Gutenberg Open Science (Univ. Mainz)
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Synthesis, supramolecular assembly, and hydrogelation of poly(amino ester) ABA triblock copolymers
No full textPoly(amino esters) derived from N-acylated-1,4-oxazepan-7-ones (OxPs) emerge as promising candidates in the development of new and degradable amphiphiles for hydrogel preparation and delivery formulations. Here, the synthesis of amphiphilic triblock copolymers by ring-opening copolymerization of OxP monomers with various pendant chains is reported. Copolymerization using organocatalysts and a bifunctional initiator afforded neutral P(OxPMe)-b-P(OxPBn)-b-P(OxPMe) and cationic P(OxPNH2+)-b-P(OxPBn)-b-P(OxPNH2+) amphiphilic triblock copolymers with controlled molar masses ranging from 4,600 to 8,500 g/mol and narrow dispersities (Đ ≤ 1.21). A panel of polymers with various block lengths and compositions was synthesized. Their self-assembly in water revealed the formation of nanostructures, including worm-like or spherical morphologies. Modulation of the copolymer composition and concentration enables control over hydrogelation and its macroscopic properties. Finally, we investigated the formulation of a hydrophobic fungicide and its inhibitory effect on spore proliferation, which shows great promise as dispensable and biodegradable hydrogel formulation for agrochemical applications
Regulation of human RNase H1 by phosphorylation
Get PDFR-loops, structures consisting of an RNA:DNA hybrid and a displaced DNA strand, are increasingly investigated as a cell-intrinsic and cancer-relevant source of replication stress (RS). On the other hand, RS stabilizes R-loops in actively replicating and transcribing regions. This suggests potential unexplored mechanisms through which cells mitigate toxic accumulation of RS-borne R-loops.
To investigate the relationship between the replication stress and R-loops, we first stratified RS by severity in HCT116 cells, reasoning that mild RS might have a distinct signaling signature in comparison to moderate or strong RS. Next, we employed multiplexed mass spectrometry-based phosphoproteomics to investigate the regulation of R-loop resolving enzymes upon induction of different levels of RS. Comparisons of aphidicolin- and oncogene-induced RS revealed similarities at the phosphoproteome level, and a common loss of phosphorylation on RNA processing factors. Interestingly, we found that RS reduces phosphorylation of a major R-loop nuclease, RNase H1, at three residues (S74, S86 and S80) adjacent to its hybrid-binding domain.
The kinase search revealed that DYRK1A phosphorylates RNase H1 at S74. Phosphoproteomics analyses revealed that the reduction in DYRK1A signaling is a driver of RS-mediated loss of phosphorylation on RNA processing factors. Finally, we explored functions of RNase H1 phosphorylation. In in vitro assays, the triple phospho-mimicking (S3xD) mutant of RNase H1 had decreased binding to RNA:DNA hybrids in comparison to wild-type or phospho-dead (S3xA) mutant, implying that phosphorylation directly impacts binding to hybrids. In cells, the S3xD mutant showed decreased separation between nucleoli and the nucleoplasm in comparison to S3xA. Finally, interactome analyses with the phospho-mutants and after DYRK1A inhibition revealed phosphorylation-based interactors of RNase H1 and implicated GSK3β in the regulation of RNase H1 stability.
In summary, this work presents major advancements in the understanding of DYRK1A signaling, and of the regulation of activity and stability of RNase H1 by phosphorylation. This could impact the use of RNase H1 as a tool in R-loop biology and advance the understanding of DYRK1A function in disease.123 Seite
Enhancing analysis and interpretation workflows for transcriptome data with an interactive R/Bioconductor toolkit
No full textOver the recent years, bulk RNA-sequencing (RNA-seq) has become the gold standard
for transcriptome analysis, leading to a significant increase in the volume of data
and results being generated. Consequently, this growth has also made the task of interpreting these results increasingly challenging, particularly for functional enrichment
analyses. Functional enrichment analysis constitutes a fundamental step in the analysis of
various omics datasets, aiming to identify differentially regulated pathways between experimental
conditions and to draw insights into the underlying molecular mechanisms of
diseases and specific phenotypes. Due to this widespread use, there are numerous tools
and implementations available to calculate these results. Despite their utility, existing
methods often yield impractical outputs comprising extensive lists of gene sets, impeding
hypothesis generation and synthesis due to inherent redundancy in the found pathways.
Additionally, prevalent approaches for processing enrichment results lack consideration
of network-based information, which is a key factor that could enhance contextualisation
by incorporating interactions among gene set members.
In order to address these issues and facilitate the analysis and interpretation of bulk
RNA-seq data, we previously published a standardised workflow for bulk RNA-seq data
analysis, promoting interactive and reproducible processes using the R packages developed
in our group [Ludt et al., 2022]. This workflow provides a step-by-step documentation
of a typical bulk RNA-seq data analysis, guiding users through the individual steps,
showcasing best practices and promoting reproducibility. However, during our work, we
recognised a significant gap in the workflow: the need for a tool specifically designed to
enhance, simplify and standardise the interpretation of functional enrichment results.
While our previously developed package, GeneTonic, provides basic functionality for
enrichment result exploration, it is certainly not tailored to this task. Consequently, many
of our collaboration partners still resorted to the classical way of functional enrichment
result interpretation: a manual inspection of the extensive list of results searching for
patterns and interesting gene sets, which they further explored using databases such as
the Gene Ontology (GO) or the Kyoto Encyclopedia of Genes and Genomes (KEGG).
However, this process can be prone to bias, as familiar and expected gene sets may be
easily recognised, while novel or unexpected findings might be overlooked, sometimes
simply due to the sheer amount of available results.
In order to evaluate whether this need was only prevalent to our research group
and collaboration partners or portrayed a larger issue within the scientific community, I
conducted a literature review. The findings confirmed that inadequate documentation
and reporting of functional enrichment methods are widespread across the scientific
community, with over 75% of reviewed studies failing to properly detail their analysis, thus
making it difficult to impossible for peers to verify and reproduce the results. Additionally,
the review revealed that published studies frequently highlight gene sets simply because
they appear at the top of the list of results due to their statistical significance. This could
overall imply that the large lists of functional enrichment results are not fully studied,
which could lead to important results and insights being lost. As part of this thesis, I developed a tool which streamlines and simplifies the interpretation
of functional enrichment results. These efforts are composed in GeDi, an
R/Bioconductor package that aggregates gene sets into meaningful clusters based on
various measures of (dis)similarity, thereby reducing redundancy and improving the clarity
of the results. GeDi achieves this by implementing a suite of Gene set Distance
metrics and clustering algorithms. Additionally, GeDi integrates protein-protein interaction
information into the analysis to provide a more comprehensive view of the biological
processes at play.
GeDi supports interactive exploration and detailed drill-down analyses within its
framework through an integrated Shiny application, while also allowing for seamless
integration into existing workflows via its stand-alone functionality. By offering multiple
entry points and accommodating a wide range of use cases, GeDi caters to a diverse
audience, particularly relevant given the increasing volume of enrichment analyses being
conducted. With interactive visualisations and result aggregations, GeDi not only
reduces the time required for researchers to analyse and interpret results but also helps
minimise bias that would be introduced by manual inspection, which is the current standard
practice in many analyses. In doing so, GeDi facilitates a more efficient and objective
interpretation of the data, as showcased in this thesis on publicly available bulk RNA-seq
data.
With its functionality for interactive data exploration, flexible stand-alone features,
and seamless integration into our standardised bulk RNA-seq workflow, GeDi aims to
improve the reporting standards of functional enrichment analyses in published research.
Additionally, GeDi promotes reproducibility through an automated report generation feature.
By making data interpretation more efficient, accessible and reproducible, GeDi has
the potential to drive new research efforts and simplify the generation of novel hypotheses,
ultimately advancing the field of omics analysis.158, [8] Seiten ; Illustrationen, Diagramm
The hadronic vacuum polarization contribution to (g−2)_µ from lattice QCD with coordinate-space methods
Get PDFPrecision calculations are nowadays of central interest for the physics community. They serve on one hand as a test of the standard model and on the other hand as a window into the search for new physics. The anomalous magnetic moment of the muon has represented a puzzle for many years now. At the 0.20 ppm level of accuracy, the experimental measurement is in strong tension with the theoretical prediction. On the theory side, the main source of uncertainty is due to hadronic contributions, which cannot be evaluated perturbatively. The hadronic vacuum polarization (HVP) is the largest such contributions. To obtain this quantity, there are two methods: The dispersive approach, which relies on experimental input from -scattering data and lattice QCD, as a framework to obtain hadronic observables from first principles. In recent years, the lattice community has made tremendous effort in order to reach sub-percent precision in the determination of the HVP contribution \ahvp.
In this thesis, we want to investigate a covariant coordinate-space (CCS) approach for the calculation of \ahvp, which has some advantages compared to the traditional time-momentum representation (TMR) used in the community.
We develop a method for estimating finite-size effects in this new method based on a field theory approach. We present a full lattice calculation of the quark-connected light and strange component to the intermediate distance window quantity at an unphysical pion mass of MeV. This calculation verifies the result obtained using the TMR method. We furthermore give a blueprint for computations of other observables in the CCS representation, especially with applications for very large lattices, which will become more relevant as computing resources become more powerful.
We then turn to the evaluation of isospin breaking corrections to \ahvp. These need to be included in order to match the accuracy of the experimental measurement. We propose a scheme for regularizing the effects from quantum electrodynamics (QED) by introducing a Pauli-Villars regulator in the photon propagator. We present a calculation of one UV-finite diagram that constitutes a major part of the QED corrections to \ahvp. This is performed on several ensembles with pion masses ranging from approximately MeV to MeV. We furthermore employ a calculation of the dominant charged pion and pseudoscalar meson contribution using an effective field theory approach to support the lattice calculation. We obtain a physical result for this partial contribution that can be seen as a benchmark quantity for the lattice calculation of QED corrections to the HVP contribution.141 Seiten ; Illustrationen, Diagramm
Untersuchung zur diagnostischen Relevanz der optisch-spektralen Transmissionsbildgebung bei rheumatoider Arthritis
Get PDFDie vorliegende Arbeit beschäftigt sich mit einer neuen Methode der Bildgebung, der optisch-spektralen Transmissionsbildgebung (OST), die bei entzündlichen Gelenkveränderungen der Hände zum Einsatz kommt. Ziel dieser Arbeit ist es, die diagnostischen Möglichkeiten der OST mit Fokus auf die rheumatoide Arthritis zu bewerten.117 Seiten ; Illustrationen, Diagramm
Electron correlation treatment via many-body expansions
Get PDFThis thesis has significantly advanced the many-body expanded full configuration interaction (MBE-FCI) method, improving its efficiency and accuracy in computing electronic correlation energies across diverse molecular systems. The enhancements prioritize accessibility, versatility, and performance of the method, enabling massively parallel computations exceeding chemical accuracy. Additionally, the many-body expanded complete active space self-consistent field method was developed, providing a framework for addressing large active spaces in statically correlated systems. This approach was applied to investigate the triplet-quintet spin gap of the iron(II) porphyrin complex, using systematically expanded active spaces of up to 50 electrons in 50 orbitals. To optimize MBE-FCI, orbital clustering and screening algorithms were introduced, reducing computational demands while preserving accuracy and ensuring robust error control. An automated algorithm for identifying reference active spaces enables the treatment of both statically and dynamically correlated systems. Furthermore, a novel symmetrization algorithm for localized molecular orbitals facilitates efficient symmetry exploitation in arbitrary molecular point groups. These advancements enable highly accurate ground-state energy calculations for benzene in a cc-pVTZ basis set, setting an unprecedented standard of precision for systems of this size. Collectively, this work establishes MBE-based methods as transformative tools for high-accuracy quantum chemical studies.Diese Dissertation hat die Many-Body Expanded Full Configuration Interaction (MBE-FCI)-Methode erheblich weiterentwickelt, indem Effizienz und Genauigkeit bei der Berechnung elektronischer Korrelationsenergien für verschiedenste molekulare Systeme gesteigert wurden. Die Schwerpunkte der Verbesserungen liegen in der Zugänglichkeit, Vielseitigkeit und Leistung dieser Methode, wodurch massiv parallele Berechnungen mit Ergebnissen jenseits der chemischen Genauigkeit ermöglicht werden. Darüber hinaus wurde die Many-Body Expanded Complete Active Space Self-Consistent Field-Methode entwickelt, die einen Ansatz für die Behandlung großer aktiver Räume in statisch korrelierten Systemen liefert. Diese Methode wurde angewandt, um die Triplett-Quintett-Spindifferenz des Eisen(II)-Porphyrin-Komplexes mit systematisch erweiterten aktiven Räumen von bis zu 50 Elektronen in 50 Orbitalen zu untersuchen. Zur Optimierung der MBE-FCI-Methode wurden Algorithmen zum Orbitalclustering und -screening eingeführt, die den Rechenaufwand verringern, dabei jedoch die Genauigkeit bewahren und eine robuste Fehlerkontrolle sicherstellen. Ein automatisierter Algorithmus zur Identifizierung von aktiven Referenzräumen ermöglicht die Behandlung sowohl statisch als auch dynamisch korrelierter Systeme. Darüber hinaus erleichtert ein neuartiger Symmetrisierungsalgorithmus für lokalisierte Molekülorbitale die effiziente Nutzung von Symmetrien in beliebigen molekularen Punktgruppen. Diese Fortschritte ermöglichen hochgenaue Berechnungen der Grundzustandsenergie von Benzol in einem cc-pVTZ-Basissatz und setzen einen beispiellosen Genauigkeitsstandard für Systeme dieser Größe. Insgesamt etabliert diese Arbeit MBE-basierte Methoden als transformative Werkzeuge für hochgenaue quantenchemische Studien.IV, 145 Seiten ; Illustrationen, Diagramm
Transfer manuell-chirurgischer Fertigkeiten zwischen Laparoskopie und Hysteroskopie
No full text80 Seiten ; Illustrationen, Diagramm
Psychopharmaka in der Schwangerschaft Auswertung der Mainzer Geburtenkohorte 1991 – 2014
No full textIV, 80 Seiten ; Illustrationen, Diagramm
Evaluation des Faktor XIII als möglichen Prädiktor von chirurgischen Komplikationen in der Leber- und Bauchspeicheldrüsenchirurgie
Get PDF80 Seiten ; Illustrationen, Diagramm
Key factors influencing long-term engagement : a quantitative analysis of Special Olympics World Games 2023 volunteers
Get PDFIntroduction: The contribution of volunteers to the success of mega sport events is very valuable, as they dedicate their time and skills without financial compensation. Despite the undiminished enthusiasm for volunteering at events, grassroots sport in Europe faces increasing challenges in retaining long-term volunteers in sports clubs. This study aims to contribute to existing research by examining the characteristics and motivations of volunteers at mega sport events, with a particular focus on the Special Olympics World Games 2023 (SOWG 23). Furthermore, it seeks to identify factors that influence long-term engagement, ultimately promoting a sustainable volunteering legacy.
Methods: A quantitative methodology was employed, utilizing a structured questionnaire survey conducted in the context of the SOWG 23 in Berlin. The questionnaire addressed various domains, including satisfaction, expectations, volunteering history, future volunteering intentions, perceptions of sport event characteristics, and socio-demographic variables. Additionally, an extended version of the VMS-ISE scale was employed in order to ascertain the motives of the surveyed volunteers. Following verification, 512 validated responses were subjected to analysis employing descriptive and inferential statistical methods and techniques.
Results: The results demonstrate that most respondents were female, married or in life partnerships, without children, of advanced age, highly educated, and with prior volunteering experience despite no parental history of volunteering. Intrinsic motivations were pivotal for volunteer engagement at the SOWG 23, while extrinsic rewards had a lesser influence. The group-specific analysis, based on individual volunteering history, identified key factors that distinguished those who became active as a result of the event from those who did not. The binomial logistic regression model developed was statistically significant significant [χ2(18) = 48.01, p < .001] and explained a large proportion of the variance (R2 = .51).
Discussion/Conclusion: This study enhances the understanding of the characteristics and motivations of volunteers engaged in the Special Olympics context, and identifies specific factors that facilitate long-term engagement. Furthermore, the findings offer invaluable insights that have informed the development of recruitment strategies aimed at fostering a volunteer legacy in both the sports and non-sports sectors