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Physics-regularized Machine Learning To Approximate 3D Ideal-MHD Equilibria At Wendelstein 7-X
(2024)
The magnetohydrodynamic (MHD) equilibrium model is one of the fundamental building blocks in the description of a magnetically confined plasma. The computational cost of constructing solutions to the 3D ideal-MHD equilibrium problem is one of the limiting factors in stellarator research and design; in particular, it limits the extent to which we can perform sample-intensive applications, applications which require many samples to be evaluated to yield meaningful results. Sample-intensive applications in stellarator research and design include, for example, equilibrium reconstruction, stellarator optimization, and flight simulators. In this thesis, we investigate how faithfully artificial neural networks (NNs) can quickly approximate ideal-MHD equilibria in stellarator geometries, starting with Wendelstein 7-X (W7-X), the world’s most advanced stellarator. In particular, we investigate (see section 1.7):
RQI: to what extent can NN models approximate the MHD equilibrium solution for different W7-X configurations and plasma profiles? What
is the speed-accuracy trade-off offered by NN models?
RQII: to what degree the NN model faithfully reproduces equilibrium quantities of interest (e. g., MHD stability)? To what extent can NN models meet the requirements of downstream applications (e. g., Bayesian
inference, stellarator optimization) in terms of equilibrium quantities
accuracy?
RQIII: whether we can exploit the implicit representation of a MHD equilibrium, i. e., the equilibrium solution should satisfy the ideal-MHD force
balance equation, to improve the NN approximation’s accuracy;
RQIV: the reconstruction of the full posterior istribution of plasma parameters and equilibrium quantities with self-consistent MHD equilibria; moreover, how does the adoption of MHD equilibria approximated by NN models affect the inferred plasma parameters?
A deep NN model is developed to learn the ideal-MHD solution operator in W7-X operational subspace, yielding 3D equilibria up to six orders of magnitude faster than currently available MHD equilibrium codes. Physics domain knowledge is embeded into the NN model: equilibrium solution symmetries are satisfied by construction, and the MHD force balance regularizes the NN model to satisfy the ideal-MHD equations. The model accurately predicts the equilibrium solution and it faithfully reproduces global equilibrium quantities and proxy functions used in stellarator optimization. Finally, the developed fast NN equilibrium model has been applied in downstream applications to obtain W7-X configurations with improved fast-particle confinement and to infer plasma parameters with self-consistent MHD equilibria at W7-X.
An already existing shortage of nurses was exacerbated by the COVID-19 pandemic. Inactive (former) nurses were regarded as a so-called silent reserve and were called upon by various agencies to volunteer for nursing. The question arose as to what factors might encourage or hinder such volunteering and facilitate deployment.
First, inactive nurses were asked via an online survey whether they had registered for deployment or not and what the reasons were for this decision. Further information on professional background was collected, including the reason for having left the profession in the first place. Based on the results of the online survey, focus group discussions were conducted with registered and unregistered inactive nurses, with nurses who had returned to the profession permanently, and with care home managers.
Only one third of the participants in the online survey said they had registered for a temporary assignment during the pandemic. The main reasons for registering were that inactive nurses ‘wanted to do their bit’ to manage the crisis, felt it was their duty and/or felt a sense of belonging to the nursing profession. The main reasons given for not having registered was that respondents ‘could not see a reason at the moment’, had health concerns, and ‘other relevant job commitments’. The majority of respondents still had jobs related to health, care or nursing.
The topics covered in the focus group discussions included the following: perception of the pandemic as a crisis, identity as a nurse and sense of professional commitment, role of current occupation in the decision to register, winning over inactive nurses with a very negative attitude towards returning to care during a crisis situation, support measures and offers regarding a deployment in nursing.
Both in the online survey and in the focus group discussions, a sense of belonging to the nursing profession was evident among many participants. However, this identity does not necessarily lead to a willingness to return to nursing during a crisis situation. Weighing up the risk of deployment against the positive or negative experiences gained during the active period can influence willingness. However, the possibility of taking a break from current work and returning to nursing at short notice is not always given. Many inactive nurses continue to work in the health sector and fulfil equally important tasks during a crisis situation which render them unavailable for deployment.
Different kinds of support for those willing to return to nursing during a crisis situation and communication on conditions of deployments need to be implemented and continuously improved to offer the inactive nurses the greatest possible security and to enable a largely unbureaucratic deployment.
Materials and Methods:
Literature search was conducted using electronic MEDLINE/ Cochrane databases, relevant references, citations and hand search was conducted. Academic Colleges were contacted to identify relevant studies and full texts. Inclusion Criteria were Randomized clinical trials, human cohort and case series reporting increasing vertical dimension and restoring worn dentition in adults suffering from tooth wear using fixed, minimal invasive and adhesive techniques.
The search period spanned from 2000 up to January 2023. Of the 550 articles identified, 111 went throw full text screening for eligibility and 12 studies were included in our study.
Failure, follow-up period for all the studies were assessed. Attrition , Bruxism, increase of vertical dimension rates and mean time of failure were calculated using random effect models.
Results:
Tooth wear was reported equally in anterior and posterior region, and restorations were done in direct and indirect manners, mostly with pre-evaluation of the needed increase of vertical dimension. The mean of increased vertical dimension was 2.3 mm. The mean observation time of the restorations was 41.3 months with a minimum observation period of 12 months and a maximum of 84 months. Failure rate of all the included studies was 9.9% (95% CI: 91.00 % to 95.80%) high heterogeneity was detected in Failure rate with I2 of (93.85). Time to fail was calculated to be 37.5 months for 2458 cases (95% CI:32.32 to 91.13%). A fixed effect model was performed to calculate the event of increasing vertical dimension , the event rate was 81.72% (95% CI: 0.00 to 88.10%).
Conclusion:
The performance of direct and indirect restorations is satisfactory, and the failure rate is low, which leads us to conclude that these non-invasive restorations are a reliable and cost-effective middle-term treatment method to restore vertical dimension in moderate to severe worn dentition.
Conflict of interest: None
Clear cell renal cell carcinoma is the most frequent malignant kidney tumor in adults. It is often associated with biallelic VHL mutations. We characterized our cell lines according to their HIF expression pattern. Cell lines RCC4, UOK-220 and CaKi-2 were assigned to subtype H1H2, cell lines 786-O and A-498 were assigned to subtype H2 and cell lines CaKi-1 and Rc-124 were assigned to subtype VHLwt.
Previous work of our group had shown, that p53 can be activated in ccRCC following irradiation but is not able to induce apoptosis. An important link to p53 activity with strong antiapoptotic qualities is the NFB pathway, which can be activated e. g. by irradiation.
We irradiated the three subtypes previously established as well as two control cell lines, SAOS-2 (p53 negative cell line) and HEK 293 (contains functioning p53) with 2 Gy and 10 Gy and analyzed several proteins of the pathway by using western blots. Several target genes with antiapoptotic qualities were analyzed by using rt-PCR.
We found, that out of the cell lines analyzed, both control cell lines (SAOS-2, HEK 293) showed the strongest response (activation of the NFB pathway) following irradiation. Among the three ccRCC subtypes the VHLwt cell lines showed the strongest response. H2 cell lines showed almost no response at all.
A connection between the missing ability of p53 to induce apoptosis and an induction of transcription factors by the NFB pathway could not be determined. We also could not determine biological differences between the subtypes.
We analyzed, whether any NFB proteins were present in the nucleus following irradiation and found, that only p50 homodimers were present in the nucleus. This might point towards p50 homodimers, which have been described to have different characteristics than heterodimers. More research is needed to analyze this important finding.
Recent experimental campaigns in the Wendelstein 7-X stellarator, a
plasma-confining device designed to investigate the Magnetic Confinement Fusion
(MCF) approach to generating electrical power, have shown that the injection of
fuelling pellets had an unexpected and considerable impact on the performance of
the plasma. Rather than simply refuelling the device and `diluting' the plasma
energy, pellet injection is followed by a significant increase in the ratio of
the ion temperature to the electron temperature. It has been suggested that this
is not merely due to the improved confinement following the reduction of
turbulent transport after the pellet material has homogenised with the bulk
plasma, but also due to a direct transfer of energy from electrons to ions. The
proposed mechanism for this energy transfer is the ambipolar expansion of the
pellet plasmoid, the localised plasma structure produced by the
ionisation of ablated pellet material, along magnetic field lines.
Early work on pellet plasmoid expansion predicted that half the heating power
deposited in plasmoid electrons by collisions with hot ambient electrons is
transferred to plasmoid ions in the form of flow velocity as the plasmoid
expands. The complicated nature of the system of the pellet plasmoid embedded in
the ambient plasma, particularly the behaviour of electrons, which experience
many collisional and collisionless phenomena on multiple disparate timescales,
means that early models of the expansion were not wholly self-consistent, but
rather made use of strong approximations that apply in some regions of the
plasmoid but not in others. For example, only electrons and ions associated with
the plasmoid were rigorously treated, meaning that the framework was one of
`expansion into vacuum'. Combined with the assumption of Maxwellian electrons,
this led to an electric potential that was unbounded at infinity. Naturally, the
validity of the conclusions of such a model are called into question because the
approximations lose their validity far from the plasmoid and as time advances,
yet predictions about the final state of the plasma are desired. A deeper
investigation is required: careful consideration of the phenomena in question
and the timescales (and lengthscales) on which they act must be made in order to
rigorously construct a model that is valid throughout the entire expansion.
The first two papers presented in this thesis iterate on the model established
in the paper that first predicted the electron-to-ion energy transfer; their aim
was to find out how the character of the expansion changes with a more
sophisticated and accurate description of various phenomena, while remaining
within the existing framework of expansion into vacuum. Ultimately, we find that
the qualitative character is unchanged, and that approximately half the heating
power deposited in plasmoid electrons is transferred to ions.
Two other papers in this thesis address the limitations of the original model.
This is achieved by properly considering the electron kinetic problem in a
plasmoid. One paper considers the electron kinetic problem when electrons are
highly isotropised. In this case the kinetic equation can be integrated to
remove all but two independent variables, which is the maximum possible
reduction considering it is a time-dependent problem. The full nonlinear
integro-differential Landau self-collision operator is integrated exactly and
few approximations are made, leading to a rather general kinetic equation.
However, for fuelling pellets some anisotropy in the electron distribution is
expected. Another paper considers the electron kinetic problem (and the entire
plasmoid expansion) allowing for electron anisotropy. Careful consideration of
the ordering of timescales of electron phenomena in a pellet plasmoid leads to a
steady-state kinetic problem that we call collisional quasi-equilibrium (QE). QE
appears in many ways similar to the collisional steady-state characterising a
true thermal equilibrium. It was found that the time-dependent kinetic problem
of the earlier paper, with isotropic electrons, produces the QE distribution
function, corroborating the existence of the QE state. We then take moments of
the electron kinetic equation that is valid on the expansion timescale, assuming
that the electron distribution is that given as the solution to the QE kinetic
problem. This is completely analogous to what is done to obtain the Braginskii
equations or any Chapman-Enskog theory. The result is a set of equations for the
long-term evolution of the macroscopic quantities that describe the distribution
function existing in a quasi-steady-state at each point in time. It is from this
point that one may feasibly describe the plasmoid expansion with an accurate
picture of the electron kinetics and finally obtain the electron-to-ion energy
transfer so desired in a rigorous model of the expansion.
From a broader point of view, the two frameworks provided by these rigorous
investigations of the electron kinetic problem serve as a basis for the future
study of plasmoids. Such a `first-principles' approach to plasmoid dynamics is
novel and interesting in its own right, but it will be demonstrated that such an
approach is essential for pellet plasmoids owing to the fact that they are
poorly described by the `standard tools' of plasma physics.
Using the QE framework it was found that, once more, about half the heating
power experienced by plasmoid electrons is transferred to plasmoid ions. The
incredible robustness of the prediction of such an energy transfer is, in the
author's opinion, the result of the self-similar nature of the expansion found
as a solution to the original model. As a rule, the profiles of self-similar
solutions tend to be attractors for the `real', more complicated, system, and
the qualitative predictions involving no parameters, of which the
electron-to-ion energy transfer is one, tend to be very sturdy.
Aside from fuelling pellets, composed of hydrogen or deuterium, one paper in
this thesis investigates the physics of high-Z pellets that are designed to
terminate the plasma safely in the event of a `disruption', where much of the
magnetic field energy is channelled into a runaway electron beam with
potentially disastrous consequences if the beam encounters a plasma-facing
component. The paper draws on the work carried out in the paper concerning the
kinetic problem of isotropised electrons in a plasmoid.
This thesis is `cumulative'; the vast majority of the work carried out is
described within a set of Papers, labelled A-E, placed at the back of the text.
There is a preceding `wrapper text' (given in numbered Sections) tasked with
introducing the reader to the topic, guiding the reader through the papers, and
expounding some of their main results. Some amount of material not present in
the papers is also provided in the wrapper text. Naturally, the wrapper text
mainly focusses on the results of the papers which are under my first
authorship. In the course of publishing papers over an extended period of time
the nomenclature is bound to vary. Although it is mostly consistent between the
papers, a few difference do arise, and the section `Common symbols and
subscripts' is provided in the frontmatter to alleviate confusion. Particular
care should be taken with the symbols x and z; both can refer to the
coordinate parallel to the magnetic field line, but in papers where z is used
for this purpose x tends to have another definition. In the wrapper text the
choice of symbols is generally chosen to reflect those in the corresponding
paper.
With high prevalence and mortality, myocardial infarction constitutes a social and economic burden in Germany and worldwide. Current guidelines for MI treatment require prompt reperfusion to salvage heart tissue and minimize short- and long-term complications. However, there are currently no treatments available to attenuate reperfusion injury. Ischemic as well as pharmacological post-conditioning have been identified as important clinical strategies to improve outcome. Membrane stabilizers, like Poloxamer 188 (P188), have been shown to improve myocardial ischemia reperfusion (IR) injury and mitochondrial function but have not yet been proven to directly offer mitochondrial protection. Mitochondrial function is crucial for cardiomyocyte function, and mitochondrial dysfunction plays an important role in myocardial injury.
In this study, hearts from 79 Sprague Dawley rats were isolated and perfused ex-vivo with oxygenated Krebs Buffer for 20 min before 30 min of no-flow ischemia. Hearts were reperfused for 10 min with Krebs buffer or 1 mM P188. Cardiac mitochondria were isolated with 1 mM P188 vs 1 mM polyethylene glycol (PEG) vs vehicle by differential centrifugation. Mitochondrial function was assessed as adenosine triphosphate (ATP) synthesis, oxygen consumption and calcium retention for complex I and II substrates of the respiratory chain.
An improvement of myocardial function with 10 min P188 post-conditioning could not be shown. Direct mitochondrial protection of P188 or PEG could not be observed in this model either. Further research is needed to ascertain whether P188 has a direct protective effect on mitochondria and, if so, on what pathways of IR injury it acts.
In den Weltmeeren findet rund die Hälfte der jährlichen globalen Kohlenstofffixierung statt, davon ein großer Anteil in küstennahen Regionen. Hier kommt es zu wiederkehrenden saisonalen Algenblüten, die durch eine zeitlich begrenzte explosionsartige Vermehrung von Mikroalgen (hauptsächlich Diatomeen und Coccolithophoren) charakterisiert sind. Vor allem Frühjahrsblüten (März-Mai) haben aufgrund ihrer zeitlichen und räumlichen Vorhersagbarkeit einen hohen Stellenwert als Modellsysteme, anhand deren sich der Kohlenstoffkreislauf der Meere untersuchen lässt.
Mikroalgen produzieren eine große Vielfalt an Makromolekülen, die für die mit ihnen vergesellschafteten Bakterien als Nahrungsgrundlage dienen. Besonders im Fokus stehen hier die für den Kohlenstoffkreislauf relevanten Polysaccharide. Im Gegensatz zu anderen natürlichen Makromolekülen wie DNA oder Proteinen können Polysaccharide aus vielen verschiedenen Monomeren mit unterschiedlichsten Bindungen bestehen. Zusätzlich finden sich an diesen Zuckermonomeren viele Modifikationen wie Acetylierungen, Methylierungen oder Sulfatierungen, die die Komplexität weiter erhöhen. Diese Variabilität bedingt eine hohe strukturelle und funktionale Diversität. So können Polysaccharide Speicherstoffe, Zellwandbestandteile oder Teile der extrazellulären Matrix darstellen.
Komplementär hierzu besitzen Polysaccharid-verwertende Bakterien entsprechend komplexe, enzymatische Abbaumechanismen. Besonders hervorzuheben sind hier die Bakterien des Phylums Bacteroidota, die sich in verschiedensten Nischen auf den Abbau von Polysacchariden spezialisiert haben. Sie finden sich in Bodenproben, als Teil der menschlichen Darmflora, oder eben auch als bedeutende Begleiter von Algenblüten.
Bacteroidota (und in marinen Systemen hauptsächlich die zu ihnen gehörenden Flavobakterien) besitzen zum Abbau diverser Polysaccharide sogenannte Polysaccharide utilization loci (PULs), genomische Inseln, die alle notwendigen Proteine zur Aufnahme und Abbau eines bestimmten Polysaccharids codieren. Hierzu gehören hochspezifische Enzyme (Carbohydrate-active enzymes, CAZymes), transkriptionelle Regulatoren sowie Transportersysteme, die initial gespaltene Oligosaccharide über die Membran in das Bakterium transportieren, wo sie von weiteren Enzymen vollständig abgebaut werden. Diese Co-Lokalisation der benötigten Gene und deren gemeinsame Regulation stellt einen enormen Selektionsvorteil der Bacteroidota dar und ist der Grund, warum sie, ähnlich wie Algen, einer jährlich wiederkehrenden Sukzession folgen, die sich gut untersuchen lässt.Die Forschungsartikel, die Teil dieser Doktorarbeit sind, untersuchen das Zusammenspiel von Polysaccharid-produzierenden Algen mit den Bakterien, die sie abbauen, aber auch darauf basierende Beziehungen der Bakterien untereinander. Die erste Publikation beschäftigt sich mit dem weit verbreiteten Speicherpolysaccharid α-Glucan, für das der Großteil der blütenbegleitenden Bakterien einen spezifischen aktiven PUL besitzt. Eine Untersuchung der in der Blüte vorhandenen Algenarten bestätigte, dass die Blüte von β-Glucan-produzierenden Algen dominiert wird. Da Bakterien aber selbst α-Glucane als Speicherpolysaccharide verwenden, konnte gezeigt werden, dass nicht die Algen selbst, sondern die Bakterien Hauptproduzent dieser Polysaccharide während einer Phytoplanktonblüte sind. Bakterielle Proteine, die dem Abbau von Algen-β-Glucan und dem daraus folgenden Aufbau von bakteriellem α-Glucan dienen, waren in Umweltproben und in Laborkulturen unter ähnlichen Bedingungen abundant. Die Untersuchung von extrahiertem bakteriellem Polysaccharid bewies, dass dieses nicht nur α-Glucan enthält, sondern dass dieses Polysaccharid auch in der Lage war, α-Glucan PULs mariner Bakterien zu induzieren. Hier zeigte sich ein innerhalb des marinen Kohlenstoffkreislaufs bisher wenig berücksichtigter Kreislauf, indem Bakterien Polysaccharide anderer Bakterien nutzen, die z.B. durch Viren lysiert wurden.
Die anderen zwei Artikel dieser Arbeit befassen sich mit dem Abbau von Zellwandpolysacchariden durch blütenassoziierte Modellbakterien. In einer der Studien wird detailliert der Abbau eines β-Mannans (ein Polysaccharid das hauptsächlich aus dem Monosaccharid Mannose besteht) durch ein Bakterium des Genus Muricauda beschrieben. Die PUL-Struktur dieses Bakteriums kam in mehreren anderen Phytoplanktonblüten-assoziierten Bakterien vor. Diese Beobachtung wies darauf hin, dass es sich hier um ein Mannan mit zusätzlichen Galactose- und Glucose-Substitutionen handelte. Proteom-Untersuchungen bestätigten, dass das Bakterium derartige Substrate unter Induktion des β-Mannan-PULs nutzen können. β-Mannan konnte durch Antikörpermarkierung in Blütenproben sowie spezifischen Mikroalgenarten (Chaetoceros, Coscinodiscus) nachgewiesen werden. Die in dieser Publikation charakterisieren β-Mannan-PUL-codierten Enzyme waren in der Lage, dieses Signal zu löschen, was bewies, dass Muricauda sp. Mannan-basierte Zellwandpolysaccharide bestimmter Arten von Mikroalgen abbauen kann.
Die dritte Studie geht näher auf den Abbau von Xylanen (bestehend aus Xylose) durch ein blütenassoziiertes Bakterium des Genus Flavimarina ein. In diesem Bakterium wurden anhand der enthaltenen Xylanasen zwei putative Xylan-PULs annotiert. Wachstumsexperimente und Proteom-Untersuchungen zeigten, dass einer dieser PULs hauptsächlich bei Wachstum auf Glucoronoxylan induziert wird, während der andere PUL aufArabinoxylane stärker reagierte. Untersuchung der PUL-CAZymes bestätigte diese Ergebnisse durch Charakterisierung mehrerer Xylanasen sowie Glucoronidasen und Arabinofuranosidasen. Zusätzlich codierten beide PULs für Esterasen, die eine Modifikation der natürlichen Substrate durch Acetylierungen oder Methylierungen nahelegen. Da all diese Merkmale von terrestrischen Xylanen geteilt werden und in Blütenproben aus Küstennahen Regionen Xylane nachgewiesen wurden, ist es möglich, dass Bakterien aus solchen Regionen sowohl Xylane terrestrischen Ursprungs (z.B. durch Flusseinspeisung) sowie marinen Ursprungs abbauen können.
Our study examined whether potentially critical indications from depression questionnaires, interviews, and single items on suicidal ideation among partici-pants in a large prospective population-based study are related to short-term sui-cides within one year. For this purpose, we studied the association between (a) the severity of depressive symptoms according to the M-CIDI and the PHQ-9, BDI-II, and CID-S depression screening and (b) elevated scores on single sui-cidal ideation items and mortality according to claims databases.
In the baseline cohort, the frequency of depressive symptoms measured by CID-S was 12.90% (SHIP-START-0). The frequency for “Moderate” to “Severe de-pression” measured by the PHQ-9 (≥ 10 points) and BDI-II (≥ 20 points) ques-tionnaires ranged from 5.40% (SHIP-LEGENDE) to 8.80% (SHIP-TREND Morbid-ity follow-up). The 1-month prevalence of unipolar depression, measured by the M-CIDI in SHIP LEGENDE, was 2.31%.
Between 5.90% (SHIP-TREND Morbidity follow-up) and 6.60% (SHIP-LEGENDE) of respondents showed a certain degree of suicidal ideation in the two weeks preceding the assessment, according to BDI-II and PHQ-9.
Our results show the high frequency of depressive symptoms in the study region, with women being affected more frequently than men, especially in the higher categories. Furthermore, women were more frequently affected by suicidal idea-tion, although this difference was not evident in the highest categories.
There was one potential suicide in the year after a SHIP examination.
From our results, we cannot conclude that severe self-reported symptoms from depression questionnaires should be reported back to participants of an obser-vational population-based study to prevent suicide deaths within one year.
The maintenance of protein homeostasis in muscle by degradation systems, e.g. the autophagy lysosomal pathway (ALP) and the ubiquitin-proteasome system (UPS), is of great importance. It prevents the accumulation of nonfunctioning and not properly folded proteins, which can lead to protein aggregate myopathies (PAMs) and several other protein storage diseases. Degradation by the UPS depends on the transfer of ubiquitin to a target protein. This happens in a cascade of E1-E2-E3 proteins. This process is also involved in protein location and regulation of protein activity. E3 ligases are often tissue specific. Muscle RING-finger proteins (MuRFs) are a family of really interesting new gene (RING)-Finger E3 ubiquitin ligases, that are almost exclusively expressed in the striated muscle. They play a role in muscle wasting, but are also important for the maintenance of the structure of striated muscle. MuRF proteins are also involved in the regulation of the striated muscle energy metabolism. Previous work has demonstrated that MuRF1/MuRF3 DKO mice show a protein surplus myopathy characterized by an accumulation of myosin heavy chain proteins in striated muscles and a reduction in function of both heart and skeletal muscle. The aim of this study was to test the hypothesis that the myopathic phenotype of MuRF1/MuRF3 DKO mice is mediated by a disturbed energy homeostasis in the heart and skeletal muscle, with focus on mitochondrial function. Because sex-specific differences have not been investigated in these mice so far, a further aim was to investigate any differences between male and female mice.
To test these hypotheses, we measured the weight of the heart and the hindlimb muscles tibialis anterior and soleus to detect a possible hypertrophy in the DKO mice. Hematoxylin and eosin staining of histological cross sections of the tibialis anterior were performed to investigate protein accumulations. Muscle function was quantitated via grip strength and specific force measurements. Possible changes in protein amounts were detected via mass spectrometry analyses and western blot analyses. Changes in gene expression were investigated by qRT-PCR. Coimmunoprecipitation was used to determine direct interactions between proteins. Protein stability and ubiquitination were investigated by cycloheximide (CHX) and ubiquitination assays, respectively.
DKO mice showed an increase in heart and skeletal muscle weights. Grip strength assays revealed limb weakness of DKO mice. H&E staining of histological cross sections of the tibialis anterior muscle (TA) showed protein aggregates within myofibers. Mass spectrometry analyses of proteins isolated from TA and heart muscle revealed an increase of muscle stress markers and structural proteins in DKO mice, while proteins involved in the energy metabolism were reduced. Especially interesting here were the proteins of the mitochondrial electron transport chain (ETC), which play a major role in the energy production of the mitochondria by catalyzing the phosphorylation of ADP to ATP, the universal energy carrier in all living organisms. These changes were more pronounced in TA compared to heart. Western blot and qRT-PCR results of ETC subunits supported our proteome data. They also revealed a sex-specific difference, in which the reduction ETC subunits was more pronounced in females than males. In female
TA NDUFB8, SDHB, UQCRC2, MTCO1 and ATP5 were significantly reduced compared to controls, while only UQCRC2 and ATP5 were decreased in male TA compared to controls. A significant reduction in gene expression of Ndufb8, Sdhb, Mtco1 and Atp5 was detected in TA of female mice compared to controls, while only Ndufb8, Sdhb and Atp5 were decreased in male TA compared to controls. We observed the same pattern in Heart of male (protein: NDUFB8; mRNA: Mtco1) and female (protein: UQCRC2, MTCO1, ATP5; mRNA: Sdhb, Mtco1) DKO mice compared to their controls. The reduction in ETC subunits was paralleled by a reduction in complex I and complex III activity in the TA of DKO mice, but not in heart. However, this was only significant in the TA of female but not male mice. Mechanistical analyses using coimmunoprecipitation, cycloheximide chase and ubiquitination assays showed that MuRF1 physically interacted with the transcriptional repressor histone deacetylase 5 (HDAC5), mediated its ubiquitination as well as its UPS-dependent degradation. The absence of MuRF1 and MuRF3 in DKO mice let to an increase in the amounts of HDAC5 in TA. Because HDAC5 binds to PGC-1α, the master regulator of mitochondrial biogenesis (encoded by Ppargc1a), we investigated its gene expression in DKO muscle and found it to be reduced.
These data connect MuRF1 and MuRF3 directly to the striated muscle energy metabolism, by regulating mitochondrial function. The results provide insights into the development of PAMs and possibly other protein storage diseases, where a decrease of mitochondrial function has already been described.
Ecological Impacts and Phenotypic Plasticity of a Global Invasive Cactus, Opuntia ficus-indica
(2023)
Biological invasions by non-native species pose one of the major threats to biodiversity, the way ecosystems function, and the well-being of humans. These invasions can occur through various means, including accidental or intentional introductions by humans, natural dispersal, and climate change. Non-native species can harm the native species and ecosystems, by homogenizing plant communities, competing for resources, changing how the ecosystem operates, and eventually causing native species to go extinct. Even though not all non-native species become invasive, changes in climate and ecosystems can cause the successful establishment and spread of non-native species. Despite the advancements in our understanding of biological invasions in recent years, research has been biased towards temperate regions, whereas arid and semi-arid regions that are highly impacted by climate change are underrepresented. Thus, particularly focusing on the impacts of biological invasions in subtropical arid and semi-arid regions, the goal of this PhD project was to explore the effects of an invasive cactus on the local native communities and investigate the mechanisms of its successful invasion. Certain species are found to take advantage of the ever-drying climates in the arid/ semi-arid regions of the world. Opuntia ficus-indica, native to Mexico, is an exceptionally successful drought-tolerant invasive cactus that successfully grows in these regions. O. ficus-indica, a most widespread invasive cactus, is considered an ecosystem engineer as it modifies the habitats of indigenous plant species and dependent animals. This project aimed to identify the ecological impacts of O. ficus-indica in the highlands of Eritrea, the competitive potential of O. ficus-indica and the plastic changes that enabled its spread and invasion (Chapters I-III). For this purpose, field observations and common garden experiments were carried out throughout the project.
We investigated the effects of Opuntia ficus-indica on the spatial diversity of native plant communities (Chapter I), its competitive ability against native species (Chapter II) and the phenotypic plasticity of O. ficus-indica (Chapter III). To investigate the main ecological effects of O. ficus-indica on the native community, field data was collected from the highlands of Eritrea and comparisons were made between O. ficus-indica invaded and noninvaded areas (Chapter I). The study aimed to understand the effects of O. ficus-indica by examining species composition, richness, and diversity across vegetation layers and revealed that O. ficus-indica homogenises the species composition of the native ecosystem. This provides evidence that the presence of O. ficus-indica reduces landscape-level heterogeneity or spatial diversity. However, O. ficus-indica did not influence the species richness and diversity of the local communities. The mechanisms of the successful homogenisation of the local communities by O. ficus-indica were attributed to the potential competitive abilities of O. ficus-indica against the native species, and the plastic and adaptive traits it developed in the non-native ranges. The first assumption was tested by setting up a common garden competition experiment between two native Eritrean species, Ricinus communis and Solanum marginatum (Chapter II). The experiment used two water availability treatments, wet and dry, and categorized plants into intraspecific (native or invasive only) and interspecific (native and invasive) competition. The study evaluated the impacts by comparing the growth of O. ficus-indica alone to the growth alongside native species which revealed the weak competitive potential of O. ficus-indica. However, O. ficus-indica was observed to outgrow the native species in several folds which can be attributed to its successful invasion. The second assumption of the successful spread of O. ficus-indica was attributed to the phenotypic plastic traits adapted by O. ficus-indica in the non-native ranges (Chapter III). The phenotypic plasticity of O. ficus-indica was assessed by exposing it to water stress across dry and wet environments. The species were cultivated from a diverse set of 12 populations, encompassing its native range in Mexico with three cultivars and nonnative ranges in Africa (Algeria, Eritrea, Ethiopia), the island of Madeira off the coast of Africa, and in Europe, Italy with two cultivars and in Portugal from three sites. In Mexico and Italy, we collected various cultivars to ensure a wide representation of genotypes. We found that the species originating from the native range of O. ficus-indica exhibited lower plasticity to conditions of elevated water availability. Furthermore, a trial gradient experiment on O. ficus-indica was conducted to determine the appropriate watering levels for the species and the experiment revealed not only the species' capacity to endure a lack of water for nine months but also its ability to withstand prolonged waterlogged conditions.
This thesis illustrates the fact that invasive species are a major threat to biodiversity and ecosystem functioning worldwide, especially in rarely studied regions with dry climates and limited resources. How can invasive plants spread and cause negative impacts on native ecosystems (Chapter I), despite their weak competitive abilities (Chapter II)? This thesis explored these questions by examining the case of O. ficus-indica, an invasive species in arid/ semi-arid climates (Chapter I). It showed that O. ficus-indica has a high growth potential that allows it to overcome resource limitations, that its growth is not affected by competition from native species (Chapter II), and that it exhibits adaptive plasticity that enhances its invasion success in different environments (Chapter III). This thesis revealed the complex mechanisms and consequences of biological invasions in dry climates and contributes to the understanding of invasive species. It also suggests that more research is needed in understudied regions to assess the impacts of O. ficus-indica or invasive species in general on native biodiversity and ecosystem services and to identify the factors that influence the competitive and adaptive potentials.
During infections, innate immune cells are crucial for initiating a pro-inflammatory immune response and clearing the invading pathogen. Delay in pathogen clearance or initiation of an immune response due to impaired functionality of immune cells can result in devastating consequences. The cellular compartment of the innate immune system comprises an array of specialized cell types: Macrophages are tissue-resident professional phagocytes that clear cellular debris, pathogens, and foreign objects. Dendritic cells (DCs) are immune sentinels specialized in antigen uptake and subsequent T cell priming. They are primary sources of cytokines in response to infection. Neutrophils are efficient effector cells that respond rapidly to infection and clear bacteria by different mechanisms. If effector mechanisms of these cells are affected by either bacterial or other factors, infections might not be resolved and can spread throughout the host. Cobalt-chromium-molybdenum biomaterial is widely used in arthroplasty. Implant-derived wear particles and ions lead to macrophage-driven adverse local tissue reactions: Such reactions have been linked to an increased risk of periprosthetic joint infection after revision arthroplasty. While metal-induced cytotoxicity is well characterized in human macrophages, direct effects on their functionality remain elusive. In Paper I, we show that local peri-implant tissue is exposed to Co and Cr in situ. Influx of macrophages is also evident. Exposure of isolated human monocytes/macrophages to Cr3+ in vitro had only minor effects. However, exposure of monocytes/macrophages to pathologic concentrations of Co2+ significantly impaired both phenotype and functionality. High concentrations of Co2+ induced loss of surface markers, including CD14 and CD16. Both Co2+ and Cr3+ impaired macrophage responses to Staphylococcus aureus infection. Co2+ -exposed macrophages, in particular, showed decreased phagocytic activity. These findings demonstrate the immunosuppressive effects of locally elevated metal ions on the innate immune response. Streptococcus pyogenes (group A streptococcus, GAS) causes a variety of diseases ranging from mild to severe necrotizing soft tissue infections (NSTIs). In the host environment hypervirulent GAS variants carrying mutations within the genes encoding for control of virulence (Cov)R/S two component system are enriched. This adaptation is associated with loss of SpeB secretion. In Paper II, we show that in vitro infections with hyper-virulent GAS variants harboring dysfunctional CovR/S suppress secretion of IL-8 and IL-18 by human monocytic cells. This phenotype was mediated by a caspase-8 dependent mechanism. Knockout of streptococcal SLO in a GAS strain carrying functional CovR/S even increased secretion of IL1β and IL-18 by moDCs. Of 67 fully sequenced GAS NSTI isolates, 28 contained covS or covR mutations that rendered the TCS dysfunctional. However, no differences in systemic IL-8 and IL-18 were detected in these patients. GAS isolates recovered from patients often display a mixed phenotype, consisting of SpeB positive (SpeB+ ) and SpeB negative (SpeB- ) clones. Irreversible loss of SpeB expression is often caused by loss of function mutations in regulatory components (CovR/S, RopB). Loss of SpeB is often associated with hyper-virulence. In Paper III, we show that the host environment induces transiently abrogated secretion of SpeB by GAS. Tissue inflammation, neutrophil influx, and degranulation correlated with increased frequencies of SpeB- GAS clones. Isolates recovered from tissue expressed but did not secrete SpeB, which was reversible. Neutrophilderived ROS were identified as the main factor responsible for abrogated SpeB secretion. Hyper-virulent SpeB- clones also exhibit better survival within and induce excessive degranulation of neutrophils.
Convolutional Neural Network-based image classification models are the current state-of-the-art for solving image classification problems. However, obtaining and using such a model to solve a specific image classification problem presents several challenges in practice. To train the model, we need to find good hyperparameter values for training, such as initial model weights or learning rate. However, finding these values is usually a non-trivial process. Another problem is that the training data used for model training is often class-imbalanced in practice. This usually has a negative impact on model training. However, not only is it challenging to obtain a Convolutional Neural Network-based model, but also to use the model after model training. After training, the model might be applied to images that were drawn from a data distribution that is different from the data distribution the training data was drawn from. These images are typically referred to as out-of-distribution samples. Unfortunately, Convolutional Neural Network-based image classification models typically fail to predict the correct class for out-of-distribution samples without warning, which is problematic when such a model is used for safety-critical applications. In my work, I examined whether information from the layers of a Convolutional Neural Network-based image classification model (pixels and activations) can be used to address all of these issues. As a result, I suggest a method for initializing the model weights based on image patches, a method for balancing a class-imbalanced dataset based on layer activations, and a method for detecting out-of-distribution samples, which is also based on layer activations. To test the proposed methods, I conducted extensive experiments using different datasets. My experiments showed that layer information (pixels and activations) can indeed be used to address all of the aforementioned challenges when training and using Convolutional Neural Network-based image classification models.
Hepatitis E virus (HEV) is emerging worldwide as a zoonotic pathogen that has remained largely undetected for decades, if not centuries. Its enormous success can be attributed to the wide range of host species, which can transmit the virus to humans, depending on the viral genotype. As a result, HEV is likely to remain a challenge even when the remaining hepatitis viruses (HAV, HBV, HCV), which are transmitted exclusively between humans, are under control. Although millions of HEV infections occur each year, little is known about this puzzling pathogen. One major issue in HEV research is the lack of reliable model systems. Established animal models are inefficient, expensive, or simply not representative of human HEV. On the other hand, cell culture systems are limited by the slow growth of the virus and inefficient replication and infection. The aim of this work is to with deepen the understanding of zoonotic HEV in animal hosts in Germany. For this purpose, a molecular and phylogenetic characterization of HEV sequences from rabbits and swine was conducted. A novel subtype of the zoonotic genotype HEV-3 was identified in a rabbit sample, further emphasizing the role of rabbits as HEV host species and possible reservoir of zoonotic HEV infections in Germany. On the other hand, a molecular biological screening of pigs and wild boars in Mecklenburg-Western Pomerania indicates a wide range of HEV-3 subtypes circulating in swine in north-east Germany. Furthermore, an optimized replicon system was established in order to enable characterization of various HEV sequences by reverse genetics. As a proof of concept, two rabbit HEV derived replicons were compared with two established, cell culture adapted HEV strains. The influence of different regions of the nonstructural protein on HEV replication was determined and quantified. In particular, a system was established, to reproducibly compare different strains and genotypes. This refined replicon system will enable the characterization of further HEV sequences and thus expand the knowledge on the determinants of the viral life cycle.
In their idealized forms, enzymes can facilitate complex reactions with extreme specificity and selectivity. Additionally, in this imaginative form, they only require mild reaction conditions, resulting in low energy consumption, and they are biodegradable, efficient, reusable, and sustainable. Unfortunately, this idealized form often deviates significantly from reality, where enzymes are more likely to be associated with marginal stability and low reaction rates, leaving them less than desirable for many industrial applications. As such, if we could master the process of engineering the configuration of a protein towards a given task, the implications could be staggering.
This thesis aims to contribute to the process of protein engineering, mainly how computational tools can be used to make the protein engineering process more efficient and accessible.
Article I explores the current state of the art in machine learning-guided directed evolution and serves as a foundation for Article II, which is a concrete application of these techniques to an engineering campaign. Despite successfully improving overall activity and selectivity, we also observe limitations and constraints within the methodology. Article III then delves into these drawbacks and attempts to lay the foundation for a more generalizable and, more importantly, efficient engineering workflow, balancing the strengths and weaknesses of computational techniques with advances in gene synthesis. We then validated this novel pipeline in Article IV, where we show the potential of this methodology. Article V describes a more standard protein engineering campaign on squalene-hopene cyclases for potentially interesting products in the flavor and fragrance industry. Lastly, Article VI outlines a PyMol plugin for molecular docking.
The combination of the Layer-by-Layer (LbL) method, a nano-material such as carbon nanotubes (CNTs), and charged polyelectrolytes (PEs) is a reliable approach to produce highly functionalized surface coatings. These coatings are stable, controllable, ultra-thin, and most importantly, biocompatible. The ability to tune their properties by varying the preparation conditions and the terminating layer opens up a wide range of applications in the fields of biology and medicine. Here, the goal was to create electrically conductive coatings on which cells grow and proliferate. To achieve this goal, a coating with a stable conductive film structure, a suitable film surface topography, and suitable surface potential (and 𝜁-potential) must be prepared.
At the beginning of this thesis, the focus was on the fabrication of electrically conductive multilayer films, whose electrical properties should be stable and adjustable in a controlled manner (Article 1). The combination of chemically modified CNTs as polyanions, a strong linear polycation like poly(diallyldimethylammonium chloride) (PDADMA), and the LbL-method allowed us to prepare such films. Their characterization was carried out in air at ambient conditions. Since PDADMA is non-conductive, the charge transfer within the film and thus the electrical conductivity itself depends mainly on the CNTs and their arrangement. It was found that four CNT/PDADMA bilayers (BL) were always necessary to create a lateral network structure with multiple CNT crossing points to enable and support electron transport within the film. Moreover, additional CNT/PDADMA BL resulted in decreasing sheet resistance, while the conductivity remained constant at ≈ 4 kS/m regardless of the number of bilayers. Increasing the PDADMA molecular weight (Mw) from 44.4 kDa to 322 kDa did not affect film properties such as thickness or electrical conductivity.
However, increasing the CNT concentration from 0.15 mg/ml to 0.25 mg/ml in the deposition suspension resulted in thicker and less conductive films. This is attributed to a faster adsorption process of the CNTs leading to more adsorption sites for the polycation. We found an increased PDADMA monomer/CNT ratio compared to films prepared with the lower CNT concentration in the deposition suspension. The electrical conductivity decreased by a factor of four down to 1.1 kS/m, which can be attributed to fewer contact points between the CNTs. Overall, we were able to prepare stable and electrically conductive multilayer films. Additionally, by varying the preparation conditions tuning of the electrical conductivity is possible.
To fulfill requirements regarding i.e., medical implants, film properties not only have to be stable and controllable in a dry state (described in Article 1) but also in a biological aqueous environment. Therefore, in Article 2 we immersed our coated samples in three different solutions usually employed in biological research and compared their properties with their dry state, respectively. Also, hydration/swelling effects that normally occur for polyelectrolyte multilayer films (PEMs) in solutions were investigated.
For the film preparation, PDADMA (Mw = 322 kDa) and a deposition suspension of modified CNTs with two different concentrations (0.15 mg/ml and 0.25 mg/ml), which aged for two years, were used. Independent of the CNT suspension concentration, it turned out that the film thickness of the samples, prepared from the aged suspension, decreased significantly compared to the film thickness previously measured in Article 1. As a cross-check a new and fresh CNT suspension was made, which allowed us to reproduce the film thickness described in Article 1.
These results indicated that something happened with the CNT suspension over a two-year period. An analysis via X-ray photoelectron spectroscopy (XPS) showed a decrease in the percentage of functional groups in the CNTs from the aged suspension. The loss of functional groups resulted in less negatively charged CNTs and thus in fewer adsorption sites for the polycation PDADMA. Consequently, the PDADMA monomer/CNT ratio decreased, which lowered the thickness per bilayer by a factor of three, compared to films prepared with a freshly prepared CNT suspension. The lower linear charge density of the aged CNTs also enhanced their hydrophobicity, which is, in combination with the electrostatic forces, another important factor for multilayer cohesion. In contrast to PEMs made from polycations and polyanions, no swelling of the films occurred when immersed in solutions. This can be attributed to the fact that the increased hydrophobicity of the CNTs and the hydrophobic nature of the PDADMA backbone prevent the incorporation of water into the multilayer film. In solution, the films slightly shrink (by ≈ 2 nm), which makes them even more compact. Yet they remain stable. The result is an increased electrical conductivity from 9.6 kS/m, in the dry state, up to 15.3 kS/m immersed in solutions. To summarize, we showed that by tuning the interpolyelectrolyte forces the swelling and the ensuing decrease of the electrical conductivity of the films can be prevented.
Regarding the application in biology and medicine, we must consider that long-term exposure of cells to nano-materials like CNTs could lead to damage and inflammation of adjacent tissue. Therefore, it is necessary to prevent direct contact between the electrically conductive multilayer, i.e., CNT/PDADMA film, and the cells. The solution to this problem is a biocompatible top film that covers the CNT/PDADMA multilayer completely and still provides a lateral surface structure that supports cell adhesion and proliferation. Additional layers consisting solely of PEs could provide such a top film.
In Article 3 we investigated the self-patterning of PEM films as function of deposition steps. After preparation in water, the films were dried, characterized in air, and in vacuum. The films were built with high and low molecular weight PEs. PDADMA was used as polycation and poly(styrene sulfonate) sodium salt (PSS) as polyanion. The observation via Atomic Force Microscopy (AFM) showed that films prepared with high molecular weight PEs are laterally homogeneous and form no patterns, due to the chain immobility. The flat surfaces are ineligible as a substrate for cell adhesion.
In contrast, films built with a short PSS, especially at Mw, PSS = 10.7 kDa, began to self-pattern after seven deposited PDADMA/PSS bilayers. With each additionally deposited bilayer, the surface got more and more structured, from grooves over stripes to circular domains. Increasing film thickness led to an increased lateral mean distance between the surface structures. Scanning Electron Microscopy (SEM) images showed that exposure to a vacuum resulted in a decrease in the film thickness attributed to water removal, while the mean distance between the domains increased. Thus, by using this self-pattering process we are able to prepare PEMs with a highly structured surface. By adding PDADMA/PSS bilayers, not only the CNT/PDADMA film can be covered completely, but also a suitable surface morphology for cells can be created. Controlling the number of deposited bilayers allows the preparation of suitable coatings for cells.
To further improve the interaction of the cell and coated substrate not only the lateral structure but also the interacting electrostatic forces between cells and substrate are important for the nature of cell adhesion, function, and proliferation. In Article 4 we investigated PEMs, consisting of strong PEs with a low (PDADMA) and high (PSS) linear charge density. We performed asymmetric force measurements with the help of the colloidal probe technique (CP). Here, the forces between a PEM-covered surface and a colloidal probe (silica sphere) glued to a cantilever were investigated. The colloidal probe was either bare or covered with polycation poly(ethylenimine) (PEI). The surfaces were immersed in NaCl solutions with different ionic strengths (INaCl), starting with deionized water, then enriched up to 1 mol/L NaCl. The interaction force between a CP and the surface was measured. Thus, insight into the surface potential/charge was obtained.
During film preparation, two growth regimes (parabolic and linear) exist. These regimes and the terminating layer determine the surface force of the PEM. PEMs with a terminating PSS layer are predominantly flat and negatively charged when the ion concentration is low and the film is in the parabolic growth regime (between 1 and ≈ 15 BL). This indicates charge reversal on PSS adsorption. At the transition point between the parabolic and linear growth regimes, the ratio between polyanion and polycation monomers starts to switch and some cationic monomers are neutralized not by anionic monomers but by monovalent ions. Therefore, the surface charge density in diluted NaCl solutions changed from slightly positive near the transition to positive in the linear growth regime. At the lowest ionic strengths (INaCL) the range of the surface potential goes from – 40.5 mV (9 BL, parabolic) up to + 50 mV (19 BL, linear).
In contrast, polycation (PDADMA) terminated films are overall positive in diluted NaCl solutions. At the beginning of the parabolic growth regime, the layers are more compact and flat. However, with each additional layer deposited, the film becomes less compact and the chains begin to loosen. The now more loosely bound chains start to protrude into the solution and form pseudo-brushes. This could already be observed for 10.5 BL.
It intensifies in the linear growth regime (begin at ≈ 15 BL) and results in steric surface forces. Changing the surrounding INaCl affects this behavior and the pseudo-brushes scale as polyelectrolyte brushes.
By controlling the number of bilayers (thus the growth regime), the surrounding ionic strength, and the conformation of PEs at the PEM surface, it is possible to prepare a suitable range of surface properties i.e., for cell adhesion and proliferation. To prove that these multilayers can provide a suitable surface and have a positive effect on cell behavior, we coated in Article 5 titanium-covered samples with PEMs. Investigated was the cell interaction with the surface at different zeta(ζ) - potentials, a parameter for dynamic surface potential. Here the cell activity is measured by the mobilization of calcium (Ca2+) within the cell as a function of the ζ - potential of the substrate and the externally applied electrical potential. The cell activity indicates if the ζ - potential, provided by the sample surface, is suitable or not for the cells. The favorable interaction with the substrate is also reflected in the cell morphology and proliferation. The results showed that highly negative ζ - potentials between - 90 and - 3 mV led to a decreasing/reduced Ca2+ mobilization which correlates with reduced cell activity. Nearly neutral to moderate positive surfaces (ζ - potential + 1 to + 10 mV) i.e., PSS-terminated PEMs are able to promote cell adhesion and growth as demonstrated by an increased Ca2+ mobilization. The access to the intracellular Ca2+ stores, provided by the external stimulus, is now more effective and suggests a higher cell activity. Increasing the ζ - potentials up to ≈ + 50 mV (highly positive), i.e., PDADMA - terminated PEMs with pseudo-brushes, resulted in restricted cell viability and impaired Ca2+ mobilization, which led to a disturbed cell morphology and proliferation. In conclusion, only surfaces, terminated with i.e., PEI, with moderate positive charges (ζ - potential + 1 to + 10 mV) are able to improve the Ca2+ mobilization and thus the cell activity and proliferation. PEMs with a PSS termination provide negative 𝜁−potentials, onto which cells adhere, and proliferate. Therefore, they are a good alternative for surface functionalization for implant surfaces. In summary, the objective set at the beginning of the thesis is addressed within articles written as part of this thesis. It is possible to fabricate PEMs with modified CNTs to produce coatings that are electrically conductive with tunable sheet resistance, whether dry in air or immersed in an aqueous solution (Articles 1 and 2). Also, for pure PEMs, it is shown that with the right molecular weight of PEs and a certain number of bilayers, a suitable surface structure for cell adhesion can be produced (Article 3). Additional surface properties such as a suitable surface charge density can be provided by PEMs which can improve the cell activity as monitored with Ca2+ mobilization (Articles 4 and 5). The next step is to combine the knowledge gained from Articles 1 – 5 and link it to the application of external electrical fields to cells.
Study of the effect of the podocyte-specific palladin knockout in mice with a 129 genetic background
(2023)
Worldwide, chronic kidney disease is one of the leading public health problems. Podocytes, highly specialized postmitotic cells in the filtration unit of the kidney glomerulus, are essential for the size selectivity of the filtration barrier. Loss of the complex 3D morphology of their interdigitating foot processes, effacement and detachment of the cells from the capillaries lead to proteinuria and often loss of kidney function.
Since the morphology of podocyte foot processes is highly dependent on an intact actin cytoskeleton and actin-binding proteins, we investigated the role of the actin-binding protein palladin in podocytes from mice with a 129 genetic background, that is more susceptible to kidney injury. PodoPalld129-/- mice were examined at 6 and 12 months of age using immunofluorescence staining, electron and 3D super-resolution microscopy as well as qRT-PCR.
Our analysis of PodoPalld129-/- mice at 6 and 12 months of age showed that podocyte- specific knockout of palladin results in dilation of the capillary tuft accompanied by loss of mesangial cells, indicating the influence of palladin on glomerular tuft formation. Besides, we observed morphological abnormalities such as an enlarged sub-podocyte space, cyst formations and an increased number of cell-cell contacts between podocytes and parietal epithelial cells in PodoPalld129-/- mice compared to controls. Moreover, palladin knockout resulted in downregulation of the slit diaphragm protein nephrin as well as an age-dependent significant increase in podocyte foot process effacement. Although there was a significant change in foot process morphology, we did not detect albuminuria in PodoPalld129-/- mice of both age groups. However, we found an increase of trefoil factor 1 (Tff1) in the urine of the mice, indicating an altered, more permeable filtration barrier.
Considering that palladin has several binding sites for important actin-binding and regulatory proteins, we studied the expression of Lasp-1, Pdlim2, VASP and Klotho in dependence on palladin. We found a remarkable reduction in, for example, phosphorylated Lasp-1 as well as Klotho, which could influence the morphology of podocyte foot processes.
Compared with PodoPalldBL/6-/- mice, PodoPalld129-/- mice showed stronger glomerular tuft dilation and developed podocytes with increased morphological abnormalities, underlining the importance of the genetic background.
In conclusion, these results demonstrate the essential role of palladin for podocyte morphology in mice with a 129 genetic background.
Global change is one of the major challenges our society faces in recent times and is becoming increasingly noticeable in all aspects of our lives. In the last ten years, reports about droughts in Europe increased, contrary to expected natural climate variations and are attributed as indicators of climate change. Droughts resulted in a severe decrease in water levels of lakes, rivers and reservoirs, posing socio-economic and environmental challenges. Climate scenarios by the Intergovernmental Panel on Climate Change (IPCC) project increasing temperatures, more frequent, longer and/or more intense heat waves and warm spells, and an increase in aridity with short-term droughts in the upcoming decades for Western and Central Europe. Some areas – such as Northeast Germany – are already affected by negative water balances and the lowering of lake and groundwater levels. Additionally to possible challenges in water availability, excess nutrients and heavy metals from industrial emissions, agricultural fertilisers and land use changes lead to declining water quality. In the past century, extensive eutrophication and environmental pollution have become major water quality issues in many freshwater bodies.
Nonetheless, water and its availability in a sufficient quantity and quality are prerequisites for life and must be prioritised in future development. The European Union aims for a good status in all surface and groundwater bodies by 2027 regarding their ecological, chemical and quantitative status. However, a profound understanding of eutrophication, pollution sources, and water bodies' reference conditions – referring to pre-anthropogenic conditions – should be available for each system to apply integrated restoration strategies. Moreover, an in-depth understanding of long-term climate variability and its dynamics is indispensable to approach these climate change challenges and reliably predict water availability.
During the past decades, numerous paleoenvironmental studies have been carried out on Northern German sediment archives, using mainly lacustrine sediments to reconstruct hydroclimatic variability, often inferring lake-level variations as key indicators. However, most studies were carried out in areas affected by more maritime or continental climate. Studies from the transition zone are rare. Only few existing studies offer high-resolution records and/or robust chronologies, which limits the understanding of past environmental changes significantly. Besides, the Northern German lowlands have been anthropogenically affected since at least the Neolithic (~5.6 ka cal BP) and, in particular, forest composition and density have recently been shown to have at least partially an impact on lake-level variations. However, a reliable distinction between climatic impacts and anthropogenic interferences is widely missing, which is a problem because many studies were conducted on rather small lacustrine systems in which expected anthropogenic signals are higher, and single events may overprint the climatic signals. These biases lead to an incoherent picture of the past hydroclimatic variability in Northern Germany during the Holocene. To overcome this situation, it is inevitable to identify a suitable sedimentary archive from the transition zone – preferably a large lacustrine system in which natural (supra-)regional paleoenvironmental signals are expected to be not overprinted by single events. Moreover, it is necessary to establish robust chronologies and apply high-resolution methods to infer past environmental changes in a high temporal resolution. Taken together, this could contribute to an enhanced understanding of past environmental and climatic changes in Northern Germany.
This thesis consolidates the evidence for Schweriner See to act as a suitable sedimentary archive in Northern Germany for (supra-)regional climate reconstructions. Schweriner See is a large lowland lake in Northern Germany located within the transition zone from maritime to continental climate. In the first step, (paleo)lacustrine landforms, i.e. beach ridges, subaerial nearshore bar, and a silting-up sequence, are investigated along the north-eastern shoreline using a combined approach of sedimentology (e.g. grain size variations) and the relatively novel method of luminescence profiling offering relative age determinations to understand depositional processes and their chronological framework. Absolute age information is mainly inferred by OSL dating. Secondly, an important prerequisite to interpreting information obtained from lacustrine sediment archives is a thorough understanding of processes controlling sedimentation. Schweriner See is characterized by a complex morphometry, which influences in-lake processes, i.e. i) in-lake productivity, ii) carbonate precipitation and iii) wind- and wave-induced processes, resulting in a distinct spatial heterogeneity. This thesis shows that it is crucial first to understand sedimentary depositional processes and controlling mechanisms to i) select suitable coring location(s) and ii) reconstruct paleoenvironmental and hydroclimatic variations reliably.
Based on bathymetric considerations and inferred in-lake processes, two main coring locations were identified to infer i) the anthropogenic impacts and ii) hydroclimatic variations. Short sediment records from the shallow water areas (< 15 m water depth) cover the most recent environmental history of Schweriner See. A well-dated sedimentary record (210Pb/137Cs and 14C dating) links distinct sedimentary and geochemical changes with historical events. Schweriner See was extensively affected by lake-wide eutrophication and contamination, closely related to sewage and population dynamics within the catchment. The water quality only improved after the German Reunification in 1990 CE when sewage was precluded from Schweriner See. Contamination trends at Schweriner See showed similar trends to different archives along the southern Baltic Sea, implying a common regional driving mechanism, e.g. environmental legalisation.
A well-dated sediment record from the profundal zone (52 m water depth) allowed the reconstruction of large-scale atmospheric conditions during the past 3 ka cal BP by inferring winter temperature variability, the moisture source region and/or evaporative lake water enrichment, which resemble variations in the North Atlantic Oscillation (NAO). The NAO greatly influences the Central European climate, affecting, for example, surface air temperature, precipitation or storm tracks. During 3-2.8 ka and 2.1-0.8 ka cal BP, predominantly positive NAO conditions are reconstructed, which are characterized by warmer winter temperatures, moisture conditions bringing isotopically enriched precipitation from the southern/central North Atlantic to Northern Central Europe and/or warmer temperatures that may result in a higher evaporative isotopic lake water enrichment as a result of northwards displaced westerlies. Conversely, during 2.8-2.1 ka and 0.8-0.1 ka cal BP, results correspond to predominantly negative NAO phases influenced by southwards displaced westerlies. Frequent atmospheric blocking allows for the intrusion of northerly or easterly winds, resulting in colder winter temperatures, isotopically depleted precipitation from the Northern Atlantic and Arctic region and/or a lower evaporative lake water enrichment. In addition to these long-term changes in atmospheric conditions, short-term hydroclimatic variations have been reconstructed, mainly reflecting lake-level variations in conjunction with precipitation variability, with the proxy signal being additionally amplified by wind speed and wave motion. Comparisons with other archives support these results.
So far, the paleoenvironmental reconstruction is limited to the Late Holocene, but initial dating results imply possible interferences until the Late Pleistocene. Therefore, future studies should focus on extending the profundal record from Schweriner See further back in time, providing a high-resolution record covering both the Holocene and possibly the Late Pleistocene.
In course of the recent results from Wendelstein 7-X, stellarators are on the brink for assessing their maturity as a fusion reactor. To this end, stellarator specific transport regimes need detailed exploration both with appropriate systematic experimental investigations and models. A way to enhance the efficiency of this process is seen in an systematic evaluation of existing experimental data. We propose appropriate tools developed in information theory for examining large datasets. Information entropy calculations, that have proven to assist the systematic assessment of datasets in many other scientific fields, are used for novelty detection.
Potentially, as a first use-case of this holistic process, this thesis attempts to link and to develop approaches to examine the stellarator specific core-electron-root-confinement (CERC) regime. The specific interest for CERC emerges from the behavior of the radial electric field. While ion-root conditions exhibit negative radial electric fields, CERC’s positive field in the very core of fusion grade plasmas adds an outward thermodynamic force to high-Z impurities and could add to potential actuators to control impurity influx as to be examined for full-metal wall operation in large stellarators. Recently, this feature received revived intent for reactor scale stellarators.
Also, in this work, parameter regions close to the transition from ion-root to CERC are
examined. At lower rotational transform (a characteristic feature of the magnetic field confining fusion grade plasmas), transitions were detected when the plasma current evolved. As in smaller stellarators, it is concluded that low-order rationals and magnetic islands are related to the transitions. This is widely supported by extensive MHD simulations which finally provide indications for the role of zonal flow oscillations. As one of the outcomes, gyrokinetic instabilities are seen interacting for the first time with the neoclassical mechanisms in experiments.
In order to cope with the vast number of highly sampled spatio-temporal plasma data, new
techniques for novelty detection are required. Fundamental prerequisites for the detailed
physics investigations were the feasibility study of entropy-based data analysis techniques, and their adaptation to detect previously unrevealed transition mechanisms. These tools were applied to multivariate bulk plasma emissivity data, which allowed the exploration of large parameter spaces and provided insights in the spatio-temporal dynamics of CERC transitions.
In this manner, this research highlights the feasibility of information flow measure analysis in fusion studies. Applications of different entropy-based complexity measures are explored and this work sheds light on the capabilities, added value and limitations of these techniques. This investigation presents the integration of information flow measures to gain deeper understanding of plasma transport phenomena, by providing an approach to fast systematic data mining suited for real-time analysis. This work paves the way for further development and implementation of information-theoretic methods for plasma data analysis.
In summary, this research highlights the gained insight on CERC transitions, while showcasing the feasibility, added values and limitations of information flow measure analysis for fusion studies, to induce theory based analysis revealing new insights in fundamental, stellarator-specific transport mechanisms.
Research into nuclear physics has enjoyed a long and rich history since the earliest experiments began investigating atomic constituents. The discovery of the atomic nucleus in the early 20th century started a complex field of research that has undergone many transformations with the advancements of modern technology. Today, atomic nuclei are not only studied to advance our understanding of the strong force but also to gain more information on the synthesis of elements in the universe, to exploit nuclear decay to investigate the weak interaction, and to search for physics beyond the standard model.
In this work, we will study the strong force in atomic nuclei, i.e. the way nucleons (protons and neutrons) arrange themselves in a many-body system governed by the repulsive Coulomb interaction and the attractive strong interaction. In particular, we will focus on nuclear structure near nuclei with a "magic number" of Z protons and N neutrons, so-called doubly-magic nuclei, exhibiting a particularly stable configuration with respect to neighboring nuclei.
Within the nuclear shell model, similar to the atomic shells, the magic numbers indicate shell closures accompanied by energy gaps. Nuclei at double-shell closures and their direct vicinity provide an important playground to benchmark nuclear theories and models that aim to predict the intricate interplay of the nucleons that lead to enhanced nuclear binding energies, significant changes in charge radii and transition strengths, etc.
Of particular interest are nuclear isomers, long-lived excited states, in which the nucleon configuration with respect to its ground state is altered, resulting in a modification of their properties despite having the same number of protons and neutrons.
The main part of this work consists of three publications, which report on nuclear structure investigations through mass measurements and laser spectroscopy near the doubly magic nuclei nickel-78, tin-100, and lead-208.
The nuclides investigated in this work include neutron-deficient indium isotopes, neutron-rich zinc isotopes, and neutron-rich mercury isotopes.
Although the outcome of patients with acute myeloid leukemia (AML) has
improved in the past decades, the overall survival is below 50% [1, 2] and there
is still an unmet need for the development of new therapeutic strategies. Here,
we aimed to identify functional vulnerabilities in AML and investigated the
therapeutic potential of target structures involved in proteostasis, cell polarity and
RNA-binding molecular pathways.
We determined that genetic deletion of the cell fate determinant and polarity
regulator Scribble delays AML development, however, its deletion also seems to
affect the proliferative capacity of normal hematopoietic cells, lowering its value
as a therapeutic target. In contrast, inactivation of YBX1 (a pleiotropic protein with
DNA/RNA binding capacity that excerpts post-transcriptional control on its
targets) and PSMB8/LMP7 (a catalytic subunit of the immunoproteasome multiprotein
complex that belongs to the ubiquitin-proteasome system (UPS)) inhibit
leukemic cells without influencing normal hematopoietic stem and progenitor cell
function, establishing these targets as potential novel therapeutic strategies
against AML.
Genetic deletion of YBX1 caused reduced proliferation and colony forming
capacity in leukemic cells independent of the oncogenic driver mutation and
delayed AML development in vivo. The role of Ybx1 in leukemia maintenance
was investigated using a conditional knockout model, confirming the functional
requirement of Ybx1 in AML maintenance. Mechanistically, YBX1 recruited
oncogenic transcripts to polysomes, increasing their translation. Displacement of
these transcripts from polysomes after YBX1 deletion decreased their protein
expression.
Genetic and pharmacologic inhibition of PSMB8/LMP7 decreased proliferation
and colony forming capacity selectively in KMT2A (MLL)-rearranged leukemic
cells. In vivo treatment with a PSMB8/LMP7 inhibitor delayed disease
development in KMT2A-rearranged leukemic mice or patient derived xenografts
(PDX). We identified the transcriptional corepressor BASP1 as a functional
effector of the immunoproteasome. BASP1 was enriched after PSMB8/LMP7
inhibition and it was found binding to KMT2A-target genes. Moreover,
pharmacologic inhibition of PSMB8/LMP7 led to decreased expression of bonafide
KMT2A-fusion target genes and enrichment for genes deregulated by
inhibitors of the KMT2A complex partners DOT1L and MEN1. This prompted us
to investigate a potential synergism between MEN1 inhibition and
immunoproteasome inhibition. Combination treatment in AML cells revealed
decreased proliferation in vitro and increased survival in vivo as compared to the
single treatments, demonstrating the therapeutic potential of combining
immunoproteasome and MEN1 inhibitors.
This thesis presents the production of polyanionic clusters within two ion storage devices:
Considering a Penning trap, the accessible range of polyanionic aluminium clusters has been expanded up to the 10th charge state. In particular, abundance curves for clusters with 5 to 9 excess electrons have been measured for the first time and analysed with respect to their lifetime-dependent appearance sizes. These sizes reveal a nearly quadratic dependency on the charge state for experimentally accessible lifetimes.
Additionally, the production of polyanionic clusters has been enabled in a radiofrequency ion trap. Therefore, the transition from a harmonic to a digital 2- and 3-state guiding signal has been investigated with respect to the ion storage. The passing of electrons through the trap during field-free periods of the guiding signal led to the first production of polyanionic clusters within a radiofrequency ion trap.
Pregnancy involves adaptations of the cellular composition in utero to establish a functioning fetal-maternal interface. Different subsets of leukocytes populate the endometrium and contribute to tolerance of the fetal allograft while protecting it from potentially threatening infections or rejection. ¬¬Innate lymphoid cells are recently discovered immune cells that, besides the gut, lung and skin, possess immunoregulatory functions in the female reproductive tract, especially during gestation. Although present at the fetal-maternal interface, the dynamics of ILC migration during pregnancy remains poorly investigated. The involvement of homing receptors in ILC migration to the uterus was the main subject of the present work.
First, the expression of homing receptors on ILCs from miscellaneous organs was assessed across the course of murine pregnancy in vivo by means of flow cytometry. Then, their migratory capacity towards pregnancy-relevant chemokines was investigated in vitro. The impact of pregnancy related hormones on the migration and homing of ILCs was then analysed in vitro via migration assays.
The results confirm altered proportions of ILCs in utero and the altered expression of homing receptors in ILCs in pregnancy. Different murine lymphoid organs showed augmented expression of chemokine receptors and decreased levels of homing integrin α4β7 in the first trimester, suggesting enhanced migration patterns of ILCs during early pregnancy. Subsequently, migration assays were used to demonstrate the role of different chemokine ligands in enhancing ILC migration.
Eventually, the alterations in homing receptor expression were correlated with female pregnancy hormones. Progesterone treatment caused similar effects on homing receptor expression in ILCs as observed during early gestation. These results represent the first study evaluating the effect of sex steroid hormones on ILC chemokine receptor distribution.
Taken together, our results indicate the involvement of pregnancy-relevant chemokines, including CCL4, CCL20 and CCL28, in the recruitment of ILCs to the uterus during pregnancy. The data highlight an endocrinological-immune crosstalk in the regulation of ILC homing to the female reproductive tract. Gestation alters chemokine receptor expression in order to regulate the access of immune cell subsets to the fetal-maternal interface. An adequate regulation is highly needed, as a lack or abundance of different subgroups could result in pregnancy complications, including fetal loss, pre-eclampsia or pre-term birth. Thus, the role of ILC chemotaxis to the pregnant uterus and its regulation are of interest in the understanding, prevention and treatment of the clinically relevant obstetric diseases.
The thesis investigates the occurrence of the Early Modern European witch-hunt within the distinctively diverse society of the Grand Duchy of Lithuania. Positioned at the intersection of Latin and post-Byzantine cultures, along with Western and Eastern Christianity, this region lay on the frontlines of the Reformation and Counter-Reformation. The research aims to analyze the specific characteristics of the witch-hunt in this area, considering it a case study of social and cultural interaction within a borderland. It focuses particularly on identifying the distinctive aspects of the Lithuanian witch-hunt, examining the social and cultural roots of the witch trials, and exploring their relationship to the broader social and cultural developments of the period.
Central to this study is a detailed examination of the witch trials and an analysis of court materials. The thesis posits a socio-cultural interpretation of witch persecutions, arguing that they were culturally influenced manifestations of social tensions, enacted through legal mechanisms. The emergence of new Early Modern challenges, such as the social consequences of agrarian reform, the expansion of manorialism, and serfdom, led to novel tensions, conflicts, and responses, including accusations of witchcraft. The importation of authoritative foreign ideas about witchcraft reinvigorated, facilitated, and shaped pre-existing moderate indigenous beliefs, a process facilitated by religious struggles and Catholic post-Tridentine confessionalization. The Lithuanian legal system provided an environment conducive to an intensive witch-hunt, with witchcraft being a secular grave felony tried in highly decentralized and poorly supervised courts. However, this potential was largely unrealized. The study argues that the cultural diversity of the society played a major role in inhibiting the spread of Western witchcraft discourse, thereby limiting the extent of the witch-hunt in the Grand Duchy of Lithuania.
In this thesis, I was able to provide answers to transport processes in lipid monolayers, which are ultimately, all of biological relevance. In particular, I was interested in lipid oxidation and dynamic compression/expansion processes of surfactant monolayers at the air-water interface:
Lipid oxidation was shown to be a consequence of the formation of a high concentration of reactive oxygen species (ROS) during cell respiration, which finally can lead to severe cell damage. It is not yet understood clearly, which part of the lipid molecules is especially prone to a ROS attack. I was particularly interested in the role of the double bonds of the acyl chains of the lipid molecules during oxidation. Further, I wanted to know the time scales of lipid interaction with the ROS.
Compared to lipid vesicles, lipid monolayers have the advantage that many parameters of the system can be adjusted easily. In our system, I made use of this by setting the lateral pressure to low values during H2O2 treatment, which facilitated the ROS to reach the double bonds in the acyl chains.
A prime example of biological systems out of thermal equilibrium was given in the alveolus surface, which is covered with a surfactant monolayer. During breathing, these monolayers undergo such a highly dynamic compression and expansion. Arising flows from breathing could disrupt a film and consequently, it would lose its protective role. One of my goals was to understand flows and their influence on domain shape. Dependent on the strength of the flows, I expected different growth regimes, with differing prevailing transport processes. Once understanding the underlying mechanisms in domain shaping would allow me to draw conclusions on biological systems.
In order to address these questions, I established two systems, both based on the compression of lipid monolayers. I used isotherms to study the phase behavior of the lipids:9 During compression, the lipids can undergo phase transitions from the gaseous phase to the liquid expanded phase (LE-phase) and further from the LE-phase to the liquid condensed phase (LC-phase). A coexistence regime is observed in between the LE-phase and the LC-phase, characterized by a flat increase of lateral pressure with decreasing molecular area. Some lipids exhibited LC-phase domains. These were further investigated with Brewster angle microscopy (BAM). The used BAM was equipped with an integrated Scheimpflug optics, enabling an overall focused image plane. Furthermore, time-resolved observation of the growth of the domains was possible by recording videos (20 frames per seconds).
The first system enabled the investigation of lipid peroxidation, when the lipids were exposed to ROS. I chose DMPC, POPC, DOPC and PLPC, since these are phospholipids differing in the number and position of double bonds in acyl chains, but not in the head group. I used a H2O2 enriched phosphate buffered saline (PBS) solution, which served as a precursor for more reactive ROS, like hydroxyls (.OH). PBS was chosen, since it resembles the cell environment best. During defined waiting times of H2O2 treatment, the ROS diffused vertically from the subphase towards the monolayer. The lipid molecules were in the LE-phase, which facilitated the ROS molecules to reach also the double bonds of the acyl chains. The oxidized monolayers were then compressed at constant compression speed. Since the corresponding isotherms could be measured with high precision, the relative area increase δA/A between oxidized and non-oxidized monolayer along the isotherm proved to be a good measure for lipid peroxidation. The area increase δA in the molecular area of the oxidized molecules was explained by the eventually added, more hydrophilic −OOH group at the position of a carbon atom adjacent to a double bond in the unsaturated acyl chain. The −OOH group is drawn to the hydrophilic head group of the lipid. This leads to a kink in the acyl chain, which increases the molecular area A by δA. A model, which explained this peroxidation process in lipid vesicles, could be adopted to monolayers.
I compared the oxidation of phospholipids, differing in the number and position of the double bonds of their acyl chains. I found that δA/A increased with the growing number of double bonds in one acyl chain. However, a comparison of DOPC with POPC also showed the importance of the position of the acyl chain. I determined a slow reaction kinetic. It could be estimated by a √t dependence of the number density N_surface, which denominates the ROS sticking on the monolayer. The transport of ROS towards the monolayer was found to be diffusive, because it was the slowest process in the reaction. This interpretation was reinforced by a comparison of the temperature dependence of the relative area increase δA/A with the Stokes-Einstein diffusion coefficient of water molecules. The initial ROS concentration c_0 in the trough could be traced back (c_0~ 50 nM), which is indeed a realistic value found in human cells.
Concluding, our results can be understood as a feasibility study. The complexity of the monolayer can be arbitrarily increased, for example by the addition of proteins, allowing the investigation of other oxidative processes occurring in the cell membrane.
The second system allowed the investigation of growth of LC domains during fast compression processes of monolayers. I chose erucic acid monolayers, due to its low line tension and a continuous nucleation phase, enabling the formation of fractal domains. The monolayers were investigated with isotherms and BAM videos. Since v_C (compression speed of the monolayer) was continuous over the whole compression time, I had a system with well-defined hydrodynamic conditions. This allowed me a complete analysis of the system, starting with descriptive features of the observed domains to a classification of the observed growth regimes by means of hydrodynamic theory, through to the distinction and quantification of different kind of flows and supersaturations, involving Ivantsov theory:
Dependent on the compression speed v_C, I observed seaweed or dendritic domains. The LE/LC phase transition pressure pi_t was slightly increased compared to pi_inf of the equilibrium isotherm. A high compression speed v_C induced a supersaturation Δc. I introduced the excess lateral pressure Δpi=pi-pi_inf as an appropriate quantity to describe the supersaturation Δc. I showed a linear behavior of Δc on Δpi. Δc is a macroscopic quantity since it is averaged over the whole monolayer area. I characterized the domains of the seaweed and dendritic regime with respect to tip radii, branch lengths, side branch separations and fractal dimensions. I calculated the growth speed of the main branches. A roughly doubling of the growth speed of dendritic domains, compared to seaweed domains was observed. This was an evidence of adjunctive (Marangoni) flow in the subphase.
For each monolayer, I observed drifts during domain growth, which I explained by an anisotropy in the LE-phase, caused by the continuous nucleation of the domains. These kind of surface flows were superimposed to bulk flows in the subphase. Since I had a well established system, I could analyze the influence of these surface flows on domain shape, in terms of magnitude, direction and duration of the surface flows. I therefore used FFT spectra and directionality histograms. At low flows, the FFT showed six-fold symmetry. Higher drifts exhibited incisions in the FFT, eventually leading to dumbbell shaped FFTs at very high drifts. The domains grew preferentially in the direction parallel to the incision.
I used directionality histograms to analyze the angular distribution of the growing domains. They showed that the drift direction always correlated with a minimum in the histogram. In order to analyze drift duration, I split the domain in downstream and upstream side. I could show that for small drift durations, downstream growth was preferred. However, for longer drift durations, the flows got more isotropic and consequently growth was more balanced then.
I could observe only a weak correlation between drift velocity v_D and compression speed v_C. However, dendrites were formed when the compression speed v_C was high, while seaweed domains were formed when v_C was small. Domain distortion occurred in the same way, independent if seaweed or dendritic domains were considered. I further showed that hydrodynamic flows in the subphase and surface flows are superimposed and scale differently. Consequently, they have different impact on domain shape: hydrodynamic flows act on μm scale and influence the domain morphology (distance between side branches, and tip radius) and the growth speed of the main branches. Surface flows act on the mm to cm scale, cause an anisotropic flow in the LE phase surrounding the domain, and thus affect the overall domain shape.
The anisotropy in the LE-phase led to a locally different degree of supersaturation. To take this into account, I introduced a local normalized supersaturation Δ, based on the Ivantsov solution. Therefore, I calculated Péclet numbers p of measured quantities of the system. I obtained values of 0.88 ≤Δ≤0.90 for the seaweed regime (p<5) and 0.93 ≤Δ≤0.96 for the dendritic regime (p>6). Since the Ivantsov solution can only be applied for purely diffusive processes, I applied a modified Ivantsov solution Δ_mod, which calculates Δ at a distance 𝛿 ahead of the dendrite tip. I was able to determine the progression of the diffusive layer 𝛿, however a quantitative determination failed.
Applying hydrodynamic theory allowed me to classify the two growth regimes with respect to the Boussinesq number Bq. Since for both growth regimes, I achieved values of Bq<1, bulk viscous losses dominated over surface viscous losses. Further, a cross-over length 𝜉 was calculated, from which one can distinguish, whether advective transport dominates over diffusion.
I further connected the two defined supersaturations Δ and Δc via the excess lateral pressure Δpi. From this, I saw differences in the seaweed and dendritic growth regimes: The local normalized supersaturation Δ of seaweed growth seemed to be quite stable for a further increase of the lateral excess pressure Δpi, whereas it reacted quite sensitive in the dendritic regime. This was found to be an indication of a non-equilibrium regime, caused by the strong coupling of the monolayer to the subphase. It reinforces therefore the theory of Marangoni-flow.
The findings of this thesis emphasize the importance of understanding highly dynamic compression/expansion processes arising in surfactant monolayers. Using the example of the compression of the alveolus surface, it can be seen that a more realistic model of the pulmonary alveolus is not only enabled by increasing the complexity of the surfactant monolayer (e.g. by adding specific proteins or lipid mixtures to the monolayer). Equally important is the understanding in transport processes and the consequences for the monolayer structure. By the analysis of domain shapes, I presented a method, which is suitable for such a study.
This dissertation focuses on the characterization of novel enzymes and metabolic pathways that fulfill crucial functions during marine carbohydrate degradation by Bacteroidetes and thus contributes to an advanced understanding of the global carbon cycle. Depolymerization and utilization of marine polysaccharides by Bacteroidetes requires a tremendous repertoire of enzymes with a wide range of functions. For instance, during the breakdown of the marine red algal polysaccharide porphyran, an oxidative demethylation of the methoxy sugar 6-O-methyl-D-galactose (G6Me) by cytochrome P450 monooxygenases occurs. This reaction produces huge amounts of cytotoxic formaldehyde, marine bacteria capable of degrading porphyran must therefore possess suitable formaldehyde detoxification pathways. Consequently, Article I focus on the identification of possible formaldehyde detoxification pathways in marine
Flavobacteriia, which led to the discovery of the ribulose monophosphate pathway as specific pathway for the detoxification of formaldehyde in certain Bacteroidetes like Zobellia galactanivorans. Furthermore, it was demonstrated in Article II that alcohol dehydrogenases play an essential role in the microbial utilization of G6Me and therefore possess a function in porphyran degradation. Discovering novel enzymes, entire enzymatic cascades or biotechnologically important microorganisms that can metabolize these marine carbohydrates also contributes to the utilization of marine polysaccharides as feedstock for potential biotechnological applications. A prospective biorefinery process was proposed in Article III by the identification of Bacillus licheniformis as promising utilizer of marine carbohydrate-derived monosaccharides and the creation of a microbial cell factory capable of growing on ulvan, a marine carbohydrate obtainable from algal bloom-dominating green algae, enabling an industrial use of the renewable and abundant algal biomass in future.
Graphene is a strictly two-dimensional honeycomb lattice of carbon atoms whose low-energy charge-carrier dynamics obey the massless pseudospin-1/2 Dirac-Weyl equation (or chiral Weyl equation) where the chiral centers (or valleys) are the corners K and K‘ of the Brillouin zone. The linear spectrum near the Dirac nodal points lends graphene its exotic and ultra-relativistic properties.
However, condensed matter systems can possess fermionic excitations with linear dispersions that have no analog in high-energy physics since the crystal space group - instead of the Poincare group - constrains the energy dispersions. Perhaps the first example in this regard is the T_3 lattice (Dice Gitter), a honeycomb-like lattice with an extra atom placed at the center of each hexagon and coupled to only one of the sublattices. The spectrum features a strictly flat band that crosses the two conical intersections of the Dirac cones at K and K' inherited from graphene. The enlarged pseudospin-1 Dirac-Weyl equation describes the low-energy dynamics. By rescaling the transfer amplitude of the additional atoms in the T_3 lattice with a parameter 0<α<1, the resulting α-T_3 lattice continously interpolates between graphene and the T_3 lattice.
In this work, we explore the behavior of generalized Dirac-Weyl quasiparticles in external magnetic and valley-dependent pseudoelectromagnetic fields induced by out-of-plane strain. First, we studied Dirac-Weyl quasiparticles in external fields confined to circular quantum dots by generalizing the infinite-mass boundary condition to the α-T_3 lattices. We verified the analytically derived valley-anisotropic eigenstates of the quantum dot by numerically solving the tight-binding lattice-model in closed (isolated) and open (contacted) systems.
Second, we considered strain fields in the α-T_3 lattices to modify the low-energy transport properties by an effective pseudo-gauge field with opposite signs at the K and K‘ valley. In particular, we showed that the inhomogeneous pseudomagnetic field generated by Gaussian out-of-plane strain at the center of a four-terminal Hall bar setup acts as a valley filter. Most interestingly, the valley polarization is most dominant when incoming electrons are excited to pseudo-Landau level subbands. These bands are linked to different iso-field orbits encircling the lobes of the pseudomagnetic field. Addittionaly, any intermediate α breaks the inversion symmetry of the α-T_3 lattice and thus splits the pseudo-Landau levels into sublattice-polarized bands.
Third, we equipped the out-of-plane strain with a time-periodic drive to induce a valley-dependent pseudoelectric field perpendicular to the pseudomagnetic field. We assessed the steady-state transport properties and found – besides the static regime for small energies – two α-dependent valley-filtering regimes due to the periodic drive. Firstly, we found an additional valley-polarization plateau at the Floquet-zone boundary between the central and first Floquet copy that also displayed a “flower”-like pattern in the local density of states. Secondly, we detected a series of transmission gaps at the center of every Floquet sideband 2mΩ related to the Floquet coupling of the flat band with the central Floquet copy. Under certain strain parameters, a novel valley-filtering regime appears near the transmission gaps where the incoming K electrons are focused through the bump by the pseudoelectric field, instead of encircling the lobes of the pseudomagnetic field. A stability analysis demonstrated that the polarization regimes are tunable by the driving frequency.
Lastly, we demonstrated that the flat band in the Haldane-dice lattice modified by a uniaxial strain along the zigzag orientation remains singular at all band crossings where the model undergoes a topological phase transition between C=+-2 and C=0. To show this, we computed the compact localized eigenstates and the quantum distance of the Bloch wave function around the band-touching points. We derived the resulting non-contractible loop states and an extended state whose components are tunabe by the system parameters.
Antimicrobial resistance (AMR) is of paramount importance in the context of One Health, an integrated and unifying approach that aims to achieve a sustainable balance in the well-being of people, domestic and wild animals, plants, and their shared environments. Whenever bacteria become resistant to the therapeutic effects of antibiotics, they can cause infections that are difficult to treat effectively, increasing the risk of severe disease progression and death. Although AMR can develop naturally over time and is per se “ancient”, the excessive use of antibiotics in human and veterinary medicine over the past century has significantly accelerated its emergence and spread. Opportunistic Gram-negative enterobacteria, particularly Escherichia coli (E. coli ) and Klebsiella pneumoniae (K. pneumoniae) strains, increasingly exhibit resistance to multiple classes of clinically used antibiotics, thus presenting multidrug-resistant (MDR) phenotypes. To make matters worse, some of these strains combine multidrug resistance with high-level virulence, posing a threat to both immunocompromised and healthy individuals. Consequently, MDR E. coli and K. pneumoniae have been designated as high-risk pathogens by the World Health Organization, underscoring the urgent need for new antibiotic development.
This thesis is motivated by the fact that only a limited number of international high-risk clonal E. coli and K. pneumoniae lineages stand out across all One Health dimensions and dominate the broad pool of MDR enterobacteria. While we only know little about the underlying drivers and contributing factors impacting their occurrence, emergence, and adaptation across different ecologies, this thesis employs a diverse range of bioinformatics and phenotypic approaches to identify the key factors important for the success of these lineages, also in rather under-explored settings. It includes three main components: (i) the analysis of genomic survey data of MDR E. coli isolates from ecologies in sub-Saharan Africa, (ii) the application of functional genomics and phenotyping techniques to characterize bacterial virulence and assess its clinical relevance in a food-borne E. coli strain, and (iii) the investigation of evolutionary pathways that promote the development of resistance to a novel drug combination and exploring compensatory mechanisms in a K. pneumoniae strain. To achieve these objectives, this research integrates genomics and transcriptomics with molecular biology and functional studies encompassing a comprehensive set of in vitro and in vivo virulence and resilience assays to explore MDR bacteria in-depth.
We provide compelling evidence for the broad occurrence of successful high-risk clonal lineages in the One Health context and their circulation among clinics, wildlife, and food in international locations. In the first study, we isolated extended-spectrum β-lactamase (ESBL)-producing E. coli strains from houseflies collected from various wards at the University Teaching Hospital of Butare (Rwanda). In a follow-up study, we then examined in-depth the genomes of additional ESBL-producing E. coli from the same clinic and obtained from hospitalized patients, their caregivers, associated community members, and pets. The analyses revealed that the sample sets from this sub-Saharan African context consisted predominantly of globally recognized E. coli lineages, including sequence types (ST)131, ST167, ST410, and ST617. They play a pivotal role in the further dissemination and stabilization of AMR across diverse habitats within the One Health context. Moreover, our genomic results emphasize that these One Health-related high-risk clonal lineages exhibit the ability to successfully combine multidrug resistance with high-level bacterial virulence.
To gain a more detailed understanding of the sophisticated interplay of virulence and AMR, we developed and refined a set of in vitro and in vivo methods for virulence phenotyping. These methodologies enabled us to characterize pathogens based on crucial clinical aspects such as biofilm formation, siderophore secretion, resistance to complement-mediated killing, and their capacity to cause mortality in Galleria mellonella larvae. By using a food-borne E. coli strain from an internationally recognized high-risk clonal lineage, we verified the remarkable combination of a MDR phenotype with clinically significant virulence properties, including synthesis of curli fibers and cellulose as part of biofilm formation, extensive secretion of siderophores, resilience against complement-containing human serum and pronounced mortality in the infection model.
Nevertheless, the success of One Health-related high-risk clonal lineages does not rely solely on an “ideal” synergistic interplay between bacterial virulence and AMR. It also depends on their ability to rapidly mitigate the fitness costs associated with AMR acquisition, as these costs manifest in the form of reduced competitiveness and virulence in the absence of antibiotics. However, this is at odds with the observation of the global distribution of One Health-related high-risk clonal lineages across various One Health dimensions, even in environments with expectedly low selection pressures. To comprehensively address this, we conducted experimental evolution studies selecting for ceftazidime-avibactam-resistant mutants, which illuminated the rapid adaptations to changing environments. The adaptations and compensatory mechanisms were seemingly driven by major bacterial regulators, including the envelope stress response regulator RpoE on genomic and transcriptomic levels.
In conclusion, the results of this thesis shed light on the fundamental principles that govern the character and interplay between AMR and bacterial virulence and advance our understanding of the contributors and drivers of successful MDR international high-risk clonal lineages in the One Health context. This is also important for effective and alternative intervention strategies to prospectively further address the global threat of AMR.
Mass spectrometry-based Proteome analysis of porcine cells infected with African swine fever virus
(2023)
ASFV, a highly contagious, pathogenic and lethal pathogen of swine, poses a major threat to domestic and wild suids worldwide as neither vaccines nor treatments are available. Compared to other well-characterized similarly complex viruses like herpesviruses or adenoviruses, the understanding of ASFV biology is poor.
To improve the understanding of ASFV biology, following the establishment of a robust protocol for the isolation of primary monocyte-derived porcine macrophages (moMΦ) and their infection with ASFV for mass spectrometry (MS)-based proteome analysis was performed.
Under both conditions, naïve and infected, the isolated cells showed cell type-specific characteristics like phagocytosis and antigen presentation and protein expression patterns, including the expression of swine leucocyte antigens and CD markers. Furthermore, moMΦ could be reproducibly infected with ASFV isolates of different genotypes and pathogenicity.
The ASFV protein expression patterns in moMΦ correlate well with those observed in established cell lines at transcript and protein level. The expression of 27 ASFV proteins was confirmed at the protein level. Among them, 9 members of multi-gene families (MGF) and 12 novel open reading frames (nORFs) were recently predicted based on transcription start site mapping.
The direct comparison of closely related ASFV genotype II isolates revealed no virulence-associated protein expression patterns beyond those expected based on the genome sequences of the isolates.
Using different MS quantification strategies, it was shown that ASFV affects both static protein expression levels and protein synthesis. These changes in protein expression impact proteins and pathways known to be targeted by ASFV, including CD-markers, ER-stress and cell death pathways, and cellular antiviral responses. Beyond these observations that further validated the moMΦ infection model, novel effects of the ASFV infection on the cellular proteome were noticed.
These effects include the decreased expression levels of cathepsins, especially cathepsins D (CTSD), H (CTSH) and L (CTSL) as well as the transient activation of MAPK14/p38 prior to its strong downregulation. In addition to MAPK14/p38 further members of the MAPK14/p38 signaling pathway, like MAPKAPK2, were affected by ASFV infection.
As these modulations of the cellular proteome would in general result in decreased pro-inflammatory responses, it did stand out that the synthesis of interferon-response related genes including MX1 and ISG15 evaded the ASFV-induced global reduction of protein synthesis. In contrast, the synthesis of genes involved in RNA processing and splicing was significantly impaired. In total, the regulations of individual host proteins assessed in the context of the whole cellular proteome integrate well with each other and other cellular responses to ASFV infection and may help to improve the understanding of host-virus interactions.
Overall, this thesis provides novel insights into the expression of ASFV-encoded ORFs of different isolates and the host response to ASFV infection. It points out that the current knowledge of the ASFV coding capacity, temporal protein expression patterns, protein functionality, post-translational modifications and host interactions is still sketchy as many aspects of ASFV replication have yet to be understood. The established moMΦ-model to study ASFV infections in vitro provides a powerful tool for future applications to increase the understanding of ASFV biology.
The exchange of water and dissolved elements between the continents and the oceans occurs via different routes in the hydrological cycle, such as rivers, atmospheric exchange, and submarine groundwater discharge (SGD). In addition, the elemental fluxes in the coastal waters may strongly depend on benthic water-solid-microbe interactions close to the sediment-water interface. It is becoming increasingly recognized that SGD can impact diagenesis and act as a source of water and dissolved substances for coastal ecosystems. The qualitative and quantitative assessment of SGD is still challenging as it requires the identification of suitable geochemical tracers for the complex hydrological and biogeochemical processes in the subterranean estuary. In this study, geochemical analyses were combined with geophysical, hydrological, and biological investigations to gain insights into the mechanisms driving SGD in coastal waters. In addition, onshore ground and surface waters were evaluated to identify the processes controlling the potential end member. The surveys were performed along the Baltic Sea coast: Warnow River and Wismar Bay in Germany, the Gulf of Gdańsk and Puck Bay in Poland, and Hanko Bay in Finland. The results suggest that the analyzed surface water system was strongly impacted by seasonal variations, while SGD displayed a much more stable composition throughout the year. New areas of SGD were also identified along the Baltic Sea. It was also observed that anthropogenic coastal infrastructures could promote SGD affecting the water balance and the benthic fluxes. At other sites, the SGD was associated with natural structures such as pockmarks. The stable isotopic composition of the fresh component of SGD was close to the meteoric water at most sites; however, old groundwaters from distinct aquifers were identified. Combining all sites, SGD showed high variability, ranging from near 0 to up to 300 L m-2 d-1, and the saline SGD was more dominant than the fresh component. The fluxes obtained at one site were even higher than the surface runoff. SGD was higher on sandy sediments, but the elemental fluxes were relatively low. Despite low SGD at muddy sites, interfacial elemental fluxes, enhanced by intense diagenesis in the top sediments, resulted in higher chemical fluxes to the water column. The sediment porewater gradients at the SGD impacted sites suggest that the advective upward flow of groundwater increased the elemental fluxes across the sediment-water interface. Therefore, the dissolved substances of SGD are partly impacted by the processes in the soil zone and aquifer during groundwater development, and partly impacted by the early diagenetic process in the surface sediments. Overall, this study shows the importance of SGD for the biogeochemical cycles of coastal waters. Moreover, 6 it can be concluded that a combination of interdisciplinary approaches can provide a better understanding and assessment of SGD in a specific environment. Although all the studies presented here are local, the methodology and results presented in this thesis can be replicated and thus provide assistance in other coastal areas.
Statistical Methods and Applications for Biomarker Discovery Using Large Scale Omics Data Set
(2023)
This thesis focuses on identifying genetic factors associated with human kidney disease progression, with three articles presented. Article I describes the identification of loci associated with UACR through trans-ethnic, European-ancestry-specific, and diabetes-specific meta-analyses. An approximate conditional analysis was performed to identify additional independent UACR-associated variants within identified loci. The genome-wide significance level of 𝛼=5×10−8 is used for both primary GWAS association and conditional analyses. However, unlike primary association tests, conditional tests are limited to specific genomic regions surrounding primary GWAS index signals rather than being applied on a genome-wide scale.
In article II, we hypothesized that the application of 𝛼=5×10−8 is overly strict and results in a loss of power. To address this issue, we developed a quasi-adaptive method within a weighted hypothesis testing framework. This method exploits the type I error (𝛼=0.05) by providing less conservative SNP specific 𝛼-thresholds to select secondary signals in conditional analysis. Through simulation studies and power analyses, we demonstrate that the quasi-adaptive method outperforms the established criterion 𝛼=5×10−8 as well as the equal weighting scheme (the Sidak-correction). Furthermore, our method performs well when applied to real datasets and can potentially reveal previously undetected secondary signals in existing data.
In article III, we extended our quasi-adaptive method to identify plausible multiple independent signals at each locus (a secondary signal, a tertiary signal, a signal of 4th, and beyond) and applied it to the publically available GWAS meta-analysis to detect additional multiple independent eGFR-associated signals. The improved quasi-adaptive method successfully identified additional novel replicated independent SNPs that would have gone undetected by applying too conservative genome-wide significance level of 𝛼=5× 10−8. Colocalization analysis based on the novel independent signals identified potentially functional genes across the kidney and other tissues.
Overall, these articles contribute to the understanding of genetic factors associated with human kidney disease progression and provide novel methods for identifying secondary and multiple independent signals in conditional GWAS analyses.
The effect of interdental cleaning on progression of caries, periodontitis and tooth loss is a highly discussed topic in dental research since these conditions are among the most common infectious diseases of mankind. Caries is a multifactorial disease defined by a demineralization process of the dental hard tissue, caused by bacteria, which, if untreated ultimately results in tooth decay and tooth loss. A study published in 2015 confirmed that untreated caries in permanent teeth is still the most prevalent condition worldwide. Gingivitis, an acute inflammation of the gingival tissue, caused by substances deduced from the microbial plaque can develop into the clinical picture of an acute periodontitis. Severe periodontitis is still the sixth-most prevalent condition globally with a prevalence of 11.2% between 1990-2010. Progression of periodontitis leads to bone loss which as well ultimately results in tooth loss, if left untreated. In our study we want to examine the use of IDA in relation to caries and periodontal diseases, thus tooth retention to gain more detailed and long-term results about the effect of IDA and therefore prevent, counteract and understand these oral diseases better.
Using data from SHIP-TREND, a population-based observational cohort study conducted in Western Pomerania (Germany), we examined effects of daily usage of interdental cleaning aids on follow-up (SHIP-TREND-1) values of oral outcomes comprising caries (DFS, interdental DFS, non-interdental-DFS), gingivitis (plaque, BOP), chronic periodontitis (mean PD, mean interdental PD, mean non-interdental PD, mean CAL, mean interdental CAL, mean non-interdental CAL, CDC/APP case definition) and tooth loss (number of missing teeth) using comprehensively adjusted linear and ordinal logistic regression models. In total, data from over 2,000 participants with a follow-up time of approximately seven years were utilized. Based on interviews, participants were asked about their habit and the regularity of using interdental aids as a cleaning aid at home. Furthermore, the type of IDA was then analyzed and differentiated into groups of IDA non-users, wooden stick users, floss users and interdental brush users.
Regular interdental aids usage was associated with reduced levels of periodontitis severity (mean PD and mean CAL) and gingivitis variables (plaque and BOP). The beneficial effect was more pronounced in participants using dental floss or interdental brushes regularly. After seven years of follow-up, odds of having higher mean PD levels were halved (Odds Ratio 0.49; 95% confidence interval (CI) 0.35;0.66) comparing dental floss users with non-users. Respective ORs were 0.61 (95%CI 0.45;0.83) for mean CAL, 0.52 (95%CI 0.36;0.77) for BOP and 0.36 (95%CI 0.24;0.54) for plaque. Similarly, ORs for interdental brush users were 0.75 (95%CI 0.55;1.02) for mean PD, 0.64 (95%CI 0.41;0.97) for BOP and 0.55 (95%CI 0.39;0.77) for plaque, compared to non-users. For wooden sticks non-significant associations were found, which does not allow any statement to be made regarding possible effects on oral health. Caries variables (DF-S) and the number of missing teeth were non-significantly associated with interdental aids usage.
In conclusion, results suggest that interdental cleaning aids usage may contribute to healthier gums and reduced inflammation, if combined with daily toothbrushing and regular dental checkups. Specifically, dental flossing and interdental brushing might notably reduce gingival inflammation and therefore prevent chronic periodontitis. These findings contribute to a more distinct picture of how IDA might help to prevent oral diseases and must be properly integrated into our daily oral hygiene program.
Age is the single biggest risk factor for most major human diseases. As such, understanding the intricate molecular changes that drive biological aging holds great promise in attempting to slow
the onset of systemic diseases and thereby increase the effective health-span in modern societies.
This thesis explores several computational approaches to capture and analyze the molecular biological alterations triggered by intrinsic and extrinsic aging using skin as a model tissue to deliver genes and pathways as potential targets for intervention strategies.
Publication 1 demonstrates the utility of multi-omics data integration strategies for aging research, leading to the identification of four latent aging phases in skin tissue through an integrated cluster analysis of gene expression and DNA methylation data. The four phases improved the detection of molecular aging signals and were shown to be associated with sunbathing habits of the test subjects. Deeper analysis revealed extensive non-linear alterations in various biological pathways particularly at the transition into the fourth aging phase, coinciding with menopause, with potentially wide-reaching functional implications. Publication 2 describes the development of a novel type of age clock, that provides a new level of interpretability by embedding biological pathway information in the architecture of an artificial neural network. The clock not only generates meaningful biological age estimates from gene expression data, but further allows simultaneous monitoring of the aging states of various biological processes through the activations of intermediate neurons. Analyses of the inner workings of the clock revealed a wide-spread impact of aging on the global pathway landscape. Simulation experiments using the transcriptomic clock recapitulated known functional aging gene associations and allowed deciphering of the pathways by which accelerated aging conditions such as chronic sun exposure and Hutchinson-Gilford progeria syndrome exert their effects. Publication 3 further explores the molecular alterations caused by the pro-aging effector UV irradiation in the skin. The multi-omics data analysis of repetitively irradiated skin revealed signs of the immediate acquisition of aging- and cancer-related epigenetic signatures and concurrent wide-spread transcriptional changes across various biological processes. Investigations into the varying resilience to irradiation between subjects revealed prognostic biomarker signatures capable of predicting individual UV tolerances, with accuracies far surpassing the traditional Fitzpatrick classification scheme. Further analysis of the transcripts and pathways associated with UV tolerance identified a form of melanin-independent DNA damage protection in individuals with higher innate UV resilience.
Together, the approaches and findings described in this thesis explore several new angles to advance our understanding of aging processes and external drivers of aging such as UV irradiation in the human skin and deliver new insight on target genes and pathways involved.
Can established parties influence the electoral success of new parties? To answer this research question, the author examined the relationships of 168 new parties in 18 highly developed democracies with their established competitors based on their respective election programmes and election results. His analysis of the textual similarity of these election manifestos shows that established parties can influence their competitors' election results by selectively changing the emphasis of their policies. However, competition among the parties must also be taken into account. This study thus contributes to a better understanding of the dynamics of party competition and the opportunities offered by computer-assisted textual analysis in the social sciences.
Background & Aim: Person-Centered-Care (PCC) requires knowledge about patient preferences. Among People living with Dementia (PlwD) only limited evidence about patient preferences, more specifically quantitative preferences, is available. Additionally, data on congruence of patient preferences with physicians’ judgements are missing. Information on patient preferences and their congruence with physicians’ judgements is expected to support Shared Decision-Making and respectively support the implementation of PCC in dementia. The aim of this dissertation was to analyze patient preferences and physicians’ judgements for PCC, including an assessment of their congruence, based on data from the mixed-methods PreDemCare-study. (Funding: Doctoral Scholarship from the Hans & Ilse Breuer-Stiftung.)
Methods: Development and conduct of a cross-sectional Analytic Hierarchy Process (AHP) survey with n=50 PlwD and n=25 physicians. Individual AHP-weights were calculated with the principal right eigenvector method and aggregated per group by Aggregation of Individual Priorities (AIP) mode. Individual consistency ratios (CRs) were calculated and aggregated per group. Group differences were analyzed descriptively by AIP-derived means and standard deviations of AHP-weights, resulting ranks, and boxplots. Additionally, differences between groups were investigated with independent paired t-tests or Mann Whitney-U tests. The sensitivity of AHP-results at the level of criteria was tested by an exclusion of inconsistent respondents in both groups, with an accepted threshold of the individual CR at ≤ 0.3 for PlwD and ≤ 0.2 for physicians.
Results: Contrary to expectation, PlwD’s and physician’s ranking of AHP-elements did not differ meaningfully. Memory Exercises was the only AHP-criterion, for which a significant difference in AHP-weights could be identified (p-value = 0.01). After inconsistent participants had been excluded, no rank reversals occurred. At the level of criteria, the mean CR for PlwD was 0.261 and 0.181 for physicians, id est (i.e.) below the
defined threshold.
Conclusion: In the selected study setting of the PreDemCare-study, patient preferences and physicians’ judgements for elements of PCC in dementia aligned well, contrary to expectations. Subject to restrictions by small sample sizes, the findings may form a basis to guide the implementation of preference-based, person-centered dementia care.
Plus‐strand RNA [(+)RNA] viruses are the largest group of viruses, medically highly relevant human pathogens, and are a socio‐economic burden. The current global pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) shows how a virus has been rapidly spreading around the globe and that– without an antiviral treatment– virus trans mission is solely dependent on human behavior. However, other (+)RNA viruses such as rhino‐, noro‐, dengue‐ (DENV), Zika, and hepatitis C virus (HCV) are constantly spreading and expanding geographically. As in the case of hepatitis C, since its first identification in the 1970s, it took more than 30 years to understand the HCV structure, genome organiza t ion, life cycle, and virus‐host interplay leading to the cure of a chronic and life‐threatening disease. However, no vaccination or antiviral treatment exists for most (+)RNA viruses. Con sequently, a precise and comprehensive analysis of the viruses, their life cycles, and parasitic interactions with their hosts remains an important field of research. In the presented thesis, we use mathematical modeling to study the life cycles of (+)RNA viruses. We analyze replication strategies of closely related (+)RNA viruses, namely HCV, DENV, and coxsackievirus B3 (CVB3), to compare their life cycles in the presence and ab sence of the host’s immune response and antiviral drug treatment and consider different viral spreading mechanisms. Host dependency factors shape the viral life cycle, contribut ing to permissiveness and replication efficiency. Our mathematical models predicted that host dependency factors, such as ribosomes, and thus the virus’ ability to hijack the host cell’s translation machinery play an essential role in the viral genome replication efficiency. Furthermore, our mathematical model suggested that the availability of ribosomes in the vi ral life cycle is a crucial factor in disease outcome: the development of an acute or chronic disease. Even though the host developed strategies to attack the virus, e.g., by degrading the viral genome, blocking the viral protein production, and preventing viral spread, viruses found strategies to countermeasure those so‐called host restriction factors derived from the immune system. Our mathematical models predicted that DENV might be highly effective in blocking the cell’s attempts to recognize the invader. Moreover, we found ongoing HCV RNAreplication even with highly effective antiviral drugs that block processes in the viral life cycle. Furthermore, we found alternative pathways of infection spread, e.g., by HCV RNA carrying exosomes, which may be a possible explanation for reported plasma HCV RNA at the end of treatment, found in a subset of patients. Hence, the mathematical models presented in this thesis provide valuable tools to study the viral replication mechanism in detail. Even though being a simplification of reality, our model predictions confirm and explain known and suggest novel biological mechanisms. In the pre sented thesis, I will summarize and discuss key findings and contextualize model predictions in the broader scientific literature to improve our understanding of the viral dynamics and the virus‐host interplay.
The respiratory epithelium acts as both, a barrier of the respiratory tract to Nipah virus (NiV) entry and at the same time as a significant determinant of virus shedding. Both, for humans and pigs, replication in the respiratory tract epithelia is considered a major factor in transmission to other hosts. To understand why the virus constitutes a high-risk pathogen for livestock and humans, knowledge about
viral replication and host responses in relevant cells and tissues is crucial. Most in vitro studies, however, have been performed in conventional cell lines or non-differentiated lung cells. Only a few examples exist where Henipavirus infections have been investigated in fully-differentiated lung
epithelial cell models.
Thus, one aim of this thesis was to investigate infection, replication, spread and host protein dynamics of NiV in primary bronchial epithelial cells (BEC) cultivated at the air-liquid-interphase (ALI). By
immunofluorescence imaging, the NiV infection dynamics in BEC-ALI cultures were monitored over a 12 day time course, in order to provide detailed information about the infection process in the
respiratory epithelium of pigs and ferrets. Compared to undifferentiated primary BEC, the specific infectivity of NiV in BEC-ALI cultures was low. Infections remained focal and complete infection of the
cultures was not observed, even at 12 dpi. Analysis of viral titers and viral mRNA indicated a limited
virion release from the infected ALI-cultures while most of the newly synthesized NiV-RNA remained
cell associated. Immunofluorescence analysis of cross sections from infected ALI-cultures revealed
large infected areas that exhibited a strong cytopathic effect (CPE). Disruption of the epithelium
resulted in apical release of virus antigen-positive cell detritus while ciliated areas and basal cells were
less affected. From these data it was concluded, that NiV transmission could be supported by
exhalation of cell debris associated NiV and thus may contribute to rapid spread of infection in swine
populations.
A second aim was to explore the dynamics of host responses to NiV infection in differentiated BEC-ALI
culture and to assess whether this differs to conventional cell line data available from literature. Even
though strong CPE appeared in later phases of NiV infection, at least the porcine PBEC-ALI cultures
remained robust enough to allow protein sampling over 12 days infection course. Subsequent MS-based proteomics enabled unprecedent insight in complex cell culture response upon NiV infection.
Previous reports indicated a lack of efficient interferon type I induction in non-differentiated pig or
human BEC which were considered a prerequisite for efficient replication in the respiratory epithelium
and virusspread. In contrast to non-differentiated pig BEC (PBEC), in PBEC-ALI cultures multiple factors
involved in interferon responses were upregulated upon NiV infection. Thereby it was demonstrated
that NiV infection induced a robust innate immune response upon infection with elevated components of antigen processing and presentation resulting in the conversion from the constitutive proteasome to the immunoproteasome. In contrast to previous reports about NiV-infected non-differentiated
PBEC or endothelial cells, incomplete immunoproteasome formation and limitations in interferon
response could be excluded. Thus, a model is proposed in which NiV infection and spread in differentiated PBECs is slowed by potent innate immune responses to the virus infection. Overall, the
findings highlight the important role of the respiratory epithelium not only as a physical barrier to virus
infections but also indicate itsrole as a primary site of adaptive immune induction through NiV induced
antigen processing and MHC I presentation.
Finally, to allow functional studies of Henipaviruses at the BSL-2 biosafety level a recombinant CedPV
was generated and rescued. An imaging based screening and quantitative analysis pipeline was established to investigate the role of cellular factors and to screen for potential virus and host gene
directed inhibitory factors. Accordingly, different host and viral genes were targeted with a siRNA-pool
either targeting virus or selected cellular mRNAs followed by the infection with the CedPV and the
quantification of infected cells. With proof of concept of the siRNA screening pipeline, the recombinant
CedPV clone was used as a backbone to insert variousfluorescence reporter genesin order to optimize
the analysis workflow by allowing direct virus quantification in live, unstained samples. Consequently,
this thesis provides a valuable proof for future approaches related to the function of virus proteins,
influence of host-factors and virusreplication and Henipavirus-inhibitorscreens at low biosafety levels.
The role of cell-penetrating peptides in the induction of T cell responses by virus-like particles
(2023)
Many viral structural proteins can self-assemble into virus-like particles (VLPs). VLPs can serve as an effective vaccine or be used as a vaccine platform. One of these structural proteins is the hepatitis B virus core antigen (HBcAg), which appears to be suitable as an antigen carrier due to its high immunogenicity. HBcAg has a major immunodominant region (MIR) that is presented on the surface of the VLPs after self-assembly. Foreign antigens can be inserted into this region. Since HBcAg VLPs, unlike the Hepatitis B virus (HBV), do not have an envelope, they are not able to penetrate cell membranes efficiently. As an extracellular antigen, HBcAg VLPs primarily induce a strong humoral immune response.
In the present study, we investigated the extent to which HBcAg can be modified to also elicit an enhanced cellular, particularly a cytotoxic, immune response. A cytotoxic CD8+ T cell response is predominantly induced by intracellular antigens. Therefore, our goal was to increase the cell penetration capacity of VLPs. We aimed to achieve this by fusing cell-penetrating peptides (CPPs) to HBcAg. CPPs can spontaneously penetrate cell membranes to enter the cytoplasm of cells. To guarantee that the CCPs were localized to the surface of the VLPs, we fused CPPs to the N-terminus of HBcAg. The CCPs were followed by a tag to allow the purification of VLPs. The T cell epitopes, against which the induced CTL should be directed, were derived from the Large T antigen and inserted into the MIR of HBcAg. Finally, we fused fluorescent proteins to the C-terminus of HBcAg to track the entry of VLPs into cells.
Modifications of HBcAg may lead to reduced stability or altered structure of VLPs. To analyze the stability of VLPs, we used nanoscale differential scanning fluorimetry (nanoDSF) analysis. This revealed that the N-terminal fusion of CPPs or the tag to HBcAg does not reduce VLP stability. However, some peptides incorporated into the MIR had a significant effect on the structure and stability of the VLPs. While the incorporation of a Flag-tag or a peptide from ovalbumin had no negative effect on VLP stability, the incorporation of peptides representing T cell epitopes of Large T antigen interfered with VLP formation. Denaturation and reassembly of the aggregates significantly improved the homogeneity of the VLPs, and the C-terminal addition of arginine-rich domains enhanced stability.
Using live cell imaging and flow cytometry, we demonstrated that HBcAg VLPs functionalized with CPP exhibited up to 40% more efficient penetration into professional antigen-presenting cells (JAWS II) than HBcAg VLPs without CPP. This resulted in the increased presentation of integrated T cell epitopes by dendritic cells. In vivo, we detected significantly increased induction of SV40 Large T antigen-specific CTL in mice immunized with CPP-conjugated VLPs compared to unconjugated VLPs.
In this study, we demonstrated that a stronger cellular immune response can be induced by CPP-functionalized HBcAg VLPs than with the unmodified HBcAg VLPs in vitro as well as in vivo. This discovery may have positive implications for future vaccine development where an enhanced cellular component of the immune response is desirable.
As the animal-to-human interface becomes increasingly narrow, transmission events of zoonotic pathogens between animals and humans become more and more probable. While SARS-CoV-2 already accomplished a spillover infection to humans and is responsible for the current pandemic, the bat H9N2 IAV with so far unknown zoonotic potential was only recently discovered. In order to identify I) the role and potential of a newly discovered, potentially pre-pandemic virus, such as the bat H9N2, or II) possible future prevailing virus mutant variants of an already known pandemic virus, such as SARS-CoV-2, it is important to characterize these emerging viruses in vivo as soon and as good as possible.
The first objective in this dissertation (Publications I and II) therefore deals with the characterization of bat H9N2 and the estimation of its zoonotic or even pandemic potential.
In Publication I, a general susceptibility of directly inoculated Egyptian fruit bats to bat H9N2 was confirmed by successful seroconversion, although exhibiting only moderate viral shedding. All three contact animals remained seronegative, though one contact bat showed slight lesions in the histopathological analysis.
Publication II further addressed the question of the zoonotic potential of this virus. Inoculation of day-old turkey hatchlings demonstrated moderate susceptibility to bat H9N2 infection with a measurable seroconversion, while day-old chicken hatchlings were not susceptible to bat H9N2. Ferrets proved to be highly susceptible to bat H9N2 with high viral shedding, a transmission efficiency rate of 100% to direct contact animals at 2 days post contact, but with only minimal clinical signs. Importantly, the virus demonstrated the ability to evade the MxA-restriction factor and to replicate efficiently in human lung tissue explants. Furthermore, seasonal IAV- and standard IAV-vaccines showed no cross reactivity against the bat-N2 protein in humans. Therefore, further research on such viruses is urgently needed in order to prevent a renewed pandemic situation in the future as caused by SARS-CoV-2.
The second objective in this dissertation dealt with the identification and characterization of emerging SARS-CoV-2 Variants of Concern (VOCs).
Therefore, in Publication III, competitive infection experiments were performed using the Syrian golden hamster, the ferret, and transgenic mouse models (K18-hACE2 and hACE2-KI). These studies revealed replicative and transmissive predominance of Alpha VOC over Beta VOC, but not over SARS-CoV-2 WT in the hamster model, although Beta VOC substantially replicated in the lungs of donor animals. In contrast, the Alpha VOC had an unambiguous replication and transmission advantage over WT SARS-CoV-2 in the ferret and both mouse models. A recombinant SARS-CoV-2 WT-SAlpha virus helped to assign the fitness advantage of this variant particularly to the spike protein-associated mutations.
In Publication IV, in vitro results inferred an early replicative fitness advantage of Omicron BA.1 over Delta VOC, although the opposite was observed in competitively inoculated hamsters, ferrets and naive hACE2-KI mice. In addition, Publication IV demonstrated a disadvantage in transmission for the VOC Omicron BA.1 over the Delta VOC and a lack of susceptibility of ferrets after a single infection with the VOC Omicron BA.1. An mRNA vaccination of K18-hACE2 mice caused a drastic reduction of infectious virus particles in organ material following an infection with a recombinant SARS-CoV-2 WT-SDelta, but not when challenged with the SARS-CoV-2 SOmicron BA.1 clone.
This dissertation includes numerous, comprehensive experimental studies that are generally important for the characterization of emerging, potentially pre-pandemic viruses and may provide crucial information about the future dominance of certain virus variants in an ongoing pandemic. Here, the need for the use of a variety of animal models becomes apparent. By characterizing and classifying potentially zoonotic strains, these methods will help to better prepare for potentially upcoming pandemics and, in the case of a zoonotic or even pandemic event, to better detect and understand the circulating strains and their evolution.
Foraging behavior, neuroanatomy and neuroplasticity in cursorial and stationary hunting spiders
(2023)
The central nervous system (CNS) is the integration center for the coordination and regulation of
all body activities of animals and the source of behavioral patterns, behavioral plasticity and
personality. Understanding the anatomy and the potential for plastic changes of the CNS not only
widens the knowledge on the biology of the respective species, but also enables a more
fundamental understanding of behavioral and ecological patterns. The CNS of species with
different sensory ecologies for example, will show specific differences in the wiring of their CNS,
related to their lifestyle. Spiders are a group of mesopredators that include stationary hunting
species that build webs for prey capture, and cursorial hunting species that do not build capture
webs. These distinct lifestyles are associated with major differences in their sensory equipment,
such as size of the different eyes.
In this thesis, I aimed to answer if a cursorial mesopredator would change its behavior due to
different levels of perceived predation risk, and if this behavior would be influenced by individual
differences (chapter 1); how the visual pathways in the brain of the cursorial hunting jumping
spider Marpissa muscosa differs from that of the nocturnal cursorial hunting wandering spider
Cupiennius salei (chapter 2); to what degree the visual systems of stationary and cursorial hunting
spiders differ and whether CNS areas that process vibratory information show similar differences
(chapter 3); and finally if the CNS in stationary and cursorial hunting spiders shows different
patterns of neuroplasticity in response to sensory input and deprivation during development
(chapter 4).
In chapter 1, I found that jumping spiders adjust their foraging behavior to the perceived level of
risk. By favoring a dark over a light substrate, they displayed a background-matching strategy.
Short pulses of acute risk, produced by simulated bird overflights, had only small effects on the
behavior. Instead, a large degree of variation in behavior was due to among-individual differences
in foraging intensity. These covaried with consistent among-individual differences in activity,
forming a behavioral syndrome. Our findings highlight the importance of consistent amongindividual
differences in the behavior of animals that forage under risk. Future studies should
address the mechanisms underlying these stable differences, as well as potential fitness
consequences that may influence food-web dynamics.
In chapter 2, I found that the visual pathways in the brain of the jumping spider M. muscosa differ
from that in the wandering spider C. salei. While the pathway of the principal eyes, which are
responsible for object discrimination, is the same in both species, considerable differences occur
in the pathway of the secondary eyes, which detect movement. Notably, M. muscosa possesses
an additional second-order visual neuropil, which is integrating information from two different
secondary eyes, and may enable faster movement decisions. I also showed that the tiny posterior
median eye is connected to a first-order visual neuropil which in turn connects to the arcuate body
(a higher-order neuropil), and is thus not vestigial as suggested before. Subsequent studies should
focus on exploring the function of the posterior median eyes in different jumping spider species,
Foraging behavior, neuroanatomy, and neuroplasticity in cursorial and stationary hunting spiders
as they show considerable inter-specific size differences that may be correlated with a differing
connectivity in the brain.
In chapter 3, I described all neuropils and major tracts in the CNS of two stationary (Argiope
bruennichi and Parasteatoda tepidariorum) and two cursorial hunting spiders (Pardosa amentata
and M. muscosa). I found major differences in the visual systems of the secondary eyes between
cursorial and stationary hunting spiders, but also within the groups. A. bruennichi has specialized
retinula cells in two of the secondary eyes, which connect to different higher-order neuropils. P.
tepidariorum has only a single visual neuropil connected to all secondary eyes, and lacks
recognizable mushroom bodies. The neuroanatomy of CNS areas that process mechanosensory
information on the other hand, is remarkably similar between cursorial and stationary hunting
species. This suggests that the same major circuits are used for the processing of mechanosensory
information in both cursorial and stationary hunting spiders. Future studies on functional aspects
of sensory processing in spiders can build on the findings of our study.
In chapter 4, I found that developmental neuroplasticity in response to sensory input differs
between a cursorial (M. muscosa) and a stationary hunting spider (P. tepidariorum). While
deprivation of sensory input leads to a volume increase in several visual and mechanosensory
neuropils M. muscosa, neither sensory deprivation nor sensory enrichment had an effect on the
volume of neuropils in P. tepidariorum. However, exposure to mechanical cues during
development had an effect on the allometric scaling slope of the leg neuropils in both M. muscosa
and P. tepidariorum. Future studies should focus on the genetic and cellular basis of
developmental neuroplasticity in response to sensory input in order to explain the observed
patterns.
Autoclaved aerated concrete (AAC) is a building material that combines heat insulation
properties with sufficient mechanical strength for masonry construction. Compared to
ordinary concrete, the matrix is highly porous (>50%) and hardened by a hydrothermal curing
process at 150°C - 200°C. During this process, quartz sand and portlandite react to form first
calcium silicate hydrates (C-(A)-S-H) with Ca/Si ratios <1.3 and then tobermorite. Especially
tobermorite, which has a much larger crystallite size than C-(A)-S-H, provides improved
mechanical strength. This reaction sequence is influenced by many parameters and
additives of which calcium sulfate is probably the most important. Despite several attempts to
investigate these hydrothermal reactions, the actual reaction mechanism involved when
adding sulfate ions is not fully understood. It has been suggested that the addition of ca.
1.5 wt% significantly improves the mechanical properties due to the enhanced formation and
arrangement of tobermorite in the porous matrix. Since the sulfate content in AAC waste is
exceeding regulatory threshold for low-quality reuse in some countries, the aim of this study
was to investigate in detail the reaction mechanisms involving sulfate addition. Such
knowledge may open up the possibility to improve AAC production and to avoid the need for
sulfate addition. To achieve this goal, this research work focused on investigating the
hydrothermal curing process to determine the sequence of hydrothermal reactions and the
spatial distribution of the phases formed. For this purpose, a new setup for in situ X-ray
diffraction was specifically designed to study hydrothermal reactions and to conduct time
intensive experiments on a normal laboratory diffractometer. In order to quantitatively
evaluate the in situ measurements by Rietveld analysis using TOPAS, it was also necessary
to develop atomistic structure models for C-(A)-S-H phases. This was made possible by
adopting a supercell approach that was previously used to describe turbostratically stacked
clay minerals. The structure models, derived from tobermorite, are placed in an otherwise
empty supercell to simulate the C-(A)-S-H nanostructure. Adopting these methodological
advances, it was possible to obtain absolute phase quantities from in situ data and to track
the reaction kinetics of the hydrothermal curing process. These results were then combined
with ex situ X-ray diffraction and scanning electron microscopy. Confirming previous studies,
the major effect of sulfate ions was the formation and decomposition of hydroxylellestadite. It
was further revealed that C-(A)-S-H formation was delayed during hydroxylellestadite
formation, which is supposed to support the silicate ion diffusion and hence the tobermorite
formation at a stage critical for improved hardening of AAC. This can be linked to the
formation of lower amounts of capillary pores in the range of 1-5 µm, as observed by
scanning electron microscopy, and therefore a lower concentration of inherent defects that
resulted in the improved mechanical properties. This research work highlights how important the spatial distribution of crystallites is for the properties of a building material and how this
distribution can be influenced by small alterations in reaction chemistry.
This dissertation explores and tries to unravel the fundamental basis of G-quadruplex end-folding as well as G-quadruplex interactions with small molecules by thermodynamic and structural approaches. Selective targeting of G-quadruplexes with ligands remains elusive, either because the ligand has
considerable binding affinity for other DNA structures or because it fails to discriminate between different G-quadruplex topologies. Unique structural motifs on the G-quadruplex may enhance or inhibit ligand binding to the G-quadruplex. For such aspects, it is necessary to understand the effect of G-quadruplex motifs or elements on the end-folding in order to better tune certain G-quadruplex topologies as model systems. Importantly for targeting G-quadruplex with ligands, motifs called Quadruplex-duplex (QD) junctions and interfaces are shown to be a binding hotspot
for various G-quadruplex ligands containing an intercalator motif. Binding affinity and selectivity of the ligands are discussed with the support of the NMR structures.
Ion traps such as Paul traps and MR-ToF (multi-reflection time-of-flight) devices are indispensable tools at radioactive ion beam facilities for the preparation of high-quality radioactive ion beams for subsequent experiments or for precise measurements of the properties of radioactive ions, such as nuclear binding energies or nuclear charge radii.
Within the work of this thesis, Doppler- and sympathetic cooling is implemented in a linear Paul-trap cooler-buncher enabling a reduction of the longitudinal emittance of radioactive ion beams resulting in a significant improvement of the ion beam quality. Moreover, a next-generation MR-ToF device is conceptualized in order to achieve isobaric pure beams with a higher ion intensity than state-of-the-art MR-ToF devices can provide. Once fully constructed and commissioned, it will operate at an unprecedented ion beam energy of 30 keV. Both of these advances are expected to become important for a wide range of experimental programs pursued at low-energy branches of RIB facilities ranging from fundamental symmetry studies, nuclear structure, rare isotope studies with antimatter, searches of physics beyond the standard model to material science and the production of medical isotopes.
The next-generation MR-ToF mass separator is based on MIRACLS’ 30-keV MR-ToF device for highly sensitive and high-resolution collinear laser spectroscopy. By storing the ions in the Multi Ion Reflection Apparatus for Collinear Laser Spectroscopy (MIRACLS), the same ion bunch is probed by a spectroscopic laser for thousands of times compared to a single passage in traditional collinear laser spectroscopy (CLS). Dedicated simulation studies show that the accuracy and resolution will be close to traditional single-passage CLS while the sensitivity is significantly enhanced. Hence, measurements of nuclear properties via fluorescence-based CLS of very rare radionuclides as well as highly sensitive and high-precision measurements of electron affinities via laser-photodetachment-threshold spectroscopy of negatively-charged (radioactive) ions will become possible.
First measurement campaigns employing MIRACLS’ 1.5-keV MR-ToF device confirm the outstanding boost in signal sensitivity and provide confidence in the application of the MIRACLS technique for the measurement of scarcely produced radioactive ions that have been so far beyond the reach of conventional techniques. Furthermore, the electron affinity of 35Cl was measured, which is in perfect agreement with the literature value. These measurements will serve as important benchmarks for modern atomic and nuclear theory, especially in its description of nuclear charge radii.
In summary, the implementation of Doppler and sympathetic cooling at RIB facilities, the conceptualization of a 30-keV MR-ToF apparatus for highly selective and high-flux mass separation as well as for highly sensitive and high-resolution fluorescence-based laser spectroscopy and the expansion of the MIRACLS technique for the study of negatively-charged ions will enable unprecedented new measurement opportunities at RIB facilities.
Increasing environmental changes primarily due to anthropogenic impacts, are affecting organisms all over the planet. In general, scientists distinguish between three different ways in which organisms can respond to environmental changes in their habitat: extinction, dispersal and adaptation. An example of organisms which are highly adaptable and can easily cope with new and changing environments are invasive species which are able to colonize new habitats with only few individuals. To successfully survive in their new environment, invasive species adapt fast to novel abiotic and biotic parameters, such as different temperature regimes. Phenotypic plasticity which enables organisms to quickly modify their phenotype to new environmental conditions, explains the success in adaptation of invasive species.
While underlying mechanisms of phenotypic plasticity are not fully understood, one possible “motor” of phenotypic plasticity is epigenetics. Especially DNA methylation could explain the fast changes of the organism’s phenotype due to plasticity when experiencing changing environments, as invasive species do. DNA methylation could even contribute to the adaptation of invasive species via phenotypic plasticity, especially with clonally reproducing species. Methods such as common garden experiments with clonally reproducing species are a useful tool to differentiate between phenotypic plasticity and genetic adaptation because the confusing effects of genetic variation are lowered in clonally reproducing species.
Our overall goal was to evaluate the genetic adaptive potential of New Zealand mud snail (Potamopyrgus antipodarum) populations from Europe since they went through an extreme bottleneck after colonizing Europe only 180-360 generations ago. Seemingly, two different clonal lineages colonized Europe because two 16 s rRNA and cytochrome b haplotypes were found across different European countries, haplotypes t and z. The NZMS is a highly successful invasive species that is nowadays nearly globally distributed. The shells of the NZMS show a habitat-dependent high variability and are a fitness-relevant trait. The high variability in shell morphology is due to both genetic variation and phenotypic plasticity. To disentangle genetic from environmental effects on the shell morphology NZMS, we conducted a common garden experiment. We kept asexually reproducing females from eleven European populations in climate cabinets with three different temperatures to produce offspring. We compared shell size and shape across three generations using the geometric morphometrics approach. Furthermore, we estimated reaction norms, maternal effects, broad-sense heritability, the coefficient of genetic variation (CVA) and evolvability (IA) in shell size and shape across different temperature conditions. Additionally, we investigated the reproductive rate of the parental generation.
Results showed that the shell morphology of the parental generation differed across populations. In contrast, the shell morphology of offspring generations became more similar. The reaction norms of the F1 generation were rather variable across the three temperatures. However, we were able to observe a haplotype-dependent pattern across the reaction norms suggesting a restricted genetic differentiation among NZMS in Europe. We detected high heritability values in size indicating a high genetic influence. Heritability values for shape were lower than in size. Generally, heritability varied slightly depending on temperature. Size seemed to have a higher evolvability than shape. However, the values of all our calculations were very low which indicates that the European NZMS populations are genetically diminished. The reproductive rate of the parental generation was rather haplotype than temperature dependent. In summary, we were able to display that the NZMS is capable to plastically adapt its shell morphology to different temperatures showing significant differences between the two haplotypes. Nevertheless, the low evolvability values indicate that little genetic variation has formed since the arrival of the NZMS in Europe and therefore, European NZMS seem to have a reduced ability to react to selection.
These results implied that phenotypic plasticity is important for the adaptation to different environmental conditions in the NZMS and maybe other molluscan species. Since classical experimental approaches can only describe the resulting phenotypes, we also intended to shed more light on the mechanistic side of environmentally induced phenotypic modifications using DNA methylation analysis. Although molluscs represent one of the most diverse taxa within the metazoan and are found in many different habitats, our knowledge of the DNA methylation in molluscs is scarce. Therefore, we aimed at deepening and summarizing our understanding about DNA methylation in molluscs. Publicly available molluscan genomic and transcriptomic data of all eight mollusc classes was downloaded to search for DNA methyltransferases (DNMTs 1-3) responsible for DNA methylation. Additionally, we estimated the normalized CpG dinucleotide content (CpG o/e) indicating the presence/absence and the frequency of DNA methylation in the genome. The CpG o/e ratio refers to the level of DNA methylation in the genome. Based on the sensitivity of methylated cytosines to mutate into thymine residues, species having a high germline methylation in genomic regions over evolutionary time, also have a lower CpG content, which is called CpG depletion. In contrary, species with a limited germline methylation in genomic regions over evolutionary time, show a higher CpG content and lack CpG depletion. The presence or absence of CpG depletion can be calculated with the CpG o/e ratio. Ultimately, the goal of our analyses was to gain insight into the evolution of methylation in molluscs.
We detected DNMTs in all eight mollusc classes and in most of the species. It is therefore plausible that the last common ancestor of molluscs has already had the enzymatic machinery which is needed for DNA methylation. However, various species did not possess the complete DNMT toolkit indicating evolutionary modification in DNA methylation. In general, we found a wide distribution of the bimodal CpG o/e pattern in six mollusc classes, resulting from CpG depletion. The genes in these groups seem to be divided into genes with a high degree of methylation and genes with a lower degree of methylation. This implies that DNA methylation seems to be rather common in molluscs. Species of Solenogastres and Monoplacophora were not or only sparsely methylated. It seems that those mollusc groups have undergone a reduction in DNA methylation. We hope that our investigations will demonstrate the lacking knowledge in epigenetics of molluscs and encourage scientist to execute and continue genetic studies on molluscs.
Emerging infectious diseases are among the greatest threats to human, animal and plant health as well as to global biodiversity. They often arise following the human-mediated transport of a pathogen beyond its natural geographic range, where host species are typically not well adapted due to a lack of co-evolutionary host-pathogen dynamics. One such pathogen is the fungus Pseudogymnoascus destructans (Pd), which causes White-Nose disease in hibernating bats. While Pd was first observed in North America where it has led to mass-mortalities in some bat species, the pathogen originates from Eurasia where infection is not associated with mortality. Most of the Pd research has focused on the invasive North American range, which likely underestimated the genetic structure of the pathogen and the role it might play in the disease dynamics.
In my work, I therefore evaluated the genetic structure of Pd in its native range with the aim of uncovering cryptic diversity and further use population genetic data to address some key ecological aspects of the disease dynamics. With an extensive reference collection of more than 5,000 isolates from 27 countries I first demonstrated strong differentiation between two monophyletic clades across several genetic measures (multi-locus genotypes, full genome long-read sequencing and Illumina NovaSeq on isolate pools). These findings are consistent with the presence of two cryptic species which are both causative agents of bat White-Nose disease (‘Pd-1’, which corresponds to P. destructans sensu stricto, and ‘Pd-2’). Both species exist in the same geographic range and co-occur in the same hibernacula (i.e., in sympatry), though with specialised host preferences. I further described the fine-scale population structure in Eurasia which revealed that most genotypes are unique to single hibernacula (more than 95% of genotypes). The associated differences in microsatellite allele frequencies among hibernacula allowed the use of assignment methods to assign the North American isolates (exclusively Pd-1) to regions in Eurasia. Hence, a region in Ukraine (Podilia) is the most likely origin of the North American introduction.
To gain further insights into the spatial and temporal dynamics of White-Nose disease on a localised scale, several hibernacula were sampled with high intensity (artificial hibernaculum in Germany and natural karst caves in Bulgaria). Low rates of Pd gene flow were observed even among closely situated hibernacula. This indicates that Pd does not remain viable on bats over summer or it would be frequently exchanged among bats (and hence hibernacula) resulting in a homogenous distribution of genotypes. Instead, bats need to become re-infected each hibernation season to explain the yearly re-occurrence of White-Nose disease. Given the distribution and richness of Pd genotypes on hibrnacula walls and infected bats of the same hibernacula, bats become infected from the hibernacula walls when they return after summer. This means that environmental reservoirs exist within hibernacula (i.e., the walls) on which Pd spores persist during bat absence and which drive the yearly re-occurrence of White-Nose disease. In an experimental setup, I confirmed the long-term viability of Pd spores on abiotic substrate for at least two years and furthermore discovered temporal variations in Pd spores’ ability to germinate. In fact, these variations followed a seasonal pattern consistent with the timing of bats absence (reduced germination) and presence (increased germination) and could indicate adaptations of Pd to the bats’ life-cycle. The infection of bats from environmental reservoirs hence seems to be a central aspect of White-Nose disease dynamics and Pd biology.
Pds ability to remain viable for extended periods outside the host increases its risk of being anthropogenically transported and might have played a role in the emergence of White-Nose disease in North America. The existence of a second species (Pd-2) poses a great additional danger to North American bats considering that its introduction there could lead to deaths and associated population declines in so-far unaffected species given what is known about differing host species preferences in Eurasian bats. Even within the native range of Pd, the movement of Pd between differentiated fungal populations could facilitate genetic exchanges (e.g., through sexual reproduction) between genetically distant genotypes. Such genetic exchanges could lead to phenotypic jumps in pathogenicity or host-species preferences and should hence be prevented.
The native range of a pathogen holds great potential to better understand the genetic and ecological basis of a (wildlife) disease. My work informs about the dangers associated with the accidental transport of Pd (and other pathogens) and highlights the need for ‘prezootic’ biosecurity-oriented strategies to prevent disease outbreaks globally. Once a pathogen has arrived in a new geographic range, and particularly if it has environmentally durable spores (as demonstrated for Pd), it will be difficult/impossible to eradicate. Furthermore, a pathogen’s ability to remain viable outside the host and infect them from environmental reservoirs has been associated with an increased risk of species extinctions and needs to be considered when designing management strategies to mitigate disease impact.
The deep geological underground represents an important georesource for the short-
term storage of renewable energy and the long-term reduction of greenhouse gas emissions. To ensure the economic viability and safety of any subsurface storage project, detailed characterisation of the quality and integrity of the reservoir and its cap rock is required. This characterisation includes the accurate determination of the petrophysical properties, such as porosity and permeability, as well as the potential mineral reactions, such as the dissolution of reactive phases, which may occur during the lifespan of such a project. Clay minerals are common components of many reservoir systems and, depending on their type and structure, can have a significant impact on storage and transport properties. These processes are, however, currently not well understood. In order to address these issues, the main focus of this thesis is on mineralogical analyses using X-ray diffraction (XRD) and microstructural studies using focused ion beam scanning electron microscopy (FIB-SEM) together with micro X-ray computed tomography (µXCT) to gain a better understanding of the influence of clay minerals on reservoir and cap rock properties.
A central part of this thesis focuses on the analysis of clay minerals and pore structures of the Bebertal Sandstone of the Parchim Formation (Early Permian, Upper Rotliegend), which is considered a natural analogue for the tight reservoir sandstones of the North German Basin. Two illite polytypes with a variety of characteristic structures have been identified in the Bebertal sandstone. Disordered 1Md illite forms the majority of the observed structures, which include omnipresent grain coatings, altered permeable feldspar grains and pore-filling meshwork structures. Trans-vacant 1M illite represents the second and youngest generation of authigenic illite and occurs as fibrous to lath-shaped particles that grew into open pore spaces and led to a significant reduction in porosity and permeability during late diagenesis. Based on these results, a model for the formation of illite polytypes in the aeolian layers of the Bebertal sandstone was developed that describes the temporal and spatial evolution of porosity and permeability during diagenesis. Information from this model was then used to improve the prediction of permeability of the Bebertal sandstone based on µXCT pore space models and direct numerical simulations. To achieve this, a micro-scale pore space model was created that allowed the simulation of permeability reduction by clay minerals by including nanoporous illite domains based on a novel morphological algorithm. By performing Navier-Stokes-Brinkman simulations, more accurate predictions of permeabilities with respect to experimentally determined values were obtained compared to conventional Navier-Stokes simulations.
The detailed characterisation of the Bebertal sandstone has shown that natural reservoir rocks are usually complex heterogeneous systems with small-scale variations in texture,
composition, porosity and permeability. Flow-through experiments on the Bebertal sandstone revealed that the coupled geochemical and hydrodynamic processes that occur during the dissolution of calcite could not be predicted by reactive transport models. Therefore, as part of this thesis, a novel approach for developing synthetic sandstones at low temperatures based on geopolymer binder was developed. It is shown that simpler and more homogeneous porous materials can be produced with porosity and permeability values in the range of natural sandstones. These can be used to better understand the dynamic and coupled processes relevant to the storage of renewable energy in reservoir rocks through improved experimental constraints.
The final part of this thesis reports on a detailed clay mineral and pore space study of
three shale formations and one mudstone that were identified as potential seals for the Mt. Simon sandstone reservoir in the Illinois Basin. During the Illinois Basin - Decatur Project, this reservoir was used for the sequestration of one megaton of supercritical carbon dioxide. In order to better assess the quality of the sealing units and to better understand the role of the intergranular clay mineral matrix as potential pathway for fluid migration, a multi-scale evaluation was conducted that included thin section analysis, quantitative evaluation of minerals by scanning electron microscopy (QEMSCAN), mercury intrusion capillary pressure (MICP) measurements, quantitative XRD and high-resolution FIB-SEM. The results allow for the classification of the studied formations into primary and secondary seals and emphasise the importance of three-dimensional clay-mineral-related pore structure characterisations in cap rock studies. XRD proved the most reliable method for the identification and quantification of clay minerals in the studied cap rocks and mudstones. In contrast, FIB-SEM and QEMSCAN provided the spacial constraints for reconstructing fluid flow pathways within the clay mineral matrix.
Overall, this thesis highlights the importance of the precise identification of clay minerals in geological reservoirs and their cap rocks. It also illustrates the need for three-dimensional characterisation and modelling of the associated small pore structures for an improved understanding of the rocks diagenetic history as well as the prediction of the transport and storage properties of these crustal reservoir systems.
Underground hard coal mining operations irreversibly disrupt the pre-existing mechanical equilibrium of the geological media. The employment of high-recovery methods modifies the stress field of the sedimentary sequence, generating movement and faulting of the rock layers above and below mined seams. These new fracture zones do affect the original conditions of the hydrogeological system by modifying flow pathways and increasing the permeability of the rock sequence. Moreover, the surface area of rock exposed to air and water is increased, conditioning the water-rock interaction. Despite this rather clear conceptualization, flow and reactive transport processes in fractured overburdens are rarely modeled simultaneously. Discrete setups that consider fractures and porous matrix require extensive characterization of both media, which is impractical for regional case studies. As a result, most post-mining models explicitly ignore fracture structures by employing the equivalent porous approach or even both media with lumped parameter models. However, omitting either medium represents a delicate simplification, considering that mining-related fractures control the rate and direction of water flow within moderately permeable but relatively highly porous rock sequences.
In this dissertation, the specific contribution of fractured and matrix continua to the transient discharge and water quality of a post-mining coal zone is quantified and evaluated. For this purpose, dual and multiple interacting continua models are employed to simulate fluid flow and reactive mass transport in fractured and variable water-saturated rock sequences. The effectiveness of the models is evaluated by simulating the origin, generation and transport of acid mine drainage (i.e., water with elevated concentrations of hydrogen, iron, sulfate and chloride) within the shallow overburden of the Ibbenbüren Westfield. Compared to other coal districts in Germany, this area is strongly delimited by the local geology and topography, resulting in a well-defined hydrogeological system to test the models. Petrographic and chemical analyses performed on core samples from the area show the strong influence of mining-derived fractures on the water-rock interaction within the Carboniferous sequence. The presence of oxidized pyrite along with amorphous iron hydroxide phases in weathering fronts on both sides of the fractures demonstrates the exchange of solutes and gases between the fractured and the porous matrix media.
Based on the previous evidence, the TOUGHREACT software is employed to characterize flow and reactive transport processes in the Westfield. However, each of the two processes is simulated at separate stages to have more control in the adjustment of sensitive parameters for which little information is available. For the flow component, a dual continuum model, with Richard’s equations is used to characterize the unsaturated water flow in both fractured and matrix media. Under this approach, the model adequately reproduces the bimodal flow behavior of the discharges measured in the mine drainage for the years 2008 and 2017. Simulation results show how the fractured continuum generates intense discharge events during the winter months while the rock matrix controls smooth discharge limbs in summer, when water is slowly released back to the fractures. With the flow component calibrated, the second part of the study incorporates the geochemical processes into the model based on actual data from the rock samples. Their simulation requires extending the two-continuum setup to a multiple continua model with five nested block strings: one for the fractures and four for the rock matrix. This further subdivision prevents under-representations of kinetic reactions with short equilibrium length scales and numerical instabilities due to lack of chemical and flow gradients. As a result, the new multiple continua model provides good agreement with respect to long- and short-term concentrations and discharge trends measured in the mine drainage. The flow of oxygen and meteoric water through the fractured continuum leads to a high and steady release of hydrogen, iron and sulfate ions derived from pyrite oxidation in the matrix continua closest to the fractures. Moreover, high chloride concentrations result from the mixing and gradual release of relatively immobile solutes in the matrix as they interact with percolating water in the fracture. Both findings are equally congruent with the reactive pyrite oxidation and iron hydroxide precipitation fronts identified in the fractured core samples.
In the end, the multiple continua models, the simulation procedure and the results of the benchmark and sensitivity analysis scenarios developed for the Westfield pave the way for the application of the approach in other mining zones. The first candidate emerges in the Ibbenbüren Eastfield, where a coupled elemental-isotopic approach included in this thesis has confirmed that water-conducting fracture zones are primary elements for solute generation and transport in the first 300 meters of the overburden. In the latter case, calibration and verification of the models can be complemented with measurements of δ34S in sulfates and δ18O, δ2H, and Tritium in water.
Introduction
The concept of thermal ablation has proven a minimally invasive alternative or accompaniment to conventional tumour therapy. Patients with hepatic primary tumours or metastases are able to profit from it. Several modalities of thermal ablation exist, including radiofrequency ablation, microwave ablation and laser ablation. They differ in regards to their indications and their physical backgrounds, yet they all share the same aim: the hyperthermic ablation of tumorous target tissue.
At this point in time the maximum ablation diameter attained in a singular session using a singular applicator is about 30 mm. The maximum attainable volume is about 23 cm3. However, the mean and median of hepatic lesions exceed that number with about 50 mm. Most hepatic tumours therefore cannot be easily ablated in toto.
One of the main limitations of thermal ablation is the periprocedural transformation of vital tissue into a boundary layer. This boundary layer prevents efficient energy transmission into peripheral tissue and thus limits the potential of thermal ablation. The boundary layer is usually located centrally around the ablation applicator. In laser ablation the formation of this boundary layer is called carbonisation.
A technically simple, yet potentially effective approach to delay or prevent the formation of this boundary layer is the usage of a spacer. This perfused spacer cools the central zone surrounding the applicator. Therefore central temperatures remain beyond the point of carbonisation.
Methods
The development of two spacer prototypes took place in cooperation with the AG “Experimentelle Radiologie” of the University Clinic Charité. The first fully closed prototype featured an internal circulation of cooling fluid without tissue perfusion. The second open prototype perfused into tissue through an opened tip.
The conduct of this study included ex vivo experiments on bovine livers (n = 15) by means of laser ablation. Ablation diameter and ablation volume were recorded through MR-guided volumetry and manual displacement volumetry. The mean values of diameter and volume that were recorded when the stand-alone applicator system was used were then compared to the mean values recorded when using the closed spacer-supported applicator system and the open spacer-supported applicator system. The difference in values between the three applicator types were then examined for statistical significance using SPSS.
To exclude covariates a preliminary experiment was conducted which aimed to maximise power input of the laser and time interval while minimising the chance of carbonisation. For that, one of the variables was increased in intervals and the ablation diameter of all three applicator types was measured until carbonisation occurred.
Results
In the preliminary experiment it was found that following the increase of the pre-set power input of the laser a proportional increase of ablation diameter followed. However when increasing power input above 25 Watt almost instantaneous carbonisation of the central tissue occurred. This was the same for all three applicator types.
When increasing the time interval > 10 minutes the stand-alone applicator system showed central carbonisation, which was not the case when using the closed spacer-supported applicator system or the open spacer-supported applicator system. The two spacer prototypes only experienced carbonisation when a time interval of > 25 minutes was set. Thus the comparison of all three applicator types was conducted at 25 Watt and 10 minutes, whereas the comparison between the closed spacer-supported applicator system and the open spacer-supported applicator system was conducted at 25 Watt and 25 minutes.
During the first experiment the stand-alone applicator system achieved mean values of 37.50 mm ablation diameter and 23.61 cm3 ablation volume. This was a statistically significant (p < 0.001) increase to the values either spacer was able to attain: the closed spacer-supported applicator system recorded a mean value of 28.67 mm ablation diameter and 18.12 cm3 ablation volume, whereas the open spacer-supported applicator system recorded a mean value of 31.00 mm ablation diameter and 18.49 cm3 ablation volume. However, setting a longer time interval was not possible when the stand-alone applicator system was used for ablation. Due to this, a second experiment comparing mean ablation diameter and volume between the two spacer prototypes followed.
During the second experiment with a time interval of 25 minutes the closed spacer-supported applicator system attained a mean value of 52.07 mm ablation diameter and 75.25 cm3 ablation volume. These values showed a statistically significant (p < 0.001) difference in comparison to the open spacer-supported applicator system with mean values of 47.60 mm ablation diameter und 72.20 cm3 ablation volume.
Discussion
Within the framework of this study it was proven that the presence of a spacer between laser applicator and hepatic tissue was able to achieve a significant increase in ablation diameter and ablation volume. By using a closed spacer an increase in volume by a 3.19 factor of change was possible. The open spacer obtained an increase in volume by a 3.06 factor of change. The concept of using a spacer in thermal ablation as a proof of concept study is therefore valid and suitable for further pre-clinical studies.
Gram-negative bacteria secrete lipopolysaccharides (LPS), leading to a host immune
response of proinflammatory cytokine secretion. Those proinflammatory cytokines are
TNF-α and IFN-γ, which induce the production of indoleamine 2,3-dioxygenase (IDO). IDO production is increased during severe sepsis, and septic shock. High IDO
levels are associated with increased mortality. This enzyme catalyzes the degradation of tryptophan (TRP) to kynurenine (KYN) along the kynurenine pathway (KP).
KYN is further degraded to kynurenic acid (KYNA). Increased IDO levels accompany
with increased levels of KYNA, which is associated with immunoparalysis.
Due to its central role, the KP is a potential target of therapeutic intervention.
The degradation of TRP to KYN by IDO was intervened by 1-Methyltryptophan (1-
MT), which is assumed to inhibit IDO. By administering 1-MT, the survival of
1-MT-treated mice suffering from sepsis increased compared to mice not treated with
1-MT. The levels of downstream metabolites such as KYN and KYNA were
expected to be decreased. Surprisingly, in healthy mice and pigs, an increase in KYNA
after 1-MT administration was reported. Those unexpected metabolite alterations after 1-MT administration, and the mode of action, were not the focus of recent
research. Hence, there is no explanation for KYNA increase, while KYN did not change.
This thesis aims to postulate a possible degradation pathway of 1-MT along the KP
with the help of ordinary differential equation (ODE) systems.
Moreover, the developed ODE models were used to determine the ability of 1-MT to
inhibit IDO in vivo. Therefore, a multiplicity of ODE models were developed, including
a model of the KP, an extension by lipopolysaccharide (LPS) administration, and 1-MT
administration.
Moreover, seven ODE models were developed, all considering possible degradation pathways of 1-MT. The most likely degradation pathway was combined with the ODE model
of LPS administration, including the inhibitory effects of 1-MT.
Those models consist of several dependent equations describing the dynamics of the KP.
For each component of the KP, one equation describes the alterations over time. Equations for TRP, KYN, KYNA, and quinolinic acid (QUIN) were developed.
Moreover, the alterations of serotonin (SER) were also included. All together belong
to the TRP metabolism. They include the degradation of TRP to SER and to KYN,
which is further degraded to KYNA and QUIN. Every degradation is catalyzed by an enzyme. Therefore, Michaelis-Menten (MM) equations were used employing the substrate
constant Km and the maximal degradation velocity Vmax. To reduce the complexity of
parameter calculation, Km values of the different enzymes were fixed to literature values.
The remaining parameters of the equations were determined so that the trajectories of
the calculated metabolite levels correspond to data. The parameters of different models were determined. To propose a degradation pathway of 1-MT leading to increased
KYNA levels, seven models were developed and compared. The most likely model was
extended to test whether the inhibitory effects of 1-MT on IDO can be determined.
Three different approaches determined the ODE model parameters of the different hypothesis of 1-MT degradation. In the first approach, ODE model parameters were fixed
to values fitted to an independent data set. In the second approach, parameters were
fitted to a subset of the data set, which was used for simulations of the different hypotheses. The third approach calculated ODE model parameters 100 times without
fixed parameters. The parameter set ending up in trajectories of the TRP metabolites,
which have the smallest distance to the data, was assumed to be the most likely. The
ODE model parameters were fitted to data measured in pigs. Two different
experimental models delivered data used in this thesis. The first experimental model
activates IDO by LPS administration in pigs. The second one combines the IDO
activation by LPS with the administration of 1-MT in pigs.
The most likely hypothesis, according to approach 1 was the degradation of 1-MT to
KYNA and TRP. For the second data set the most likely one was the direct degradation of 1-MT to KYNA. With approach 2 the most likely degradation pathways were
the combination of all degradation pathways and the degradation of 1-MT to TRP and
TRP to KYNA. With approach 3 the most likely way of KYNA increase was given by
the direct degradation of 1-MT to KYNA. In summary, the three approaches revealed
hypothesis 2, the direct degradation of 1-MT to KYNA most frequently. A cell-free
assay validated this result. This experiment combined 1-MT or TRP with or without
the enzyme kynurenine aminotransferase (KAT). KAT was already shown to degrade
TRP directly to KYNA. The levels of TRP, KYN and KYNA were measured. The
highest KYNA levels were yielded with an assay adding KAT to 1-MT, corresponding
to hypothesis 2. The models describing the inhibitory effects of 1-MT revealed that
the model without inhibitory effects of 1-MT on IDO was more likely for all three approaches.
The correctness of hypothesis 2 has to be confirmed by further in vitro experiments. It
also has to be investigated which reactions promote the degradation of 1-MT to KYNA.
The missing inhibitory properties of 1-MT on IDO, determined by the in silico ODE
models, align with previous research. It was shown that the saturation of 1-MT was too
low, e.g. in pigs, to inhibit IDO efficiently.
In this study, the first possible degradation pathway of 1-MT along the KP is proposed.
The reliability of the results depends on the quality of the experimental data, and the
season, when data were measured. Moreover, the results vary between the different
approaches of parameter fitting. Different approaches of parameter fitting have to be
included in the analysis to get more evidence for the correctness of the results.
Posttranslational modifications are involved in the regulation of virtually all cellular processes, including immune response, nevertheless, they are also targets manipulated by invading pathogens. The first investigated example is protein citrullination which is an important posttranslational modification that acts on a multitude of processes like supervision of cell pluripotency and rheumatoid arthritis. Citrullination of targeted arginine residues is performed by the Peptidylarginine deiminase. Within the first published manuscript, being part of this thesis, it was possible to show the use of this posttranslational modification by the human pathogen Porphyromonas gingivalis to facilitate innate immune evasion at three distinct level. P. gingivalis was demonstrated to citrullinate proteins by Porphyromonas peptidylarginine deiminase resulting in diminished phagocytosis and subsequent killing by neutrophils. Furthermore, it was shown that citrullination of histone H3 enables P. gingivalis to survive in neutrophil extracellular traps and incapacitate the lysozyme-derived peptide LP9.
The second investigated posttranslational modification is ubiquitination and its role in respiratory tract infections. Ubiquitination is the covalent attachment of a small protein that consisting of only 76 amino acids to the ε-amino group of lysine residues to posttranslational modify proteins. Acute infections of the lower respiratory tract such as viral and bacterial co-infections are among the most prevalent reasons of fatal casualties worldwide. Therefore, the interactions between host and pathogens resulting in the impairment of the hosts immune response and immune evasion of the pathogens, need to be elucidated. To get new insights in the infection driven changes in protein polyubiquitination and alterations in the abundance of ubiquitin E3 ligases involved in ubiquitination, cellular proteomes were monitored in detail by high resolution mass spectrometry. Therefore, the epithelial cell lines 16HBE14o- (Manuscript II) and A549 (Manuscript III) were co-infected with influenza A virus H1N1 and Streptococcus pyogenes or Staphylococcus aureus or with influenza A virus H1N1 and Streptococcus pneumoniae, respectively. Here, it could be shown in 16HBE14o- cells that co-infection of epithelial cells is not characterized by decreased cell survival and that observable effects on the proteome and ubiquitinome are mostly additive rather than synergistic. S. pyogenes infection affected the mitochondrial function, cell-cell adhesion, endocytosis and actin organization. Viral infection affected mRNA processing and Rho signaling. Viral and bacterial co-infection was detected to affect processes that were already affected by both of the corresponding single infections. No further pathways were strongly affected by the co-infection. A similar result has been observed in A549 cells co-infected IAV and S. pneumoniae. Overrepresented gene ontology terms depict the sum of those observed in the viral and bacterial single infection. Moreover, no significant change in cell survival upon co-infection compared to single bacterial infection was noticed for A549 cells either. This led to the suggestion that co-infection of investigated epithelial cells under examined conditions possesses additive rather than synergistic effect and thus, may not worsen the outcome of the infection within the studied conditions. Infections in other systems, may provide varying results and thus should be examined in future studies.
Background
This study aimed to analyze the impact of low-value medications (Lvm), that is, medications unlikely to benefit patients but to cause harm, on patient-centered outcomes over 24 months.
Methods
This analysis was based on longitudinal data of patients with dementia. The impact of Lvm on health-related quality of life (HRQoL), hospitalizations, and health care costs were assessed using multiple regression models.
Results
Over 24 months, Lvm was highly prevalent and significantly increased the risk of hospitalization, increased health care costs, and reduced patients' HRQoL.
Conclusion
More than every second patient received Lvm, negatively impacting patient-reported HRQoL, hospitalizations, and costs. Innovative approaches are needed to encourage prescribers to avoid and replace Lvm in dementia care.