Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
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[18F]Fluoride as a Nucleophile for the Ring Opening of Cyclic Ammonium Salts
Get PDFThis thesis describes the development of novel methods for the preparation of radiofluorinated aliphatic amines. Specifically, DABCO (1,4-diazabicyclo[2.2.2]octane) and 3-hydroxyazetidinium salts were investigated as precursors for nucleophilic ring opening with [18F]fluoride under “minimalist” conditions.
The nucleophilic ring opening of DABCO salts was investigated. Starting with a 3-phenylpropyl DABCO salt as an aliphatic model compound for optimization studies, the radiofluorinated ring opening product, the corresponding N'-2-[18F]fluoroethylpiperazine could be prepared with RCCs of 96 ± 4%. Thereafter, aliphatic DABCO salts with alkyne and azide motifs were synthesized and evaluated as radiofluorination precursors, which afforded the 18F-labeled products with RCCs of 63 ± 4% and 48 ± 2%, respectively. Furthermore, several N'-2-[18F]fluoroethylpiperazines were synthesized by ring-opening of suitable DABCO salt intermediates, which were prepared in situ by treating benzoyl chloride, tosyl chloride, bromo-iodo-pyridine or 4-trifluoromethanesulfonate benzaldehyde with DABCO in tetrahydrofuran (THF). Subsequent radiofluorination under minimalist conditions demonstrated that the DABCO motif in these salts acts as an effective leaving group, affording the respective N'-2-[18F]fluoroethylpiperazines with RCCs of 28 ± 1%, 32 ± 1%, 46 ± 3%, and 47 ± 3%, respectively.
Next, a phenyl DABCO salt was synthesized as aromatic model compound and radiofluorinated under reaction conditions optimized to account for the higher reactivity. This afforded the corresponding 18F-labeled product with RCCs of up to 98 ± 1%. Subsequent screening of additional DABCO salts confirmed excellent radiolabeling efficiencies, with RCCs of 66 ± 5% to 98 ± 1% for various aromatic model compounds, and 38 ± 1% for an azide-substituted compound.
Several attempts were made to apply this method to the radiolabeling of pharmaceutical compounds. Synthesis of amino acids and PSMA (prostate-specific membrane antigen) ligand precursors containing the N-alkyl-substituted DABCO motif was explored but proved unsuccessful. Further efforts to prepare and radiofluorinate DABCO-substituted prosthetic groups and linkers for conjugation with pharmacophores also failed. Likewise, attempts to prepare a DABCO-based precursor for the radiosynthesis of PSMA ligands did not yield viable results.
Next, the radiofluorination of a model 3-hydroxyazetidinium salt was optimized with regard to the heating method (conventional vs. inductive) and other reaction parameters. The best radiochemical conversions (RCCs) of 65 ± 10% were obtained in MeCN with an inductive heater at 110 °C for 5 minutes. These conditions were then applied for the preparation of 18F-labeled more complex, clickable azetidines. The radiofluorination of a 3-propargoxy-substituted 3-hydroxyazetidinium salt did not yield any radiolabeled product, while the corresponding azide-substituted salt was successfully radiolabeled with RCCs of 26 ± 1%.
In conclusion, while the methods developed in this study show significant potential, their practical application to radiopharmaceutical synthesis remains not unfold. The challenges encountered in their application for PET-tracer synthesis underscore the need for further optimization and refinement to make them viable for practical radiopharmaceutical applications
Split Ergativity in Ch’orti’ Maya: A Contribution to a Diachronic Typology of Alignment Change
Get PDFThis dissertation provides a new historical explanation for the alignment split and the third set of indexes ("set C") in Ch’orti’ Maya. Using the historical-comparative method and diachronic typological analysis, this study challenges existing theories that derive set C from set A and instead proposes that set C originates from set B in its use as part of the independent pronoun paradigm, which is attested in Hieroglyphic Maya. On the typological side, the thesis highlights the role of discourse-driven syntactic reanalysis in the development of alignment systems and demonstrates how focus structures can serve as a bridge for the evolution of grammar
Health Inequalities in the Covid-19 Pandemic – The Association of Socioeconomic Status and Covid-19 Infections and Outcomes
Get PDFThis dissertation examines the role of socioeconomic factors and social deprivation in the course of the COVID-19 pandemic, with a particular focus on health inequalities. The aim of the thesis is to explore the relationships between socioeconomic status (SES) and COVID-19 infection rates and disease severity and to analyze how deprivation as a specific indicator of socioeconomic disadvantage influences the risk of severe COVID-19 outcomes. This study focuses on two central research questions: (1) To what extent can a relationship be established between SES and COVID-19 in terms of severity and infection rates? (2) To what extent does deprivation as an SES indicator influence negative COVID-19 outcomes such as hospitalizations, intensive care and deaths, and which mediators of this relationship are identified in the current literature? To answer these questions, the dissertation is based on a narrative review and a systematic review with meta-analysis. The analysis is divided into several chapters, starting with a theoretical consideration of the social determinants and their effects on health. The empirical part follows, in which study results on the relationship between social factors and COVID-19 are evaluated and critically discussed. The theoretical framework of this dissertation is based on established models of Social Determinants of Health (SDoH) and Fundamental Causes of Disease (FCoD) theory. The SDoH theory illustrates how external social and economic influences, including income, level of education and housing conditions, shape individual risk and health opportunities. People in socioeconomically disadvantaged positions often have poorer access to health resources, a higher incidence of health burdens and thus an increased risk of illness. The theory of fundamental causes of disease complements this approach and shows that fundamental social and economic inequalities are the causes of health disparities and are often obscured by the focus on immediate health risks, such as individual behavior. In this paper, deprivation is understood as a multidimensional measure of socio-economic disadvantage that takes into account social and environmental influences in addition to material resources. The term therefore differs from SES, as it describes a more comprehensive dimension of social disadvantage that goes beyond financial aspects and includes various living conditions. SES often encompasses income, educational attainment and occupational status, while deprivation includes additional factors such as living environment and access to social services. This differentiated view of SES and deprivation is considered throughout the dissertation and precisely distinguished from one another. The narrative review of this dissertation analyzes studies that shed light on the relationship between SES and COVID-19 mortality or infection rates in order to gain initial insights. The systematic review and meta-analysis, on the other hand, specifically uses studies that use deprivation indices to examine the relationship between social deprivation and negative COVID-19 trajectories in detail. This methodological dichotomy makes it possible both to look at early findings on the general relationship between SES and COVID-19 and to provide an in-depth analysis of the specific effects of deprivation. The empirical results of the dissertation support the hypothesis that low SES and high deprivation have a significant negative impact on the risk of infection and the course of COVID-19. Particularly noteworthy are health risk factors that often occur in socially disadvantaged population groups and increase susceptibility to severe disease progression. Comorbidities such as diabetes, high blood pressure and obesity, which correlate strongly with a low SES, contribute to the fact that the people affected have an increased risk of severe COVID-19 progression. The analysis also shows that people with low SES often work in occupations that entail a higher risk of infection or live in cramped living conditions, which further favors the spread of SARS-CoV-2. In summary, it can be concluded that socioeconomic disadvantages have a significant impact on the course of COVID-19. The work underlines the importance of targeted, socially equitable health policies that aim to reduce social inequalities and better protect particularly disadvantaged population groups. The dissertation makes the case for integrating social determinants of health more strongly into pandemic prevention and working towards a more equitable distribution of health resources in order to optimize health care in times of crisis
Proximal Aortic Landing Zone Dilation Following Thoracic Endovascular Aortic Repair for Type B Aortic Dissection: Incidence and Clinical Implications
No full textChronic Lymphocytic Leukemia: 2025 Update on the Epidemiology, Pathogenesis, Diagnosis, and Therapy
No full textDisease Overview: Chronic lymphocytic leukemia (CLL) is the most frequent type of leukemia. It typically occurs in older patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that interfere with the regulation of proliferation and apoptosis in clonal B‐cells. Diagnosis: The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B‐lymphocytes, which identify a clonal B‐cell population carrying the CD5 antigen as well as typical B‐cell markers. Prognosis and Staging: Two clinical staging systems, Rai and Binet, provide prognostic information by using the results of physical examination and blood counts. Various biological and genetic markers provide additional prognostic information. Deletions of the short arm of chromosome 17 (del(17p)) and/or mutations of the TP53 gene predict a shorter time to progression with most targeted therapies. The CLL international prognostic index (CLL‐IPI) integrates genetic, biological, and clinical variables to identify distinct risk groups of patients with CLL. The CLL‐IPI retains its significance in the era of targeted agents, but the overall prognosis of CLL patients with high‐risk stages has improved. Therapy: Only patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. When treatment is indicated, several therapeutic options exist: combinations of the BCL2 inhibitor venetoclax with obinutuzumab, or venetoclax with ibrutinib, or monotherapy with one of the inhibitors of Bruton tyrosine kinase (BTK). At relapse, the initial treatment may be repeated if the treatment‐free interval exceeds 3 years. If the leukemia relapses earlier, therapy should be changed using an alternative regimen. Future Challenges: Combinations of targeted agents now provide efficient therapies with a fixed duration that generate deep and durable remissions. These fixed‐duration therapies have gained territory in the management of CLL, as they are cost‐effective, avoid the emergence of resistance, and offer treatment free time to the patient. The cure rate of these novel combination regimens is unknown. Moreover, the optimal sequencing of targeted therapies remains to be determined. A medical challenge is to treat patients who are double‐refractory to both BTK and BCL2 inhibitors. These patients need to be treated within experimental protocols using novel drugs
Entwicklung eines formalen Beschreibungsmodells für das geisteswissenschaftliche Forschungsdatenmanagement - eine qualitative Untersuchung von Beratungsprotokollen zur bedarfsorientierten Beschreibung, Strukturierung und Modellierung des Managements von digitalen Forschungsdaten
No full textIm Rahmen der Dissertation "Entwicklung eines formalen Beschreibungsmodells für das geisteswissenschaftliche Forschungsdatenmanagement - eine qualitative Untersuchung von Beratungsprotokollen zur bedarfsorientierten Beschreibung, Strukturierung und Modellierung des Managements von digitalen Forschungsdaten" von Patrick Helling wurde ein formales Beschreibungsmodell zur Definition des Forschungsdatenmanagements (FDM) mit einem Fokus auf die Geistes- und Sozialwissenschaften entwickelt. Das Modell wurde mit Hilfe einer qualitativen Inhaltsanalyse, die auf ein anonymisiertes Korpus bestehend aus 146 FDM-Beratungsprotokollen angewendet wurde, entwickelt. Entsprechende qualitative und quantitative Analysen des kodierten Korpus ermöglichen die datenbasierte Beschreibung, Definition und Konkretisierung von FDM-Bedarfsmustern sowie notwendiger Kompetenzprofile zur Bedienung ebenjener FDM-Bedarfe. Das formale Beschreibungsmodell fungiert dabei als gemeinsame Sprache für ein neues Tiefenverständnis über das Management von Forschungsdaten, das in seiner Form sowohl methodisch als auch inhaltlich Pionierstatus hat. Eine vorgelagerte quantitative Beforschung der FDM-Versorgungslandschaft mit Fokus auf die organisatorische, strukturelle und inhaltliche Ausgestaltung von FDM-Beratungsservices im deutschsprachigen Raum situiert das Beschreibungsmodell grundsätzlich
Mitofusin 2 displays fusion-independent roles in proteostasis surveillance
No full textMitochondria are essential organelles and their functional state dictates cellular proteostasis. However, little is known about the molecular gatekeepers involved, especially in absence of external stress. Here we identify a role of MFN2 in quality control independent of its function in organellar shape remodeling. MFN2 ablation alters the cellular proteome, marked for example by decreased levels of the import machinery and accumulation of the kinase PINK1. Moreover, MFN2 interacts with the proteasome and cytosolic chaperones, thereby preventing aggregation of newly translated proteins. Similarly to MFN2-KO cells, patient fibroblasts with MFN2-disease variants recapitulate excessive protein aggregation defects. Restoring MFN2 levels re-establishes proteostasis in MFN2-KO cells and rescues fusion defects of MFN1-KO cells. In contrast, MFN1 loss or mitochondrial shape alterations do not alter protein aggregation, consistent with a fusion-independent role of MFN2 in cellular homeostasis. In sum, our findings open new possibilities for therapeutic strategies by modulation of MFN2 levels
Factors influencing role preferences in decision-making of healthy women with BRCA1/2 pathogenic variants: subanalysis from a randomised controlled decision coaching trial
No full textBackground: Patients who actively engage in their medical decision-making processes can experience better health outcomes. This exploratory study aimed to identify predictors of preferred and actual roles in decision-making in healthy women with BRCA1/2 pathogenic variants (PVs). Methods: Women with BRCA1/2 PVs without a history of breast and/or ovarian cancer were recruited in six centres across Germany. Those returning the baseline questionnaires (T1) were randomly assigned to the intervention or control group (IG, CG). The IG completed a decision-coaching (DC) programme, the CG received standard care. A second survey (T2) followed after 12 weeks. Ordinal regression analyses were performed. Sociodemographic and outcome-related baseline variables were used to identify predictors of (i) desired role at T1 in the total group and (ii) actual role at T2 in the CG and the IG. Role preferences were measured with the Control Preferences Scale. Results: 389 women completed the baseline questionnaires, 191 were randomised to the CG and 198 to the IG. At T1, high decisional conflict (OR 1.016, 95% CI 1.001–1.023, p = 0.038) and a negative self-concept (OR 1.030, 95% CI 1.008–1.054, p = 0.009) were significant predictors for preferring a more passive role. At T2, high baseline decisional conflict significantly predicted taking a more passive role in the CG, whereas in the IG, baseline decisional conflict showed no influence. Furthermore, in the IG, younger age (OR 1.049, 95% CI 1.001–1.098, p = 0.044) and a non-academic education (OR 0.46, 95% CI 0.213–0.775, p = 0.006) were identified as significant predictors for taking a more active role. Conclusions: High initial decisional conflict was identified as an important predictor for preferring and taking a passive role in decision-making among women with BRCA1/2 PVs. Participating in the DC programme can counteract passivating effects of an initially high decisional conflict and particularly support younger PV carriers and those with lower educational status to take an active role. With this profile, the DC programme expands the existing counselling and care concept to include a measure that can also specifically cover the support needs of younger women and those with a lower education level. Trial registration ; DRKS-ID: DRKS00015527. Registered 30/10/2019
Regulation der Hippo-Signalkaskade durch das Nephronophthise Protein Nima-Related Kinase 8 (NEK8/NPHP9)
No full textDie Nephronophthise ist eine erbliche, zystische Nierenerkrankung und die häufigste genetische Ursache für terminales Nierenversagen bei Kindern und Jugendlichen. Ihre genetischen Ursachen sind komplex, und es sind Mutationen in über 20 Genen beschrieben, wobei Veränderungen in NPHP1 am häufigsten sind. Bei 10% bis 20% der Patient:innen treten extrarenale Manifestationen auf, wobei Augen-, Zentralnervensystem-, Leber-, Knochen-, Herz- und Lungenbeteiligungen vorherrschend sind. Die betroffenen Gene kodieren Proteine, die Nephrozystine genannt werden, und in primären Zilien lokalisiert sind. Primäre Zilien sind sensorische Organellen, die in fast allen menschlichen Geweben und Zellen vorhanden sind und Signale aus der Zellumgebung ins Zellinnere übertragen. Die "ziliäre Hypothese" verknüpft den Verlust der renalen primären Zilien mit der Entstehung zystischer Nierenerkrankungen.
Der Hippo-Signalweg ist eine Signalkaskade, die die Zellproliferation und Apoptose reguliert und somit eine wichtige Rolle bei zystischen Nierenerkrankungen spielen könnte. In Säugetieren wird bei Aktivierung durch verschiedene Stimuli die zentrale Kinase MST aktiviert, die wiederum LATS aktiviert und die Effektorproteine TAZ und YAP phosphoryliert. Dadurch werden TAZ und YAP inaktiviert, indem sie nach ihrer Phosphorylierung an 14-3-3 gebunden und im Zytoplasma zurückgehalten oder abgebaut werden. Bei Inaktivität der Kaskade wird die Phosphorylierung unterbunden und TAZ und YAP translozieren in den Kern, was zu erhöhter Proliferation und reduzierter Apoptoserate führt. Das Nephronophthise-Protein NPHP4 wurde bereits als negativer Regulator des Hippo-Signalweges identifiziert und stellt die erste Verbindung zwischen der Hippo-Kaskade und Nephronophthise her. Ein ähnlicher Effekt wurde für NPHP9 vermutet. In der vorliegenden Arbeit konnte nun gezeigt werden, dass NPHP4 mit NPHP9 interagiert. Weitere Befunde ergaben, dass NPHP4 zu einer nukleären Anreicherung von NPHP9 führt. Nukleäres NPHP9 stabilisiert wiederum nukleäres TAZ und aktiviert eine TAZ-abhängige Transkription. TAZ wurde bereits als Onkogen in Brustkrebszellen identifiziert, mit einer deutlichen Korrelation zwischen Überexpression von TAZ und Invasivität dieser Zellen. In weiteren Experimenten konnte gezeigt werden, dass Zelllinien mit stabil exprimiertem TAZ eine höhere Proliferationsrate aufweisen und dass die TAZ-induzierte Hyperproliferation durch NPHP9-Suppression teilweise reversibel ist. Dieser antiproliferative Effekt durch NPHP9-Regulation wurde auch in endogen TAZ-dysregulierten MCF-7-Brustkrebszelllinien nachgewiesen. Die Ergebnisse legen nahe, dass NPHP9 ein attraktiver Angriffspunkt für zukünftige zielgerichtete antiproliferative Therapien sein könnte
Specifying Precision in Visual-orthographic Prediction Error Representations for a Better Understanding of Efficient Reading
No full textAbstract: Efficient visual word recognition presumably relies on orthographic prediction error (oPE) representations. On the basis of a transparent neurocognitive computational model rooted in the principles of the predictive coding framework, we postulated that readers optimize their percept by removing redundant visual signals, allowing them to focus on the informative aspects of the sensory input (i.e., the oPE). Here, we explore alternative oPE implementations, testing whether increased precision by assuming all-or-nothing signaling and more realistic word lexicons results in adequate representations underlying efficient word recognition. We used behavioral and electrophysiological data (i.e., EEG) for model evaluation. More precise oPE representations (i.e., implementing a binary signaling and a frequency-sorted lexicon with the 500 most common five-letter words) explained variance in behavioral responses and electrophysiological data 300 msec after stimulus onset best. The original less-precise oPE representation still best explains early brain activation. This pattern suggests a dynamic adaption of represented visual-orthographic information, where initial graded prediction errors convert into binary representations, allowing accurate retrieval of word meaning. These results offer a neurocognitive plausible account of efficient word recognition, emphasizing visual-orthographic information in the form of prediction error representations central to the transition from perceptual processing to the access of word meaning