Gutenberg Open Science (Univ. Mainz)
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Molekulare Untersuchungen onkologisch relevanter Biomarker als Baustein für die personalisierte Medizin
Get PDFMolekulare Untersuchungen onkologisch-relevanter Biomarker sind entscheidend für die personalisierte Medizin, da sie die Diagnose von Krebserkrankungen präzisieren und die Entwicklung zielgerichteter Therapien ermöglichen können. Durch die grundlagenwissenschaftliche Analyse von Tumor-assoziierten Strukturen können individuelle Tumoreigenschaften identifiziert und somit maßgeschneiderte Behandlungsstrategien entwickelt werden.
Die Threonin Aspartase 1 (Taspase1) wurde in diesem Zusammenhang als onkologisch-relevante Protease mit Biomarker-Potential für verschiedene Tumorentitäten charakterisiert. Taspase1 spielt eine entscheidende Rolle bei der Aktivierung von Mixed Lineage Leukemia (MLL)-Fusionsproteinen und demzufolge bei der Entstehung aggressiver Leukämien. Darüber hinaus wurde eine funktionelle Überexpression von Taspase1 bei einer Reihe von soliden Tumoren, wie auch den Kopf-Hals-Tumoren (head and neck squamous cell carcinoma, HNSCC) gezeigt. Die Erforschung neuartiger Biomarker ist insbesondere auch für HNSCC notwendig, da HNSCC-Patienten durch Metastasierung und Rezidive eine äußerst schlechte Prognose aufweisen. Hier kann Taspase1 nicht nur als prognostischer Biomarker, sondern auch als mögliches therapeutisches Zielprotein dienen.
Zur detaillierten Charakterisierung der onkologischen Aktivität von Taspase1 wurde im Rahmen dieser Arbeit ein besonderer Fokus auf Protein-Interaktionen und subzellulären Transportmechanismen gelegt, welche entscheidend an der Regulation ihrer proteolytischen Aktivität und somit ihrer onkogenen Wirkung beteiligt sind. Einer der wichtigsten und zugleich onkologisch-relevanten Interaktionspartner von Taspase1, welcher der Protease den Zugang zum Nukleus und insbesondere zum Nukleolus ermöglicht, ist Nucleophosmin1 (NPM1). Da eine Hemmung der spezifischen Taspase1-NPM1-Interaktion einen innovativen Ansatz zur Taspase1-Hemmung darstellt, wurde zunächst die Interaktionsdomäne beider Proteine identifiziert. Die hierfür generierte Deletions- und Lokalisationsmutanten von NPM1 wiesen auf eine funktionell bedeutsame Region im N-Terminus von NPM1 hin. Veränderungen im Bereich von ±100 Aminosäuren im N-Terminus beeinträchtigen die nukleoläre Lokalisation der NPM1-Mutanten. Die Aktivität von NPM1 wird zudem durch die Oligomerisationsdomäne gesteuert, wie Untersuchungen mit NPM1-knockdown-Zellen und Mutanten ohne Oligomerisationsdomäne belegen. Darüber hinaus wird die Interaktion von NPM1 mit Taspase1 hauptsächlich durch die N-terminale Oligomerisations-/Chaperondomäne gesteuert, wobei die C-terminale Region (aa187-260) ebenfalls eine wichtige Rolle spielt.
Um die NPM1-Taspase1-Interaktion im Detail zu verstehen, wurden weitere Untersuchungen mit Hilfe von chimären Proteinen aus humaner und Drosophila Taspase1 (dTasp) durchgeführt. Im Gegensatz zur humanen Taspase1, zeigt die homologe Protease aus Drosophila keine Interaktion mit NPM1. Die proteolytisch aktive Taspase1 besteht aus zwei Untereinheiten, der α- und β- Untereinheit, welche in den hergestellten chimären Varianten aus unterschiedlichen Spezies stammen (α-hTasp/β-dTasp und α-dTasp/β-hTasp). Beide Taspase1-Chimären zeigten keine Interaktion mit endogenem NPM1. Lokalisationsstudien und Messung der proteolytischen Aktivität der chimären Proteasen verdeutlichten, dass die subzelluläre Taspase1-Lokalisation von der α-Untereinheit abhängt, während die proteolytische Aktivität von der β-Untereinheit gesteuert wird.
Interessanterweise zeigen Zellen, welche NPM1-Mutanten in Kombination mit Taspase1 exprimieren, eine erhöhte Viabilität, was auf eine unterstützende Wirkung von Taspase1 auf NPM1 hinweist. Des Weiteren führte eine Taspase1-Überexpression zur gesteigerten Empfindlichkeit von HNSCC-Zellen gegenüber der chemotherapeutischen Behandlung mit Cisplatin. Eine kombinierte Chemo- und Strahlentherapie erwies sich als besonders effektiv, wobei höhere Cisplatin-Dosen einen synergistischen Effekt mit der Bestrahlung aufweisen. Neben der molekularen Untersuchung der Taspase1-NPM1-Interaktion, wurden zudem neuartige Möglichkeiten zur Etablierung von zirkulierenden Biomarkern für die Tumor-Diagnostik erforscht. Um einerseits die Behandlungsoption der Patienten zu optimieren und auf das Niveau einer personalisierten Therapie zu bringen, und andererseits eine frühere Diagnose der Erkrankung stellen zu können, wurden die im Rahmen von „liquid biopsy“ zirkulierende Tumorzellen im Blut von HNSCC-Patienten untersucht. Verschiedene Detektionssysteme und Kulturmethoden zur Isolierung und Identifikation dieser Zellen wurden optimiert. Kleine extrazelluläre Vesikel, sogenannte Exosomen, erwiesen sich als potenzielle Biomarker für die Frühdiagnostik. Experimente zur Isolierung und Untersuchung ihrer Interaktion mit anderen Zellen und Partikeln, sowie die zelluläre Aufnahme von Exosomen durch Makrophagen lieferten neue Einblicke in die Transportmechanismen innerhalb von Zellen. Diese Erkenntnisse legen nahe, dass Exosomen als diagnostische Biomarker, therapeutische Zielstrukturen oder Nanosysteme zur Medikamentenverabreichung genutzt werden könnten.
Zusammenfassend konnten im Rahmen dieser Arbeit wichtige Erkenntnisse gewonnen werden, welche neben ihrer grundlagenwissenschaftlichen Relevanz zudem das Potential haben, zukünftige Strategien der Krebs-Diagnostik und -Therapie zu beeinflussen.224 Seiten ; Illustrationen, Diagramm
Volume uptake of carbonyls during diffusional ice crystal growth
Get PDFCarbonyls are highly relevant atmospheric constituents that influence tropospheric photochemistry and oxidative capacity. They can be removed from the upper troposphere via ice phase deposition scavenging. The gas-volume uptake coefficients for 14 different carbonyl compounds were determined using a flowtube apparatus. Ice crystals were grown from vapor deposition in the presence of gas phase carbonyls at −20, −30, and −40 °C. Using van't Hoff analysis, the entropy and enthalpy of uptake were determined. An inverse relationship between uptake coefficients and temperature was observed for all species except methyl vinyl ketone. A linear correlation between ΔS and ΔH arose which was statistically validated and determined with 99 % confidence to not be a statistical artifact. This compensation behavior could be an indication of a surface liquid layer or quasi-liquid layer behavior involved in the uptake process and could also indicate a single dominant influence on a compound's uptake. The most significant physicochemical properties correlated with uptake were identified to be vapor pressure and molar mass, which indicate that smaller compounds with higher vapor pressures are more readily taken into the ice phase. The volume uptake coefficients observed here are below the 10 mol m−3 Pa−1 threshold given by Crutzen and Lawrence (2000) to be considered a substantial atmospheric removal process
Assessing the helical stability of polyXYs at the boundaries of intrinsically disordered regions with MD simulations
Get PDFIntrinsically disordered regions (IDRs) of proteins lack a stable structure. Their high content of hydrophilic and charged residues prevents them from forming globular domains and contributes to their flexibility and accessibility. Naturally, regions with a reduced amino acid composition (low complexity regions; LCRs) are found within IDRs. Disorder and low complexity of protein sequences are linked to various biological functions, including phase separation, regulation, and molecular interactions, and mutations in these regions can contribute to several diseases, including cancer. Understanding these biological properties requires examining the structural properties of IDRs and the LCRs they contain, but their inherently dynamic nature requires specific approaches combining sequence analysis, structure predictions, and molecular dynamics (MD) simulations. Here, we leverage our previous work, where we identified that certain types of LCRs combining two residues (polyXY) are frequent within IDRs and confer them with a propensity to form helical conformations. We identified a significant accumulation of these polyXYs at the ends of IDRs, following alpha helices that begin outside the IDR and can extend through the polyXY into the IDR, particularly from the N-terminal end of the IDR. MD simulations support the dynamic nature of these helical conformations. Our results suggest a mechanism by which the evolutionary emergence of LCRs at IDR ends could provide proteins with flexible regions for fold-upon-binding
Immunoadsorption study Mainz in adults with post-COVID syndrome (IAMPOCO) : a single-blinded sham-controlled crossover trial to evaluate the effect of immunoadsorption on post-COVID syndrome
Get PDFBackground
Post-COVID syndrome (PCS) affects up to 43% of all SARS-CoV-2-infected persons and describes ongoing symptoms months after the acute infection. Despite the large number of affected people, there is still very little evidence about therapeutic options. Some studies suggest at least partially a role of autoantibody-mediated autoimmunity. Immunoadsorption is an extracorporeal therapy to remove circulating antibodies which is used successfully in several autoimmune diseases. We conceived the IAMPOCO trial to evaluate the therapeutic effect of immunoadsorption in patients with PCS.
Methods
IAMPOCO is a single-center randomized sham-controlled trial with a crossover design which will enroll 40 participants with PCS and a symptom severity of at least 2 on post-COVID functional scale. All participants will undergo 5 immunoadsorption treatments and after a washout period of 8 weeks 5 sham treatments or vice versa. Which modality is conducted first will be randomized. Patients but not providers of therapy are blinded for which modality is conducted. Primary outcome is the efficacy of IA to the severity of PCS measured by the change of several symptom scores and hand grip strength. Secondary outcomes are the frequency of adverse events and the prevalence of relevant autoantibodies in participants with PCS as well as the concentration of autoantibodies before and after therapy and sham treatment.
Discussion
The trial addresses the lack of evidence for treatment options in PCS. By using a crossover design and including a sham treatment arm, the study aims to compare the effects of immunoadsorption and sham therapy within the same patients. The trial also benefits from recruiting participants from a cohort study on PCS prevalence, ensuring a thorough evaluation of symptoms. Objective assessments of symptoms are challenging due to their subjective nature, but various scoring systems and tests are being utilized. Despite the lack of data from RCTs, the results of this study have the potential to significantly improve PCS therapy and support evidence-based treatment decisions
Stabilization and observation of large-area ferromagnetic bimeron lattice
Get PDFSymmetry engineering is an effective approach for generating emergent phases and quantum phenomena. In magnetic systems, the Dzyaloshinskii-Moriya (DM) interaction is essential for stabilizing chiral spin textures. The symmetry manipulation of DM vectors, described in three dimensions, could provide a strategy toward creating abundant topologically magnetic phases. Here, we have achieved breaking the rotational and mirror symmetries of the three-dimensional DM vectors in a strongly correlated ferromagnet, which were directly measured through the nonreciprocal spin-wave propagations in both in-plane and out-of-plane magnetic field geometries. Combining cryogenic magnetic force microscopy and micromagnetic simulations, we discover a bimeron phase that emerges between the spin spiral and skyrmion phases under an applied magnetic field. Such an artificially manipulated DM interaction is shown to play a critical role in the formation and evolution of the large-area bimeron lattice, a phenomenon that could be realized across a broad range of materials. Our findings demonstrate that symmetry engineering of the DM vectors can be practically achieved through epitaxial strain, paving the way for the creation of diverse spin topologies and the exploration of their emergent functionalities
Roman masculinity and latin poetic funerary epigraphy in the North-Western provinces (1st century B.C. - 3rd century A.D.)
Get PDFThis dissertation investigates the construction and representation of Roman masculinity through Latin poetic funerary inscriptions from the north-western provinces of the Roman Empire between the first century B.C. and the third century A.D. While studies of Roman masculinity have traditionally relied on elite literary sources, this research employs funerary verse epigraphy as an alternative lens to explore how gendered ideals were expressed by a broader social spectrum, including freedmen, soldiers, artisans, and provincial citizens. By analysing the epigraphic language of emotion and virtue, two fundamental dimensions of Roman masculine identity, this study examines how men and women in the provinces articulated moral and emotional values within commemorative contexts.
This research demonstrates that ancient Roman emotions, as represented in funerary verse, were not as rigidly gendered as literary sources suggest. Rather, emotional expression appears to have transcended gender boundaries, indicating that Roman men were equally capable of displaying feelings such as grief, love, and joy. For the concept of virtue, both men and women were depicted in funerary epigraphy as embodying Roman moral values, expressed either explicitly or through symbolic allusion. Most references were brief and formulaic, though verse inscriptions occasionally offered fuller reflections on moral character. The most frequently invoked virtues (pietas, fides, and innocentia) were not selected along gendered lines but rather according to relational or social relevance.
By integrating gender theory, epigraphic studies, and emotion- and virtue research, this dissertation contributes to the broader understanding of Roman identity formation, showing that masculinity in antiquity was not a monolithic ideal but a negotiated, performative construct: one materially and poetically inscribed across the empire’s funerary landscapes.xiii, 514 Seite
Transcatheter edge-to-edge repair of atrial secondary mitral regurgitation positively influences atrial remodelling
Get PDFBackground:
Atrial secondary mitral valve regurgitation (ASMR) is a distinct anatomical subset of secondary mitral regurgitation (SMR). Evidence of the effect of transcatheter edge-to-edge repair (TEER) on left atrial (LA) anatomy and function, especially reverse remodelling (LARR), is still sparse.
Methods and results:
We retrospectively evaluated all consecutive patients treated with TEER for mitral regurgitation (MR) in our centre between January 2013 and October 2023. Of the 597 patients with SMR, 103 patients (17.3%) met the inclusion criteria for ASMR. All patients in the ASMR group (mean age 79.4 ± 6.8 years, 71% female) were symptomatic (89% NYHA ≥ III) and had a mean logistic EuroScore of 22.5 ± 12.4%. TEER was successfully performed in all patients, and invasive LA mean pressures decreased intraprocedurally from 17.8 ± 5.7 to 13.1 ± 4.8 mmHg (P < 0.001). At hospital discharge, 94% of patients had mild residual or non/trace MR. At 1YFUP, the prevalence of residual moderate MR was 7% and 1% had severe MR. A significant reduction in LA volume compared with baseline, both at end-systole (151.4 ± 64 vs. 113 ± 64 mL, P < 0.001) and at end-diastole (119.8 ± 56 vs. 91.2 ± 56.9 mL, P < 0.001) could be observed. Seventy per cent of patients had a sustained decrease in NYHA class ≤ II. LARR, defined as LAESV decrease ≥15% at 1YFUP, was documented in 59% of patients. These patients were more likely to have lower post-interventional mitral valve mean pressure gradients (2.2 ± 0.8 mmHg vs. 2.8 ± 1.1 mmHg, P = 0.02) and lower BNP at discharge and at 1 month follow-up [319 (197.8 to 526) vs. 560 (279.3 to 929), P = 0.07, and 287.5 (191.3 to 386.3) vs. 506.5 (223.3 to 935.5), P = 0.06, respectively]. A multivariate logistic regression analysis identified pre-procedural MPG (P = 0.06, OR 0.92, CI 95% 0.85–1.00) and BNP at discharge (P = 0.11, OR 0.99, CI 95% 0.99–1.00) as independent predictors for the occurrence of LARR at 1 year.
Conclusions:
Transcatheter mitral valve repair by edge-to-edge therapy represents a safe and effective therapeutic option in symptomatic patients with atrial secondary mitral regurgitation and might have the potential to induce left atrial reverse remodelling
Testing convergence among attachment methods : adult attachment interview, relationship-specific attachment scale, and implicit association test
Get PDFAttachment theory describes the framework of how individuals relate in intimate relationships, including their confidence in receiving support and comfort from attachment figures. Three primary research directions, which have led to different methods, are used to investigate the attachment concept: developmental psychology, personality and socio-psychological research, and cognitive psychology. Conceptual differences and the need for convergence among these methods are of high interest to researchers. The present study explores convergence across different research traditions. The study involved 318 participants, including clinical and non-clinical groups matched for age and gender. Various psychometric instruments, including the Adult Attachment Interview (AAI), Relationship-Specific Attachment Scale (BBE), and Mother-Implicit Association Test (IAT), were used to measure attachment and related constructs. The hypothesized associations were investigated by structural equation models. Small correlations among the different methods were found, with stronger associations in the patient sample compared to that of the healthy individuals. The latent correlation was significant and small. Model fit indices indicated a much better fit in healthy controls. Even though there were moderate correlations among the different methods, the associations were generally stronger in the patient sample compared to that of the healthy individuals, even though the instruments were developed based on healthy individuals. The model fit was generally good in the healthy sample but less so in the patient sample. Due to the large differences in the theoretical and developmental background of the methods, it can be proposed that attachment representations may vary depending on the sample and method used
Not all exclamatives behave the same
Get PDFThis article challenges the claim that exclamative sentences lack an illocutionary force of exclamation and are semantically equivalent to emotive assertions. Drawing on German data, we show that there are different classes of exclamatives that vary with respect to deniability and do not function well as answers to information-seeking questions but rather serve as replies in discourse. We argue that all the different classes need to be taken into account to arrive at appropriate generalizations for the phenomena under discussion
Die Bedeutung der IL-1-Zytokinfamilie für die Entwicklung der Metabolischen Dysfunktion-assoziierten steatotischen Lebererkrankung
Get PDFVI, 115 Seiten ; Illustrationen, Diagramm