melodischen, harmonischen und motivisch-thematischen Strukturkonstruktionen verwendet und als Beispiele einer zeitgenössischen türkischen Kunstmusik interpretiert werden. Dabei wurde herausgearbeitet, wie Saygun Elemente der türkischen Kunst- und Volksmusik verwendete, diese zunächst in tradierte Formen westeuropäischer klassischer Musik einbettete, um unter Hinzuziehung von eigenen kunstphilosophischen Ansätzen eine Form von ‚universaler Musik‘ zu kreieren.
Mechanistic characterization of photoisomerization reactions in organic molecules and photoreceptors
(2023)
In dieser Arbeit wurden verschiedene Einflüsse auf die Dynamik von Photoisomerisierungen in Phytochromen und indigoiden Photoschaltern untersucht. Beide Forschungsgebiete teilen wesentliche Aspekte wie die Kontrolle durch sterische Wechselwirkungen und den starken Einfluss der Polarität oder der ionischen Umgebung.
Auf dem Gebiet der Phytochrome wurde die relative Positionierung der knotenlosen Phytochrome innerhalb der Superfamilie der Phytochrome in Bezug auf ihre Photodynamik und den Effekt von Grundzustandsheterogenität herausgearbeitet. Es wurde anhand von ultraschnellen, zeitaufgelösten Anrege-Abtast-Experimenten der einzelnen GAF-Domäne All2699g1 im Vergleich mit dem vollständigen knotenlosen Phytochrom All2699g1g2 und dem strukturell ähnlichen knotenlosen Phytochrom SynCph2 gezeigt, dass knotenlose Phytochrome in ihrer Vorwärtsdynamik eine komplexe mehrphasige Kinetik mit einem langlebigen angeregten Zustand (~100 ps) aufweisen. Die beobachtete mehrphasige Kinetik konnte einer initialen Chromophordynamik sowie einer nicht exponentiellen Reorganisation der chromophor-umgebenden Proteinmatrix zugeordnet werden. Dies steht im starken Kontrast zur im Gebiet der Phytochrome etablierten Beschreibung derartiger mehrphasiger Kinetiken mittels heterogener Grundzustände. Stattdessen wurde ein konserviertes kinetisches Muster identifiziert, welches die mehrphasige Dynamik beschreibt und in allen in dieser Arbeit untersuchten Phytochrome beobachtet wurde. Zudem konnte dieses Muster in einem Phytochrom der Gruppe I und einem Phytochrom der Gruppe III, die einen ähnlichen Pr Dunkelzustand aufweisen, gezeigt werden, was eine breite Anwendbarkeit des damit verbundenen Mechanismus vermuten lässt. Weiterhin konnte die zentrale Rolle eines konservierten Tyrosins in der Photoisomerisierung anhand von Mutationsstudien in All2699g1 herausgearbeitet werden. Diese konservierte Aminosäure muss im Rahmen der Reorganisation der Proteinmatrix vom Chromophor weggezogen werden, damit die sterische Blockade abgebaut werden kann, die die Isomerisierung des Chromophors zunächst verhindert. Da diese Bewegung von diversen Faktoren in der den Chromophor umgebenden Proteinmatrix abhängt, weist sie eine nicht exponentielle Kinetik auf, die je nach Phytochrom, der spezifischen Flexibilität und dem vorhandenen Raum in der Bindetasche unterschiedliche Lebenszeiten aufweist.
Die Rückreaktion knotenloser Phytochrome konnte ebenfalls im Rahmen dieser Arbeit charakterisiert werden, welche im Pikosekundenbereich abläuft, und damit signifikant schneller ist als die Vorwärtsreaktion. Im Gegensatz zur Vorwärtsreaktion nimmt Grundzustandsheterogenität in der Rückreaktion eine weitaus bedeutendere Rolle ein. Hier weisen die in All2699g1 vorhandenen heterogenen Grundzustandspopulationen jeweils eine eigene Kinetik ihres angeregten Zustands auf, während die homogenen Grundzustände von All2699g1g2 und SynCph2 jeweils nur einen Zerfall des angeregten Zustands zeigen. Der Ursprung dieser Heterogenität konnte im Wasserstoffbrückennetzwerk des Chromophors lokalisiert und mit dem konservierten Tyrosin und einem konservierten Serin in der PHY-Domäne verknüpft werden. Die Anwesenheit der PHY-Domäne sorgt demnach für eine Verringerung der Grundzustandsheterogenität und des vorhandenen Raums in der Bindetasche, wodurch die Effizienz der Photoreaktion optimiert wird.
Zuletzt konnte die Millisekundendynamik knotenloser Phytochrome und der Einfluss der PHY-Domäne auf diese aufgeklärt werden. Die PHY-Domäne sorgt hierbei durch den verringerten Raum in der Bindetasche dafür, dass die zunächst stattfindende thermische Relaxation des Chromophors signifikant verlangsamt wird, während spätere Änderungen im Photozyklus nur wenig beeinflusst werden.
Auf dem Gebiet der indigoiden Photoschalter konnte, anhand eines sterisch überladenen Hemithioindigo Photoschalters, der Photoisomerisierungsmechanismus des Hula-Twists beobachtet und eine starke Lösungsmittelabhängigkeit der entsprechenden Kinetik aufgezeigt werden. Aus den durchgeführten zeitaufgelösten Anrege-Abtast-Experimenten in verschiedenen Lösungsmitteln konnte ein Modell für die Photodynamik des verwendeten Hemithioindigo Photoschalters entwickelt werden. In unpolaren Lösungsmitteln muss eine hohe Barriere zur produktiven konischen Durchschneidung überwunden werden, was zu Lebenszeiten des angeregten Zustands im Nanosekundenbereich führt. Der Weg zur produktiven konischen Durchschneidung folgt dabei dem Hula-Twist Mechanismus. Dieser Pfad ist in polaren Lösungsmitteln unerreichbar, weshalb eine schnelle Relaxation über eine unproduktive konische Durchschneidung stattfindet.
Im zweiten Projekt auf dem Gebiet der indigoiden Photoschalter wurde anhand der neuartigen Klasse der Iminothioindoxyl Photoschalter ein Schwingungsenergiedonor für Schwingungsenergietransferstudien entwickelt. Das daraus entwickelte Modellsystem, bestehend aus einer künstlichen Aminosäure auf Basis des Iminothioindoxyl Photoschalters und einem daran gekoppelten Schwingungsenergiesensor, wurde charakterisiert und die primäre Photoreaktion untersucht. Es konnte gezeigt werden, dass der angeregte Zustand des Modellsystems kurzlebig ist und unter Abgabe von großen Mengen an Schwingungsenergie zerfällt, unabhängig von der Anregungswellenlänge und dem verwendeten Lösungsmittel. Somit zeigt das entwickelte System vorteilhafte Eigenschaften für Schwingungsenergietransferstudien.
Insgesamt konnten somit die Mechanismen der Photoisomerisierungsreaktionen in knotenlosen Phytochromen und indigoiden Photoschaltern aufgeklärt und daraus die Relevanz der Umgebung für derartige Reaktionen herausgearbeitet werden.
Auszubildende sollen durch die Berufsausbildung u.a. die Kompetenz erlangen, berufliche Probleme zu lösen. Abschlussprüfungen dienen der Kompetenzerfassung, schriftlich-kaufmännische Prüfungsaufgaben bilden allerdings noch unzureichend Problemsituationen ab, deren Lösung Problemlösekompetenz erfordert. An der Erstellung von Prüfungsaufgaben sind auch Lehrkräfte kaufmännisch-beruflicher Schulen beteiligt. In der Arbeit wird untersucht, wie sie in der ersten und zweiten Phase der Lehrer*innenbildung auf das Erstellen problemhaltiger Aufgaben zu summativ-diagnostischen Zwecken vorbereitet werden. Hierfür werden Dokumentenanalysen zu beiden Phasen der Lehrer*innenbildung durchgeführt. Die Ergebnisse werden mittels einer Fragebogenstudie mit Studiengangsleiter*innen sowie Interviews mit Fachleiter*innen der Studienseminare gesichert. Um die Wahrnehmung angehender Lehrkräfte zu erfahren, werden Interviews mit Masterstudierenden der Wirtschaftspädagogik sowie Lehrkräfte im Vorbereitungsdienst (LiV) an kaufmännisch-beruflichen Schulen durchgeführt.
Durch die Vorstudien gelingt es, Optimierungsbedarfe in der Ausbildung von Lehrkräften kaufmännisch-beruflicher Schulen festzuhalten. Davon ausgehend wird ein Trainingskonzept begründet ausgewählt. Die Evaluation dessen erfolgt mittels einer quasi-experimentellen Studie mit Masterstudierende und LiV. Zur qualitativen Evaluation werden Interviews mit Teilnehmenden der Interventionsgruppe durchgeführt. Die Ergebnisse zeigen, dass die Teilnehmenden das Training als Intervention überwiegend positiv wahrnehmen und dieser, zumindest mit Blick auf das Erstellen von problemhaltigen Aufgaben, zu einem Lernzuwachs führt. Durch die bedarfsorientierte Intervention und dessen Evaluationsergebnisse wird ein Konzept vorgeschlagen, welches eine Lösung zur Deckung bestehender Optimierungsbedarfe bietet. Die Ergebnisse der Arbeit haben das Potential, langfristig einen Beitrag zur Verbesserung der Lehrer*innenbildung zu leisten und somit u.a. Assessmentaufgaben valider zu gestalten.
In this dissertation, different aspects of turbulent transport and thermally driven flows over complex terrain are investigated. Two publications concentrate on the vertical heat and moisture exchange in the convective boundary layer over mountainous terrain. To study this, Large-Eddy Simulation (LES) is used. Both turbulent and advective transport mechanisms are evaluated over the simple orography of a quasi-two-dimensional, periodic valley with prescribed surface fluxes. Here, terrain elevation varies along only one of the horizontal coordinate axes. Even a relatively shallow orography, possibly unresolved in existing numerical weather prediction models, modifies the domain-averaged moisture and temperature profiles. For the analysis, the flow is decomposed into a local turbulent part, a local mean circulation, and a large-scale part. An analysis of the turbulent kinetic energy and turbulent heat and moisture flux budgets shows that the thermal circulation significantly contributes to the vertical transport. It is found that thermal upslope winds are important for the moisture transport from the valley to the mountain tops. In total, moisture export out of the valley is mostly accomplished by the mean circulation. On the temperature distribution, which is horizontally relatively homogeneous, the thermal circulation has a weaker impact. If an upper-level wind is present, it interacts with the thermal circulation. This weakens the vertical transport of moisture and thus reduces its export out of the valley. The heat transport is less affected by the upper-level wind because of its weaker dependence on the thermal circulation. These findings were corroborated in a more realistic experiment simulating the full diurnal cycle using radiation forcing and an interactive land surface model.
Based on these results, coherent turbulent structures in the convective boundary layer over non-flat terrain are studied in further detail. A conditional sampling method based on the concentration of a decaying passive tracer is implemented in order to identify the boundary-layer plumes objectively. Conditional sampling allows to quantify the contribution of plume structures to the vertical transport of heat and moisture. In case of the idealized valley, vertical transport by coherent structures is the dominant contribution to the turbulent components of both heat and moisture flux. It is comparable in magnitude to the advective transport by the mean slope-wind circulation, although it is more important for heat than for moisture transport. A set of less idealized simulations considers the flow over three-dimensional terrain. In this case, conditional sampling is carried out by using a simple domain-decomposition approach. We demonstrate that thermal updrafts are generally more frequent on hill tops than over the surroundings, but they are less persistent on the windward sides when large-scale winds are present in the free atmosphere.
The tools for flow decomposition and budget analysis are also applied in another idealized case with a quasi-two-dimensional valley featuring the stable boundary layer. Here, the formation of a low stratus cloud is investigated. The main driver for the cloud formation is radiative cooling due to outgoing longwave radiation. Despite a purely horizontal flow, the advection terms in the prognostic equations for heat and moisture produce vertical mixing across the upper cloud edge leading to a loss of cloud water content. However, this behavior is not due to any kind of thermally-driven circulation. Instead, this spurious mixing is caused by the diffusive error of the advection scheme in regions where the sloping surfaces of the terrain-following vertical coordinate intersect the cloud top. It is shown that the intensity of the (spurious) numerical diffusion strongly depends on the horizontal resolution, the order of advection, and the choice of the scalar advection scheme. A LES with 4 m horizontal resolution serves as a reference. For horizontal resolutions of a few hundred meters, carried out with a model setup as it is used in Numerical Weather Prediction, a strong reduction of the simulated liquid-water path is observed. In order to keep the (spurious) numerical diffusion at coarser resolutions small, at least a fifth-order advection scheme should be used. In the present case, a WENO scalar advection scheme turns out to increase the numerical diffusion along a sharp cloud edge compared to an upwind scheme. Furthermore, the choice of the vertical coordinate has a strong impact on the simulated liquid-water path over orography. With a modified definition of the terrain-following sigma coordinate, it is possible to produce cloud water where the classical sigma coordinate does not allow any cloud formation.
Eine überlebenswichtige Eigenschaft von Mensch und Tier ist es, sich bei Gefahr durch eine Schreckreaktion in Sicherheit zu bringen. Doch woran erkennt ein Organismus, in welcher Situation es „sinnvoll“ wäre, sich zu erschrecken und welche Eigenschaften sensorischer Stimuli tragen zu dem Gefahreneindruck bei? Bei plötzlich eintretenden, lauten auditorischen Reizen kann es zur Auslösung der akustischen Schreckreaktion kommen. Dies führt bei Menschen, aber auch bei kleineren Säugetieren zu einer reflexartigen Kontraktion der Nacken-, Gesichts- und Skelettmuskulatur. Die Erforschung der akustisch evozierten Schreckreaktion (ASR) dient dem besseren Verständnis der neurobiologischen Grundlagen sensorischer Verarbeitung. Modulationen der ASR mithilfe von Präpulsen (Präpulsinhibition) ermöglichen Einblicke in die Funktion der Kochlea, des Hörnervs, der Hirnstammstrukturen und anderer beteiligter Gehirnregionen.
In dieser Arbeit wurden kurzzeitige Änderungen von Frequenz oder Intensität des akustischen Hintergrundes als neuartige Präpulse untersucht. Die Bedeutung verschiedener Reizparameter dieser Präpulse wurde in der vorliegenden Arbeit zum ersten Mal systematisch erforscht. Um zu prüfen, welche Präpulsstimulationen eine Inhibition der ASR auslösen können, wurde eine Reihe von Parametern umfassend getestet. In einem weiteren Schritt wurde analysiert, ob es mithilfe von gezielten Änderungen von Frequenz oder Intensität möglich sein könnte, Unterscheidungsschwellen, oder gar Hörschwellen von Versuchstieren zu bestimmen.
Die Experimente zur Modulation der ASR wurden mit weiblichen Sprague Dawley-Ratten durchgeführt. Dabei wurde eine Vielzahl von Verhaltensparadigmen untersucht. Dazu zählten Präpulse mit unterschiedlichem Frequenzgehalt und variabler Dauer. Zusätzlich wurden neuartige Paradigmen etabliert, um die Fähigkeit zur Frequenz- und Intensitätsdiskriminierung zu untersuchen. Hierbei wurde der Frequenzgehalt oder die Intensität einer kontinuierlichen Hintergrundstimulation verändert, um eine Präpulswirkung zu erzeugen. Um die Möglichkeiten der Bestimmung von Hörschwellen mittels der Präpulsinhibition (PPI) zu ergründen, wurde die Intensität von Präpulsen systematisch verändert. Die so generierten Schwellenwerte wurden durch die Messung früher akustisch evozierter Hirnstammpotenziale verifiziert. Schließlich sollten, unter Zuhilfenahme der Signaldetektionstheorie, aus den erhobenen Daten diverse Schwellen bestimmt werden: Für die Intensitätsänderungen der Präpulse in Stille wurden Hörschwellen bestimmt, während bei Änderungen der Frequenz und Intensität Unterscheidungsschwellen bestimmt werden sollten.
Mit steigender Größe eines Frequenzsprungs in einer kontinuierlichen Hintergrundstimulation war eine stärkere Inhibition der ASR feststellbar; ein Effekt, der stark von der Hintergrundfrequenz abhängig war. Bei einer Stimulation mit 8 kHz konnten signifikant höhere Inhibitionswerte erzielt werden als mit 16 kHz. Bei der Untersuchung des Zeitablaufs der Stimulation ergab sich, dass eine abgesetzte Stimulation mit einer Abweichung von 80 ms Dauer bis 50 ms vor dem Schreckreiz für die höchsten Inhibitionen sorgte.
Die durch eine Intensitätsänderung einer kontinuierlichen Hintergrundstimulation ausgelöste PPI hing primär von der Größe und Richtung des Intensitätssprungs ab. Mit zunehmender Sprunggröße stiegen die Inhibitionswerte an. Eine Erhöhung der Hintergrundintensität um 10 dB hatte einen signifikanten Einfluss auf die Inhibitionswerte. Auch hier zeigte sich eine höhere Sensitivität in Form von höheren Inhibitionen für Stimuli mit einer Hintergrundfrequenz von 8 kHz als für alle anderen getesteten Hintergrundfrequenzen.
Die Bestimmung von Hörschwellen mittels intensitätsabhängiger PPI wies im Vergleich mit den elektrophysiologisch bestimmten Hörschwellen ein heterogenes Bild mit starken individuellen Schwankungen auf: Bei etwa der Hälfte der Tiere waren die Hörschwellen beider Messungen sehr vergleichbar, bei den übrigen Tieren konnten mittels PPI für eine oder mehrere Frequenzen keine aussagekräftigen Hörschwellen erzielt werden. Die elektrophysiologisch bestimmten Hörschwellen waren am sensitivsten, während PPI-Stimulationen signifikant höher waren. Außerdem bewirkten PPI-Stimulationen mit Reintönen signifikant sensitivere Hörschwellen im Vergleich zu einem Schmalbandrauschen.
Für die Bestimmung der Unterscheidungsschwellen von Frequenzänderungen konnte beobachtet werden, dass die Tiere auf Frequenzsprünge hin zu niedrigeren Frequenzen signifikant sensibler reagierten, als hin zu Aufwärtssprüngen (-1.2 bzw. +4.5%). Bei der Intensitätsunterscheidung hingegen konnte beobachtet werden, dass die Tiere signifikant sensitiver auf Intensitätserhöhungen als auf Erniedrigungen reagierten (-5.9 bzw. +2.7 dB).
Zusammenfassend konnte in der vorliegenden Arbeit festgestellt werden, dass die PPI zur Bestimmung von absoluten Hörschwellen starken Schwankungen unterlag, sodass diese Methode nur eingeschränkt als Alternative zu operanter Konditionierung oder elektrophysiologischen Ableitungen in Frage kommt. Des Weiteren erzeugten bereits kleine Änderungen des Frequenzgehalts oder der Intensität einer Hintergrundstimulation eine robuste PPI. Somit können reflexbasierte Messungen mit überschwelligen Stimuli genutzt werden, um Unterscheidungsschwellen in Versuchstieren zu bestimmen. Diese Herangehensweise stellt also eine vielversprechende Methode dar, um Hörstörungen zu untersuchen, die nach einem Schalltrauma auftreten können. In einem nächsten Schritt könnte sie zur weiteren Charakterisierung von verstecktem Hörverlust beitragen.
Seed dispersal is a key ecosystem function for plant regeneration, as it involves the movement of seeds away from the parental plants to particular habitats where they can germinate and transition to seedlings and ultimately adult plants. Seed dispersal is shaped by a diversity of abiotic and biotic factors, particularly by associations between plants and climate and between plants and other species. Due to the ongoing loss of biodiversity and changing global conditions, such interactions are prone to change and pose a severe threat to plant regeneration. One way to address this challenge is to study associations between plant traits and abiotic and biotic factors to understand the potential impacts of global change on plant regeneration. Plant communities have long been analyzed through the lens of vegetative traits, mainly ignoring how other traits interact and respond to the environment. For instance, while associations between vegetative traits (e.g., specific leaf area, leaf nitrogen content) and climate are well studied, there are few case studies of reproductive traits in relation to trait-environment associations in the context of global change.
Thus, the overarching aim of this dissertation is to explore how trait-environment associations, with a special focus on reproductive traits, can improve our understanding of the effect that global change may have on seed dispersal, and ultimately on plant regeneration. To this end, my research focuses on studying associations between plant traits and abiotic and biotic factors along an elevational gradient in both forests and deforested areas of tropical mountains. This dissertation addresses three principal research objectives.
First, I investigate the extent to which reproductive (seed and fruit traits) and vegetative traits (leaf traits) are related to abiotic and biotic factors for communities of fleshy-fruited plants in the Ecuadorian Andes. I used multivariate analyses to test associations between four (a)biotic factors and seven reproductive traits and five vegetative traits measured on 18 and 33 fleshy fruited plant species respectively. My analyses demonstrate that climate and soil conditions are strongly associated with the distribution of both reproductive and vegetative traits in tropical tree communities. The production of “costly” vs. “cheap” seeds, fruits and leaves, i.e., the production of few rewarding fruits and acquisitive leaves versus the production of many less-rewarding fruits and conservative leaves, is primarily limited by temperature, whereas the size of plant organs is more related to variation in precipitation and soil conditions. My findings suggest that associations between reproductive and vegetative traits and the abiotic environment follow similar principles in tropical tree communities.
Second, I assess how climate and microhabitat conditions affect the prevalence of endozoochorous plant species in the seed rain of tropical montane forests in southern Ecuador. I analyzed seed rain data for an entire year from 162 traps located across an elevational gradient spanning of 2000 m. I documented the microhabitat conditions (leaf area index and soil moisture next to each seed trap) at small spatial scale as well as the climatic conditions (mean annual temperature and rainfall in each plot) at large spatial scale. After a one-year of sampling, I counted 331,838 seeds of 323 species/morphospecies. My analyses demonstrate that the prevalence of endozoochorous plant species in the seed rain increases with temperature across elevations and with leaf area index within elevations. These results show that the prevalence of endozoochory is shaped by the interplay of both abiotic and biotic factors at large and small spatial scales.
Third, I examine the potential of seed rain to restore deforested tropical areas along an elevational gradient in southern Ecuador. For this chapter, I collected seed rain using 324 seed traps installed in 18 1-ha plots in forests (nine forest plots) and in pastures (nine deforested plots) along an elevational gradient of 2000 m. After a sampling period of three months, I collected a total of 123,039 seeds of 255 species/morphospecies from both forests and pastures along the elevational gradient. I did not find a consistent decrease in the amount and richness of seed rain between forests and pastures, but I detected a systematic change in the type of dispersed seeds, as heavier seeds and a higher proportion of endozoochorous species were found in forests compared to pastures at all elevations. This finding suggests that deforestation acts as a strong filter selecting seed traits that are vital for plant regeneration.
Understanding the role that trait-environment associations play in how plant communities regenerate today could serve as a basis for predicting changes in regeneration processes of plant communities under changing global conditions in the near future. Here, I show how informative the measurement of reproductive traits and trait environment associations are in facilitating the conservation of forest habitats and the restoration of deforested areas in the context of global change.
Der Einfluss von Trauma-aktiviertem platelet-rich fibrin auf mesenchymale Stammzellen in vitro
(2023)
Ziel dieser Arbeit war es, die Wechselwirkung zwischen MSC und PRF von Traumapatienten herauszuarbeiten und zu überprüfen, ob ein therapeutischer Einsatz der Kombination von MSC und Trauma-aktiviertem PRF in Frakturen sinnvoll erscheint.
Hierfür wurden MSC mit PRF über einen Zeitraum von 24 oder 120 Stunden co-inkubiert und die metabolische Aktivität, definierte Faktoren im Überstand (IL-6, CXCL10, VEGF und IDO-2) und die Genexpression ausgewählter Faktoren (MAPK8, MAPK14, IL-6, CXCL10,IDO-1, TNFAIP6, VEGFA, RUNX2 und COL1A) in bis zu drei Messzeitpunkten überprüft. Die Versuche erfolgten vergleichend mit Traumapatienten und gesunden Probanden.
Es konnte gezeigt werden, dass Trauma-aktiviertes PRF verglichen mit PRF von gesunden Probanden die metabolische Aktivität von MSC nach 120 Stunden erhöhen kann. Zudem stellten sich erhöhte Werte des inflammatorischen Faktors IL-6 im Überstand bei Traumapatienten nach 24 und 72 Stunden dar, welche bis zum dritten Messzeitpunkt nach 120 Stunden wieder abfielen. Ein ähnlicher Verlauf zeigte sich bei den Messwerten von VEGFA, einem Faktor, welcher eine große Rolle bei der Angiogenese spielt.
Über alle Messzeitpunkte hinweg konnten niedrigere Werte in der Genexpression von COL1A und RUNX2 im Vergleich zu den Kontrollmessungen erfasst werden.
Die Ergebnisse zeigen, dass im Vergleich zu PRF gesunder Probanden Trauma-aktiviertes PRF die Möglichkeit besitzt, die Proliferation von MSC zu stimulieren. Außerdem wurde beobachtet, dass Trauma-aktiviertes PRF ein inflammatorisches und angiogenetisches Potenzial nach 72 Stunden besitzt, welches nach 120 Stunden allerdings wieder abfällt. Möglicherweise kann durch den Einfluss von MSC der Inflammation entgegengewirkt werden. Ein signifikantes osteogenes Potenzial des Trauma-aktivierten PRFs konnte zu keinem Messzeitpunkt nachgewiesen werden.
Inwiefern der Einsatz von MSC in Kombination mit Trauma-aktiviertem PRF die Frakturheilung verbessern kann, konnte in der vorliegenden Studie nicht eindeutig geklärt werden. Es kann allerdings davon ausgegangen werden, dass die Implantation von Trauma-aktiviertem PRF und MSC in den Defekt erst nach Verstreichen einer bestimmten Zeitperiode nach dem Trauma durchgeführt werden sollte. Die Gründe für diese Annahme sind das erhöhte proliferative und verringerte inflammatorische Potenzial im Verlauf. Eine Ursache für das Fehlen der osteogenen Differenzierung der MSC kann der kurze Messzeitraum sein.
Weitere Studien sollten folgen, um das Potenzial der Kombination von MSC und Trauma-aktiviertem PRF als therapeutisches Verfahren zu überprüfen.
Die Krebsstammzellforschung gelangte in den letzten Jahren vermehrt in den Fokus der Tumorforschung. Im Tumor bilden Krebsstammzellen eine kleine Population an Zellen mit Stammzelleigenschaften, wodurch sie eine große Rolle bei der Entstehung von Rezidiven, Metastasen, sowie der Entwicklung von Chemotherapieresistenzen spielen. Um eine gezielte Bekämpfung von Krebsstammzellen zu ermöglichen, müssen diese im
Tumor zunächst zuverlässig durch Krebsstammzellmarker detektiert werden können.
Gerade bei soliden pädiatrischen Tumoren, wie dem Hepatoblastom, ergeben sich hierbei Schwierigkeiten dadurch, dass im sehr heterogenen Tumorgewebe viele Zellen aufgrund der embryonalen Natur des Tumors bereits Stammzellmarker exprimieren, ohne dass es sich bei diesen Zellen um Krebsstammzellen handelt. Das Hepatoblastom ist mit 2/3 der Lebertumore des Kindes die häufigste maligne Leberneoplasie im Kindesalter.
Auch wenn es bereits Hinweise auf das Vorliegen von Krebsstammzellen im Hepatoblastom gibt, so konnten diese bisher nicht genauer durch fest definierte Krebsstammzellmarker identifiziert werden.
Um dies zu erreichen, wurden in dieser Arbeit die beiden Hepatoblastomzelllinien HuH6 und HepG2 auf die Expression der bereits bekannten Krebsstammzellmarker CD90, CD34 und CXCR4 überprüft. Zusätzlich wurde auf eine Bindung des „oval cell“ Antikörpers, OV-6, untersucht. Mittels Durchflusszytometrie-Analysen konnte eine Zellpopulation gefunden werden, welche die Oberflächenmarker CD34 und CD90 koexprimiert und gleichzeitig den OV-6 Antikörper bindet. Im nächsten Schritt wurden die Zellen auf einige Krebsstammzelleigenschaften überprüft. Zur weiteren Untersuchung dieser Subpopulation erfolgte mittels MACS (magnetic activated cell sorting) eine Anreicherung der CD90 exprimierenden Zellen. Diese wurde mittels qPCR auf die Expression der Pluripotenzmarker Oct4 und Nanog, sowie der Zytidindeaminase AID untersucht. Es konnte eine signifikant erhöhte Expression von AID und Oct4 detektiert werden. Im Gegensatz hierzu zeigte sich die Expression von EpCAM, c-myc und Albumin, welche als Kontrollgene untersucht wurden, nicht signifikant erhöht. Um auf das Metastasierungspotential der CD90 angereicherten Zellen rückzuschließen, wurde ein Migrationsassay mit angereicherten und depletierten Zellen durchgeführt. Hier wiesen die CD90 angereicherten Zellen, im Vergleich zu den depletierten Zellen eine erhöhte Migration auf. Im Tumorsphäroid-Assay war die HepG2 Zelllinie in der Lage Tumor-61 -sphäroide auszubilden. Nach der Passagierung zeigten diese eine erhöhte Expression der Krebsstammzellmarker CD90 und CD34, sowie der Pluripotenzmarker Oct4 und Nanog.
Zusammengefasst kann mit den Krebsstammzellmarkern CD90, CD34 und OV-6 eine Subpopulation im Hepatoblastom identifiziert werden, die nach unseren Analysen Krebsstammzelleigenschaften aufweisen. Mithilfe dieses Markersets können nun neue Therapieansätze auf ihre Effektivität, Krebsstammzellen gezielt zu eliminieren, getestet werden.
Brain development is a complex and highly organized process that relies on the coordinated interaction between neurons and vessels. These cell systems form a neurovascular link that involves the exchange of oxygen, ions, and other physiological components necessary for proper neuronal and vascular function. This physiologically coupled process is executed through analogous structural and molecular signaling mechanisms shared by both cell types. At the neurovascular interface, the cellular crosstalk via these shared signaling mechanisms allows for the synchronized expansion and integration of neurons and vessels into complex cellular networks. This study investigated the role of VEGFR2, a receptor for vascular endothelial growth factor (VEGF), during postnatal neuronal development in the mouse hippocampus. Prior studies have revealed physiological roles of VEGF, a pro-angiogenic morphogen, in nervous system development. However, it was unclear if VEGF signaling had a direct effect on neuronal physiology and function through neuronal-expressing receptors. In this investigative work, we identified a previously unknown function of VEGFR2, whereby VEGF-induced signaling coordinates the development and circuitry integration of CA3 pyramidal neurons in the early postnatal mouse hippocampus. Mechanistically, we found that VEGFR2 signaling requires receptor endocytosis, a process mediated by ephrinB2. We also found that VEGF-induced cooperative signaling between VEGFR2 and ephrinB2 is functionally required for the dendritic arborization and spine maturation of developing CA3 neurons during the first few postnatal weeks. Moreover, in a collaborative effort with the research group of Carmen Ruiz de Almodovar, formerly at the University of Heidelberg, we simultaneously studied VEGF-induced VEGFR2 signaling in CA3 axonal development. Together, we aimed to gain a comprehensive understanding of the complex interplay between VEGF and VEGFR2 signaling during the early postnatal development of CA3 neurons. Ruiz de Almodovar’s research group found that, unlike the branch and spine development of CA3 dendrites, VEGF-VEGFR2 signaling promotes axonal development through mechanisms that are independent of ephrinB2 function. Our findings on CA3 dendritic development are reported in the published manuscript, Harde et al. (2019), and the complementary work on CA3 axonal development from Ruiz de Almodovar's group is presented in the co-published manuscript, Luck et al. (2019). Although the totality of Ruiz de Almodovar's group's work on CA3 axons is not fully discussed here, it is referenced where noted to provide biological context for our findings on CA3 dendritic development.
VEGFR2 signaling within neurovascular niches is known to play a role in the neurogenesis of neural progenitor cells during embryonic development and within the adult brain. However, the precise localization of neuronal VEGFR2 expression and functional role within the nervous system during postnatal brain development was unknown. To investigate this, we used immunohistochemistry to identify the spatial expression of VEGFR2 within the mouse hippocampus during the first few weeks after birth. Our results showed that VEGFR2 was predominantly expressed within the hippocampal vasculature, consistent with prior studies. However, we also observed localized VEGFR2 expression in pyramidal cell neurons of the hippocampal CA3 region by postnatal day 10 (P10). This spatially restricted postnatal expression of VEGFR2 in CA3 neurons suggested a potential role in the development of these neurons during this developmental stage.
The first two weeks after birth in the mouse hippocampus is a critical period for the development of neuronal circuits, as neurons undergo extensive dendritic arborization and spine formation. To explore the role of VEGFR2 in the postnatal nervous system, we used a Nes-cre VEGFR2lox/- mouse line to target the deletion of VEGFR2 expression within the nervous system while preserving normal receptor expression in all other cell types. We also generated corresponding control mice that were negative for Nes-cre. By breeding these mice with Thy1-GFP reporter mice, we could analyze the functional consequences of VEGFR2 by assessing the morphologies of CA3 dendritic trees and spine density and maturation at P10 and P15, respectively. Our analysis showed that CA3 neurons in Nes-cre VEGFR2lox/- mice had less complex dendritic arbors compared to control mice. There were significant reductions in total length and branch points, particularly in areas located 100-250 μm from the cell soma within the stratum radiatum layer. Additionally, Nes-cre VEGFR2lox/- mice exhibited a significant decrease in spine density accompanied by an increased proportion of immature spines. These findings suggest that VEGFR2 plays a crucial role in the proper development of CA3 dendrites and spines during the early postnatal weeks.
In view of a growing world population and the finite nature of fossil resources, the development of eco-friendly production processes is essential for the transition towards a sustainable industry. Methanol, which can be produced both petrochemically and from renewable resources, offers itself as bridging technology and attractive alternative raw material for biotechnological processes. This work describes developments for the progress of the well-studied methylotrophic α proteobacterium Methylorubrum extorquens AM1 towards an efficient methylotrophic cell factory. Although many homologous and heterologous production routes have already been described and realized for M. extorquens in a laboratory scale, no industrial process has yet been realized. Three major reasons can be identified for this: (1) A limited choice of tools for genetic modifications, (2) a lack of understanding of carbon fluxes and side reactions occurring in modified strains, such as product reimports, and (3) the lack of tailored production strains for profitable target products and optimized bioprocessing protocols. The aim of the present work was to achieve developments for the mentioned areas. As a model application, the high-level production of chiral dicarboxylic acids from the substrate methanol was chosen. Enantiomerically pure chiral compounds are of great interest, e.g., as building blocks for chiral drugs. The ethylmalonyl CoA metabolic pathway (EMCP) which is part of the primary metabolism of M. extorquens, harbors unique chiral CoA-ester intermediates. Their acid derivatives can be released by cleavage of the CoA-moiety using heterologous enzymes. The dicarboxylic acids 2 methylsuccinic acid and mesaconic acid were produced in a previous study by introducing the heterologous thioesterase YciA into M. extorquens. In the said study, a combined product titer of 0.65 g/L was obtained in shake flask experiments. These results serve as the basis for the developments in the present work.
First, the previously described reuptake of products was thoroughly investigated and dctA2, a gene encoding for an acid transporter, was identified as target for reducing the product reuptake. In addition, reuptake of mesaconic acid was prevented by converting it to (S)-citramalic acid, a product not metabolizable by M. extorquens, by the introduction of a heterologous mesaconase. Together with 2-methylsuccinic acid, for which a high enantiomeric excess of (S)-2-methylsuccinic acid was determined, a second chiral molecule was thus added to the product spectrum. For the release of dicarboxylic acid products, YciA, a broad-range thioesterase that accepts a variety of CoA-esters with different chain lengths as substrates, was chosen. The enzyme should theoretically be able to hydrolyze all CoA-esters of interest present in the EMCP. However, in culture supernatants of M. extorquens strains that were overexpressing the corresponding yciA gene, only mesaconic acid and 2 methylsuccinic acid could be detected. To expand the substrate spectrum of YciA thioesterase with respect to other EMCP intermediates, semi-rational enzyme engineering was attempted. Screening of the corresponding strains carrying the respective YciA variants did not result in strains capable of producing new dicarboxylic acid products. However, the experiments revealed an amino acid position that strongly affected the production of mesaconic acid and 2-methylsuccinic acid in vivo. By substituting the according amino acid in YciA, the maximum titers of mesaconic acid and 2-methylsuccinic acid could be increased substantially. Application of an improved thioesterase variant in a second E. coli-based process confirmed the enhanced activity of the enzyme. The desired extension of the product spectrum by another chiral molecule (2-hydroxy-3-methylsuccinic acid, presumably the (2S,3R)-form) was finally achieved by using an alternative thioesterase. Tailored fermentation strategies were developed for the high-level production of the above-mentioned products.
As second part of the work, two novel genetic tools for M. extorquens were developed and characterized. The pBBR1-derived plasmid pMis1_1B was shown to be stably maintained in M. extorquens cells. In addition, its suitability for co-transformations with other plasmids was demonstrated. The second tool, the cumate-inducible promoter Ps6, is tailored for expression of pathways with toxic products, as the transcription of genes controlled by Ps6 is strongly repressed in the absence of an inducer.
Overall, the present work demonstrates the enormous potential of using M. extorquens as a methylotrophic cell factory. In the applications shown, the biotechnological production of high-priced chiral molecules is combined with the use of an attractive alternative substrate. In addition, new achievements and approaches are presented to facilitate the development of future M. extorquens production strains.
The single-source shortest-path problem is a fundamental problem in computer science. We consider a generalization of the shortest-path problem, the $k$-shortest path problem. Let $G$ be a directed edge-weighted graph with $n$ nodes and $m$ edges and $s,t$ be two fixed nodes. The goal is to compute $k$ paths $P_1,\dots,P_k$ between two fixed nodes $s$ and $t$ in non-decreasing order of their length such that all other paths between $s$ and $t$ are at least as long as the $k$\nth path $P_k$. We focus on the version of the $k$-shortest path problem where the paths are not allowed to visit nodes multiple times, sometime referred to as $k$-shortest simple path problem.
The probably best known $k$-shortest path algorithm is Yen's algorithm. It has a worst-case time complexity of O(kn\cdot scp(n,m)), where scp(n,m) is the complexity of the single-source shortest-path algorithm used as a subroutine. In case of Dijkstra's algorithm scp(n,m) is O(m + n\log n). One of the more recent improvements of Yen's algorithm is by Feng.
Even though Feng's algorithm is much faster in practice, it has the same worst-case complexity as Yen's algorithm.
The main results presented in this thesis are upper bounds on the average-case of Yen's and Feng's algorithm, as well as practical improvements and a parallel implementation of Yen's and Feng's algorithms including these improvements. The implementation is publicly available under GPLv3 open source license.
We show in our analysis that Yen's algorithm has an average-case complexity of O(k \log(n)\cdot scp(n,m)) on G(n,p) graphs with at least logarithmic average-degree and random edge weights following a distribution with certain properties.
On G(n,p) graphs with constant to logarithmic average-degree and uniform random edge-weights over $[0;1]$, we show an average-case complexity of O(k\cdot\frac{\log^2 n}{np}\cdot scp(n,m)). Feng's algorithm has an even better average-case complexity of O(k\cdot scp(n,m)) on unweighted G(n,p) graphs with logarithmic average-degree and for constant values of $k$. We further provide evidence that the same holds true for G(n,p) graphs with uniform random edge-weights over $[0;1]$.
On the practical side, we suggest new heuristics to prune even more single-source shortest-path computations than Feng's algorithm and evaluate all presented algorithms on G(n,p) and Grid graphs with up to 256 million nodes. We demonstrate speedups by a factor of up to 40 compared to Feng's algorithm.
Finally we discuss two ways to parallelize the suggested algorithms and evaluate them on grid graphs showing speedups by a factor of 2 using 4 threads and by a factor of up to 8 using 16 threads, respectively.
Artificial intelligence in heavy-ion collisions : bridging the gap between theory and experiments
(2023)
Artificial Intelligence (AI) methods are employed to study heavy-ion collisions at intermediate collision energies, where high baryon density and moderate temperature QCD matter is produced. The experimental measurements of various conventional observables such as collective flow, particle number fluctuations, etc. are usually compared with expensive model calculations to infer the physics governing the evolution of the matter produced in the collisions. Various experimental effects and processing algorithms can greatly affect the sensitivity of these observables. AI methods are used to bridge this gap between theory and experiments of heavy-ion collisions. The problems with conventional methods of analyzing experimental data are illustrated in a comparative study of the Glauber MC model and the UrQMD transport model. It is found that the centrality determination and the estimated fluctuations of the number of participant nucleons suffer from strong model dependencies for Au-Au collisions at 1.23 AGeV. This can bias the results of the experimental analysis if the number of participant nucleons used is not consistent throughout the analysis and in the final model-to-data comparison. The measurable consequences of this model dependence of the number of participant nucleons are also discussed. In this context, PointNet-based AI models are developed to accurately reconstruct the impact parameter or the number of participant nucleons in a collision event from the hits and/or reconstructed track of particles in 10 AGeV Au-Au collisions at the CBM experiment. In the last part of the thesis, different AI methods to study the equation of state (EoS) at high baryon densities are discussed. First, a Bayesian inference is performed to constrain the density dependence of the EoS from the available experimental measurements of elliptical flow and mean transverse kinetic energy of mid rapidity protons in intermediate energy collisions. The UrQMD model was augmented to include arbitrary potentials (or equivalently the EoSs) in the QMD part to provide a consistent treatment of the EoS throughout the evolution of the system. The experimental data constrain the posterior constructed for the EoS for densities up to four times saturation density. However, beyond three times saturation density, the shape of the posterior depends on the choice of observables used. There is a tension in the measurements at a collision energy of about 4 GeV. This could indicate large uncertainties in the measurements, or alternatively the inability of the underlying model to describe the observables with a given input EoS. Tighter constraints and fully conclusive statements on the EoS require accurate, high statistics data in the whole beam energy range of 2-10 GeV, which will hopefully be provided by the beam energy scan programme of STAR-FXT at RHIC, the upcoming CBM experiment at FAIR, and future experiments at HIAF and NICA. Finally, it is shown that the PointNet-based models can also be used to identify the equation of state in the CBM experiment. Despite the uncertainties due to limited detector acceptance and biases in the reconstruction algorithms, the PointNet-based models are able to learn the features that can accurately identify the underlying physics of the collision. The PointNet-based models are an ideal AI tool to study heavy-ion collisions, not only to identify the geometric event features, such as the impact parameter or the number of participant nucleons, but also to extract abstract physical features, such as the EoS, directly from the detector outputs.