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Photoannulierungen zu Dihydrophenalenonen und 1-Tetralonen
No full textDie Reaktionsbedingungen der Photozyklisierung des Cyclopropylesters zum Dihydrophenalen wurden erfolgreich optimiert und ergaben das Produkt in einer Ausbeute von 93% unter Standardbedingungen. Eine sensitivity assessment wurde durchgeführt, um Erkenntnisse für eine verbesserte Reproduzierbarkeit zu gewinnen. 17 Derivate des Dihydrophenalens wurden mit Ausbeuten im Bereich von 50 – 99% über die entwickelte Methode dargestellt. Zudem konnte der Reaktionsmechanismus experimentell mittels Cyclovoltammetriemessungen, einem Deuterium Labeling-Experiment und weiteren Kontrollexperimenten untersucht und einem Photoredoxprozess zugeordnet werden. Die Bestimmung des KIEs zeigte, dass sich die Reaktion an einem deuterierten Substrat signifikant verlangsamt. Über die visual kinetic analysis (VKA) wurde ermittelt, dass die Reaktion durch die Bildung des Produktes beeinträchtigt wird (product inhibition).
Die erstmalig Beobachtete Photohydroacylierung zum Tetralon wurde optimiert, mittels sensitivity assessment untersucht und erfolgreich auf 15 Substrate angewendet, die mit Ausbeuten im Bereich von 55 - 99% erhalten wurden. Der neuartige Reaktionsmechanismus wurde eingehend untersucht. Ein Deuterium-Labeling-Experiment wurde durchgeführt, das zu der Beobachtung eines selektiven 1,5 HAT-Prozesses führte. Zudem wurde der Reaktionsmechanismus mithilfe von Radikal Uhr Experimenten und Deuterium-scrambling-Experiment als eine Retro-Norrish-Typ-I Reaktion kategorisiert. Die Reaktion wurde außerdem mittels VKA untersucht und der postulierte Mechanismus wurde theoretisch über DFT-Berechnungen unterstützt. Somit wurde eine neue Photoreaktion erfunden, entwickelt und untersucht, die den anfangs gewählten Kriterien (Raumtemperatur, kurze Reaktionszeit, ohne Additive) entspricht.The reaction conditions of the photocyclization of cyclopropyl ester to dihydrophenalene were successfully optimized, giving the product in a yield of 93% under standard conditions. A sensitivity analysis was conducted to gain insights for enhanced reproducibility. 17 derivatives of dihydrophenalenes were prepared with yields ranging from 50 to 99% using the developed method. Furthermore, the reaction mechanism was experimentally investigated through cyclovoltammetry measurements, a deuterium labeling experiment, and additional control experiments, attributing it to a photoredox process. Determination of the KIEs showed that the reaction slows down with a deuterated substrate, and visual kinetic analysis (VKA) revealed that the reaction is affected by the formation of the product (product inhibition).
The newly observed photohydroacylation to tetralone was optimized, investigated by a sensitivity assessment, and successfully applied to 15 substrates, yielding products in the range of 55 - 99%. The unprecedented reaction mechanism was intensively investigated. A deuterium labeling experiment was conducted to investigate a selective 1,5 HAT process. Additionally, the reaction mechanism was categorized as a Retro-Norrish-type-I reaction using strategic radical clock experiments and deuterium scrambling experiments. The reaction was also examined via VKA, and the postulated mechanism was supported theoretically through DFT-calculations. Thus, a new photochemical reaction was invented, developed and investigated, meeting the initially chosen criteria (room temperature, short reaction time, no additives)
Getting cells into shape by calcium-dependent actin cross-linking proteins
No full textThe actin cytoskeleton represents a highly dynamic filament system providing cell
structure and mechanical forces to drive a variety of cellular processes. The
dynamics of the actin cytoskeleton are controlled by a number of conserved
proteins that maintain the pool of actin monomers, promote actin nucleation,
restrict the length of actin filaments and cross-link filaments into networks or
bundles. Previous work has been established that cytoplasmic calcium is an
important signal to rapidly relay information to the actin cytoskeleton, but the
underlying mechanisms remain poorly understood. Here, we summarize new
recent perspectives on how calcium fluxes are transduced to the actin
cytoskeleton in a physiological context. In this mini-review we will focus on
three calcium-binding EF-hand-containing actin cross-linking proteins, α-actinin,
plastin and EFHD2/Swiprosin-1, and how these conserved proteins affect the cell’s
actin reorganization in the context of cell migration and wound closure in
response to calcium.Gefördert durch den Open-Access-Publikationsfonds der UB Marburg
Forecasting Market Diffusion of Innovative Battery-Electric and Conventional Vehicles in Germany under Model Uncertainty
No full textIn this research paper accuracies (percentage errors, MAPE) of different procedures (growth, ARIMA(X), exponential smoothing and deterministic trend models) in forecasting new passenger car registrations in Germany are presented. It is found that the Logistic Growth Model provides rather accurate predictions of the number of new registrations (total number, which still refers to predominantly conventional gasoline and diesel vehicles) for the forecast period of the study. However, the Bass diffusion model is recommended for predicting the new registration numbers of the innovative battery-electric technology. Furthermore, it is exemplarified that the Bass coefficient of imitation q, in contrast to the coefficient of innovation p, is robust to a variation of the assumed market potential M. Therefore, q should also contribute to a stable short-term forecast (given a variation of M), provided that a period in the early phase of the product life cycle is considered. The study also shows that with the bulk of the procedures, percentage forecast errors are obtained which lie in a narrow margin for the established product passenger car, but not for the innovative battery-electric propulsion technology. So while the careful selection of the forecasting model seems rather negligible for the established product, it is essential for the innovative product. In addition, new registration figures in the German federal states were forecasted, which in turn were used to calculate pooled forecasts for Germany. In general, no increase in forecast accuracy was achieved by means of pooling compared with direct forecasting (i.e. from the national time series)
Health anxiety amplifies fearful responses to illness‑related imagery
No full textSevere health anxiety (HA) is characterized by excessive worry and anxiety about one’s health, often
accompanied by distressing intrusive imagery of signs of a serious illness or potentially receiving
bad news about having a life-threatening disease. However, the emotional responses to these
illness-related mental images in relation to HA have not been fully elucidated. Emotional responses
to mental imagery of 142 participants were assessed in a well-controlled script-driven imagery
task, systematically comparing emotional responses to illness-related imagery with neutral and
standard fear imagery. The results revealed that participants reported higher anxiety, aversion,
emotional arousal, and a stronger avoidance tendency during imagery of fear and illness-related
scenes compared to neutral scenes. Importantly, the emotional modulation varied by the level of
HA, indicating that individuals with higher HA experienced stronger emotional responses to illnessrelated
imagery. This association between HA and fearful imagery could not be better accounted for
by other psychological factors such as trait anxiety, anxiety sensitivity, somatic symptom severity,
or symptoms of depression and anxiety. Fearful responding to standard threat material was not
associated with HA. The present findings highlight the importance of considering fear responding to
mental imagery in understanding and addressing HA.Gefördert durch den Open-Access-Publikationsfonds der UB Marburg
Political Leaders’ Socioeconomic Background and Public Budget Deficits: Evidence from OECD Countries
No full textThis paper empirically analyses the relationship between political leaders’ socioeconomic backgrounds and public budget deficits utilising panel data on 21 OECD countries from 1980 to 2008. Building on sociological, as well as economic, research, we argue that the socioeconomic status of political decision-makers, i.e., presidents or prime ministers, is an important determinant of fiscal budget decisions. Our theory-consistent findings show that the tenures of lower-class leaders—i.e., leaders of low socioeconomic status—are associated with a deficit-to-GDP ratio which is 1.6 percentage points higher than that during tenures of upperclass leaders
Changes in the degree of substitution of HES in vivo and their influence on methods for determining HES concentrations in plasma
No full textThe degree of substitution (DS) of HES describes the average proportion of substituted glucose molecules in a starch molecule. Although no quantitative studies of the in vivo behavior of the DS have been conducted so far, most pharmacokinetic studies to date have measured HES concentrations using the enzymatic method. This method assumes that at any point in time after an infusion, the DS in a serum remains constant and is identical to the DS in the infused solution. In the present study, we examined the changes in the DS of HES 130/0.42 in vivo in an animal model and compared two methods of measuring HES concentrations in plasma (the enzymatic and the o-Toluidine method).
We randomized 22 pigs into 2 groups. After induction of anesthesia, the pigs received 500 ml or 1000 ml of HES 130/0.42 (Tetraspan®). The DS was measured directly after the infusion, then after 30, 60, 120 and 240 minutes. In determining the DS, the hydroxyethyl starch was extracted from the plasma and hydrolyzed with hydrochloric acid to form non-substituted glucose and hydroxyethyl glucose. Subsequently, the concentration of free unsubstituted glucose was determined enzymatically and the total concentration of all (i.e., substituted and unsubstituted) glucose molecules was determined using the o-Toluidine method. From this, the concentration of the substituted glucose (hydroxyethyl glucose) and the DS could be calculated. In addition, the HES concentration was measured first in vitro and then in vivo at any point after the infusion by both the enzymatic method and the o-Toluidine method.
The DS increased significantly directly after the infusion from 0.42 to 0.53 (for 500ml) or to 0.50 (for 1000ml); 4 hours later this had further increased to 0.55 and 0.54, respectively (p <0.0001).
The HES concentration in vitro showed no significant difference (p = 0.17) when determined with the enzymatic and the o-Toluidine method.
In contrast, the serum concentrations in vivo displayed significant differences (p<0.0001) between the two measurement methods. Immediately after the infusion of 500ml HES, the concentration measured with the o-Toluidine method was 31% higher than the one measured with the enzymatic method; 4 hours later, this discrepancy was still at 25%. For 1000 ml HES, the differences amounted to 16% and 25%, respectively.
The DS of HES in vivo increases significantly over time. As a result, an HES concentration measured with the enzymatic method in vivo will be significantly lower than the same concentration determined with the o-Toluidine method.
In future pharmacokinetic studies, HES concentrations should be measured using a method that takes into account changes in the DS in vivo.Gefördert durch den Open-Access-Publikationsfonds der UB Marburg
Citizens‘ preferences for inter-municipal cooperation in rural areas: evidence from a survey in three Hessian counties
No full textIn rural areas, small and medium-sized municipalities are challenged by demographic change and intensified competition for capital and high-skilled labor. Inter-municipal cooperation (IMC) is often regarded as a significant element of a strategy to meet these challenges. Based on a survey in three rural counties in the German state of Hesse, we present first evidence on citizens’ policy preferences regarding IMC. Policy preferences are found to be driven primarily by individual characteristics. The strongest factor reducing citizens’ support is the belief that IMC reduces citizens’ influence and control. Support is higher among citizens who assess the current service quality as low and/or assess the future perspective of their home municipality as negative. Trust in local politicians and a high degree of emotional attachment to the home municipality have a negative impact on subjects’ support for IMC. None of the municipal characteristics like municipal size or fiscal stress, nor the availability of suitable partner municipalities are found to drive citizens’ preferences
Rate of Complications after Hip Fractures Caused by Prolonged Time-to-Surgery Depends on the Patient’s Individual Type of Fracture and Its Treatment
No full textIntroduction: Hip fractures are common injuries in the elderly and are usually treated with timely surgery. While severe postoperative complications are reported for up to 10% of patients, many studies identified predictive factors for the occurrence of complications postoperatively. A controversially discussed factor is “time-to-surgery”. The aim of the study was to examine if time-to-surgery was associated with the occurrence of complications and if the complication rate differed between the patient individual fracture types of intracapsular on the one hand and extracapsular hip fractures on the other hand. We hypothesized that time-to-surgery had less impact on complications in intracapsular hip fractures compared to extracapsular ones, and therefore, guidelines should pay attention to the patient individual case scenario. Materials and Methods: All patients who were admitted to the Department of Trauma and Orthopaedic Surgery of an academic teaching hospital for hip fracture surgery (n = 650) over a five-year period were included in the study. After the application of the exclusion criteria, such as periprosthetic or pathologic fractures, cases needed immediate surgical treatment, and after outlier adjustment, 629 cases remained in the study. Hip fractures were classified into intracapsular fractures (treated by hip arthroplasty) and extracapsular fractures (treated by intramedullary nailing osteosynthesis). The occurrence of severe complications in patients treated within 24 h was compared with patients treated later than 24 h after injury. For statistical evaluation, a multivariate logistic regression analysis was performed to investigate the impact of time-to-surgery interval on the occurrence of complications. Results: Patients with an extracapsular fracture, which was treated with intramedullary nailing (44.5%), rarely suffered a serious complication when surgery was performed within 24 h after injury. However, when the interval of the time-to-surgery was longer than 24 h, the complication rate increased significantly (8.63% vs. 25.0%, p = 0.002). In contrast to this finding in patients with intracapsular fractures (55.5%), which were treated with cemented arthroplasty, complication rates did not depend on the 24 h interval (26.17% vs. 20.83%, p = 0.567). Conclusions: The occurrence of complications after surgical treatment of hip fractures is associated with the time interval between injury and surgery. A 24 h time interval between injury and surgical procedure seems to play a major role only in extracapsular fractures treated with osteosynthesis but not in intracapsular fractures treated with arthroplasty. Therefore, guidelines should take notice of the patient individual case scenario and, in particular, the individual hip fracture type.Gefördert durch den Open-Access-Publikationsfonds der UB Marburg
Sourcing from Conflict Regions: Policies to Improve Transparency in International Supply Chains
No full textIn this paper, we set up a theoretical model to study how unilateral policies aimed at improving transparency for consumers concerning the source of certain raw materials influence prices, illegal mining activities and welfare. The model distinguishes two regions in the world, North and South. Firms in the North import natural resources from the South to produce final consumption goods. In one of the countries, in the South, local groups attempt to access natural resources, which results in rent seeking conflicts with the government and illegal mining. We find that a unilateral embargo against the conflict country as well as certification of legal mines can reduce rent seeking and illegal mining with different welfare consequences in the countries involved
Entwicklung, Herstellung und Validierung von patientenspezifischen 3D-Bereichsmodulatoren für die sehr schnelle Bestrahlung von sich bewegenden Tumoren in der Partikeltherapie
No full textParticle therapy has established clinically in the last decades as it can deliver dose to the target in a highly precise and conformal manner and has been shown to be especially beneficial and effective for certain types of cancer.
Its application for moving targets, however, is challenging due to the relatively long irradiation time and the resulting “interplay” effects between the scanned beam and the target motion, which lead to dose deterioration. In addition, ultra-high dose rate FLASH irradiation, which is expected to enhance the therapeutic window, cannot be achieved with the conventional active raster scanning method due to the switching time between the single iso-energy layers.
This dissertation presents the concept of static range-modulating devices manufactured by rapid prototyping for the very fast dose application with only one fixed energy and a scanned particle beam. The development of 2D range-modulators (RM) is shown and their application is validated in a research project for high-precision water calorimetry. The concept is extended to a 3D range-modulator (3D RM), optimized and customized to a patient-specific target shape.
The modulators are manufactured with high-quality 3D printers, different materials and printing techniques. The resulting dose distribution is first validated by simulations and then by fast, completely automated and high resolution measurements using a water phantom system.
Overall, an end-to-end process chain is demonstrated, from the RM development to the final dose evaluation. Highly homogeneous dose distributions are achieved with a very good agreement between the predicted and measured data. In the case of the 3D RM, the delivered dose is additionally conformed to both the proximal and distal edge of the target. Most importantly, the modulators manage to deliver the prescribed dose in a fraction of the time required for conventional scanned particle therapy.
The presented work demonstrates the feasibility of using 3D-printed 3D range-modulators in particle therapy. The 3D RM concept combines extremely short irradiation times with a high degree of dose conformity and homogeneity, promising clinically applicable dose distributions for lung and/or FLASH treatment, potentially comparable and competitive to those from conventional irradiation techniques.Die Partikeltherapie hat sich in den letzten Jahrzehnten klinisch etabliert, da sie die Dosis hochpräzise und konform im Ziel applizieren kann und sich für bestimmte Krebsarten als besonders wirksam erwiesen hat. Bewegte Tumoren stellen allerdings aufgrund der relativ langen Bestrahlungszeiten eine Herausforderung dar, weil „Interplay“ Effekte zwischen dem gescannten Strahl und der Tumorbewegung zu starken Dosisinhomogenitäten führen können. Außerdem ist die Anwendung des üblichen Multi-Energy Rasterscanning-Verfahren für FLASH-Bestrahlung aufgrund der Umschaltzeiten zwischen den einzelnen Energieschichten nicht möglich.
In dieser Dissertation wird das Konzept statischer, durch Rapid Prototyping hergestellter Reichweitenmodulatoren, vorgestellt. In Kombination mit einer einzigen Energie und einem gescannten Feld können solche Modulatoren die Bestrahlungszeit deutlich senken. Es wird die Entwicklung von 2D Modulatoren gezeigt und ihre Anwendung in einem Forschungsprojekt für hochpräzise Wasserkalorimetrie validiert. Zudem wird das Konzept auf einen 3D-Reichweitenmodulator ausgeweitet, der für eine patientenspezifische Tumorform optimiert und angepasst ist.
Die Modulatoren werden mit hochqualitativen 3D-Druckern, verschiedenen Materialien und Druckverfahren hergestellt. Die resultierende Dosisverteilung wird zunächst durch Simulationen und dann durch schnelle, automatisierte und hochaufgelöste Messungen mit einem Wasserphantom validiert.
Insgesamt wird eine komplette Prozesskette demonstriert, von der Modulatorentwicklung bis zur abschließenden Dosisauswertung. Die simulierten und gemessenen Dosisverteilungen stimmen sehr gut überein und weisen hohe Homogenität auf. Im Falle des 3D RM wird die applizierte Dosis zusätzlich sowohl an die proximale als auch an die distale Kante des Tumors angepasst. Vor allem aber gelingt es, mit den Modulatoren die verschriebene Dosis in einem Bruchteil der Zeit zu applizieren, die für das konventionelle Rasterscan Verfahren benötigt wird.
Die vorgestellte Arbeit demonstriert die mögliche Verwendung von 3D-gedruckten 3D Modulatoren in der Partikeltherapie. Das 3D RM Konzept kombiniert extrem kurze Bestrahlungszeiten mit hoher Dosiskonformität und -homogenität und verspricht aber gleichzeitig klinische Dosisverteilungen für die Lungen- und/oder FLASH-Behandlung, die mit denen konventioneller Bestrahlungstechniken vergleichbar und konkurrenzfähig sind