Insights into the regulation of aging

Aging is doubtlessly one of the most complex and multi-factorial biological processes we have encountered since the beginning of modern life sciences and the systematic study of human and animal biology. Despite many remarkable findings, aging remains an incompletely understood mechanism, causing several severe diseases, such as cardiovascular diseases, neurodegenerative diseases or cancer. It is associated with a progressive loss of cell functions that lead to a decline of tissue functions and finally resulting in death. Uncountable studies were performed over the last five decades to identify possible causes of how and why we age. Nevertheless, there is a still ongoing debate about the true molecular source of aging, giving rise to a variety of competing theories. Due to its highly complex nature, we have investigated aging from various perspectives, based on the gene expression of different species and tissues. We analyzed a huge set of RNA-Seq transcriptomic data to obtain new insights into the genetic regulation of aging and to identify conserved molecular processes that might be responsible for aging-related disorders. We found that each tissue shows its own distinct pattern of gene expressional changes with age, because they have to respond to different types of stress over time, leading to differing sources of molecular damage and subsequent stress responses. In particular, we could show this for four wellstudied aging-related processes: cellular senescence, inflammation, oxidative stress response and circadian rhythms. In addition, we could show that alternative splicing (i.e., the generation of multiple mRNA isoforms from single genes) is in general only slightly affected by aging and probably plays a secondary role in the overall aging process. In contrast, we found microRNAs (very small regulatory RNA molecules) to be important modulators of aging in all investigated pecies and tissues. Concluding, the results presented in this thesis describe aging as a stochastic process, leading to an accumulation of different kinds of molecular damage and the respective cellular stress responses. We have identified several genetic factors that could serve as potential diagnostic markers or even therapeutic targets, that could help in the future to slow down the progression of age-associated disorders or preventing them. Nevertheless, the subject of aging remains a challenging research field and many open questions still wait to be answered.Das Altern ist zweifellos einer der komplexesten und faktorenreichsten biologischen Prozesse, dem wir seit Beginn der modernen Lebenswissenschaften und der systematischen Erforschung der Human- und Tierbiologie begegnet sind. Trotz vieler bemerkenswerter Erkenntnisse bleibt das Altern ein unvollständig verstandener Mechanismus, der mit vielen schweren Krankheiten assoziert ist, wie etwa Herz-Kreislauf-Erkrankungen, neurodegenerative Erkrankungen oder Krebs. Es geht mit einem fortschreitenden Verlust von Zellfunktionen einher, der zu einer Abnahme der Organfunktionen und schließlich zum Tod führt. In den letzten fünf Jahrzehnten wurden unzählige Studien durchgeführt, um mögliche Quellen zu finden, wie und warum wir altern. Auch heutzutage wird noch intensiv über die eigentliche molekulare Ursache des Alterns gestritten, was zu einer Vielzahl konkurrierender Theorien führt. Aufgrund seiner hohen Komplexität haben wir in der vorliegenden Arbeit das Altern aus verschiedenen Perspektiven untersucht, basierend auf der Genexpression verschiedener Spezies und Gewebstypen. Wir haben eine Vielzahl an RNA-Seq Transkriptomdaten analysiert, um neue Einblicke in die genetische Regulation des Alterns zu erhalten und um konservierte molekulare Prozesse zu identifizieren, die möglicherweise für altersbedingte Gebrechen und Krankheiten verantwortlich sind. Wir fanden heraus, dass jedes Gewebe mit dem Alter ein eigenes Muster von Genexpressionsänderungen aufweist, da es im Laufe der Zeit auf verschiedene Arten von Stress reagieren muss, was zu unterschiedlichen Ursachen für molekulare Schäden und nachfolgende Stressreaktionen führt. Insbesondere konnten wir dies für vier gut untersuchte, altersbedingte Prozesse zeigen: zelluläre Seneszenz, Entzündungsreaktionen, oxidative Stressreaktion und zirkadiane Rhythmen. Außerdem konnte gezeigt werden, dass alternatives Spleißen (d. H., die Erzeugung mehrerer mRNAIsoformen aus einzelnen Genen) im Allgemeinen nur geringfügig vom Altern betroffen ist und wahrscheinlich eine untergeordnete Rolle im gesamten Alterungsprozess spielt. Im Gegensatz dazu haben wir festgestellt, dass microRNAs (sehr kleine regulatorische RNA-Moleküle) in allen untersuchten Spezies und Geweben wichtige Alterungsmodulatoren sind. Abschließend beschreiben die in dieser Arbeit vorgestellten Ergebnisse das Altern als einen stochastischen Prozess, der zu einer Anhäufung verschiedener Arten von molekularen Schäden und den jeweiligen zellulären Stressreaktionen führt. Wir haben mehrere genetische Faktoren identifiziert, die als potenzielle diagnostische Marker oder sogar als therapeutische Ziele dienen könnten, die in Zukunft dazu beitragen könnten, das Fortschreiten altersbedingter Erkrankungen zu verlangsamen oder zu verhindern. Trotzdem bleibt das Thema Altern weiterhin ein herausforderndes Forschungsfeld und viele offene Fragen warten noch auf ihre Beantwortung

Robustness during Aging—Molecular Biological and Physiological Aspects

Understanding the process of aging is still an important challenge to enable healthy aging and to prevent age-related diseases. Most studies in age research investigate the decline in organ functionality and gene activity with age. The focus on decline can even be considered a paradigm in that field. However, there are certain aspects that remain surprisingly stable and keep the organism robust. Here, we present and discuss various properties of robust behavior during human and animal aging, including physiological and molecular biological features, such as the hematocrit, body temperature, immunity against infectious diseases and others. We examine, in the context of robustness, the different theories of how aging occurs. We regard the role of aging in the light of evolution

Public Disclosure im Versicherungsmarkt : erste Erfahrungen mit dem Bericht über die Finanzlage

Die vorliegende Studie untersucht die ersten Erfahrungen mit der neuen Offenlegungspflicht (Public Disclosure) im Schweizer Versicherungsmarkt. Die gewonnenen Erkenntnisse lassen vermuten, dass sich die Resonanz für den Bericht über die Finanzlage unter den Versicherungsnehmern bis anhin in Grenzen hält. Aus Sicht vieler der befragten Versicherer übersteigen die Kosten den Nutzen und die Public Disclosure wird als Pflichtübung mit geringem Mehrwert wahrgenommen

An Upgrade for the 1.4 MeV/u Gas Stripper at the GSI UNILAC

The GSI UNILAC will serve as part of an injector system for the future FAIR facility, currently under construction in Darmstadt, Germany. For this, it has to deliver short-pulsed, high-current, heavy-ion beams with highest beam quality. An upgrade for the 1.4 MeV/u gas stripper is ongoing to increase the yield of uranium ions in the desired charge state. The new setup features a pulsed gas injection synchronized with the beam pulse transit to increase the effective density of the stripper target while keeping the gas load for the differential pumping system low. Systematic measurements of charge state distributions and energy-loss were conducted with 238U-ion beams and different stripper gases, including H2 and He. By using H2 as a stripper gas, the yield into the most populated charge state was increased by over 50%, compared to the current stripper. Furthermore, the high gas density, enabled by the pulsed injection, results in increased mean charge states

A Pulsed Gas Stripper for Stripping of High-Intensity, Heavy-Ion Beams at 1.4 MeV/u at the GSI UNILAC

The GSI UNILAC in combination with SIS18 will serve as a high-current, heavy-ion injector for the future FAIR. It has to meet high demands in terms of beam brilliance at a low duty factor (100 mus beam pulse length, 2.7 Hz repetition rate). An advanced 1.4 MeV/u gas stripper setup has been developed, aiming at an enhanced yield into the required charge states. The setup delivers short, high-density gas pulses in synchronization with the beam pulse. This provides an increased gas density at a reduced gas load for the differential pumping system. In recent measurements, high-intensity, heavy-ion beams of U⁴⁺ were successfully stripped and separated for the desired charge state. The modified stripper setup, as well as major results, are presented, including a comparison to the present gas stripper based on a N₂ gas-jet. The stripping efficiency into the desired 28⁺ charge state was significantly increased by up to 60 % using a hydrogen stripper target while the beam quality remained similar

Direct and indirect effects of a pH gradient bring insights into the mechanisms driving prokaryotic community structures

Background: pH is frequently reported as the main driver for prokaryotic community structure in soils. However, pH changes are also linked to "spillover effects" on other chemical parameters (e.g., availability of Al, Fe, Mn, Zn, and Cu) and plant growth, but these indirect effects on the microbial communities are rarely investigated. Usually, pH also co-varies with some confounding factors, such as land use, soil management (e.g., tillage and chemical inputs), plant cover, and/or edapho-climatic conditions. So, a more comprehensive analysis of the direct and indirect effects of pH brings a better understanding of the mechanisms driving prokaryotic (archaeal and bacterial) community structures. Results: We evaluated an agricultural soil pH gradient (from 4 to 6, the typical range for tropical farms), in a liming gradient with confounding factors minimized, investigating relationships between prokaryotic communities (16S rRNA) and physical-chemical parameters (indirect effects). Correlations, hierarchical modeling of species communities (HMSC), and random forest (RF) modeling indicated that both direct and indirect effects of the pH gradient affected the prokaryotic communities. Some OTUs were more affected by the pH changes (e.g., some Actinobacteria), while others were more affected by the indirect pH effects (e.g., some Proteobacteria). HMSC detected a phylogenetic signal related to the effects. Both HMSC and RF indicated that the main indirect effect was the pH changes on the availability of some elements (e.g., Al, Fe, and Cu), and secondarily, effects on plant growth and nutrient cycling also affected the OTUs. Additionally, we found that some of the OTUs that responded to pH also correlated with CO2, CH4, and N2O greenhouse gas fluxes. Conclusions: Our results indicate that there are two distinct pH-related mechanisms driving prokaryotic community structures, the direct effect and "spillover effects" of pH (indirect effects). Moreover, the indirect effects are highly relevant for some OTUs and consequently for the community structure; therefore, it is a mechanism that should be further investigated in microbial ecology.Peer reviewe

Direct and indirect effects of a pH gradient bring insights into the mechanisms driving prokaryotic community structures

Background: pH is frequently reported as the main driver for prokaryotic community structure in soils. However, pH changes are also linked to "spillover effects" on other chemical parameters (e.g., availability of Al, Fe, Mn, Zn, and Cu) and plant growth, but these indirect effects on the microbial communities are rarely investigated. Usually, pH also co-varies with some confounding factors, such as land use, soil management (e.g., tillage and chemical inputs), plant cover, and/or edapho-climatic conditions. So, a more comprehensive analysis of the direct and indirect effects of pH brings a better understanding of the mechanisms driving prokaryotic (archaeal and bacterial) community structures. Results: We evaluated an agricultural soil pH gradient (from 4 to 6, the typical range for tropical farms), in a liming gradient with confounding factors minimized, investigating relationships between prokaryotic communities (16S rRNA) and physical-chemical parameters (indirect effects). Correlations, hierarchical modeling of species communities (HMSC), and random forest (RF) modeling indicated that both direct and indirect effects of the pH gradient affected the prokaryotic communities. Some OTUs were more affected by the pH changes (e.g., some Actinobacteria), while others were more affected by the indirect pH effects (e.g., some Proteobacteria). HMSC detected a phylogenetic signal related to the effects. Both HMSC and RF indicated that the main indirect effect was the pH changes on the availability of some elements (e.g., Al, Fe, and Cu), and secondarily, effects on plant growth and nutrient cycling also affected the OTUs. Additionally, we found that some of the OTUs that responded to pH also correlated with CO2, CH4, and N2O greenhouse gas fluxes. Conclusions: Our results indicate that there are two distinct pH-related mechanisms driving prokaryotic community structures, the direct effect and "spillover effects" of pH (indirect effects). Moreover, the indirect effects are highly relevant for some OTUs and consequently for the community structure; therefore, it is a mechanism that should be further investigated in microbial ecology.Peer reviewe

Identification of altered miRNAs and their targets in placenta accreta

Placenta accreta spectrum (PAS) is one of the major causes of maternal morbidity and mortality worldwide with increasing incidence. PAS refers to a group of pathological conditions ranging from the abnormal attachment of the placenta to the uterus wall to its perforation and, in extreme cases, invasion into surrounding organs. Among them, placenta accreta is characterized by a direct adhesion of the villi to the myometrium without invasion and remains the most common diagnosis of PAS. Here, we identify the potential regulatory miRNA and target networks contributing to placenta accreta development. Using small RNA-Seq followed by RT-PCR confirmation, altered miRNA expression, including that of members of placenta-specific miRNA clusters (e.g., C19MC and C14MC), was identified in placenta accreta samples compared to normal placental tissues. In situ hybridization (ISH) revealed expression of altered miRNAs mostly in trophoblast but also in endothelial cells and this profile was similar among all evaluated degrees of PAS. Kyoto encyclopedia of genes and genomes (KEGG) analyses showed enriched pathways dysregulated in PAS associated with cell cycle regulation, inflammation, and invasion. mRNAs of genes associated with cell cycle and inflammation were downregulated in PAS. At the protein level, NF-κB was upregulated while PTEN was downregulated in placenta accreta tissue. The identified miRNAs and their targets are associated with signaling pathways relevant to controlling trophoblast function. Therefore, this study provides miRNA:mRNA associations that could be useful for understanding PAS onset and progression