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Einfluss der Uhrzeit des Trainings auf die Fastendauer und deren Auswirkungen auf die metabolische Gesundheit
No full textHintergrund: Time-restricted eating (TRE) fokussiert sich auf den Zeitraum der Mahlzeiteneinnahme. Längere Fastendauern können Körpermasse/Körperfettmasse, Insulinresistenz/Insulinsensitivität, systolischen Blutdruck und Lipidprofil verbessern. Inwiefern Trainings- oder TRE-Interventionen auf das Lipidprofil/ Hämoglobin A1c (HbA1c) wirken, wurde schon breit diskutiert, mit inkonsistenten Ergebnissen. Noch fehlt es an Forschung zum Einfluss der Trainingszeit auf die Mahlzeiteneinnahme. Verlängerungen oder Verkürzungen der Fastendauer könnten dadurch resultieren und Vorteile des Fastens hervorbringen.
Methoden: Die EPOCH-Studie ist eine doppelblinde, dreiarmige und randomisiert kontrollierte Studie. 40 ProbandInnen (60-80 Jahre, BMI 18.5-30kg/m2) wurden eingeschlossen und führten einen Mid-Thigh Pull zu vier Tageszeiten (08:00, 12:00, 16:00, 20:00) durch, um sie in vier Interventionsgruppen und eine Kontrollgruppe einzuteilen. Die Interventionsgruppen trainierten während zwölf Wochen zweimal wöchentlich Kraft und einmal Ausdauer zu festgelegten Uhrzeiten (08:00, 12:00, 16:00, 20:00). Das Ernährungsverhalten wurde mittels Food-Photography Methode in Woche 0, 3, 12 erfasst und von der Studienleitung mithilfe von PRODI® ausgewertet. Blutproben wurden nüchtern zur Bestimmung des Lipidprofils/HbA1c entnommen. Für die statistische Auswertung wurden Kovarianzanalysen, t-test und lineare Regression durchgeführt.
Resultate: Es zeigte sich nach Adjustierung auf Woche 0 kein Unterschied der Fastendauer zwischen Interventionsgruppen und Kontrollgruppe (p-Wert Gruppenfaktor = 0.324). ProbandInnen mit verlängerter Fastendauer während der Intervention wiesen höhere total CHOL-, LDL-, HDL-, TG- und HbA1c-Werte auf als jene mit verkürzter Fastendauer. Es bestand kein linearer Zusammenhang zwischen Fastendauer und Lipidprofil/HbA1c (R2 < 0.03).
Schlussfolgerung: Die Fastendauern der Trainingsgruppen unterschieden sich nicht genügend, um eine Uhrzeit des Trainings herauszustreichen, welche zur Verlängerung oder Verkürzung der Fastendauer führte. Auch zeigte sich eine Verlängerung der Fastendauer nicht mit einem verbesserten Lipidprofil/HbA1c-Wert
Chimeric antigen receptor T cell therapy and tumor-associated myeloid cell reprogramming for combined immunotherapy of glioblastoma
No full textGBM remains uniformly lethal, with a median survival of little more than a year from diagnosis. While immunotherapies have revolutionized the SOC for many cancers, patients with GBM have not greatly benefitted from those developments so far. CAR T cell therapy has proven remarkably effective in treating hematological malignancies. However, for solid tumors, especially GBM, CAR T cell therapy remains inefficient mainly due to pronounced tumor immunosuppression and heterogeneous expression of tumor-specific antigens, leading to adaptive resistance and antigen escape. The iTME of GBM plays an essential role in the tumor’s response to immunotherapies. MG and tumor-infiltrating MdCs are among the most prevalent immune cell types in the GBM iTME. In response to the blockade of the CD47-SIRPA tumor-immune checkpoint axis, these GBM-associated MG and MdCs, collectively termed GAMs, regain their phagocytic effector function against GBM cells. In this work, I present the development of a novel CAR T cell to target GBM via the tumor-specific EGFRvIII and reprogram the GBM immunosuppressive iTME through paracrine secretion of a SIRPG-related protein, termed SGRP, which blocks CD47, eliciting phagocytosis. As a proof of concept, I show the therapeutic potential of an anti-EGFRvIII-SGRP CAR T cell in orthotopic GBM and anti-CD19-SGRP CAR T cell in peripheral lymphoma mouse xenograft models. Here, I describe the following significant findings: (1) anti-EGFRvIII-SGRP CAR T cells eradicate EGFRvIII-mosaic GBM, resulting in the long-term survival of GBM mouse xenografts; (2) the combination of conventional anti-EGFRvIII CAR T cells with anti-CD47 antibodies does not warrant comparable efficacy, highlighting the importance of sustained paracrine myeloid cell modulation; (3) anti-EGFRvIII-SGRP CAR T cell treatment induces myeloid-mediated tumor cell uptake in the brain and elicits a peripheral innate chemotactic cytokine response; (4) anti-CD19-SGRP CAR T cell treatment significantly prolongs survival of lymphoma mouse xenografts compared to conventional anti-CD19 CAR T cell therapy. This work provides evidence that tumor-targeting by CAR T cells and paracrine modulation of tumor-associated myeloid cells via a SIRPG-derived molecule is a compelling novel combinatorial therapeutic approach to mitigate the impact of GBM immunosuppression and heterogeneity, encouraging clinical translation in GBM and other myeloid-infiltrated cancers
From predator to partner: investigation of molecular mechanisms and function of "Bartonella" Gene Transfer Agent
No full textGene Transfer Agents are mobile genetic elements mediating horizontal gene transfer in diverse groups of prokaryotes. GTAs originate from bacteriophages and represent a type of rudimentary, domesticated phages endogenized and utilized by prokaryotes. Five distinct types of GTAs are known that share no common origin and represent an example of convergent evolution. GTAs transfer random bacterial genes however the function of GTAs remains debatable. This is associated with the lysis-driven release of GTAs from the producing cells ultimately leading to cellular death. Such a bacterial companion imposes a fitness cost on the host bacterium and would not be selected unless it provides a benefit that balances the cost.
In this work, I investigate the role of the Bartonella Gene Transfer Agent, or BaGTA, in the lifestyle of Bartonella. In contrast to other known GTAs, BaGTA has two separate functional modules: ROR enabling a position-specific amplification of the transferred DNA and BaGTA machinery for its packaging and transfer. This mechanism is a highly conserved feature of pathogens of the genus Bartonella. Moreover, it is suggested to be one of the key innovations underlying their evolutionary success.
In the published Research article I, we investigated an immunogenic surface protein and identified that it is a highly dynamic autotransporter essential for the infection. I use this autotransporter and specific antibodies as tools to address the BaGTA function in the pathogenesis of Bartonella.
I further go into the molecular details of BaGTA functioning and address the interplay of BaGTA with ROR. In Research article II, we investigate the genetic network enabling the coordination of these two distinct components. We found that the ROR encodes a set of regulatory proteins that control the expression of the BaGTA locus. The control is achieved by premature termination of the BaGTA locus transcription and BrrG-mediated processive antitermination. We proposed that additional regulators are involved in controlling BaGTA and speculated about the potential universality of processive antitermination in alphaproteobacterial GTA. We outlined the potential direction for further investigations. Bartonella and BaGTA constitute an interesting model which provides insights into the evolution of pathogens shaped by GTA. GTAs are present in distinct lineages of both bacteria and archaea, and are prevalent in up to 60% of alphaproteobacterial genomes. Thus, GTAs claim to be a widespread mechanism of HGT whose full potential, we believe, is yet to be uncovered
Ecological drivers at the warm edge of species’ distribution
Get PDFWhy are species not evenly distributed all over the globe but are restricted to certain areas? This question has fascinated biologists for a long time. By studying ecology and evolution, biologists try to understand the limits in species geographic distribution and the restriction of adaptation to environmental stresses. Past research has shown that the low latitudinal range edges are often characterised by abiotic environmental factors. The aim of my thesis was to systematically study two pivotal environmental factors, temperature and precipitation, of the model species, Arabidopsis lyrata. In a transplant experiment, I showed that the increase in temperature and variability of precipitation patterns, caused by climate change, negatively affect plant performance. Specifically, germination and flowering success, as well as survival rates were reduced. A greenhouse experiment focusing on the effects of heat, drought, and their combination was conducted to study the adaptation strategies to the different stresses. Even though exposure to heat or drought alone did not affect survival rates much, the combination of both stresses caused a high mortality rate. Populations originating at the warm range edge displayed a slightly better performance and plants had a higher specific leaf area and root-to-shoot ratio. However, plant performance is also dependent on the interaction with the rhizosphere microbiome. Therefore, I analysed how different plant traits correlate with microorganisms under different environmental conditions. I compared the correlations of plant traits with different primary root exudate compounds and rhizosphere bacteria and fungi under different watering treatments. The composition of root exudates and bacteria changed significantly between a moist and a drought treatment. Essentially, more high positive correlations were found under drought, confirming the importance of plant-microbe interactions under stress conditions. In summary, my thesis emphasises the threat of global warming to population persistence at the warm range edge, even if populations originating at the warm edge are adapted to a certain degree. With ongoing climate change, the range optima are likely to shift northwards, despite the beneficial interactions in the rhizosphere
The effect of low root temperature on water uptake in temperate tree species
No full textSummary
Low temperature is one of the main drivers controlling plant growth, reproduction and species distribution range limits. As the limit for tree growth in general, most of studies focused on the general cold edge of the life-form tree at high elevations or latitudes, the fundamental range limits for a tree, but in fact, individual tree species that reach their distribution limits below treeline have their species-specific low temperature extremes as well. While our understanding of the direct cold temperature induced restrictions of cambial and meristematic activity has increased substantially over the last decades, other physiological effects that might also contribute to the cold temperature limit of tree growth have gained much less attention so far. Especially, the potential effects of restricted water uptake and deteriorated hydraulic relations at low root zone temperatures might be additional drivers for the cold limit of tree growth. A relatively limited number of studies delivered strong evidence that even in cold-tolerant tree species, cool root zone temperatures well above 0 °C can have significantly negative effects on the capacity of root water uptake and root hydraulic conductance. Negative cold soil effects on the hydraulic conductivity of trees can thus potentially amplify the direct effects of cold temperatures growth and contribute to the cold limit of temperate tree species. However, the assumption that the restricted water conductivity of roots at low soil temperature for grow limits can not be tested up to date.
As a consequence, a series of experimental studies in this dissertation aimed to provide new insights into the biophysiological mechanism responsible for the cold-temperature limits of temperate trees and the possible explanation for the species-specific cold limits of tree growth. The results of this work revealed that species-specific cold sensitivity in root water uptake might be a fundamental role for the cold range limits for temperate tree species behind the limiting of new cell growth at cold climate. The further study of this dissertation found the prolonged cold soil temperature can lead to the consistent reduction in root water uptake, inducing the occurrence of phenological signal that controlled the preparation for winter dormancy. Furthermore, the results also provide an experimental evidence that the long-term cold acclimation would potentially enhance the capacity of plant root water uptake in temperate trees, while can not improve the physiological threshold of trees controlling the sensitivity of root water uptake in general. Overall, this dissertation with different studies disentangled the physiological and ecological mechanisms behind the elevational or latitudinal cold limits of tree species below the treeline, and highlight the importance of species-specific physiological threshold controlling their sensitivity of root hydraulic conductance for tree growth and tree distribution models in nature
Distinct roles of LARP1 and 4EBP1/2 in regulating translation and stability of 5′TOP mRNAs
Get PDFVertebrate cells have evolved a simple, yet elegant, mechanism for coordinated regulation of ribosome biogenesis mediated by the 5′ terminal oligopyrimidine (5′TOP) motif. This motif allows cells to rapidly adapt to changes in the environment by specifically modulating the translation of messenger RNAs (mRNAs) encoding the translation machinery. The core signaling pathway which links nutrient availability with the production of ribosomes is the mechanistic target of rapamycin complex 1
(mTORC1), which integrates a variety of nutrient cues to modulate the translation of 5′TOP mRNAs. While the role ofmTORC1 in regulating the translation of 5′TOP mRNA has been well established, the identity of the key factor which binds to the 5′TOP motif to regulate translation has been challenging to elucidate.
Recently, La-related protein 1 (LARP1) was proposed to be the specific regulator of 5′TOP mRNA translation downstream of mTORC1, while eIF4E-binding proteins 1 and 2 (4EBP1/2) were suggested to have a general role in translational repression of all transcripts. To address these questions, we employed single-molecule translation site imaging of 5′TOP and canonical mRNAs to study the translation of single mRNAs in living cells. We reveal that 4EBP1/2 play a dominant role in the translational repression of both 5′TOP and canonical mRNAs during pharmacological inhibition of mTOR. In contrast, we find that LARP1 selectively protects 5′TOP mRNAs from degradation in a transcriptome-wide analysis of mRNA half-lives. Our results clarify the roles of 4EBP1/2 and LARP1 in regulating 5′TOP mRNAs and provide a framework to further study how these factors control cell growth during development and disease
Grenzgängerinnen und Grenzgänger: Berner Selbstzeugnisse um 1700
Get PDFDie zu Grunde liegende These der Dissertation ist, dass Mobilität nicht nur Grenzerfahrungen mit sich bringt, sondern auch zum Schreiben veranlasst. Bewegung wird dabei im weitesten Sinne verstanden – geographisch, sozial, kulturell. Wer sich bewegt, schafft Differenz und Verbindung zugleich, gerät in Kontakt mit Anderem, Unbekanntem, findet, überschreitet und produziert Grenzen und setzt sich mit ihnen auseinander. Dabei wird in Selbstzeugnissen untersucht, was in diesen Schwellenbereichen und Grenzräumen um 1700 passiert, wie die Verfasserinnen und Verfasser darüber schreiben, den Grenzraum produzieren, was dies für eine Gesellschaft oder jedenfalls die schreibenden Teile davon bedeutet, und wie es sich auswirkt
„Schwierige“ Kinder. Abklärung, Therapie und Forschung in der ambulanten Kinder und Jugendpsychiatrie, 1950–1980
No full textOstracism in everyday life: unprecedented insights through experience sampling
Get PDFThis thesis leverages experience sampling as an innovative approach to investigate real-life experiences of ostracism (i.e., being ignored and excluded), filling gaps left by traditional survey and experimental approaches. In three projects, I explore the frequency, behavioral responses, risk factors, and perceived reasons for everyday ostracism. First, I discuss how Büttner, Ren et al. (2024) use event-contingent and time-contingent experience sampling to quantify ostracism frequency in daily life. Further, this project investigates the behaviors that follow ostracism. Büttner, Ren et al. (2024) propose and find support for a framework suggesting that the severity of need threat after ostracism influences whether individuals approach, avoid, or behave antisocially towards others. In the second project, Büttner, Rudert, & Kachel (2024) identify sexual minorities as a group that is particularly at risk for experiencing frequent ostracism. A complementing experiment reveals that the reason why sexual minorities frequently face ostracism is their deviation from gender-role expectations. Finally, Büttner & Greifeneder (2024) investigate how depression critically shapes targets’ frequency, experience, and attribution of ostracism. Depressed individuals not only experience more frequent everyday ostracism and exhibit heightened need threat responses; their depression also leads to maladaptive attributions of ostracism. Together, the three presented projects underscore the value of experience sampling in providing nuanced insights into the psychological impact of real-life ostracism. Traditional survey and experimental approaches alone are insufficient to capture the dynamics and the pervasive, immediate impact of ostracism in everyday life, but experience sampling bridges this gap. The presented projects not only deepen the empirical understanding of ostracism but also set a precedent for future research and practical applications to mitigate the effects of ostracism through targeted interventions
Helically-shaped peri-oligo-naphthylenes and organophotocatalytic flow oxygenation of phenols
No full textHelically-Shaped peri-Oligo-Naphthylenes
The development of helically-shaped peri-oligonaphthylenes represents a significant advancement in the field of molecular systems, offering unique structural motifs with promising applications in organic synthesis and material science. In this thesis, the synthesis and structural characterization of multiaxial peri-oligonaphthylenes are explored, aiming to elucidate their unique architecture. Leveraging Suzuki–Miyaura cross-coupling sequences, a selection of peri-oligonaphthylenes with various chain elongation building blocks is successfully synthesized. Notably, substrate-controlled diastereoselectivity was observed during the Miyaura-borylation of substrates. X-ray analysis of an advanced structure provides valuable structural information, confirming the all-trans configuration of specific motifs. These structurally intriguing, configurationally stable oligomers could potentially serve as valuable scaffolds, facilitating the precise and predictable placement of substituents within a defined spatial relationship.
Catalytic Combes Reaction to Access 4-Arylquinolines
Quinolines represent an important class of heterocyclic nitrogen-based compounds with prevalent structures in natural products and hold immense promise in drug discovery and biological research. Consequently, devising a catalytic synthetic route to access these molecules is crucial. In this study, an organocatalytic Combes quinoline reaction is presented using readily accessible building blocks and anilines. The resulting heterobiaryl compounds could, upon further modification, potentially serve as platform for catalysis as ligands or aid in the development of synthetic methodologies for new pharmaceutical agents.
Organophotocatalytic Flow Oxygenation of Phenols
In response to the environmental challenges posed by large-scale vitamin E production, which relies on benzoquinone building blocks, a critical demand for a sustainable alternative has emerged. Current processes involve harsh conditions and generate substantial amounts of detrimental metal waste, causing environmental pollution. To tackle this issue, an eco-friendly approach is proposed, utilizing a mild organophotocatalytic phenol oxygenation method with a cost-effective organophotocatalyst under visible light and air overpressure conditions. Products for diverse applications, encompassing the synthesis of vitamins and a prodrug, were obtained in high yields by means of a simple modular continuous flow photoreactor set-up with precise control panels. The reactor design permits the use of low photocatalyst loadings to promote singlet oxygen generation. This approach is expected to contribute to a circular economy and sustainable synthesis by facilitating the efficient gas-liquid reaction for the high-yielding formation of quinones with air, thereby avoiding the production of hazardous metal waste streams and the use of chlorinated solvents