Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
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Investigating the role of PDK-1 in longevity and healthy ageing using Drosophila Melanogaster
Get PDFOrganismal aging is characterized by a progressive decline in physiological functions, often accompanied by age-related diseases (ARDs) that significantly impair quality of life and lack effective treatments. The insulin/insulin-like growth factor signaling (IIS) and target of rapamycin (TOR) networks are crucial regulators of growth, metabolism, and longevity. In Drosophila, phosphoinositide-dependent kinase-1 (PDK-1) plays a key role in modulating these pathways through two distinct activation mechanisms: one involving the pleckstrin homology (PH) domain, and the other through the PDK-1 interactive fragment (PIF) pocket. PH domain-dependent signaling delays development, reduces size and fecundity, but enhances stress resistance and promotes longevity. Notably, intestinal over-proliferation and reduced climbing ability—common ARDs in Drosophila—were delayed in onset and significantly less severe in these mutants. In contrast, mutations in the PIF pocket similarly reduced size and fecundity while boosting stress resistance, lifespan, and healthspan. However, intestinal over-proliferation was not mitigated by PIF mutations. Furthermore, humanizing PDK-1 in Drosophila did not affect lifespan. Understanding the signaling cascades involved in aging opens the potential for repurposing existing FDA and EMA-approved medications to treat age-related diseases, offering a novel approach to combating aging and its associated disorders
Modeling the Tissue-Specific Somatic Mutation Rate Along the Genome Based on Genomic Features
Get PDFSomatic mutations, arising from unresolved DNA damage, play a critical role in driving cancer development and progression. Previous studies have demonstrated that mutation rates vary throughout the genome and are affected by large-scale genomic determinants. However, they frequently overlooked important genomic features or lacked the resolution to thoroughly examine changes that are particular to different tissues and mutation types.
To address these limitations, we developed a base-pair resolution model to predict somatic mutation rates in the exome. Using cancer mutation datasets and a diverse set of genomic features, we trained and compared several predictive models, including Random Forest, Generalized Linear Models, and LASSO with stability selection. Random Forest performed the best among them and was selected for the majority of analyses. Our findings highlight robust predictive performance, with improved accuracy for specific tissues and mutation types. Key predictors of mutation rate included GC content, replication timing, DNA methylation, histone marks (H3K27ac, H3K4me3, and H3K9ac), RNA expression, transcription factor binding site density, and eQTL annotations. These results underscore the central role of characteristics linked to transcriptional activity in determining local mutation rates.
Remarkably, our models showed a high degree of tissue similarity, and tissue-specific models could be transferred between tissues without losing their predictive power. This finding suggested that the same mutational mechanisms are at play across tissues, enabling the use of a single, generalized model to predict mutation rates effectively across tissues. Extending the approach to the whole genome demonstrated that intergenic areas are subject to the same mutational processes as exonic regions. The models were validated on data from healthy tissues, further supporting their broad applicability.
This study provides a detailed and comprehensive characterization of somatic mutational patterns, leveraging base-pair resolution and an extensive array of genomic predictors. These insights advance our understanding of mutation processes and have the potential to enhance tumor evolution models and driver mutation discovery
Parent-child relationships and older adults’ (mental) health in Europe and the United States
Get PDFWith population aging in many Western societies, the (mental) health of older adults has gained political and societal importance, with research emphasizing both the supportive role of strong parent-child ties and the complex dynamics of ‘too strong’ or weak ties for older parents’ well-being. Against this back-ground, this dissertation has two main objectives: first, to address two frequent methodological issues in social science—reverse causality and omitted variable bias—when examining the reciprocal links be-tween support from adult children, geographic proximity and parents’ (mental) health, to provide clarity on previously inconsistent findings. Second, to expand the focus beyond strong parent-child ties and also consider weak parent-child ties, or parent-child disconnectedness, and their potential effects on and associations with mental health, paying particular attention to differences across marital status groups and gender. Data came from the German Ageing Survey, the Health and Retirement Study and the Sur-vey of Health, Ageing and Retirement in Europe. The first two studies explored the bidirectional links between parent-child ties and parents’ (mental) health, finding that, first, instrumental help from children and older adults’ self-rated health are not interrelated among German older adults, instead both are pre-dicted by their prior levels. Second, intergenerational coresidence, but not close proximity, negatively impacts parental mental health, particularly for fathers and ‘White’ U.S. older adults, with no reciprocal effects. The third and fourth studies examined parent-child disconnectedness, revealing, third, that dis-connectedness in Europe is more common among never married, divorced, and cohabiting men, though its mental health association is greater for parents, particularly mothers, with more stable relationships. Finally, disconnectedness during critical life transitions, such as a “silver split,” has significant long-term mental health consequences for European silver splitters. Overall, this dissertation highlights the im-portance of applying advanced longitudinal methods when studying parent-child ties and older adults’ (mental) health and focusing not only on strong, but also weak ties as potential factors of social isolation and mental health issues
Navigating the Branding Landscape: The Relevance of Brands and Brand Measures for Consumers and Firms
No full textThe cumulative dissertation “Navigating the Branding Landscape: The Relevance of Brands and Brand Measures for Consumers and Firms” investigates the antecedents and consequences of brand relevance and different brand measures from both the consumer and firm perspectives. It consists of three papers. Paper 1 examines the relevance of brands to consumers in their decision-making across 30 categories over five waves of data collection. Model-free evidence demonstrates significant changes in brand relevance over time with high heterogeneity across categories. Model-based analyses using a Bayesian hierarchical linear model suggest that dynamic category factors and the business cycle drive these changes. Paper 2 examines the impact of changes in brand relevance over time on the relationship between brand equity and firm value. The results show a significant positive moderation effect: In categories where brand relevance is high, the stock market reacts more positively towards changes in brand equity. However, if changes in brand relevance over time are not accounted for in the model, this moderating effect becomes insignificant. Finally, Paper 3 investigates the isolated and combined effects of traditional survey-based brand measures and social media-based real-time brand measures on firm value. The findings show that combining both brand measures in a single model yields the highest explanatory power in explaining firm value, indicating a complementary effect. However, this complementary effect is heterogeneous across brands and especially beneficial for manufacturing brands
Invasive Strategy With Intended Percutaneous Coronary Intervention Versus Conservative Treatment in Older People With ST‐Segment–Elevation Myocardial Infarction: A Meta‐Analysis
No full textBackground: Patients ≥80 years old were underrepresented or excluded from landmark trials demonstrating the superiority of primary percutaneous coronary intervention (PCI) in ST‐segment–elevation myocardial infarction. The current meta‐analysis assessed the effects of an invasive strategy with intended PCI compared with conservative treatment in older people (≥80 years) with ST‐segment–elevation myocardial infarction. Methods: A structured literature search was performed. The primary outcome was overall survival. Secondary outcome analyses included but were not limited to 30‐day and 1‐year mortality. Results: Thirteen studies reporting on 102 158 older adults were included. Of these, 31 629 (31%) were assigned to PCI and 70 529 (69%) were treated conservatively. The overall survival was 76.5% in PCI and 67.2% in conservative treatment at the time of longest available follow‐up (odds ratio [OR], 2.18 [95% CI, 1.79–2.66], P <0.001, I 2 =88%, favoring PCI). The follow‐up period ranged from 30 days to 26.5 months. The 30‐day. (OR, 0.39 [95% CI, 0.31–0.50], P <0.001, I 2 =0%) and 1‐year mortality (OR, 0·34 [95% CI, 0.25–0.46], P <0.001, I 2 =0%), were lower in the PCI group. Conclusions: This meta‐analysis indicates a potential underuse of PCI in older adults with ST‐segment–elevation myocardial infarction. PCI was advantageous in short‐ and long‐term survival, but these results were affected by confounding. Nonetheless, every second patient not referred for invasive treatment survived at least 1 year. These findings have hypothesis generating implications, but they indicate ageism and emphasize that PCI should not be automatically withheld in older patients
Persistent epigenetic memory of SARS-CoV-2 mRNA vaccination in monocyte-derived macrophages
No full textImmune memory plays a critical role in the development of durable antimicrobial immune responses. How precisely mRNA vaccines train innate immune cells to shape protective host defense mechanisms remains unknown. Here we show that SARS-CoV-2 mRNA vaccination significantly establishes histone H3 lysine 27 acetylation (H3K27ac) at promoters of human monocyte-derived macrophages, suggesting epigenetic memory. However, we found that two consecutive vaccinations were required for the persistence of H3K27ac, which matched with pro-inflammatory innate immune-associated transcriptional changes and antigen-mediated cytokine secretion. H3K27ac at promoter regions were preserved for six months and a single mRNA booster vaccine potently restored their levels and release of macrophage-derived cytokines. Interestingly, we found that H3K27ac at promoters is enriched for G-quadruplex DNA secondary structure-forming sequences in macrophage-derived nucleosome-depleted regions, linking epigenetic memory to nucleic acid structure. Collectively, these findings reveal that mRNA vaccines induce a highly dynamic and persistent training of innate immune cells enabling a sustained pro-inflammatory immune response
Funktionen von Kollagen XII und XXII in Zähnen und im parodontalen Ligament
No full textZahnanomalien sind ein Thema, dem sowohl in der Forschung als auch im Alltag eine besondere Bedeutung zukommt, da sie die Funktion und Ästhetik der Zähne erheblich beeinträchtigen können. Ihr Auftreten ist häufig genetisch bedingt, wobei solche genetischen Veränderungen oft zu einer fehlerhaften Synthese von Kollagenen führen. Kollagene sind essenzielle Strukturproteine, die maßgeblich zur Stabilität und Funktion des Zahns beitragen. Ein exemplarisches Krankheitsbild ist die Osteogenesis imperfecta, bei der eine gestörte Synthese von Kollagen Typ I – einem essenziellen Bestandteil des Dentins – zur Dentinogenesis imperfecta führt. Ziel meiner Dissertation war es, die Rolle der Kollagene XII und XXII sowie eines spezifischen Subtyps der Osteogenesis imperfecta zu analysieren, um deren Einfluss auf die Zahnstruktur und -entwicklung detailliert zu charakterisieren.
Kollagen XXII, ein Mitglied der FACIT-Proteine, ist primär an der Dentin-Enamel-Junction (DEJ) eines Zahnes lokalisiert. Die Verteilung der Immunfärbung von Kollagen XXII verändert sich im Laufe der Entwicklung. Histologische Färbungen zeigten keinen signifikanten Unterschied zwischen WT und KO. Die innovative Karamoto-Technik ermöglicht es, das DEJ intakt zu halten, ohne einen Zahn zu entkalken. Diese Technik sollte daher genutzt werden, um die Funktion von Kollagen XXII näher zu untersuchen.
Kollagen XII ist bereits bei P2 in der Pulpa und im PDL des Schneidezahns lokalisiert. Mit fortschreitender Entwicklung nimmt die Intensität der Immunfärbung für Kollagen XII im Zahn ab. Im Gegensatz zu Osteoblasten scheinen Odontoblasten bei Col12-/- nicht beeinträchtigt zu sein. Hingegen wird Kollagen XII im PDL exprimiert, wo Veränderungen beobachtet werden konnten. Bei Col12-/- Mäusen ist das Cementum, welches üblicherweise Kollagen I enthält und mit Pikro-Siriusred-Färbung unter einem Polarisationsmikroskop sichtbar ist, nicht mehr erkennbar. Dennoch kann das Cementum bei Col12-/- mittels Cementum-Marker (Osteopontin) angefärbt werden. Solche diskrepanten Färbeergebnisse sollten jedoch mit Vorsicht interpretiert werden, da histologische Unterschiede nicht zwangsläufig funktionelle Veränderungen widerspiegeln. Das Cementum dient als Verankerungsstelle für den PDL und verbindet ihn über den PDL mit dem Alveolarknochen. Bei fehlendem Kollagen XII ist das Kollagen I im Cementum nicht vorhanden, was die Verbindung von PDL zum Zahn schwächt. Auf molekularer Ebene wurde festgestellt, dass bei Abwesenheit von Kollagen XII die Konzentration von Periostin ansteigt. Da Periostin ebenfalls ein wichtiger PDL-Marker ist und eine Schlüsselrolle für die Kaufunktion und den Zusammenhalt des Kauapparats spielt, deutet dies darauf hin, dass die durch das Fehlen von Kollagen XII verursachte Kauschwäche oder PDL-Inkompetenz durch eine erhöhte Periostin-Produktion teilweise kompensiert wird. Andere molekular ähnliche Proteine zeigten jedoch eine normale Intensität bei KO. Die Kieferknochendichte wurde mittels µcT in sagittalen und horizontalen Ebenen um die mesiale Wurzel analysiert. Während in der horizontalen Ebene keine signifikanten Unterschiede in den gemessenen Parametern festgestellt wurden, zeigten sich in der sagittalen Ebene bei der Trabekelabstandsmessung (Tb.Sp) und der Trabekeldichte (Tb.Th) größere Streuungen, jedoch ebenfalls keine signifikanten Unterschiede zwischen WT und KO. Insgesamt blieben die Unterschiede in beiden Ebenen unauffällig.
Bei den KDELR2-Mäusen wurde durch H&E-Färbung eine signifikante Veränderung der Zahnhartsubstanz festgestellt, die möglicherweise auf eine Entwicklungsverzögerung zurückzuführen ist
Impact of perioperative anticoagulation management on free flap survival in reconstructive surgery: a retrospective analysis
No full textBackground: Despite advancements in surgical techniques and perioperative care for free flap reconstructive surgery, concerns persist regarding the risk of free flap failure, with thrombosis and bleeding being the most common complications that can lead to flap loss. While perioperative anticoagulation management is crucial for optimizing outcomes in free flap reconstructive surgery, standardized protocols remain lacking. This study aims to investigate the role of anticoagulation and perioperative practices in free flap reconstructive surgery and their impact on surgical outcomes. Methods: This retrospective, single-center study included all adult patients undergoing free flap surgery from 2009 to 2020. Patients were retrospectively divided based on intraoperative (UFH or no UFH) and postoperative anticoagulation management (UFH only, Aspirin and UFH, Aspirin only). The relationship between anticoagulation protocols, PTT values, and flap survival was assessed. Results: A total of 489 free flap surgeries were included. Most flaps were taken from the upper extremity (49.5%), primarily for tumor-related reconstructions (85.7%). Flap loss occurred in 14.5% of cases, with a median time to flap loss of 3 days post-surgery. Intraoperative UFH (20 IU/kg) was administered to 63.6% of patients and significantly predicted flap survival (OR = 0.45, 95% CI [0.24, 0.82]). PTT values on day 1 post-surgery were significantly related to flap survival (P = 0.03), with each unit increase reducing the relative probability of flap loss by 5.2%. There was no significant difference in flap survival between patients treated with heparin alone and those treated with both heparin and aspirin. The small sample size in the aspirin-only group limited the statistical relevance of this subgroup. Conclusion: Our findings highlight the importance of intraoperative UFH and PTT-guided postoperative management in improving free flap survival. Standardized anticoagulation protocols are essential for enhancing outcomes in free flap reconstructive surgery
Structural reversal of disc cupping measured in Bruch’s membrane opening-based OCT morphometry after PRESERFLO microshunt implantation for open-angle glaucoma
No full text[Article number 26] Background/ Aims: To analyze the longitudinal change in Bruch’s membrane opening minimal rim width (BMO-MRW) and peripapillary retinal nerve fiber layer (pRNFL) thickness using optical coherence tomography (OCT) after implantation of a PRESERFLO® microshunt for surgical glaucoma management in adult glaucoma patients. Methods: Retrospective data analysis of 59 eyes of 59 participants undergoing implantation of a PRESERFLO microshunt between 2019 and 2022 at a tertiary center for glaucoma management. Surgical management included primary temporary occlusion of the glaucoma shunt to prevent early hypotony. Pre- and post-operative OCT examinations of the optic nerve head (ONH) and intraocular pressure (IOP) were assessed. Longitudinal change in morphometric spectral domain OCT parameters of the ONH was correlated to change in IOP. Results: BMO-MRW increased significantly between baseline (BL) and follow-up (FU) within the first three months after surgery (BL = 171.15 ± 66.80 μm; FU = 180.78 ± 70.394 μm; p = 0.034). For the same postoperative period, the mean preoperative IOP of 24.97 ± 7.22mmHg was lowered after surgery to 13.70 ± 5.09 mmHg. Eighteen months after surgery, there was no significant change in BMO-MRW compared to baseline (BL = 169.83 ± 52.69 μm; FU = 164.98 ± 55.85 μm; p = 0.271), while mean IOP was 13.08 ± 4.48 mmHg. A decrease in IOP correlated significantly with a change in BMO-MRW ( r = 0.453, p 0.16) and significantly decreased in later follow-up ( p = 0.009). Conclusion: PRESERFLO® microshunt implantation with primary temporary occlusion leads to a significant transient increase in BMO-MRW. This phenomenon is also known as structural reversal of disc cupping (SRDC). The effect seems to be less pronounced and of shorter duration when compared to previous data after trabeculectomy with comparable pre- and postoperative IOP levels