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Die zentrale Frage dieser Studie lautet: Wann ist eine stetige Funktion auf einem kompakten Raum, welche Werte in einem lokalkonvexen Raum annimmt, (Pettis-)integrierbar?
Im ersten Kapitel wird definiert, was konvexe Kompaktheit ist. Es wird das Pettis-Integral vorgestellt, und der Zusammenhang zwischen der konvexen Kompaktheitseigenschaft (oder ccp) und dem Pettis-Integral wird erläutert. Außerdem stellt dieses Kapitel dar, inwiefern die ccp aus stärkeren Eigenschaften lokalkonvexer Räume folgt oder schwächere impliziert. Das zweite Kapitel beweist hauptsächlich den Satz von Krein, der einen Zusammenhang zwischen Vollständigkeit unter der Mackey-Topologie und der ccp unter der schwachen Topologie herstellt. Das dritte Kapitel erläutert mit Gegenbeispielen, inwiefern die in Kapitel 1 vorgestellten Vollständigkeitseigenschaften lokalkonvexer Räume notwendig gegeneinander abgegrenzt sind. Das vierte Kapitel stellt zuerst das Bochner-Integral und das starke OperatorIntegral vor, um dann die starke konvexe Kompaktheitseigenschaft oder sccp einzufuhren, eine Eigenschaft, welche der ccp verwandt ist. Es wird fur einen Raum beispielhaft bewiesen, daß er diese Eigenschaft besitzt. Zuletzt wird der Zusammenhang von sccp und ccp ausfuhrlicher dargestellt.
Diese Arbeit wendet sich an Leser, denen die Grundlagen der Theorie lokalkonvexer Räume schon vertraut sind. Insbesondere ist Vertrautheit mit den Begriffen tonneliert, ultrabornologisch, bornologisch, polare Topologie unterstellt. Man findet eine kurze und einfach verständliche Einfuhrung im Werk [RR]. Alle über diese Grundlagen hinausgehenden Resultate werden in dieser Arbeit mit Beweis ausgefuhrt, oder es wird mit Angabe der Fundstelle auf die Literatur verwiesen.
The transcription factor ∆Np63 is a master regulator of epithelial cell identity and essential for the survival of squamous cell carcinoma (SCC) of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ∆Np63 and maintains elevated ∆NP63 levels in SCC by counteracting its proteasome‐mediated degradation. Impaired USP28 activity, either genetically or pharmacologically, abrogates the transcriptional identity and suppresses growth and survival of human SCC cells. CRISPR/Cas9‐engineered in vivo mouse models establish that endogenous USP28 is strictly required for both induction and maintenance of lung SCC. Our data strongly suggest that targeting ∆Np63 abundance via inhibition of USP28 is a promising strategy for the treatment of SCC tumours.
The question of whether nuclear energy—as a source with relatively low carbon dioxide emissions—can be classified as a sustainable energy source has come into focus in connection with climate change. There is a controversy over securing independence from fossil fuels and gas supplies from other countries through a revival of nuclear energy. On the other hand, some viewpoints are critical: the handling of nuclear waste and the still unclear risks to human health and the environment, especially in light of recent perils from Russian military attacks on Ukrainian nuclear plants. To evaluate the worldwide publications on nuclear energy under health and environmental aspects, socio-economic parameters were included to provide an informed background for all stakeholders, from scientists to decision-makers. The correlation between the number of nuclear power plants and the publication output of the countries is proven to be highly significant. Thus, the operating countries publish the most. It has been shown that the development and economic use of nuclear energy are major stimuli for scientific endeavors. Reactor accidents have also spurred research. Mathematical risk modeling has been the area with the highest citation rate to date, but environmental and health aspects have become more important, especially after major accidents. The results show the importance of economic interests in research on nuclear energy from health and environmental aspects. Against the background of transnational hazards, global research participation should be encouraged. Moreover, the international debate should not ignore the reality of threats and their possible impacts.
Despite antagonizing attempts from the tobacco industry, passive inhalation of tobacco smoke is known to be cancerogenic and toxic to human health for decades. Nonetheless, millions of non-smoking adults and children are still victims of second-hand smoke. Accumulation of particulate matter (PM) in confined spaces such as the car are particularly harmful due to high concentrations. We here aimed to analyze the specific effects of ventilation conditions in the setting of a car. By the use of the measuring platform TAPaC (tobacco-associated particulate matter emissions inside a car cabin), 3R4F reference cigarettes, Marlboro red, and Marlboro gold were smoked in a car interior with a volume of 3.709 m3. Seven different ventilation conditions (C1–C7) were analyzed. Under C1, all windows were closed. Under C2–C7, the car ventilation was turned on power level 2/4 with the air directed towards the windshield. Only the passenger side window was opened, where an outer placed fan could create an airstream speed of 15.9–17.4 km/h at one meter distance to simulate a driving car. C2: Window 10 cm opened. C3: Window 10 cm opened with the fan turned on. C4: Window half-opened. C5: Window half-opened with the fan turned on. C6: Window fully opened. C7: Window fully opened with the fan turned on. Cigarettes were remotely smoked by an automatic environmental tobacco smoke emitter and a cigarette smoking device. Depending on the ventilation condition the cigarettes emitted different mean PM concentrations after 10 min under condition C1 (PM10: 1272–1697 µg/m3, PM2.5: 1253–1659 µg/m3, PM1: 964–1263 µg/m3) under C2, C4, and C6 (PM10: 68.7–196.2 µg/m3, PM2.5: 68.2–194.7 µg/m3, PM1: 66.1–183.8 µg/m3) C3, C5, and C7 (PM10: 73.7–139 µg/m3, PM2.5: 72–137.9 µg/m3, PM1:68.9–131.9 µg/m3). Vehicle ventilation is insufficient to protect passengers from toxic second-hand smoke completely. Brand-specific variations of tobacco ingredients and mixtures markedly influence PM emissions under ventilation conditions. The most efficient ventilation mode to reduce PM exposure was achieved by opening the passenger´s window 10 cm and turning the onboard ventilation on power level 2/4. In-vehicle smoking should be banned to preserve innocent risk groups (e.g., children) from harm.
Oncogenic transformation of lung epithelial cells is a multi-step process, frequently starting with the inactivation of tumor suppressors and subsequent activating mutations in proto-oncogenes, such as members of the PI3K or MAPK family. Cells undergoing transformation have to adjust to changes, such as metabolic requirements. This is achieved, in part, by modulating the protein abundance of transcription factors, which manifest these adjustments. Here, we report that the deubiquitylase USP28 enables oncogenic reprogramming by regulating the protein abundance of proto-oncogenes, such as c-JUN, c-MYC, NOTCH and ΔNP63, at early stages of malignant transformation. USP28 is increased in cancer compared to normal cells due to a feed-forward loop, driven by increased amounts of oncogenic transcription factors, such as c-MYC and c-JUN. Irrespective of oncogenic driver, interference with USP28 abundance or activity suppresses growth and survival of transformed lung cells. Furthermore, inhibition of USP28 via a small molecule inhibitor reset the proteome of transformed cells towards a ‘pre-malignant’ state, and its inhibition cooperated with clinically established compounds used to target EGFRL858R, BRAFV600E or PI3KH1047R driven tumor cells. Targeting USP28 protein abundance already at an early stage via inhibition of its activity therefore is a feasible strategy for the treatment of early stage lung tumours and the observed synergism with current standard of care inhibitors holds the potential for improved targeting of established tumors.
Electronic circular dichroism unravels atropisomers of a broadly absorbing fulgide derivative
(2022)
We prepared and studied six atropisomers with different chiroptical properties emerging from a single, robust, broadly-absorbing fulgide photoswitch. After separation of the different atropisomers via HPLC on a chiral column, their isomerization processes at room temperature and the energy barriers of the different species were investigated in detail using spectroscopic and theoretical methods.
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
Oncogenic transformation of lung epithelial cells is a multistep process, frequently starting with the inactivation of tumour suppressors and subsequent development of activating mutations in proto-oncogenes, such as members of the PI3K or MAPK families. Cells undergoing transformation have to adjust to changes, including altered metabolic requirements. This is achieved, in part, by modulating the protein abundance of transcription factors. Here, we report that the ubiquitin carboxyl-terminal hydrolase 28 (USP28) enables oncogenic reprogramming by regulating the protein abundance of proto-oncogenes such as c-JUN, c-MYC, NOTCH and ∆NP63 at early stages of malignant transformation. USP28 levels are increased in cancer compared with in normal cells due to a feed-forward loop, driven by increased amounts of oncogenic transcription factors such as c-MYC and c-JUN. Irrespective of oncogenic driver, interference with USP28 abundance or activity suppresses growth and survival of transformed lung cells. Furthermore, inhibition of USP28 via a small-molecule inhibitor resets the proteome of transformed cells towards a ‘premalignant’ state, and its inhibition synergizes with clinically established compounds used to target EGFRL858R-, BRAFV600E- or PI3KH1047R-driven tumour cells. Targeting USP28 protein abundance at an early stage via inhibition of its activity is therefore a feasible strategy for the treatment of early-stage lung tumours, and the observed synergism with current standard-of-care inhibitors holds the potential for improved targeting of established tumours.
Background: Particulate matter (PM) emission caused by tobacco combustion leads to severe health burdens worldwide. Second-hand smoke exposure is extraordinarily high in enclosed spaces (e.g., indoor rooms, car cabins) and poses a particular threat to the health of vulnerable individuals (e.g., children, elderly, etc.). This study aimed to establish a new measuring platform and investigate PM emissions under four different ventilation conditions inside a car cabin without exposing any person to harmful tobacco smoke.
Methods: PM concentrations were measured during the smoking of 3R4F reference cigarettes in a Mitsubishi Space Runner (interior volume 3.709 m3). The cigarettes were smoked with a machine, eliminating exposure of the researchers. Cigarettes were extinguished 4.5 min after ignition, and PM measurements continued until 10 min after ignition.
Results: High mean PM concentrations were measured for cigarettes without ventilation after 4.5 min (PM10: 1150 µg/m3, PM2.5: 1132 µg/m3, PM1: 861.6 µg/m3) and after 10 min (PM10: 1608 µg/m3, PM2.5: 1583 µg/m3, PM1: 1133 µg/m3). 3R4F smoked under conditions with turned on ventilation resulted in reduction of PM compared to those smoked without ventilation after 4.5 min (PM10:-47.5 to -58.4%, PM2.5:-47.2 to -58%, PM1:-39.6 to -50.2%) and after 10 min (PM10:-70.8 to -74.4%, PM2.5:-70.6 to -74.3%, PM1:-64.0 to -68.0%). Cigarettes smoked without ventilation generated high PM peaks at 4.5 min (PM10: 2207 µg/m3, PM2.5: 2166 µg/m3, PM1: 1421 µg/m3) and at 10 min (PM10: 1989 µg/m3, PM2.5: 1959 µg/m3, PM1: 1375 µg/m3). PM peaks of cigarettes smoked under different ventilation modes varied at 4.5 min (PM10: 630-845 µg/m3, PM2.5: 625-836 µg/m3, PM1: 543 - 693 µg/m3) and 10 min (PM10: 124 - 130 µg/m3, PM2.5: 124 - 129 µg/m3, PM1: 118 - 124 µg/m3).
Conclusion: The new measuring platform provides a safer way for researchers to investigate PM emissions of cigarettes. These data are comparable to published research and show that smoking in a parked vehicle with the windows closed generates harmful PM emissions even when the vehicle ventilation is in operation. Future studies should be carried out using the new measuring platform investigating PM exposure and PM distribution of in-vehicle smoking under a wide range of conditions.