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Sonstige beteiligte Institutionen
- IZKF Nachwuchsgruppe Geweberegeneration für muskuloskelettale Erkrankungen (5)
- Bernhard-Heine-Centrum für Bewegungsforschung (4)
- Zentraleinheit Klinische Massenspektrometrie (3)
- Fraunhofer-Institut für Silicatforschung ISC (2)
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- Krankenhaushygiene und Antimicrobial Stewardship (Universitätsklinikum) (2)
- Wilhelm-Conrad-Röntgen-Forschungszentrum für komplexe Materialsysteme (2)
- ALPARC - The Alpine Network of Protected Areas (1)
- Albert-Ludwigs-Universität Freiburg (1)
- Arizona State University, Tempe, Arizona, USA (1)
Our starting point is the Jacobsthal function \(j(m)\), defined for each positive integer \(m\) as the smallest number such that every \(j(m)\) consecutive integers contain at least one integer relatively prime to \(m\). It has turned out that improving on upper bounds for \(j(m)\) would also lead to advances in understanding the distribution of prime numbers among arithmetic progressions. If \(P_r\) denotes the product of the first \(r\) prime numbers, then a conjecture of Montgomery states that \(j(P_r)\) can be bounded from above by \(r (\log r)^2\) up to some constant factor. However, the until now very promising sieve methods seem to have reached a limit here, and the main goal of this work is to develop other combinatorial methods in hope of coming a bit closer to prove the conjecture of Montgomery. Alongside, we solve a problem of Recamán about the maximum possible length among arithmetic progressions in the least (positive) reduced residue system modulo \(m\). Lastly, we turn towards three additive representation functions as introduced by Erdős, Sárközy and Sós who studied their surprising different monotonicity behavior. By an alternative approach, we answer a question of Sárközy and demostrate that another conjecture does not hold.
Novel appraches to the molecular beam epitaxy of core-shell nanowires in the group II telluride material system were explored in this work. Significant advances in growth spurred the development of a flexible and reliable platform for a charge transport characterization of the topological insulator HgTe in a tubular nanowire geometry. The transport results presented provide an important basis for the design of future studies that strive for the experimental realization of topological charge transport in the quantum wire limit.
Diarrheal diseases are a major cause of death in developing countries. Vaccinating against the causative pathogens could reduce mortality and morbidity in these countries. Unfortunately, only for some of the most common enteral pathogens are vaccines available. Some of these available vaccines have limitations in terms of effectiveness and duration of protection. There is therefore an urgent need to develop new vaccine strategies that can generate protection against enteral pathogens.
The presence of all-trans retinoic acid (ATRA) during lymphocyte maturation is known to imprint a phenotype on lymphocytes that enables them to home to the intestines. Additionally, ATRA is known to play a role in B cell class switch to IgA, which is the dominant immunoglobulin in the intestines.
The aim of this study was therefore to investigate whether the addition of all-trans retinoic acid (ATRA) or a retinoic acid receptor agonist (AM80) to a parenteral vaccination could provide protection at the intestinal mucosa against enteric pathogens.
C57BL/6 mice received s.c. priming and boosting immunizations with Ovalbumin followed by several s.c. injections with either ATRA, AM80 or the respective solvent as control substance. Feces, serum, saliva and vaginal lavage samples were collected and analyzed by ELISA for detection and relative quantification of antigen-specific antibodies. B cell populations in the draining lymph nodes were investigated after immunization using flow-cytometry. Antigen-specific antibodies producing cells were visualized in the small intestine of vaccinated animals using two-photon microscopy.
Animals that were vaccinated and were exposed to AM80, and to a lesser extent ATRA exposed mice, had higher serum, fecal, saliva and vaginal lavage antigen-specific IgA titers when compared to animals that were vaccinated but did not receive ATRA/AM80. Antigen-specific IgG titers were not altered in any of the investigated tissues. In the draining lymph nodes, IgA+ and IgG+ B cells were increased after vaccination and AM80 exposure at several time points within 14 days after vaccination. Antigen-specific IgA+ cells were found in the small intestine of immunized and AM80-exposed but not control substance-exposed mice.
These results suggest that the addition of ATRA or AM80 to parenteral vaccine formulations increases the abundance of antigen-specific antibodies at mucosal surfaces, and therefore have the potential to generate protective antibody titers at those mucosal surfaces.
Measles is an ancient disease with historical records as early as the 9th century.
Extensive study as well as advances in scientific knowledge of virology have led to
identification of the viral pathogen and subsequent development of an effective vaccine
leading to global efforts towards measles elimination. In 2018, around 140,000 deaths were
reported due to measles with incomplete vaccine coverage being one of the leading causes
of resurgence. Measles is highly contagious and often regarded as a childhood illness.
However, measles is associated with a number of complications and persistent infections
like subacute sclerosing panencephalitis (SSPE), which have brought into focus the need
for specific anti-viral therapies.
The aim of this study was to target host and viral factors to optimize anti-measles virus
therapy. Our approach was to test a panel of compounds known to inhibit host cell
functions or viral factors for their antiviral effect on measles replication. Primary human
lymphocytes, persistently infected NT2 cells and post-mitotic neurons were used as in vitro
model systems of acute, persistent and neuronal infection respectively to test the inhibitors.
Using the inhibitors Ceranib-2 and SKI-II to target the sphingolipid metabolism enzymes
acid ceramidase and sphingosine kinase in infected human primary lymphocytes, we
observed a decreased protein translational capacity mediated by mTORC1, EIF4E and
ribosomal protein S6 phosphorylation that probably contributes to the antiviral effect. In
the persistently infected neural NT2 cells and post-mitotic neurons derived from LUHMES
cells, we observed effective infection inhibition and viral clearance upon treatment with a
small non-nucleoside inhibitor (ERDRP-0519) specifically targeting the Morbillivirus
large polymerase. Other inhibitors such as Ribavirin and Favipiravir were less effective. To
conclude, 1) we identified a mTOR associated protein translation axis associated with the
sphingolipid metabolism, which affects measles virus replication and 2) In vitro
persistently infected neuronal and post-mitotic neuron models were successfully used as a
rapid method to test antivirals against measles virus.
The recently observed consistent loss of β-diversity across ecosystems indicates increasingly homogeneous communities in patches of landscapes, mainly caused by increasing land-use intensity. Biodiversity is related to numerous ecosystem functions and stability. Therefore, decreasing β-diversity is also expected to reduce multifunctionality. To assess the impact of homogenization and to develop guidelines to reverse its potentially negative effects, we combine expertise from forest science, ecology, remote sensing, chemical ecology and statistics in a collaborative and experimental β-diversity approach. Specifically, we will address the question whether the Enhancement of Structural Beta Complexity (ESBC) in forests by silviculture or natural disturbances will increase biodiversity and multifunctionality in formerly homogeneously structured production forests. Our approach will identify potential mechanisms behind observed homogenization-diversity-relationships and show how these translate into effects on multifunctionality. At eleven forest sites throughout Germany, we selected two districts as two types of small ‘forest landscapes’. In one of these two districts, we established ESBC treatments (nine differently treated 50x50 m patches with a focus on canopy cover and deadwood features). In the second, the control district, we will establish nine patches without ESBC. By a comprehensive sampling, we will monitor 18 taxonomic groups and measure 21 ecosystem functions, including key functions in temperate forests, on all patches. The statistical framework will allow a comprehensive biodiversity assessment by quantifying the different aspects of multitrophic biodiversity (taxonomical, functional and phylogenetic diversity) on different levels of biodiversity (α-, β-, γ-diversity). To combine overall diversity, we will apply the concept of multidiversity across the 18 taxa. We will use and develop new approaches for quantification and partitioning of multifunctionality at α- and β- scales. Overall, our study will herald a new research avenue, namely by experimentally describing the link between β-diversity and multifunctionality. Furthermore, we will help to develop guidelines for improved silvicultural concepts and concepts for management of natural disturbances in temperate forests reversing past homogenization effects.
Latency is an inherent problem of computing systems. Each computation takes time until the result is available. Virtual reality systems use elaborated computer resources to create virtual experiences. The latency of those systems is often ignored or assumed as small enough to provide a good experience.
This cumulative thesis is comprised of published peer reviewed research papers exploring the behaviour and effects of latency. Contrary to the common description of time invariant latency, latency is shown to fluctuate. Few other researchers have looked into this time variant behaviour. This thesis explores time variant latency with a focus on randomly occurring latency spikes. Latency spikes are observed both for small algorithms and as end to end latency in complete virtual reality systems. Most latency measurements gather close to the mean latency with potentially multiple smaller clusters of larger latency values and rare extreme outliers. The latency behaviour differs for different implementations of an algorithm. Operating system schedulers and programming language environments such as garbage collectors contribute to the overall latency behaviour. The thesis demonstrates these influences on the example of different implementations of message passing.
The plethora of latency sources result in an unpredictable latency behaviour. Measuring and reporting it in scientific experiments is important. This thesis describes established approaches to measuring latency and proposes an enhanced setup to gather detailed information. The thesis proposes to dissect the measured data with a stacked z-outlier-test to separate the clusters of latency measurements for better reporting.
Latency in virtual reality applications can degrade the experience in multiple ways. The thesis focuses on cybersickness as a major detrimental effect. An approach to simulate time variant latency is proposed to make latency available as an independent variable in experiments to understand latency's effects. An experiment with modified latency shows that latency spikes can contribute to cybersickness. A review of related research shows that different time invariant latency behaviour also contributes to cybersickness.
The Role of Acid Sphingomyelinase in \(Staphylococcus\) \(aureus\) Infection of Endothelial Cells
(2022)
Staphylococcus aureus is a human bacterial pathogen responsible for a variety of diseases including bacterial pneumonia and sepsis. Recent studies provided an explanation, how S. aureus and its exotoxins contribute to the degradation of endothelial junction proteins and damage lung tissue [4]. Previous findings were indicating an involvement of acid sphingomyelinase (ASM) activity in cell barrier degradation [5]. In the presented study the impact of singular virulence factors, such as staphylococcal α-toxin, on in vitro cell barrier integrity as well as their ability to elicit an activation of ASM were investigated.
Experiments with bacterial supernatants performed on human endothelial cells demonstrated a rapid dissociation after treatment, whereas murine endothelial cells were rather resistant against cell barrier degradation. Furthermore, amongst all tested staphylococcal toxins it was found that only α-toxin had a significant impact on endothelial junction proteins and ASM activity. Ablation of this single toxin was sufficient to protect endothelial cells from cell barrier degradation and activation of ASM was absent.
In this process it was verified, that α-toxin induces a recruitment of intracellular ASM, which is accompanied by rapid and oscillating changes in cytoplasmic Ca2+ concentration and an increased exposure of Lysosomal associated membrane protein 1 (LAMP1) on the cell surface. Recruitment of lysosomal ASM is associated, among other aspects, to plasma membrane repair and was previously described to be involved with distinct pathogens as well as other pore forming toxins (PFT). However, with these findings a novel feature for α-toxin has been revealed, indicating that the staphylococcal PFT is able to elicit a similar process to previously described plasma membrane repair mechanisms.
Increased exposure and intake of surface membrane markers questioned the involvement of ASM activity in S. aureus internalization by non-professional phagocytes such as endothelial cells. By modifying ASM expression pattern as well as application of inhibitors it was possible to reduce the intracellular bacterial count. Thus, a direct connection between ASM activity and S. aureus infection mechanisms was observed, therefore this study exemplifies how S. aureus is able to exploit the host cell sphingolipid metabolism as well as benefit of it for invasion into non-professional phagocytic cells
Humans and animals alike use the sun, the moon, and the stars to guide their ways.
However, the position of celestial cues changes depending on daytime, season, and
place on earth. To use these celestial cues for reliable navigation, the rotation of the
sky has to be compensated. While humans invented complicated mechanisms like the
Antikythera mechanism to keep track of celestial movements, animals can only rely on
their brains. The desert ant Cataglyphis is a prime example of an animal using celestial
cues for navigation. Using the sun and the related skylight polarization pattern as a
compass, and a step integrator for distance measurements, it can determine a vector
always pointing homewards. This mechanism is called path integration. Since the sun’s
position and, therefore, also the polarization pattern changes throughout the day,
Cataglyphis have to correct this movement. If they did not compensate for time, the
ants’ compass would direct them in different directions in the morning and the evening.
Thus, the ants have to learn the solar ephemeris before their far-reaching foraging
trips.
To do so, Cataglyphis ants perform a well-structured learning-walk behavior during the
transition phase from indoor worker to outdoor forager. While walking in small loops
around the nest entrance, the ants repeatedly stop their forward movements to perform
turns. These can be small walked circles (voltes) or tight turns about the ants’ body
axes (pirouettes). During pirouettes, the ants gaze back to their nest entrance during
stopping phases. These look backs provide a behavioral read-out for the state of the
path integrator. The ants “tell” the observer where they think their nest is, by looking
back to it. Pirouettes are only performed by Cataglyphis ants inhabiting an environment
with a prominent visual panorama. This indicates, that pirouettes are performed to
learn the visual panorama. Voltes, on the other hand, might be used for calibrating the
celestial compass of the ants.
In my doctoral thesis, I employed a wide range of state-of-the-art techniques from
different disciplines in biology to gain a deeper understanding of how navigational
information is acquired, memorized, used, and calibrated during the transition phase
from interior worker to outdoor forager. I could show, that celestial orientation cues that
provide the main compass during foraging, do not guide the ants during the look-backbehavior
of initial learning walks. Instead Cataglyphis nodus relies on the earth’s
magnetic field as a compass during this early learning phase. While not guiding the
ants during their first walks outside of the nest, excluding the ants from perceiving the
natural polarization pattern of the skylight has significant consequences on learning-related
plasticity in the ants’ brain. Only if the ants are able to perform their learning-walk
behavior under a skylight polarization pattern that changes throughout the day,
plastic neuronal changes in high-order integration centers are induced. Especially the
mushroom bogy collar, a center for learning and memory, and the central complex, a
center for orientation and motor control, showed an increase in volume after learning
walks. This underlines the importance of learning walks for calibrating the celestial
compass. The magnetic compass might provide the necessary stable reference
system for the ants to calibrate their celestial compass and learn the position of
landmark information. In the ant brain, visual information from the polarization-sensitive
ocelli converge in tight apposition with neuronal afferents of the mechanosensitive
Johnston’s organ in the ant’s antennae. This makes the ants’ antennae an interesting
candidate for studying the sensory bases of compass calibration in Cataglyphis ants.
The brain of the desert navigators is well adapted to successfully accomplish their
navigational needs. Females (gynes and workers) have voluminous mushroom bodies,
and the synaptic complexity to store large amount of view-based navigational
information, which they acquire during initial learning walks. The male Cataglyphis
brain is better suited for innate behaviors that support finding a mate.
The results of my thesis show that the well adapted brain of C. nodus ants undergoes
massive structural changes during leaning walks, dependent on a changing celestial
polarization pattern. This underlies the essential role of learning walks in the calibration
of orientation systems in desert ants.
Biodiversity is in rapid decline worldwide. These declines are more pronounced in areas that are currently biodiversity rich, but economically poor – essentially describing many tropical regions in the Global South where landscapes are dominated by smallholder agriculture. Agriculture is an important driver of biodiversity decline, through habitat destruction and unsustainable practices. Ironically, agriculture itself is dependent on a range of ecosystem services, such as pollination and pest control, provided by biodiversity. Biodiversity on fields and the delivery of ecosystem services to crops is often closely tied to the composition of the surrounding landscape – complex landscapes with a higher proportion of (semi-)natural habitats tend to support a high abundances and biodiversity of pollinators and natural enemies that are beneficial to crop production. However, past landscape scale studies have focused primarily on industrialized agricultural landscapes in the Global North, and context dependent differences between regions and agricultural systems are understudied. Smallholder agriculture supports 2 billion people worldwide and contributes to over half the world’s food supply. Yet smallholders, particularly in sub-Saharan Africa, are underrepresented in research investigating the consequences of landscape change and agricultural practices. Where research in smallholder agriculture is conducted, the focus is often on commodity crops, such as cacao, and less on crops that are directly consumed by smallholder households, though the loss of services to these crops could potentially impact the most vulnerable farmers the hardest. Agroecology – a holistic and nature-based approach to agriculture, provides an alternative to unsustainable input-intensive agriculture. Agroecology has been found to benefit smallholders through improved agronomical and food-security outcomes. Co-benefits of agroecological practices with biodiversity and ecosystem services are assumed, but not often empirically tested. In addition, the local and landscape effects on biodiversity and ecosystem services are more commonly studied in isolation, but their potentially interactive effects are so far little explored. Our study region in northern Malawi exemplifies many challenges experienced by smallholder farmers throughout sub-Saharan Africa and more generally in the Global South. Malawi is located in a global biodiversity hotspot, but biodiversity is threatened by rapid habitat loss and a push for input-intensive agriculture by government and other stakeholders. In contrast, agroecology has been effectively promoted and implemented in the study region. We investigated how land-use differences and the agroecological practices affects biodiversity and ecosystem services of multiple taxa in a maize-bean intercropping system (Chapter 2), and pollination of pumpkin (Chapter 3) and pigeon pea (Chapter 4). Additionally, the effects of local and landscape scale shrub- to farmland habitat conversion was investigated on butterfly communities, as well as the potential for agroecology to mitigate these effects (Chapter 5).
Ongoing changes in spaceflight – continuing miniaturization, declining costs of rocket launches and satellite components, and improved satellite computing and control capabilities – are advancing Satellite Formation Flying (SFF) as a research and application area. SFF enables new applications that cannot be realized (or cannot be realized at a reasonable cost) with conventional single-satellite missions. In particular, distributed Earth observation applications such as photogrammetry and tomography or distributed space telescopes require precisely placed and controlled satellites in orbit.
Several enabling technologies are required for SFF, such as inter-satellite communication, precise attitude control, and in-orbit maneuverability. However, one of the most important requirements is a reliable distributed Guidance, Navigation and Control (GNC) strategy. This work addresses the issue of distributed GNC for SFF in 3D with a focus on Continuous Low-Thrust (CLT) propulsion satellites (e.g., with electric thrusters) and concentrates on circular low Earth orbits. However, the focus of this work is not only on control theory, but control is considered as part of the system engineering process of typical small satellite missions. Thus, common sensor and actuator systems are analyzed to derive their characteristics and their impacts on formation control. This serves as the basis for the design, implementation, and evaluation of the following control approaches: First, a Model Predictive Control (MPC) method with specific adaptations to SFF and its requirements and constraints; second, a distributed robust controller that combines consensus methods for distributed system control and $H_{\infty}$ robust control; and finally, a controller that uses plant inversion for control and combines it with a reference governor to steer the controller to the target on an optimal trajectory considering several constraints. The developed controllers are validated and compared based on extensive software simulations. Realistic 3D formation flight scenarios were taken from the Networked Pico-Satellite Distributed System Control (NetSat) cubesat formation flight mission. The three compared methods show different advantages and disadvantages in the different application scenarios. The distributed robust consensus-based controller for example lacks the ability to limit the maximum thrust, so it is not suitable for satellites with CLT. But both the MPC-based approach and the plant inversionbased controller are suitable for CLT SFF applications, while showing again distinct advantages and disadvantages in different scenarios.
The scientific contribution of this work may be summarized as the creation of novel and specific control approaches for the class of CLT SFF applications, which is still lacking methods withstanding the application in real space missions, as well as the scientific evaluation and comparison of the developed methods.
The investigation of the Earth system and interplays between its components is of utmost importance to enhance the understanding of the impacts of global climate change on the Earth's land surface. In this context, Earth observation (EO) provides valuable long-term records covering an abundance of land surface variables and, thus, allowing for large-scale analyses to quantify and analyze land surface dynamics across various Earth system components. In view of this, the geographical entity of river basins was identified as particularly suitable for multivariate time series analyses of the land surface, as they naturally cover diverse spheres of the Earth. Many remote sensing missions with different characteristics are available to monitor and characterize the land surface. Yet, only a few spaceborne remote sensing missions enable the generation of spatio-temporally consistent time series with equidistant observations over large areas, such as the MODIS instrument.
In order to summarize available remote sensing-based analyses of land surface dynamics in large river basins, a detailed literature review of 287 studies was performed and several research gaps were identified. In this regard, it was found that studies rarely analyzed an entire river basin, but rather focused on study areas at subbasin or regional scale. In addition, it was found that transboundary river basins remained understudied and that studies largely focused on selected riparian countries. Moreover, the analysis of environmental change was generally conducted using a single EO-based land surface variable, whereas a joint exploration of multivariate land surface variables across spheres was found to be rarely performed.
To address these research gaps, a methodological framework enabling (1) the preprocessing and harmonization of multi-source time series as well as (2) the statistical analysis of a multivariate feature space was required. For development and testing of a methodological framework that is transferable in space and time, the transboundary river basins Indus, Ganges, Brahmaputra, and Meghna (IGBM) in South Asia were selected as study area, having a size equivalent to around eight times the size of Germany. These basins largely depend on water resources from monsoon rainfall and High Mountain Asia which holds the largest ice mass outside the polar regions. In total, over 1.1 billion people live in this region and in parts largely depend on these water resources which are indispensable for the world's largest connected irrigated croplands and further domestic needs as well. With highly heterogeneous geographical settings, these river basins allow for a detailed analysis of the interplays between multiple spheres, including the anthroposphere, biosphere, cryosphere, hydrosphere, lithosphere, and atmosphere.
In this thesis, land surface dynamics over the last two decades (December 2002 - November 2020) were analyzed using EO time series on vegetation condition, surface water area, and snow cover area being based on MODIS imagery, the DLR Global WaterPack and JRC Global Surface Water Layer, as well as the DLR Global SnowPack, respectively. These data were evaluated in combination with further climatic, hydrological, and anthropogenic variables to estimate their influence on the three EO land surface variables. The preprocessing and harmonization of the time series was conducted using the implemented framework. The resulting harmonized feature space was used to quantify and analyze land surface dynamics by means of several statistical time series analysis techniques which were integrated into the framework. In detail, these methods involved (1) the calculation of trends using the Mann-Kendall test in association with the Theil-Sen slope estimator, (2) the estimation of changes in phenological metrics using the Timesat tool, (3) the evaluation of driving variables using the causal discovery approach Peter and Clark Momentary Conditional Independence (PCMCI), and (4) additional correlation tests to analyze the human influence on vegetation condition and surface water area.
These analyses were performed at annual and seasonal temporal scale and for diverse spatial units, including grids, river basins and subbasins, land cover and land use classes, as well as elevation-dependent zones. The trend analyses of vegetation condition mostly revealed significant positive trends. Irrigated and rainfed croplands were found to contribute most to these trends. The trend magnitudes were particularly high in arid and semi-arid regions. Considering surface water area, significant positive trends were obtained at annual scale. At grid scale, regional and seasonal clusters with significant negative trends were found as well. Trends for snow cover area mostly remained stable at annual scale, but significant negative trends were observed in parts of the river basins during distinct seasons. Negative trends were also found for the elevation-dependent zones, particularly at high altitudes. Also, retreats in the seasonal duration of snow cover area were found in parts of the river basins. Furthermore, for the first time, the application of the causal discovery algorithm on a multivariate feature space at seasonal temporal scale revealed direct and indirect links between EO land surface variables and respective drivers. In general, vegetation was constrained by water availability, surface water area was largely influenced by river discharge and indirectly by precipitation, and snow cover area was largely controlled by precipitation and temperature with spatial and temporal variations. Additional analyses pointed towards positive human influences on increasing trends in vegetation greenness. The investigation of trends and interplays across spheres provided new and valuable insights into the past state and the evolution of the land surface as well as on relevant climatic and hydrological driving variables. Besides the investigated river basins in South Asia, these findings are of great value also for other river basins and geographical regions.
Metallic nano-optical systems allow to confine and guide light at the nanoscale,
a fascinating ability which has motivated a wide range of fundamental as well
as applied research over the last two decades. While optical antennas provide
a link between visible radiation and localized energy, plasmonic waveguides
route light in predefined pathways. So far, however, most experimental demonstrations
are limited to purely optical excitations, i.e. isolated structures are
illuminated by external lasers. Driving such systems electrically and generating
light at the nanoscale, would greatly reduce the device footprint and pave the
road for integrated optical nanocircuitry. Yet, the light emission mechanism as
well as connecting delicate nanostructures to external electrodes pose key challenges
and require sophisticated fabrication techniques. This work presents various
electrically connected nano-optical systems and outlines a comprehensive
production line, thus significantly advancing the state of the art. Importantly,
the electrical connection is not just used to generate light, but also offers new
strategies for device assembly. In a first example, nanoelectrodes are selectively
functionalized with self-assembled monolayers by charging a specific electrode.
This allows to tailor the surface properties of nanoscale objects, introducing an
additional degree of freedom to the development of metal-organic nanodevices.
In addition, the electrical connection enables the bottom-up fabrication of tunnel
junctions by feedback-controlled dielectrophoresis. The resulting tunnel barriers
are then used to generate light in different nano-optical systems via inelastic
electron tunneling. Two structures are discussed in particular: optical Yagi-Uda
antennas and plasmonic waveguides. Their refined geometries, accurately fabricated
via focused ion beam milling of single-crystalline gold platelets, determine
the properties of the emitted light. It is shown experimentally, that Yagi-Uda
antennas radiate light in a specific direction with unprecedented directionality,
while plasmonic waveguides allow to switch between the excitation of two
propagating modes with orthogonal near-field symmetry. The presented devices
nicely demonstrate the potential of electrically connected nano-optical systems,
and the fabrication scheme including dielectrophoresis as well as site-selective
functionalization will inspire more research in the field of nano-optoelectronics.
In this context, different future experiments are discussed, ranging from the
control of molecular machinery to optical antenna communication.
Reading skills are among the most important basic skills in society. However, not all readers are able to adequately understand texts or decode individual words. Findings from the Progress in International Reading Literacy Study (PIRLS; German: IGLU) show that about one fifth of fourth graders can only establish coherence at the local level, and in some cases they only have a rudimentary understanding of the text they read (Bremerich-Vos et al., 2017). In addition, these reading deficits persist and have a negative impact on academic and professional success (Jimerson, 1999). Therefore, identifying the causes of these deficits and creating opportunities for interventions at an early stage is an important research objective.
The aim of this dissertation was to examine the relationship between the aspects of reading fluency and their influence on reading comprehension. Despite the increasing scientific interest in reading fluency in recent years, a research gap still exists in the relationship between word recognition accuracy and both speed and the relevance of prosodic patterns for reading comprehension.
Study 1 investigated whether German fourth graders (N = 826) were required to reach a certain word-recognition accuracy threshold before their word-recognition speed improved. In addition, a sub-sample (n = 170) with a pre-/posttest design was examined to assess the extent that the existing word-recognition accuracy can influence the effects of a syllable-based reading intervention on word-recognition accuracy and word-recognition speed. Results showed that word-recognition speed improved after children achieved a word-recognition accuracy of 71%. A positive intervention effect was also found on word-recognition accuracy for children who were below the 71% threshold before the intervention, whereas the intervention effect on word-recognition speed was positive for all children. However, a positive effect on reading comprehension was only found for children who were above the 71% threshold before the intervention.
Study 2 investigated the relationship between word-recognition accuracy threshold and word-recognition speed shown in the first study in a longitudinal design with German students (N = 1,095). Word-recognition accuracy and speed were assessed from the end of Grade 1 to 4, whereas reading comprehension was assessed from the end of Grade 2 to 4. The results showed that the developmental trajectories of word recognition speed and reading comprehension were steeper in children who reached the word-recognition accuracy threshold by the end of the first grade than in children who later reached or had not reached this threshold.
In Study 3, recurrence analysis (RQA) was used to extract prosodic patterns from reading recordings of struggling and skilled readers in the second (n = 67) and fourth grade (n = 69) and was used for the classification into struggling and skilled readers. In addition, the classification based on the prosodic patterns from the recurrence quantification analysis was compared with the classification of prosodic features from the manual transcription of the reading recordings. The results showed that second-grade struggling readers have lengthier pauses within or between words and take more time between pauses on average, whereas fourth-grade struggling readers spend more time between recurring stresses and have multiple diverse patterns in pitch and more recurring accents. Although the recurrence analysis had a good goodness of fit and provided additional information about the relationship of prosody with reading comprehension, the model using prosodic features from transcription had a better fit.
In summary, the three studies in this dissertation provide four important insights into reading fluency in German. First, a threshold in word-recognition accuracy must be achieved before word-recognition speed improves. Second, the earlier this accuracy level is reached, the greater the gain in word-recognition speed and reading comprehension. Third, the intervention effects of a primary school reading intervention are influenced by the accuracy level. Fourth, although incorrect pauses within or between words play an important role in identifying and describing struggling readers in second grade, the importance of prosodic patterns increases in fourth grade.
The extragalactic gamma-ray sky is dominated by blazars, active galactic nuclei (AGN) with a relativistic jet that is closely aligned with the line of sight. Galaxies develop an active nucleus if the central supermassive black hole (BH) accretes large amounts of ambient matter and magnetic flux. The inflowing mass accumulates around the plane perpendicular to the accretion flow's angular momentum. The flow is heated through viscous friction and part of the released energy is radiated as blackbody or non-thermal radiation, with luminosities that can dominate the accumulated stellar luminosity of the host galaxy. A fraction of the accretion flow luminosity is reprocessed in a surrounding field of ionised gas clouds. These clouds, revolving around the central BH, emit Doppler-broadened atomic emission lines. The region where these broad-line-emitting clouds are located is called broad-line region (BLR).
About one in ten AGN forms an outflow of radiation and relativistic particles, called a relativistic jet. According to the Blandford-Znajek mechanism, this is facilitated through electromagnetic processes in the magnetosphere of a spinning BH. The latter induces a magnetospheric poloidal current circuit, generating a decelerating torque on the BH and inducing a toroidal magnetic field. Consequently, rotational energy of the BH is converted to Poynting flux streaming away mainly along the rotational axis and starting the jet. One possibility for particle acceleration near the jet base is realised by magnetospheric vacuum gaps, regions temporarily devoid of plasma, such that an intermittent electric field arises parallel to the magnetic field lines, enabling particle acceleration and contributing to the mass loading of the jets.
Magnetised structures, containing bunches of relativistic electrons, propagate away from the galactic nucleus along the jets. Assuming that these electrons emit synchrotron radiation and that they inverse-Compton (IC) up-scatter abundant target photons, which can either be the synchrotron photons themselves or photons from external emitters, the emitted spectrum can be theoretically determined. Additionally taking into account that these emission regions move relativistically themselves and that the emission is Doppler-boosted and beamed in forward direction, the typical two-hump spectral energy distribution (SED) of blazars is recovered.
There are however findings that challenge this well-established model. Short-time variability, reaching down to minute scales at very high energy gamma rays, is today known to be a widespread phenomenon of blazars, calling for very compact emission regions. In most models of such optically thick emission regions, the gamma-ray flux is usually pair-absorbed exponentially, without considering the cascade evolving from the pair-produced electrons. From the observed flux, it is often concluded that emission emanates from larger distances where the region is optically thin, especially from outside of the BLR. Only in few blazars gamma-ray attenuation associated with pair absorption in the BLR was clearly reported.
With the advent of sophisticated high-energy or very high energy gamma-ray detectors, like the Fermi Large Area Telescope or the Major Atmospheric Gamma-ray Imaging Cherenkov telescopes, besides the extraordinarily fast variability spectral features have been found that cannot be explained by conventional models reproducing the two-hump SED. Two such narrow spectral features are discussed in this work. For the nearby blazar Markarian 501, hints to a sharp peak around 3 TeV have been reported from a multi-wavelength campaign carried out in July 2014, while for 3C 279 a spectral dip was found in 2018 data, that can hardly be described with conventional fitting functions. In this work it is examined whether these spectral peculiarities of blazar jet emission can be explained, if the full radiation reprocessing through an IC pair cascade is accounted for.
Such a cascade is the multiple concatenation of IC scattering events and pair production events. In the cascades generally considered in this work, relativistic electrons and high-energy photons are injected into a fixed soft target photon field. A mathematical description for linear IC pair cascades with escape terms is delivered on the basis of preliminary works. The steady-state kinetic equations for the electrons and for the photons are determined, whereby it is paid attention to an explicit formulation and to motivating the correct integration borders of all integrals from kinematic constraints. In determining the potentially observable gamma-ray flux, both the attenuated injected flux and the flux evolving as an effect of IC up-scattering, pair absorption and escape are incorporated, giving the emerging spectra very distinct imprints.
Much effort is dedicated to the numerical solution of the electrons' kinetic equation via iterative schemes. It is explained why pointwise iteration from higher to lower Lorentz factors is more efficient than iterating the whole set of sampling points. The algorithm is parallelised at two positions. First, several workers can perform pointwise iterations simultaneously. Second, the most demanding integral is cut into a number of part integrals which can be determined by multiple workers. Through these measures, the Python code can be readily applied to simulate steady-state IC pair cascades with escape.
In the case of Markarian 501 the developed framework is as follows. The AGN hosts an advection-dominated accretion flow with a normalised accretion rate of several \(10^{-4}\) and an electron temperature near \(10^{10}\) K. On the one hand, the accretion flow illuminates the few ambient gas clouds with approximate radius \(10^{11}\) m, which reprocess a fraction 0.01 of the luminosity into hydrogen and helium emission lines. On the other hand, the gamma rays from the accretion flow create electrons and positrons in a sporadically active vacuum gap in the BH magnetosphere. In the active gap, a power of roughly 0.001 of the Blandford-Znajek power is extracted from the rotating BH through a gap potential drop of several \(10^{18}\) V, generating ultra-relativistic electrons, which subsequently are multiplied by a factor of about \(10^6\) through interaction with the accretion flow photons. This electron beam propagates away from the central engine and encounters the photon field of one passing ionised cloud. The resulting IC pair cascade is simulated and the evolving gamma-ray spectrum is determined. Just above the absorption troughs due to the hydrogen lines, the spectrum exhibits a narrow bump around 3 TeV. When the cascaded emission is added to the emission generated at larger distances, the observed multi-wavelength SED including the sharp peak at 3 TeV is reproduced, underlining that radiation processes beyond conventional models are motivated by distinct spectral features.
The dip in the spectrum of 3C 279 is addressed by a similar cascade model. Three types of injection are considered, varying in the ratio of the photon density to the electron density and varying in the spectral shape. The IC pair cascade is assumed to happen either in the dense BLR photon field with a luminosity of several \(10^{37}\) W and a radial size of few \(10^{14}\) m or in the diluted photon field outside of the BLR. The latter scenario is however rejected as the spectral slope around several 100 MeV and the dip at few 10 GeV cannot be reconciled within this model. The radiation cascaded in the BLR can explain the observational data, irrespective of the assumed injected rate. It is therefore concluded that for this period of gamma-ray emission, the radiation production happens at the edge of the BLR of 3C 279.
Both investigations show that IC pair cascades can account for fine structure seen in blazar SEDs. It is insufficient to restrict the radiation transport to pure exponential absorption of an injection term. Pair production and IC up-scattering by all generations of photons and electrons in the optically thick regime critically shape the emerging spectra. As the advent of future improved detectors will provide more high-precision spectra, further observations of narrow spectral features can be expected. It seems therefore recommendable to incorporate cascading into conventional radiation production models or to extend the model developed in this work by synchrotron radiation.
Obesity is a serious disease that can affect both physical and psychological well-being. Due to weight stigmatization, many affected individuals suffer from body image disturbances whereby they perceive their body in a distorted way, evaluate it negatively, or neglect it. Beyond established interventions such as mirror exposure, recent advancements aim to complement body image treatments by the embodiment of visually altered virtual bodies in virtual reality (VR). We present a high-fidelity prototype of an advanced VR system that allows users to embody a rapidly generated personalized, photorealistic avatar and to realistically modulate its body weight in real-time within a carefully designed virtual environment. In a formative multi-method approach, a total of 12 participants rated the general user experience (UX) of our system during body scan and VR experience using semi-structured qualitative interviews and multiple quantitative UX measures. Using body weight modification tasks, we further compared three different interaction methods for real-time body weight modification and measured our system’s impact on the body image relevant measures body awareness and body weight perception. From the feedback received, demonstrating an already solid UX of our overall system and providing constructive input for further improvement, we derived a set of design guidelines to guide future development and evaluation processes of systems supporting body image interventions.
Understanding the causal relationship between genotype and phenotype is a major objective in biology. The main interest is in understanding trait architecture and identifying loci contributing to the respective traits. Genome-wide association mapping (GWAS) is one tool to elucidate these relationships and has been successfully used in many different species. However, most studies concentrate on marginal marker effects and ignore epistatic and gene-environment interactions. These interactions are problematic to account for, but are likely to make major contributions to many phenotypes that are not regulated by independent genetic effects, but by more sophisticated gene-regulatory networks. Further complication arises from the fact that these networks vary in different natural accessions. However, understanding the differences of gene regulatory networks and gene-gene interactions is crucial to conceive trait architecture and predict phenotypes.
The basic subject of this study – using data from the Arabidopsis 1001 Genomes Project – is the analysis of pre-mature stop codons. These have been incurred in nearly one-third of the ~ 30k genes. A gene-gene interaction network of the co-occurrence of stop codons has been built and the over and under representation of different pairs has been statistically analyzed. To further classify the significant over and under- represented gene-gene interactions in terms of molecular function of the encoded proteins, gene ontology terms (GO-SLIM) have been applied. Furthermore, co- expression analysis specifies gene clusters that co-occur over different genetic and phenotypic backgrounds. To link these patterns to evolutionary constrains, spatial location of the respective alleles have been analyzed as well. The latter shows clear patterns for certain gene pairs that indicate differential selection.
The subject of this thesis is the investigation of the transport properties of topological and massive surface states in the three-dimensional topological insulator Hg(Mn)Te. These surface states give rise to a variety of extraordinary transport phenomena, making this material system of great interest for research and technological applications. In this connection, many physical properties of the topological insulator Hg(Mn)Te still require in-depth exploration. The overall aim of this thesis is to analyze the quantum transport of HgTe-based devices ranging from hundreds of micrometers (macroscopic) down to a few micrometers in size (microscopic) in order to extend the overall understanding of surface states and the possibilities of their manipulation.
In order to exploit the full potential of our high-quality heterostructures, it was necessary to revise and improve the existing lithographic fabrication process of macroscopic three-dimensional Hg(Mn)Te samples. A novel lithographic standard recipe for the fabrication of the HgTe-based macrostructures was developed. This recipe includes the use of an optimized Hall bar design and wet etching instead of etching with high-energy \(\mathrm{{Ar^{+}}}\)-ions, which can damage the samples. Further, a hafnium oxide insulator is applied replacing the SiO\(_{2}\)/Si\(_{3}\)N\(_{4}\) dielectric in order to reduce thermal load. Moreover, the devices are metallized under an alternating angle to avoid discontinuities of the metal layers over the mesa edges. It was revealed that the application of gate-dielectric and top-gate metals results in n-type doping of the devices. This phenomenon could be attributed to quasi-free electrons tunneling from the trap states, which form at the interface cap layer/insulator, through the cap into the active layer. This finding led to the development of a new procedure to characterize wafer materials. It was found that the optimized lithographic processing steps do not unintentionally react chemically with our heterostructures, thus avoiding a degradation of the quality of the Hg(Mn)Te layer. The implementation of new contact structures Ti/Au, In/Ti/Au, and Al/Ti/Au did not result in any improvement compared to the standard structure AuGe/Au. However, a novel sample recipe could be developed, resulting in an intermixing of the contact metals (AuGe and Au) and fingering of metal into the mesa. The extent of the quality of the ohmic contacts obtained through this process has yet to be fully established.
This thesis further deals with the lithographic realization of three-dimensional HgTe-based microstructures measuring only a few micrometer in size. Thus, these structures are in the order of the mean free path and the spin relaxation length of topological surface state electrons. A lithographic process was developed enabling the fabrication of nearly any desired microscopic device structure. In this context, two techniques suitable for etching microscopic samples were realized, namely wet etching and the newly established inductively coupled plasma etching. While wet etching was found to preserve the crystal quality of the active layer best, inductively coupled plasma etching is characterized by high reproducibility and excellent structural fidelity. Hence, the etching technique employed depends on the envisaged type of experiment.
Magneto-transport measurements were carried out on the macroscopic HgTe-based devices fabricated by means of improved lithographic processing with respect to the transport properties of topological and massive surface states. It was revealed that due to the low charge carrier density present in the leads to the ohmic contacts, these regions can exhibit an insulating behavior at high magnetic fields and extremely low temperatures. As soon as the filling factor of the lowest Landau levels dropped below a critical value (\(\nu_{\mathrm{{c}}}\approx0.8\)), the conductance of the leads decreased significantly. It was demonstrated that the carrier density in the leads can be increased by the growth of modulation doping layers, a back-gate-electrode, light-emitting diode illumination, and by the application of an overlapping top-gate layout. This overlapping top-gate and a back-gate made it possible to manipulate the carrier density of the surface states on both sides of the Hg(Mn)Te layer independently. With this setup, it was identified that topological and massive surface states contribute to transport simultaneously in 3D Hg(Mn)Te. A model could be developed allowing the charge carrier systems populated in the sample to be determined unambiguously. Based on this model, the process of the re-entrant quantum Hall effect observed for the first time in three-dimensional topological insulators could be explained by an interplay of n-type topological and p-type massive surface states. A well-pronounced \(\nu=-1\rightarrow\nu=-2\rightarrow\nu=-1\) sequence of quantum Hall plateaus was found in manganese-doped HgTe-based samples. It is postulated that this is the condensed-matter realization of the parity anomaly in three-dimensional topological insulators. The actual nature of this phenomenon can be the subject of further research. In addition, the measurements have shown that inter-scattering occurs between counter-propagating quantum Hall edge states. The good quantization of the Hall conductance despite this inter-scattering indicates that only the unpaired edge states determine the transport properties of the system as a whole. The underlying inter-scattering mechanism is the topic of a publication in preparation.
Furthermore, three-dimensional HgTe-based microstructures shaped like the capital letter "H" were investigated regarding spin transport phenomena. The non-local voltage signals occurring in the measurements could be attributed to a current-induced spin polarization of the topological surface states due to electrons obeying spin-momentum locking. It was shown that the strength of this non-local signal is directly connected to the magnitude of the spin polarization and can be manipulated by the applied top-gate voltage. It was found that in these microstructures, the massive surface and bulk states, unlike the topological surface states, cannot contribute to this spin-associated phenomenon. On the contrary, it was demonstrated that the population of massive states results in a reduction of the spin polarization, either due to the possible inter-scattering of massive and topological surface states or due to the addition of an unpolarized electron background. The evidence of spin transport controllable by a top-gate-electrode makes the three-dimensional material system mercury telluride a promising candidate for further research in the field of spintronics.
In the Spessart, a low mountain range in central Germany, a feud during the Middle Ages led to the construction of numerous castles in this region. This study analyzes the mutual influence of (paleo-)relief development and medieval building activity using a geomorphological and geoarchaeological multimethod approach to expand the knowledge of human-environmental interactions during this time. For this purpose, GIS-based terrain analysis and geophysical measurements were conducted and combined with sedimentological information to create 1D-3D models of the subsurface and to assess knowledge of the landscape and relief evolution at various medieval castle and mining sites. The interpretation of all these data led to the answering of numerous site-specific questions on various geomorphological, geoarchaeological, geologic, and archaeological topics that have been explored in this work and have greatly increased our knowledge of each study site. In addition to these key contributions to the archaeological and geomorphological interpretation of individual study sites, a quantification of the anthropogenic influence on the relief development was conducted, a generalized model of the influence was derived, and new methodological and interpretative approaches were developed. Overall, this study links geomorphological/geological and (geo-)archaeological investigations at five medieval sites and delivers important information on human-environmental interactions within the Spessart and beyond.
Platelets play an essential role in haemostasis. Through granule secretion of second wave mediators and aggregation, they secure vascular integrity. Due to incorrect activation, platelet aggregation and subsequent thrombus formation can cause blood vessel occlusion, leading to ischemia. Patients with defects in platelet production have a low platelet count (thrombocytopenia), which can cause an increased bleeding risk. In vitro platelet generation is still in its development phase. So far, no convincing results have been obtained. For this reason, the health care system still depends on blood donors. Platelets are produced by bone marrow megakaryocytes (MKs), which extend long cytoplasmic protrusions, designated proplatelets, into sinusoidal blood vessels. Due to shear forces, platelets are then released into the bloodstream. The molecular mechanisms underlying platelet production are still not fully understood. However, a more detailed insight of this biological process is necessary to improve the in vitro generation of platelets and to optimise treatment regimens of patients.
Optogenetics is defined as “light-modulation of cellular activity or of animal behaviour by gene transfer of photo-sensitive proteins”. Optogenetics has had a big impact on neuroscience over the last decade. The use of channelrhodopsin 2 (ChR2), a light-sensitive cation channel, made it possible to stimulate neurons precisely and minimally invasive for the first time. Recent developments in the field of optogenetics intend to address a broader scope of cellular and molecular biology.
The aim of this thesis is to establish optogenetics in the field of MK research in order to precisely control and manipulate MK differentiation. An existing “optogenetic toolbox“ was used, which made it possible to light-modulate the cellular concentration of specific signalling molecules and ion conductance in MKs. Expression of the bacterial photoactivated adenylyl cyclase (bPAC) resulted in a significant increase in cAMP concentration after 5 minutes of illumination. Similarly, intracellular cGMP concentrations in MKs expressing photoactivated guanylyl cyclase (BeCyclop) were elevated. Furthermore, proplatelet formation of MKs expressing the light-sensitive ion channels ChR2 and anion channelrhodopsin (ACR) was altered in a light-dependent manner. These results show that MK physiology can be modified by optogenetic approaches. This might help shed new light on the underlying mechanisms of thrombopoiesis.
Takotsubo syndrome (TTS), a transient form of dysfunction in the heart's left ventricle, occurs predominantly in postmenopausal women who have emotional stress. Earlier studies support the concept that the human circulatory system is modulated by a cortical network (consisting of the anterior cingulate gyrus, amygdala, and insular cortex (Ic)) that plays a pivotal role in the central autonomic nervous system in relation to emotional stressors. The Ic plays a crucial role in the sympathovagal balance, and decreased levels of female sex hormones have been speculated to change functional cerebral asymmetry, with a possible link to autonomic instability. In this review, we focus on the Ic as an important moderator of the human brain–heart axis in association with sex hormones. We also summarize the current knowledge regarding the sex-specific neuroanatomy in TTS.
Platelets, derived from megakaryocytes (MKs) in the bone marrow (BM), are small, anucleated cells that circulate in the bloodstream and are critical for thrombosis and hemostasis. Megakaryo- and subsequent thrombopoiesis are highly orchestrated processes involving the differentiation and maturation of MKs from hematopoietic stem cells (HSCs), after which MKs are able to release platelets into the bloodstream, a process termed proplatelet formation (PPF). Here, the MK penetrates the endothelial lining and releases cytoplasmic portions (proplatelets) into the blood stream, which finally mature into platelets within the ciruculation. PPF requires an extensive crosstalk as well as a tight regulation of the MK cytoskeleton, in which small GTPases of the Rho family, such as RhoA and Cdc42 are critically involved and play opposing roles. MK and platelet specific Cdc42 or RhoA-deficiency in mice results in macrothrombocytopenia. Moreover, RhoA deficient mice displayed a frequent mislocalization of entire MKs into BM sinusoids, a finding that was reverted upon concomitant lack of Cdc42 but accompanied by an aggravated macrothrombocytopenia. Whether receptors are involved in the process of transendothelial MK migration, however, remained unclear.
In the first part of this thesis, a centrifugation-based method (‘spin isolation’) to harvest murine BM cells was established, which not only reduces experimental time, costs and animals but is also highly suitable for studies on primary and in vitro cultured BM-derived cells. The spin isolation was used particularly for MK studies during the course of the thesis.
In the second part of this thesis, a MK- and platelet-specific RhoA/Cdc42 double-deficiency was shown to result in reduced expression of a variety of MK-specific glycoproteins and cytoskeletal regulators of importance during MK maturation and PPF, a phenotype culminating in virtually abolished platelet biogenesis. We thus uncovered that RhoA/Cdc42-regulated gene expression is a prerequisite for cytoplasmic MK maturation, but dispensable for endomitosis.
In the third part of this thesis we analyzed mice double-deficient in RhoA and prominent MK receptors which are potentially involved in the regulation of PPF in the BM environment. We were able to show that integrins as well as the inhibitory receptor G6b-B are dispensable for transendothelial migration of RhoA-deficient MKs. Surprisingly however, the myelofibrosis and concomitant osteosclerosis observed in G6b-B single-deficient mice was attenuated in RhoA/G6b B double-deficient mice, thus implying an important role of RhoA during myelofibrotic disease progression. BM transplantation experiments furthermore revealed that not only the macrothrombocytopenia but also the transmigration of RhoA-deficient MKs is due to cell-intrinsic defects and not related to possible Pf4-Cre off-target effects in non-hematopoietic cells.
In the last part of this study we demonstrated that the new approach for MK- and platelet-specific gene ablatation using Gp1ba-Cre deleter mice is associated with intrinsic MK defects and in addition results in insufficient depletion of RhoA compared to the Pf4-Cre model, positioning the latter still as the gold standard for studying MK biology.
This work involves the synthesis and reactivity of pseudohalide-substituted boranes and borylenes. A series of compounds of the type (CAAC)BR2Y (CAAC = cyclic alkyl(amino)carbene; R = H, Br; Y = CN, NCS, PCO) were prepared first. The two-electron reduction of (CAAC)BBr2Y (Y = CN, NCS) in the presence of a second Lewis base L (L = N-heterocyclic carbene) resulted in the formation of the corresponding doubly Lewis base-stabilized pseudohaloborylenes (CAAC)(L)BY. These borylenes show versatile reactivity patterns, including their oxidation to the corresponding radical cations, coordination via the respective pseudohalide substituent to group 6 metal carbonyl complexes, as well as a boron-centered protonation with Brønsted acids to boronium cations. Reduction of (CAAC)BBr2(NCS) in the absence of a second donor ligand, led to the formation of boron-doped thiazolothiazoles via reductive dimerization of two isothiocyanatoborylenes. These B,N,S-heterocycles possess a low degree of aromaticity as well as interesting photophysical properties and can furthermore be protonated as well as hydroborated. Additionally, CAAC adducts of the parent boraphosphaketene (CAAC)BH2(PCO) could be prepared, which readily reacted with boroles [Ph4BR'] (R' = aryl) via decarbonylation in a ring expansion reaction. The obtained 1,2-phosphaborinines represent B,P-isosteres of benzene and consequently could be coordinated to metal carbonyl complexes of the chromium triade via η6-coordination, resulting in new half-sandwich complexes thereof.
Recurrent medulloblastomas are associated with survival rates <10%. Adequate multimodal therapy is being discussed as having a major impact on survival. In this study, 93 patients with recurrent medulloblastoma treated in the German P-HIT-REZ 2005 Study were analyzed for survival (PFS, OS) dependent on patient, disease, and treatment characteristics. The median age at the first recurrence was 10.1 years (IQR: 6.9–16.1). Median PFS and OS, at first recurrence, were 7.9 months (CI: 5.7–10.0) and 18.5 months (CI: 13.6–23.5), respectively. Early relapses/progressions (<18 months, n = 30/93) found mainly in molecular subgroup 3 were associated with markedly worse median PFS (HR: 2.34) and OS (HR: 3.26) in regression analyses. A significant survival advantage was found for the use of volume-reducing surgery as well as radiotherapy. Intravenous chemotherapy with carboplatin and etoposide (ivCHT, n = 28/93) showed improved PFS and OS data and the best objective response rate (ORR) was 66.7% compared to oral temozolomide (oCHT, n = 47/93) which was 34.8%. Intraventricular (n = 43) as well as high-dose chemotherapy (n = 17) at first relapse was not related to a significant survival benefit. Although the results are limited due to a non-randomized study design, they may serve as a basis for future treatment decisions in order to improve the patients' survival.
(1) Background: Locoregional lymphadenectomy (LND) in adrenocortical carcinoma (ACC) may impact oncological outcome, but the findings from individual studies are conflicting. The aim of this systematic review and meta-analysis was to determine the oncological value of LND in ACC by summarizing the available literature. (2) Methods: A systematic search on studies published until December 2020 was performed according to the PRISMA statement. The primary outcome was the impact of lymphadenectomy on overall survival (OS). Two separate meta-analyses were performed for studies including patients with localized ACC (stage I–III) and those including all tumor stages (I–IV). Secondary endpoints included postoperative mortality and length of hospital stay (LOS). (3) Results: 11 publications were identified for inclusion. All studies were retrospective studies, published between 2001–2020, and 5 were included in the meta-analysis. Three studies (N = 807 patients) reported the impact of LND on disease-specific survival in patients with stage I–III ACC and revealed a survival benefit of LND (hazard ratio (HR) = 0.42, 95% confidence interval (95% CI): 0.26–0.68). Based on results of studies including patients with ACC stage I–IV (2 studies, N = 3934 patients), LND was not associated with a survival benefit (HR = 1.00, 95% CI: 0.70–1.42). None of the included studies showed an association between LND and postoperative mortality or LOS. (4) Conclusion: Locoregional lymphadenectomy seems to offer an oncologic benefit in patients undergoing curative-intended surgery for localized ACC (stage I–III).
Prostate-specific membrane antigen (PSMA)-directed positron emission tomography/computed tomography (PET/CT) is increasingly utilized for staging of men with prostate cancer (PC). To increase interpretive certainty, the standardized PSMA reporting and data system (RADS) has been proposed. Using PSMA-RADS, we characterized lesions in 18 patients imaged with \(^{18}\)F-PSMA-1007 PET/CT for primary staging and determined the stability of semi-quantitative parameters. Six hundred twenty-three lesions were categorized according to PSMA-RADS and manually segmented. In this context, PSMA-RADS-3A (soft-tissue) or -3B (bone) lesions are defined as being indeterminate for the presence of PC. For PMSA-RADS-4 and -5 lesions; however, PC is highly likely or almost certainly present [with further distinction based on absence (PSMA-RADS-4) or presence (PSMA-RADS-5) of correlative findings on CT]. Standardized uptake values (SUV\(_{max}\), SUV\(_{peak}\), SUV\(_{mean}\)) were recorded, and volumetric parameters [PSMA-derived tumor volume (PSMA-TV); total lesion PSMA (TL-PSMA)] were determined using different maximum intensity thresholds (MIT) (40 vs. 45 vs. 50%). SUV\(_{max}\) was significantly higher in PSMA-RADS-5 lesions compared to all other PSMA-RADS categories (p ≤ 0.0322). In particular, the clinically challenging PSMA-RADS-3A lesions showed significantly lower SUV\(_{max}\) and SUV\(_{peak}\) compared to the entire PSMA-RADS-4 or -5 cohort (p < 0.0001), while for PSMA-RADS-3B this only applies when compared to the entire PSMA-RADS-5 cohort (p < 0.0001), but not to the PSMA-RADS-4 cohort (SUV\(_{max}\), p = 0.07; SUV\(_{peak}\), p = 0.08). SUV\(_{mean}\) (p = 0.30) and TL-PSMA (p = 0.16) in PSMA-RADS-5 lesions were not influenced by changing the MIT, while PSMA-TV showed significant differences when comparing 40 vs. 50% MIT (p = 0.0066), which was driven by lymph nodes (p = 0.0239), but not bone lesions (p = 0.15). SUV\(_{max}\) was significantly higher in PSMA-RADS-5 lesions compared to all other PSMA-RADS categories in \(^{18}\)F-PSMA-1007 PET/CT. As such, the latter parameter may assist the interpreting molecular imaging specialist in assigning the correct PSMA-RADS score to sites of disease, thereby increasing diagnostic certainty. In addition, changes of the MIT in PSMA-RADS-5 lesions had no significant impact on SUV\(_{mean}\) and TL-PSMA in contrast to PSMA-TV.
One rarely finds practical guidelines for the implementation of complex optical setups. Here, we aim to provide technical details on the decision making of building and revising a custom sensor-based adaptive optics (AO) direct stochastic optical reconstruction microscope (dSTORM) to provide practical assistance in setting up or troubleshooting similar devices.
The foundation of this report is an instrument constructed as part of a master's thesis in 2021, which was built for deep tissue imaging. The setup is presented in the following way: (1) An optical and mechanical overview of the system at the beginning of this internship is given. (2) The optical components are described in detail in the order at which the light passes through, highlighting their working principle and implementation in the system. The optical component include (2A) a focus on even sample illumination, (2B) restoring telecentricity when working with commercial microscope bodies, (2C) the AO elements, namely the deformable mirror (DM) and the wavefront sensor, and their integration, and (2D) the separation of wavefront and image capture using fluorescent beads and a dichroic mirror. After addressing the limitations of the existing setup, modification options are derived. The modifications include the implementation of adjustment only light paths to improve system stability and revise the degrees of freedom of the components and changes in lens choices to meet the specifications of the AO components. Last, the capabilities of the modified setup are presented and discussed: (1) First, we enable epifluorescence imaging of bead samples through 180 µm unstained murine hippocampal tissue with wavefront error correction of ~ 90 %. Point spread function, wavefront shape and Zernike decomposition of bead samples are presented. (2) Second, we move from epifluorescent to dSTORM imaging of tubulin stained primary mouse hippocampal cells, which are imaged through up to 180 µm of unstained murine hippocampal tissue. We show that full width at half maximum (FWHM) of prominent features can be reduced in size by nearly a magnitude from uncorrected epiflourescence images to dSTORM images corrected by the adaptive optics. We present dSTORM localization count and FWHM of prominent features as as a function of imaging depth.
Re-induction with immune checkpoint blockade (ICB) needs to be considered in many patients with uveal melanoma (UM) due to limited systemic treatment options. Here, we provide hitherto the first analysis of ICB re-induction in UM. A total of 177 patients with metastatic UM treated with ICB were included from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of ICB re-induction, two cohorts were compared: patients who received at least one ICB re-induction (cohort A, n = 52) versus those who received only one treatment line of ICB (cohort B, n = 125). In cohort A, a transient benefit of overall survival (OS) was observed at 6 and 12 months after the treatment start of ICB. There was no significant difference in OS between both groups (p = 0.1) with a median OS of 16.2 months (cohort A, 95% CI: 11.1–23.8) versus 9.4 months (cohort B, 95% CI: 6.1–14.9). Patients receiving re-induction of ICB (cohort A) had similar response rates compared to those receiving ICB once. Re-induction of ICB may yield a clinical benefit for a small subgroup of patients even after resistance or development of toxicities.
Platelets are the second most abundant blood cells and their main function is maintenance of vascular integrity. In addition, platelets are increasingly recognized as cells with immune functions, as they participate in the recruitment of immune cells and modulate the progression and severity of an immune response. So-called lipid mediators, which are – besides other cells – released by activated platelets, influence the immune response. LTB4 is one of these potent lipid mediators and is able to activate neutrophils and induce their infiltration into injured tissue.
In order to investigate the involvement of platelets in inflammatory processes, a murine model of hepatic ischemia reperfusion injury as well as confocal intravital microscopy of the liver were established. Both methods were used to analyze the influence of platelets on the inflammation that follows sterile liver inflammation. We found platelet function to be unaltered after three hours of reperfusion and platelet aggregation to be irrelevant for the outcome of hepatic ischemia reperfusion injury. However, a strong impact of the GPIb-vWF axis could be observed, as antibody mediated blockade of GPIb as well as vWF-deficiency significantly reduced liver damage markers and decreased neutrophil infiltration. GPIb-IL-4R mice were used to exclude the possibility that the protective effects of the anti-GPIbα antibody treatment (p0p/B) results from something else than blocking GPIbα. Furthermore, the slope of neutrophil infiltration was decreased in p0p/B-treated mice, leading to overall decreased neutrophil numbers in the liver after three hours of reperfusion. Blockade of the integrin αIIbβ3, however, showed no reduction in neutrophil infiltration into the post-ischemic liver, in line with unaltered liver damage.
To study the role of leukotriene B4, conditional and constitutive knockout mice for the LTA4 hydrolase, which catalyzes the last step in LTB4 synthesis, were generated. Lta4h deficiency did not affect general platelet functionality in hemostasis and thrombosis. Interestingly,
Lta4h-/- mice were not protected from cellular damage following hepatic ischemia, despite lower neutrophil numbers in the post-ischemic liver.
Intravital microscopy of the pancreas was established and revealed increased CD4+ T cell numbers in GPVI-deficient animals compared to WT controls in line with the pre-diabetic phenotype of Gp6-/- mice that was revealed in Grzegorz Sumara’s group. Furthermore, platelet ‘behavior’ in pancreatic islets was observed following glucose injection. We found a high number of platelets adherent to islet sinusoids under basal conditions and no rolling/decelerating of platelets following glucose injection. This was accompanied by temporary sinusoidal constriction and stop of the blood flow. This phenomenon was not observed in control settings (injection of PBS, insulin or L-glucose).
In a side project, which was carried out jointly with Tobias Heib, a side by side comparison of the classical syringe-based flushing and the centrifugation-based spinning method to isolate murine bone marrow was conducted. Flow cytometry revealed no differences in the distribution of hematopoietic stem cells and immune cells and functional analysis with primary and cultured megakaryocytes (MKs) showed comparable results in all conducted assays. Thus, our data demonstrated that the faster and more efficient spinning method can be used for the isolation of bone marrow cells.
Improving retention of learned content by means of a practice test is a learning strategy that has been researched since a century and has been consistently found to be more effective than comparable learning strategies such as restudy (i.e., the testing effect). Most importantly, practicing test questions has been found to outperform restudy even when no additional information about the correct answers was provided to practice test takers, rendering practice tests effective and efficient in fostering retention of learning content. Since 15 years, additional scientific attention is devoted to this memory phenomenon and additional research investigated to what extend practicing test questions is relevant in real-world educational settings. This dissertation first presents the evidence for testing effects in applied educational settings by presenting key publications and presenting findings from a methodological review conducted for this purpose. Within this dissertation, theories are presented why practicing test questions should benefit learning in real-world educational settings even without the provision of additional information and key variables for the effectiveness of practicing test questions are presented. Four studies presented in this dissertation aimed at exploring these assumptions in actual university classrooms while also trying to implement new methods of practicing learning content and thus augment course procedures. Findings from these studies—although not often consistent—will be incorporated and interpreted in the light of the theoretical accounts on the testing effect. The main conclusion that can be drawn from this dissertation is that, given the right circumstances, practicing test questions can elicit beneficial effects on the retention of learning content that are independent of additional information and thus taking a practice test per se, can foster retention of real-world learning content.
Numerous experiments have shown that an evaluative and passive process, known as validation, accompanies activation and integration, which are fundamental processes of text comprehension. During the construction of a mental model, validation implicitly assesses the plausibility of incoming information by checking its consistency with world knowledge, prior beliefs, and contextual information (e.g., the broader discourse context). However, research on potential influences that shape validation processes has just started. One branch of research is investigating how world knowledge and contextual information contribute to integration and validation. World knowledge usually influences validation more strongly because information plausibility is the primary criterion for validation, but strong contextual information can yield influences as well.
Contextual information that may be specifically relevant for routine validation is the credibility of a source providing text information. Source credibility bears a strong conceptual relationship to the validity of information. However, a dearth of research has investigated joint effects of plausibility and source credibility for routine validation. To fill this research gap, the aim of the present dissertation was to examine the role of source credibility in routine validation processes of text information. This dissertation argues that both source credibility and plausibility are considered in these processes. In particular, information plausibility is proposed as the primary criterion, but source credibility may modulate validation as an additional criterion. To this end, three studies with five self-paced reading experiments were conducted in which reading times served as an implicit indicator of validation and plausibility judgments as an explicit indicator, and the convergence or divergence between the two indicators was interpreted.
The first study examined the interplay of plausibility and source credibility for the validation of world-knowledge consistent versus inconsistent text information embedded in short narratives. This highly plausible or highly implausible information was provided by a high- or low-expertise source. In Study 1, plausibility dominated validation as suggested by faster reading times and higher plausibility judgments for world-knowledge consistent information. Importantly, source credibility modulated the validation of highly implausible information but seemed to not matter for plausible information. High-credible sources increased the implausibility of highly implausible information to a greater extent compared with low-credible sources as indicated by longer reading times and lower plausibility judgments. These results diverged from recent findings from Foy et al. (2017).
The second study investigated whether the modulating role of source credibility depends on the degree of implausibility of an information. Thus, Study 2 extended Study 1 by an intermediate, somewhat implausible level of plausibility (comparable to the implausible claims in Foy et al., 2017). Similar to Study 1, plausibility dominated validation as indicated by lower reading times and plausibility judgments with higher world-knowledge inconsistency. Again, source credibility had no effect on the routine validation of plausible information. However, high-credible sources mitigated the implausibility of somewhat implausible information as indicated by faster reading times and higher plausibility judgments but exacerbated the implausibility of highly implausible information as indicated by slower reading times and lower plausibility judgments.
In short, Study 2 findings not only integrates the seemingly divergent results of Study 1 and Foy et al. (2017) but also provides strong support for the assumption that the degree of implausibility determines the modulating role of source credibility for validation.
The third study examined the relationship of source credibility and plausibility in an ecologically valid social media setting with short Twitter messages varying in world-knowledge and text-belief consistency by trustworthy and untrustworthy sources. In sum, plausibility and to a lesser extent source credibility mattered for routine validation and explicit evaluation of text information as indicated by reading times and plausibility judgments. However, the pattern partly diverged from Study 1 and 2, possibly because the source information was more salient.
In sum, the present dissertation yielded three insights. First, the findings further extends evidence for routine validation based on world-knowledge and prior beliefs. Second, the studies suggest that source credibility can modulate validation. Readers used source credibility cues for routine validation and the explicit evaluation of text information in all studies. Third, the impact of source credibility seems to depend on the degree of implausibility of information.
The present findings have theoretical implications for theories of validation and text comprehension as well as practical implications for targeting threats associated with the prevalence of inaccurate information, for example, on the World Wide Web. Future research using eye-tracking methodology could further disentangle the routine and strategic underlying processes of the relationship between source credibility and plausibility.
Over the past centuries, anthropogenic utilization has fundamentally changed the appearance of European forest ecosystems. Constantly growing and changing demands have led to an enormous decline in ecological key elements and a structural homogenization of most forests. These changes have been accompanied by widespread declines of many forest-dwelling and especially saproxylic, i.e. species depending on deadwood. In order to counteract this development, various conservation strategies have been developed, but they primarily focus on a quantitative deadwood enrichment. However, the diversity of saproxylic species is furthermore driven by a variety of abiotic and biotic determinants as well as interactions between organisms. A detailed understanding of these processes has so far been largely lacking. The aim of the present thesis was therefore to improve the existing ecological knowledge of determinants influencing saproxylic species and species communities in order to provide the basis for evidence-based and adapted conservation measures.
In chapter II of this thesis, I first investigated the impact of sun exposure, tree species, and their combination on saproxylic beetles, wood-inhabiting fungi, and spiders. Therefore, logs and branches of six tree species were set up under different sun exposures in an experimental approach. The impact of sun exposure and tree species strongly differed among single saproxylic taxa as well as diameters of deadwood. All investigated taxa were affected by sun exposure, whereby sun exposure resulted in a higher alpha-diversity of taxa recorded in logs and a lower alpha-diversity of saproxylic beetles reared from branches compared to shading by canopy. Saproxylic beetles and wood-inhabiting fungi as obligate saproxylic species were additionally affected by tree species. In logs, the respective impact of both determinants also resulted in divergent community compositions. Finally, a rarefaction/extrapolation method was used to evaluate the effectiveness of different combinations of tree species and sun exposure for the conservation of saproxylic species diversity. Based on this procedure, a combination of broadleaved and coniferous as well as hard- and softwood tree species was identified to support preferably high levels of saproxylic species diversity.
The aim of chapter III was to evaluate the individual conservational importance of tree species for the protection of saproxylic beetles. For this, the list of tree species sampled for saproxylic beetles was increased to 42 different tree species. The considered tree species represented large parts of taxonomic and phylogenetic diversity native to Central Europe as well as the most important non-native tree species of silvicultural interest. Freshly cut branches were set up for one year and saproxylic beetles were reared afterwards for two subsequent years.
The study revealed that some tree species, in particular Quercus sp., host a particular high diversity of saproxylic beetles, but tree species with a comparatively medium or low overall diversity were likewise important for red-listed saproxylic beetle species. Compared to native tree species, non-native tree species hosted a similar overall species diversity of saproxylic beetles but differed in community composition.
In chapter IV, I finally analysed the interactions of host beetle diversity and the diversity of associated parasitoids by using experimentally manipulated communities of saproxylic beetles and parasitoid Hymenoptera as a model system. Classical approaches of species identification for saproxylic beetles were combined with DNA-barcoding for parasitoid Hymenoptera. The diversity of the host communities was inferred from their phylogenetic composition as well as differences in seven functional traits. Abundance, species richness, and Shannon-diversity of parasitoid Hymenoptera increased with increasing host abundance. However, the phylogenetic and functional dissimilarity of host communities showed no influence on the species communities of parasitoid Hymenoptera. The results clearly indicate an abundance-driven system in which the general availability, not necessarily the diversity of potential hosts, is decisive.
In summary, the present thesis corroborates the general importance of deadwood heterogeneity for the diversity of saproxylic species by combining different experimental approaches. In order to increase their efficiency, conservation strategies for saproxylic species should generally promote deadwood from different tree species under different conditions of sun exposure on landscape-level in addition to the present enrichment of a certain deadwood amount. The most effective combinations of tree species should consider broadleaved and coniferous as well as hard- and softwood tree species. Furthermore, in addition to dominant tree species, special attention should be given to native, subdominant, silviculturally unimportant, and rare tree species.
G protein-coupled receptors (GPCRs) constitute the largest class of membrane proteins, and are the master components that translate extracellular stimulus into intracellular signaling, which in turn modulates key physiological and pathophysiological processes. Research within the last three decades suggests that many GPCRs can form complexes with each other via mechanisms that are yet unexplored. Despite a number of functional evidence in favor of GPCR dimers and oligomers, the existence of such complexes remains controversial, as different methods suggest diverse quaternary organizations for individual receptors. Among various methods, high resolution fluorescence microscopy and imagebased fluorescence spectroscopy are state-of-the-art tools to quantify membrane protein oligomerization with high precision. This thesis work describes the use of single molecule fluorescence microscopy and implementation of two confocal microscopy based fluorescence fluctuation spectroscopy based methods for characterizing the quaternary organization of two class A GPCRs that are important clinical targets: the C-X-C type chemokine receptor 4 (CXCR4) and 7 (CXCR7), or recently named as the atypical chemokine receptor 3 (ACKR3). The first part of the results describe that CXCR4 protomers are mainly organized as monomeric entities that can form transient dimers at very low expression levels allowing single molecule resolution. The second part describes the establishment and use of spatial and temporal brightness methods that are based on fluorescence fluctuation spectroscopy. Results from this part suggests that ACKR3 forms clusters and surface localized monomers, while CXCR4 forms increasing amount of dimers as a function of receptor density in cells. Moreover, CXCR4 dimerization can be modulated by its ligands as well as receptor conformations in distinct manners. Further results suggest that antagonists of CXCR4 display distinct binding modes, and the binding mode influences the oligomerization and the basal activity of the receptor: While the ligands that bind to a “minor” subpocket suppress both dimerization and constitutive activity, ligands that bind to a distinct, “major” subpocket only act as neutral antagonists on the receptor, and do not modulate neither the quaternary organization nor the basal signaling of CXCR4. Together, these results link CXCR4 dimerization to its density and to its activity, which may represent a new strategy to target CXCR4.
In the past decade, poly(2-oxazoline)s (POx) and very recently poly(2-oxazine)s (POzi) based amphiphiles have shown great potential for medical applications. Therefore, the major aim of this thesis was to further explore the pharmaceutical and biomedical applications of POx/POzi based ABA triblock and AB diblock copolymers, respectively with the special emphasis on structure property relationship (SPR). ABA triblock copolymers (with shorter side chain length in the hydrophobic block) have shown high solubilizing capacity for hydrophobic drugs. The issue of poor aqueous solubility was initially addressed by developing a (micellar) formulation library of 21 highly diverse, hydrophobic drugs with POx/POzi based ABA triblock copolymers. Theoretically, the extent of compatibility between polymers and drug was determined by calculating solubility parameters (SPs). The SPs were thoroughly investigated to check their applicability in present systems. The selected formulations were further characterized by various physico-chemical techniques. For the biomedical applications, a novel thermoresposive diblock copolymer was synthesized which has shown promising properties to be used as hydrogel bioink or can potentially be used as fugitive support material. The most important aspect i.e. SPR, was studied with respect to hydrophilic block in either tri- or di-block copolymers. In triblock copolymer, the hydrophilic block played an important role for ultra high drug loading, while in case of diblock, it has improved the printability of the hydrogels. Apart from the basic research, the therapeutic applications of two formulations i.e. mitotane (commercially available as tablet dosage form for adrenocortical carcinoma) and BT-44 (lead compound for nerve regeneration) were studied in more detail.
This project explores Tan Yunxian's journey of becoming a female doctor in the Ming dynasty. Among all the surviving Ming medical books, Tan Yunxian's medical case book is the only one that was written by a woman. It seems natural, considering she had both scholar-official and medical family backgrounds. Yet, social expectations consider it more suitable for a lady to remain in the household, and not treat patients outside. To legitimize Tan Yunxian's pursuit of a medical career, she applied several strategies to resolve potential criticism toward her and her family. These strategies are analyzed through her autobiographical preface in her medical case book. The project also explores Ming male literatis' perspectives toward Tan Yunxian, the factors that contributed to the preservation and publication of her medical case book, and examined her medical cases under the social-historical and micro-history contexts.
Optimization problems with composite functions deal with the minimization of the sum
of a smooth function and a convex nonsmooth function. In this thesis several numerical
methods for solving such problems in finite-dimensional spaces are discussed, which are
based on proximity operators.
After some basic results from convex and nonsmooth analysis are summarized, a first-order
method, the proximal gradient method, is presented and its convergence properties are
discussed in detail. Known results from the literature are summarized and supplemented by
additional ones. Subsequently, the main part of the thesis is the derivation of two methods
which, in addition, make use of second-order information and are based on proximal Newton
and proximal quasi-Newton methods, respectively. The difference between the two methods
is that the first one uses a classical line search, while the second one uses a regularization
parameter instead. Both techniques lead to the advantage that, in contrast to many similar
methods, in the respective detailed convergence analysis global convergence to stationary
points can be proved without any restricting precondition. Furthermore, comprehensive
results show the local convergence properties as well as convergence rates of these algorithms,
which are based on rather weak assumptions. Also a method for the solution of the arising
proximal subproblems is investigated.
In addition, the thesis contains an extensive collection of application examples and a detailed
discussion of the related numerical results.
In this thesis, non-modified POx, namely PnPrOx and PcycloPrOx, with an LCST in the physiological range between 20 and 37°C have been utilized as materials for three different biofabrication approaches. Their thermoresponsive behavior and processability were exploited to establish an easy-to-apply coating for cell sheet engineering, a novel method to create biomimetic scaffolds based on aligned fibrils via Melt Electrowriting (MEW) and the application of melt electrowritten sacrificial scaffolds for microchannel creation for hydrogels.
Chapter 3 describes the establishment of a thermoresponsive coating for tissue culture plates. Here, PnPrOx was simply dissolved in water and dried in well plates and petri dishes in an oven. PnPrOx adsorbed to the surface, and the addition of warm media generated a cell culture compatible coating. It was shown that different cell types were able to attach and proliferate. After confluency, temperature reduction led to the detachment of cell sheets. Compared to standard procedures for surface coating, the thermoresponsive polymer is not bound covalently to the surface and therefore does not require specialized equipment and chemical knowledge. However, it should be noted that the detachment of the cell layer requires the dissolution of the PnPrOx-coating, leading to possible polymer contamination. Although it is only a small amount of polymer dissolved in the media, the detached cell sheets need to be washed by media exchange for further processing if required. ...
We consider a multi-species gas mixture described by a kinetic model. More precisely, we are interested in models with BGK interaction operators. Several extensions to the standard BGK model are studied.
Firstly, we allow the collision frequency to vary not only in time and space but also with the microscopic velocity. In the standard BGK model, the dependence on the microscopic velocity is neglected for reasons of simplicity. We allow for a more physical description by reintroducing this dependence. But even though the structure of the equations remains the same, the so-called target functions in the relaxation term become more sophisticated being defined by a variational procedure.
Secondly, we include quantum effects (for constant collision frequencies). This approach influences again the resulting target functions in the relaxation term depending on the respective type of quantum particles.
In this thesis, we present a numerical method for simulating such models. We use implicit-explicit time discretizations in order to take care of the stiff relaxation part due to possibly large collision frequencies. The key new ingredient is an implicit solver which minimizes a certain potential function. This procedure mimics the theoretical derivation in the models. We prove that theoretical properties of the model are preserved at the discrete level such as conservation of mass, total momentum and total energy, positivity of distribution functions and a proper entropy behavior. We provide an array of numerical tests illustrating the numerical scheme as well as its usefulness and effectiveness.
Extracellular vesicle (EV)-mediated intercellular communication through exosomes, microvesicles (MVs) and apoptotic bodies has been shown to be implicated in various physiological as well as pathological processes such as the development and progression of atherosclerosis. While the cellular machinery controlling EV formation and composition has been studied extensively, little is known about the underlying morphological processes. This study focuses on a detailed ultrastructural analysis of the different steps of EV formation and release in Myocardial Endothelial (MyEnd) and Aortic Endothelial (AoEnd) cells cultured under serum starvation and inflammatory stimulation with TNF-α. Detailed morphological analyses were conducted applying and comparing different high- resolution light and electron microscopic methods. In this study, we could depict all steps of MV biogenesis named in literature. However, during the study of exosome biogenesis, we discovered a yet undescribed process: Instead of a direct fusion with the plasma membrane, multivesicular bodies were incorporated into a new distinct cellular compartment bound by fenestrated endothelium first. This may present a novel step in exosome biogenesis and warrants further study. Regarding the conditions of cell cultivation, we observed that the commonly used serum starvation causes MyEnd cells, but not AoEnd cells, to enter apoptosis after 48 hours. When preparing functional EV studies, we therefore recommend assessing the morphological condition of the serum-starved cells at different cultivation points first. When evaluating MV production, a statistical analysis showed that the more time AoEnd cells spent in cultivation under serum starvation, the higher the percentage of MV producing cells. However, additional TNF-α stimulation induced a significantly higher MV production than serum starvation alone. Lastly, our results show that TNF-α stimulation of AoEnd cells in vitro leads to the upregulation of CD44, an adhesion molecule critical in the early stages of atherosclerosis. CD44 was then depicted on the surface of generated MVs and exosomes. We conclude that under inflammatory conditions, EVs can mediate the transfer of CD44 from endothelial cells to target cells. This could be a novel mechanism by which MVs contribute to the development and progression of atherosclerotic disease and should be clarified by further studies.
Universal prevention of nonsuicidal self-injury for children and adolescents – A systematic review –
(2022)
In a synopsis of the current state of research regarding NSSI, there are two key findings of this thesis: Firstly, there is a severe scarcity of studies and currently no evidence base for effective universal prevention of NSSI in youth. Secondly, not only the number but also quality of those few studies found was considered too low to draw wide-ranging conclusions and no meta-analysis could be conducted. This conclusion based – among other factors listed in chapter six – on the application of the EPHPP quality assessment tool (Evans, Lasen et al. 2015), which revealed distinct deficiencies and a weak overall study quality for all seven studies.
Even if the high prevalence of NSSI among adolescents and the importance of this field of research is increasingly emphasized in contemporary literature (Muehlenkamp, Walsh et al. 2010, Wasserman, Carli et al. 2010, Brunner, Kaess et al. 2014, Plener, Schumacher et al. 2015), the shortage of concrete programs addressing the issue is manifest. The potential to tackle NSSI via prevention is underlined in view of the fact that many recent studies prove the high potential of primary prevention regarding NSSI incidences (Evans, Hawton et al. 2005, Fortune, Sinclair et al. 2008).
From the studies included for this review, it can be concluded that most interventions show positive effects in raising awareness, knowledge, understanding of risk factors and help-seeking attitudes among school staff or students, particularly when starting with low knowledge at baseline (Robinson, Gook et al. 2008). Yet, most studies focus on training of gatekeepers and only two programmes address students directly and primarily measure actual NSSI behaviour. This finding highlights the importance of more investigation into concrete NSSI measurement targeting mainly the group of youth.
There is a severe lack of literature on primary prevention with suitable contexts and target groups, while reviews on secondary targeted prevention deliver much more potential in the quantity of research (Kothgassner, Robinson et al. 2020, Kothgassner, Goreis et al. 2021). Until that changes, secondary prevention approaches of NSSI should be relied upon first.
Looking into the future, several considerations may help advance universal approaches to NSSI. Regarding study planning, it is crucial for future research to pursue a thorough background research, examine the feasibility of interventions, and evaluate the appropriateness of study samples chosen. Moreover, research groups are expected to ensure a close observation of participants in cases of adverse events, in order to offer support, but also detect potential deficiencies in the study organisation. Additionally – in accordance with other research in this field (Plener, Brunner et al. 2010) – findings of this review highlight the necessity to expand fundamental research on functions of NSSI and its (neurobiological) mechanism of formation in order to enhance the knowledge of correlations and improve effective preventive approaches. As psychoeducational methods have shown risks of iatrogenic effects (e.g. in patients with eating disorders) (Stice, 2007 #10063), it might be worthwhile to focus on improving emotion regulation in order to strengthen protective factors and improve adolescents’ management of their everyday lives rather than on merely mitigating possible risk factors. Regarding intervention costs, it appears indispensable to include more cost calculations in the study planning of future research. In contrast to therapeutic interventions of NSSI, which are usually conducted in an in-patient setting and entail high measurable expenses as compared to preventive interventions, preventive approaches may in case of success result in a reduction of clinical presentation (O’Connell, Boat et al. 2009).
A promising outlook is entailed by study protocol presenting a skills-based universal prevention program of NSSI “DUDE”, a cluster randomized controlled trial scheduled for 16 German schools with a total of 3.200 adolescents (Buerger, Emser et al. 2022). The program is tailored to decrease the incidence of NSSI and avert potential and associated long-term consequences like suicidality among adolescents. It is aimed to provide easy access for adolescents due to its implementation during lesson time at school and is declared cost-effective. Furthermore, DUDE is a promising approach to effective NSSI prevention, as it is intended to improve mental health through the pathway of emotion regulation. It remains to await the implementation of the protocol, which is currently delayed due to the SARS-CoV-19 pandemic.
In sum, initial research is promising and suggests that the approach to tackle NSSI via prevention is meaningful. Yet, high-quality studies on the development and evaluation of universal NSSI prevention in adolescents are urgently needed.
Despite belonging to the best described patterns in ecology, the mechanisms driving biodiversity along broad-scale climatic gradients, like the latitudinal gradient in diversity, remain poorly understood. Because of their high biodiversity, restricted spatial ranges, the continuous change in abiotic factors with altitude and their worldwide occurrence, mountains constitute ideal study systems to elucidate the predictors of global biodiversity patterns. However, mountain ecosystems are increasingly threatened by human land use and climate change. Since the consequences of such alterations on mountainous biodiversity and related ecosystem services are hardly known, research along elevational gradients is also of utmost importance from a conservation point of view. In addition to classical biodiversity research focusing on taxonomy, the significance of studying functional traits and their prominence in biodiversity ecosystem functioning (BEF) relationships is increasingly acknowledged. In this dissertation, I explore the patterns and drivers of mammal and dung beetle diversity along elevational and land use gradients on Mt. Kilimanjaro, Tanzania. Furthermore, I investigate the predictors of dung decomposition by dung beetles under different extinction scenarios.
Mammals are not only charismatic, they also fulfil important roles in ecosystems. They provide important ecosystem services such as seed dispersal and nutrient cycling by turning over high amounts of biomass. In chapter II, I show that mammal diversity and community biomass both exhibited a unimodal distribution with elevation on Mt.Kilimanjaro and were mainly impacted by primary productivity, a measure of the total food abundance, and the protection status of study plots. Due to their large size and endothermy, mammals, in contrast to most arthopods, are theoretically predicted to be limited by food availability. My results are in concordance with this prediction. The significantly higher diversity and biomass in the Kilimanjaro National Park and in other conservation areas underscore the important role of habitat protection is vital for the conservation of large mammal biodiversity on tropical mountains.
Dung beetles are dependent on mammals since they rely upon mammalian dung as a food and nesting resource. Dung beetles are also important ecosystem service providers: they play an important role in nutrient cycling, bioturbation, secondary seed dispersal and parasite suppression. In chapter III, I show that dung beetle diversity declined with elevation while dung beetle abundance followed a hump-shaped pattern along the elevational gradient. In contrast to mammals, dung beetle diversity was primarily predicted by temperature. Despite my attempt to accurately quantifiy mammalian dung resources by calculating mammalian defecation rates, I did not find an influence of dung resource availability on dung beetle richness. Instead, higher temperature translated into higher dung beetle diversity.
Apart from being important ecosystem service providers, dung beetles are also model organisms for BEF studies since they rely on a resource which can be quantified easily. In chapter IV, I explore dung decomposition by dung beetles along the elevational gradient by means of an exclosure experiment in the presence of the whole dung beetle community, in the absence of large dung beetles and without any dung beetles. I show that dung decomposition was the highest when the dung could be decomposed by the whole dung beetle community, while dung decomposition was significantly reduced in the sole presence of small dung beetles and the lowest in the absence of dung beetles. Furthermore, I demonstrate that the drivers of dung decomposition were depend on the intactness of the dung beetle community. While body size was the most important driver in the presence of the whole dung beetle community, species richness gained in importance when large dung beetles were excluded. In the most perturbed state of the system with no dung beetles present, temperature was the sole driver of dung decomposition. In conclusion, abiotic drivers become more important predictors of ecosystem services the more the study system is disturbed.
In this dissertation, I exemplify that the drivers of diversity along broad-scale climatic gradients on Mt. Kilimanjaro depend on the thermoregulatory strategy of organisms. While mammal diversity was mainly impacted by food/energy resources, dung beetle diversity was mainly limited by temperature. I also demonstrate the importance of protected areas for the preservation of large mammal biodiversity. Furthermore, I show that large dung beetles were disproportionately important for dung decomposition as dung decomposition significantly decreased when large dung beetles were excluded. As regards land use, I did not detect an overall effect on dung beetle and mammal diversity nor on dung beetle-mediated dung decomposition. However, for the most specialised mammal trophic guilds and dung beetle functional groups, negative land use effects were already visible. Even though the current moderate levels of land use on Mt. Kilimanjaro can sustain high levels of biodiversity, the pressure of the human population on Mt. Kilimanjaro is increasing and further land use intensification poses a great threat to biodiversity. In synergy wih land use, climate change is jeopardizing current patterns and levels of biodiversity with the potential to displace communities, which may have unpredictable consequences for ecosystem service provisioning in the future.
Spatiotemporal dynamics of freshwater macrophytes in Bavarian lakes under environmental change
(2022)
Macrophytes are key components of freshwater ecosystems because they provide habitat, food, and improve the water quality. Macrophyte are vulnerable to environmental change as their physiological processes depend on changing environmental factors, which themselves vary within a geographical region and along lake depth. Their spatial distribution is not well understood and their importance is publicly little-known. In this thesis, I have investigated the spatiotemporal dynamics of freshwater macrophytes in Bavarian lakes to understand their diversity pattern along different scales and to predict and communicate potential consequences of global change on their richness.
In the introduction (Chapter 1), I provide an overview of the current scientific knowledge of the species richness patterns of macrophytes in freshwater lakes, the influences of climate and land-use change on macrophyte growth, and different modelling approaches of macrophytes.
The main part of the thesis starts with a study about submerged and emergent macrophyte species richness in natural and artificial lakes of Bavaria (Chapter 2). By analysing publicly available monitoring data, I have found a higher species richness of submerged macrophytes in natural lakes than in artificial lakes. Furthermore, I showed that the richness of submerged species is better explained by physio-chemical lake parameters than the richness of emergent species. In Chapter 3, I considered that submerged macrophytes grow along a depth gradient that provides a sharp environmental gradient on a short spatial scale. This study is the first comparative assessment of the depth diversity gradient (DDG) of macrophytes. I have found a hump-shaped pattern of different diversity components. Generalised additive mixed-effect models indicate that the shape of the DDG is influenced mainly by light quality, light quantity, layering depth, and lake area. I could not identify a general trend of the DDG within recent years, but single lakes show trends leading into different directions. In Chapter 4, I used a mechanistic eco-physiological model to explore changes in the distribution of macrophyte species richness under different scenarios of environmental conditions across lakes and with depths. I could replicate the hump-shaped pattern of potential species richness along depth. Rising temperature leads to increased species richness in all lake types, and depths. The effect of turbidity and nutrient change depends on depth and lake type. Traits that characterise “loser species” under increased turbidity and nutrients are a high light consumption and a high sensibility to disturbances. “Winner species” can be identified by a high biomass production. In Chapter 5, I discuss the image problem of macrophytes. Unawareness, ignorance, and the poor accessibility of macrophytes can lead to conflicts of use. I assumed that an increased engagement and education could counteract this. Because computer games can transfer knowledge interactively while creating an immersive experience, I present in the chapter an interactive single-player game for children.
Finally, I discuss the findings of this thesis in the light of their implications for ecological theory, their implications for conservation, and future research ideas (Chapter 6). The findings help to understand the regional distribution and the drivers of macrophyte species richness. By applying eco-physiological models, multiple environmental shaping factors for species richness were tested and scenarios of climate and land-use change were explored.
Background: Anemia remains one of the most common comorbidities in intensive care patients worldwide. The cause of anemia is often multifactorial and triggered by underlying disease, comorbidities, and iatrogenic factors, such as diagnostic phlebotomies. As anemia is associated with a worse outcome, especially in intensive care patients, unnecessary iatrogenic blood loss must be avoided. Therefore, this scoping review addresses the amount of blood loss during routine phlebotomies in adult (>17 years) intensive care patients and whether there are factors that need to be improved in terms of patient blood management (PBM). Methods: A systematic search of the Medline Database via PubMed was conducted according to PRISMA guidelines. The reported daily blood volume for diagnostics and other relevant information from eligible studies were charted. Results: A total of 2167 studies were identified in our search, of which 38 studies met the inclusion criteria (9 interventional studies and 29 observational studies). The majority of the studies were conducted in the US (37%) and Canada (13%). An increasing interest to reduce iatrogenic blood loss has been observed since 2015. Phlebotomized blood volume per patient per day was up to 377 mL. All interventional trials showed that the use of pediatric-sized blood collection tubes can significantly reduce the daily amount of blood drawn. Conclusion: Iatrogenic blood loss for diagnostic purposes contributes significantly to the development and exacerbation of hospital-acquired anemia. Therefore, a comprehensive PBM in intensive care is urgently needed to reduce avoidable blood loss, including blood-sparing techniques, regular advanced training, and small-volume blood collection tubes.
Herpes Simplex Virus type 1 (HSV-1) is an ubiquitous neurotropic human pathogen that infects a large majority of the world’s population. It is the causative agent of the common cold sore but also responsible for life-threatening infections (e.g., encephalitis), particularly in immunocompromised individuals and neonates. Like other herpesviruses, HSV-1 takes over the cellular RNA machinery to facilitate productive infection while efficiently shutting down host gene expression by targeting multiple steps of RNA metabolism. The two viral proteins, vhs and ICP27, play a crucial role in this process. Delivered by the tegument of the incoming virus, the virion host shut-off (vhs) endonuclease rapidly starts cleaving both cellular and viral mRNAs. With the onset of viral gene expression, the HSV-1 immediate-early protein ICP27 promotes the expression of viral early and late genes through various mechanisms, including mRNA processing, export, and translation.
Prior research by the Dölken lab demonstrated that lytic HSV-1 infection results in the disruption of transcription termination (DoTT) of most cellular genes by the viral ICP27 protein. This significantly contributes to HSV-1 induced host shut-off. DoTT results in transcription for tens of thousands of nucleotides beyond poly(A) sites and into downstream genes. Interestingly, this was found to be accompanied by a dramatic increase in chromatin accessibility downstream of the affected poly(A) sites. This is consistent with the formation of extensive downstream open chromatin regions (dOCR) and indicative of impaired histone repositioning in the wake of RNA polymerase II (Pol II) downstream of the affected poly(A) sites.
In my PhD thesis, I demonstrate that dOCR formation is dependent on the viral ICP22 protein when poly(A) read-through transcription is triggered by the ectopic expression of ICP27 or salt stress. I show that dOCR formation occurs when a high level of transcriptional activity arises downstream of genes due to the HSV-1-induced DoTT. To investigate whether histone composition is affected downstream of genes, I established the ChIPmentation approach to study associated changes and the influence of DoTT and dOCR formation on major histone modification marks. In HSV-1 WT infection, dOCR formation was reflected in alterations of canonical H1 histone downstream of affected genes, which was absent in ICP22 infection. To elucidate the underlying molecular mechanism, two major histone chaperones SPT6 and FACT (SPT16 and SSRP1), which govern histone repositioning and may thus play a role in H1 homeostasis, were extensively studied. Both histone chaperones have been recently shown to be recruited to the viral genome by interactions with ICP22 protein. To investigate whether the depletion of SSRP1 or SPT6 would complement the loss of ICP22 to induce dOCR, T-HF cells with doxycycline-inducible knock-down of either of the two factors were generated. ATAC-seq analysis revealed that the interaction between the two histone chaperones and ICP22 is not involved in HSV-1-induced dOCR formation, suggesting the involvement of other proteins. In summary, this work sheds new light on a fundamental molecular mechanism of the cellular transcriptional machinery that is manipulated by the concerted actions of the two HSV-1 immediate-early proteins ICP22 and ICP27.
The “active self” approach suggests that any object we manipulate voluntarily and foreseeably becomes part of our “self” in the sense that we feel control over this object (sense of agency) and experience it as belonging to our own body (sense of ownership). While there is considerable evidence that we can indeed experience both a sense of agency and a sense of ownership over a broad variety of objects when we control these through our actions, the approach has also been criticized for exaggerating the flexibility of the human self. In this thesis, I investigate the influence that the relationship between the body movements controlling an object and the movements of the object itself has on the process of integrating an object into the self. I demonstrate that fully controlling an object is not sufficient for it to be integrated into the self since both explicit and implicit measures of the sense of agency and the sense of ownership indicate less or no integration when body movements are transformed into inverted object movements. Furthermore, I show that such inversions lead to the downregulation of sensory signals either from the body or from the controlled object in order to deal with the conflicting multisensory information when performing such actions. I argue that this downregulation is the underlying factor behind the diminished or eliminated integration of inverted body and object movements and I discuss further pathways for possible future studies building up on these findings.
This thesis includes measurements that were recorded by cooperation partners. The EPR spec‐ trosa mentioned in section 5.2 were recorded by Michael Auth from the Dyakonov Group (Ex‐ perimental Physics VI, Julius‐Maximilians‐Universität, Würzburg). The TREFISH experiments and transient absorption in section 5.4 spectra were performed by Jašinskas et al. from the V. Gulbi‐ nas group (Center for Physical Sciences and Technology, Vilnius, Lithuania). This dissertation investigated the interactions of semiconducting single‐walled carbon nanotubes (SWNTs) of (6,5) chirality with their environment. Shear‐mixing provided high‐quality SWNT sus‐ pensions, which was complemented by various film preparation techniques. These techniques were in turn used to prepare heterostructures with MoS2 and hBN, which were examined with a newly constructed photoluminescence microscope specifically for this purpose. Finally, the change of spectral properties of SWNTs upon doping was investigated in more detail, as well as the behaviour of charge carriers in the tubes themselves. To optimise the SWNT sample preparation techniques that supplied the other experiments, the sample quality of shear‐mixed preparations was compared with that of sonicated samples. It was found that the quantum efficiency of sheared suspensions exceeds that of sonicated suspensions as soon as the sonication time exceeds 30 min. The higher PLQY is due to the lower defect concentration in shear‐mixed samples. Via transient absorption, a mean lifetime of 17.3 ps and a mean distance between defects of 192.1 nm could be determined. Furthermore, it was found that the increased efficiency of horn sonication is probably not only due to higher shear forces acting on the SWNT bundles but also that the shortening of PFO‐BPy strands plays a significant role. Sonication of very long polymer strands significantly increased their effectiveness in shear mixing. While previous approaches could only achieve very low concentrations of SWNTs in suspensions, pre‐sonicated polymer yielded results which were comparable with much shorter PFO‐BPy batches. Reference experiments also showed that different aggregation processes are relevant during production and further processing. Initial reprocessing of carbon nanotube raw material requires 7 h sonication time and over 24 h shear mixing before no increase in carbon nano concentration is detectable. However, only a few minutes of sonication or shear mixing are required when reprocessing the residue produced during the separation of the slurry. This discrepancy indicates that different aggregates are present, with markedly different aggregation properties. To study low‐dimensional heterostructures, a PL microscope was set up with the ability to ob‐ serve single SWNTs as well as monolayers of other low‐dimensional systems. Furthermore, sam‐ ples were prepared which bring single SWNTs into contact with 2D materials such as h‐BN andMoS2 layers and the changes in the photoluminescence spectrum were documented. For h‐BN, it was observed whether previous methods for depositing SWNTs could be transferred for photo‐ luminescence spectroscopy. SWNTs were successfully deposited on monolayers via a modified drip coating, with the limitation that SWNTs aggregate more at the edges of the monolayers. Upon contact of SWNTs with MoS2, significant changes in the emission properties of the mono‐ layers were observed. The fluorescence, which was mainly dominated by excitons, was shifted towards trion emission. Reference experiments excluded PFO‐BPy and toluene as potential causes. Based on the change in the emission behaviour of MoS2, the most plausible explanation is a photoinduced charge transfer leading to delocalised charge carriers on MoS2. In contrast, on SWNTs, the introduction of additional charges would constitute a quenching centre, which would quench their PL emission, making them undetectable in the PL image. In the last chapter, the electronic properties of doped SWNTs and the behaviour of charge carri‐ ers inside the tubes should be investigated. First, the change in the conductivity of SWNT films with increasing doping levels was docu‐ mented. The resistance of the films drops drastically at minimum doping. After the initial in‐ troduction of charges, the resistance drops with increasing dopant concentration according to a double logarithmic curve. The initial drop could be due to a reduction of contact resistances within the SWNT network film, but this could not be further investigated within the scope of this PhD thesis. In cooperation with Andreas Sperlich and Michael Auth, the spin concentration of SWNTs at different doping levels was determined. The obtained concentrations were compared with the carrier concentrations determined from PL and absorption spectra. At low spin densities, good agreement with previous models was found. Furthermore, the presence of isolated spins strongly suggests a localised charge carrier distribution at temperatures around 10 K. When the charge density is increased, the spin density deviates significantly from the charge carrier con‐ centration. This discrepancy is attributed to the increasing delocalisation of charge carriers at high charge densities and the interactions of neighbouring spins. These results strongly indicate the existence of localised charge carriers in SWNTs at low temperatures. Next, the effect of doping on the Raman spectra of SWNT suspensions was investigated. In gen‐ eral, doping is expected to reduce the intensity of the Raman bands, i.e. a consequence of the reduced resonance gain due to bleaching of the S2 transition. However, similar to the resistivity measurements, the oscillator strength of the G+ band drops sharply in the first doping steps. It was also found that the G+ band decreases more than would be expected due to loss of reso‐ nance condition. Furthermore, the G‐ is bleached faster than the G+ band. All these anomalies suggest that resonance enhancement is not the only relevant effect. Another much faster deac‐ tivation path for the excitons may be introduced by doping. This would leave less time for the scattering process to occur and reduce the oscillator strength of the Raman bands. In cooperation with Vidmantas et al., the photoinduced charge carrier behaviour of SWNT/PCBM films was investigated. The required films were prepared by drop coating. The SWNT suspen‐ sions required for this were obtained from sheared SWNT preparations. Using transient absorp‐ tion and TREFISH, a number of charge transfer effects were identified and their dynamics in‐ vestigated: the recombination of neutral excitons (< 50 ps), the electron transfer from carbon nanotubes to PCBM molecules (< 1 ps), the decay of charge‐transfer excitons (∼200 ps), the recombination of charge carriers between charge‐transfer excitons (1 ns to 4 ns) and finally the propagation through the SWNT network (∼20 ns)
Nanodiamond (ND) is a versatile and promising material for bio-applications. Despite many efforts, agglomeration of nanodiamond and the non-specific adsorption of proteins on the ND surface when exposed to bio-fluids remains a major obstacle for biomedical applications. An assortment of branched and linear molecules with superior ability to colloidally stabilize nanoparticles in salt and cell media environment, for up to 30 days, was attached to the ND’s surface.
The building box system with azide as external groups offers a huge variety of binding with many molecules, such as drugs, dyes or targeting molecules, is possible. Clicking, for instance, zwitterions moieties to the chain protects ND surface from protein corona forming when the particles get in contact with biofluids containing proteins.
Thermogravimetric analysis results of the ND surface loading show a significant prevention of up to 98 % of the protein adsorption compared with NDs without zwitterionic headgroups and long colloidal stability when tetraethylene glycol (TEG) are attached to the surface.
The versatility of the modular system to bind not only zwitterionic chains but also clickable functional molecules to fluorescent nanodiamonds (fNDs) demonstrates the potential of the system at the nanodiamond. Using defect structures, such as nitrogen-vacancy (NV) centers, diamond particles, due to their widely non-toxic behavior, can be used as fNDs for photostable labeling, bioimaging and nanoscale sensing in living cells and organisms. To functionalize the fND surface a novel milling technique with diazonium salts was established to perform grafting on poorly reactive HPHT fNDs yielding in high surface loading and high negative zeta potential.
Combining the benefits of TEG and zwitterion containing groups with antibody enabled nucleus targeting ability on fND confirms the enhanced colloidal stability in living cells experiments for the first time. Furthermore, the results indicate an improved corona repulsion compared with fND without zwitterion containing headgroups. As a result, the circulation times were enlarged from 4 (fND without zwitterion chain but with antibody) to 17 (with antibody and zwitterion chains) hours.
In non-biomedical applications, the modular system can be used as a probe for heavy metals by binding it to dyes. Detection of metals in different environments with high selectivity and specificity is one of the prerequisites of the fight against environmental pollution with these elements. Pyrenes are well suited and known for fluorescence sensing in different media.
The applied sensing principle typically relies on the formation of intra- and intermolecular excimers, which is however limiting the sensitivity range due to masking of e.g. quenching effects by the excimer emission. This study shows a highly selective, structurally rigid chemical sensor based on the monomer fluorescence of pyrene moieties bearing triazole groups.
This probe can quantitatively detect Cu2+, Pb2+ and Hg2+ in organic solvents over a broad concentration range, even in the presence of ubiquitous ions such as Na+, K+, Ca2+ and Mg2+. The strongly emissive sensor’s fluorescence with a long lifetime of 165 ns is quenched by a 1:1 complex formation upon addition of metal ions in acetonitrile. Upon addition of a tenfold excess of the metal ion to the sensor, agglomerates with a diameter of about 3 nm are formed. Due to complex interactions in the system, conventional linear correlations are not observed for all concentrations. Therefore, a critical comparison between the conventional Job plot interpretation, the method of Benesi-Hildebrand, and a non-linear fit is presented. The reported system enables the specific and robust sensing of medically and environmentally relevant ions in the health-relevant nM range and could be used e.g. for the monitoring of the respective ions in waste streams.
Nonetheless, often these waste streams end up in sensitive aquacultures, where such sensor technology only works if the probe is water-soluble to monitor the spread and formation of environmental damage from heavy metals. Many chemosensors only work quantitatively in specific solvents and under highly pure conditions. In this thesis a method to stabilize water-insoluble chemosensors on nanodiamonds in saline water while maintaining the sensor efficacy and specificityas as well as colloidal stability is presented. Additionally, the sensor capability is retained in organic solvents. This study provides insight into the absorptivity of pyrene derivatives to the nanodiamond surface and a way to reversibly desorb them.
Moreover, the system proves that in presence of 95 % oxygen atmosphere while the fluoresce measurement the results of the do not vary from the one in argon atmosphere. Furthermore, the presence of common ions in water do not disturb the colloidal stability of the NDs and also no influence the sensor functionality and thus is highly promising candidate for measurement without cumbersome preparation steps.
The future of water-derived hydrogen as the “sustainable energy source” straightaway bets on the success of the sluggish oxygen-generating half-reaction. The endeavor to emulate the natural photosystem II for efficient water oxidation has been extended across the spectrum of organic and inorganic combinations. However, the achievement has so far been restricted to homogeneous catalysts rather than their pristine heterogeneous forms. The poor structural understanding and control over the mechanistic pathway often impede the overall development. Herein, we have synthesized a highly crystalline covalent organic framework (COF) for chemical and photochemical water oxidation. The interpenetrated structure assures the catalyst stability, as the catalyst’s performance remains unaltered after several cycles. This COF exhibits the highest ever accomplished catalytic activity for such an organometallic crystalline solid-state material where the rate of oxygen evolution is as high as ∼26,000 μmol L\(^{–1}\) s\(^{–1}\) (second-order rate constant k ≈ 1650 μmol L s\(^{–1}\) g\(^{–2}\)). The catalyst also proves its exceptional activity (k ≈ 1600 μmol L s\(^{–1}\) g\(^{–2}\)) during light-driven water oxidation under very dilute conditions. The cooperative interaction between metal centers in the crystalline network offers 20–30-fold superior activity during chemical as well as photocatalytic water oxidation as compared to its amorphous polymeric counterpart.
The Amduat is one of the most important Netherworld Books which was recorded in various kinds of Ancient Egyptian sources since the beginning of the 18th dynasty, especially the walls of the royal tombs. The main theme of the Amduat is the journey of the sun god through the underworld where the solar bark and its crew is the central scene of the journey. The study focuses on finding the reasons of choosing the crew’s members who manage the sun bark’s journey in the Amduat. It also aims at illustrating the functions and responsibilities of each crew member. Following a historical approach, the study analyzes the Pyramid Texts and Coffin Texts as the most important documents before the New Kingdom, and proceeding to the inscriptions and writings of the monuments which contain portrayals and inscriptions of the Amduat in the New Kingdom. Furthermore, it sheds some light on the solar cycle’s main features and primary aspects, and tries to scrutinize the date, meaning, and symbolisms of the Amduat and its indications in the earlier sources.
Background: Treatment options for NAFLD are still limited. Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB), has been shown to improve metabolic and histologic markers of NAFLD. Glucagon-like-peptide-1 (GLP-1) analogues lead to improvements in phase 2 clinical trials. We directly compared the effects of RYGB with a treatment using liraglutide and/or peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\)) in a rat model for early NAFLD. Methods: Obese male Wistar rats (high-fat diet (HFD)-induced) were randomized into the following treatment groups: RYGB, sham-operation (sham), liraglutide (0.4 mg/kg/day), PYY\(_{3-36}\) (0.1 mg/kg/day), liraglutide+PYY\(_{3-36}\), and saline. After an observation period of 4 weeks, liver samples were histologically evaluated, ELISAs and RNA sequencing + RT-qPCRs were performed. Results: RYGB and liraglutide+PYY\(_{3-36}\) induced a similar body weight loss and, compared to sham/saline, marked histological improvements with significantly less steatosis. However, only RYGB induced significant metabolic improvements (e.g., adiponectin/leptin ratio 18.8 ± 11.8 vs. 2.4 ± 1.2 in liraglutide+PYY\(_{3-36}\)- or 1.4 ± 0.9 in sham-treated rats). Furthermore, RNA sequencing revealed a high number of differentially regulated genes in RYGB treated animals only. Conclusions: The combination therapy of liraglutide+PYY\(_{3-36}\) partly mimics the positive effects of RYGB on weight reduction and on hepatic steatosis, while its effects on metabolic function lack behind RYGB.
After implementing a reliable mass spectrometry based kinetic study the indole conjugation with different organometallic indoles led to questions about the electronical and sterical influences on reactivity. The substitution pattern of the ferrocene functionalized indoles at the six-membered ring determines the electron density on the C3 atom, which reacts with the formed Schiff base. Since the experimental results showed the exact opposite trend, covalent docking studies were performed elucidating the importance of surface interactions. These studies were in harmony with the experimental results and determined lysine 33 as most preferable conjugation site as well as substitution in 6-position as most favourable pattern. The amine motif in compounds 6, 7 and 8 proofed to be easily fragmented by the ESI method used. The amide linker in 10 remains intact but shows a lower conversion. Those two inherent characteristics are however preferable for well-defined and site-specific bioconjugation. The synthesis and evaluation of piano stool complex derivatives with manganese and rhenium metal centre 15, 16, 18 and 22 gave additional guidance by the interpretation of applicable structural motifs. The electron-withdrawing carbonyl groups lead to the hindrance of fulvene formation and thus to no fragmentation as seen with the ferrocene group. The total conversion is low compared to 8, only 22 shows a good enough conversion to mainly monoconjugate of 45% and a possible radio-labelling application as 99mTc analogue. As consequence manganese complexes with a stable facial tricarbonyl unit and a tridentate chelator with 4-, 5- and 6-substituted aminomethylindole conjugated through an amide bond were synthesized and consecutively evaluated. The resulting organometallic indole derivatives 29, 30 and 31 all showed a total conversion around 40% similar to 16, but at the same time a rate constant in the range of 10-4 s-1 like the organic indole. Besides the similar conversion, the rate constants followed the trend of the 6-substituted derivative as fastest and then 5- and 4- substituted derivative with decreasing reactivity. For underlining the usage as technetium label for the best out of the series 31, a rhenium analogue was prepared. The resulting compound 32 was especially interesting, because the conversion was even higher than the 70% of 8 with a total of 88%. Additionally, the rate constant was a tenfold higher as well. This rendered compound 32 as best possible 99mTc analogue for further application as radio-label. After the success of 32 and realizing the sterical benefits resulting from the flexible tridentate ligand-system, substitution at the five-membered ring was explored. The complexes 33, 34 and 35 are based on indole-2-carboxylic acid and with the difference of the length of the alkyl spacer between amide and complex to probe for the influence and sterical hindrance, but all three derivatives showed no conjugation which excludes functionalization in 2-position. As the C3 is used for the actual bioconjugation, the last possible derivatization was realized on the indole-N1 by using 1-(3-bromopropyl)indole as building block during the synthesis of the ligand-system. The corresponding manganese 36 and rhenium 37 complexes both showed similar properties of a moderate conversion like 22 and a rate constant in the range of 10-5 s-1. In conclusion the rhenium complex 32 with the 6-substitution pattern at the tridentate indole-bearing ligand remains the most promising structure.
The here developed liquid chromatography coupled mass spectrometry-based assay for the determination of inhibitory activity of drug candidates against the 3CLpro of the sever acute respiratory syndrome coronavirus type 2 was successfully implemented and especially designed to give, due to the available absorption spectra and corresponding mass traces, further insight in the otherwise through fluorescence resonance energy transfer-based assays neglected influences on the inhibition results. Starting with a literature-known quinolone containing covalent inhibitor 42 an N1-methylated derivative 43 and their analogues 44 and 45 in which the benzoic acid was exchanged for ferrocene carboxylic acid were synthesized. The inhibition of 3CLpro was evaluated by the concentration of initial 15mer peptide left after incubation and for that purpose the for 280 nm defined molar attenuation coefficient of (26.41±0.59) L*mol-1*cm-1 determined and used. The results showed a reaction of DL dithiothreitol with the less stable benzoic acid esters leading to a moderate inhibitory effect. The methylation in N1-position showed an increase in stability. The methylated and with ferrocene carboxylic acid functionalized derivative showed a complete inhibition during the timeframe of the assay. In search of a fluorescent and therefore traceable inhibitor, 4 hydroxycoumarin was used to synthesize the analogue with benzoic acid 49 and ferrocene carboxylic acid 50. Both derivatives were less stable than their analogues but exhibited the same trend of a more stable ferrocene-derived compound, which exerted a higher inhibition as well. After preparing and testing the model thioester 53 and showing an inactivation of the established inhibitor ebselen, it was concluded that the reaction with DL dithiothreitol reduces the concentration of active intact inhibitor and therefore decreases the inhibition rate during the assay. The next step was proofing the reducing agent as non-essential for the fast assay conducted in a timeframe of 5 min to circumvent the negative influence of DL dithiothreitol. By excluding every inhibition-altering part, the resulting method is the perfect tool for precise statements in relation of inhibitory activity. Then the inhibition assay was repeated for ebselen and the best out of the here introduced organometallic inhibitors 45. Both give equivalent results of a complete inhibition during the measurement. The implemented liquid chromatography coupled mass spectrometry-based assay has many advantages over the fluorescence resonance energy transfer-based assays in which all the information and insight accumulated by the evaluation of uv/vis traces and mass spectra are not available leading to wrong or deviating results regarding the inhibitory capacity of inhibitor candidates.
Squamous cell carcinomas (SCC) frequently have an exceptionally high mutational burden. As consequence, they rapidly develop resistance to platinum-based chemotherapy and overall survival is limited. Novel therapeutic strategies are therefore urgently required. SCC express ∆Np63, which regulates the Fanconi Anemia (FA) DNA-damage response in cancer cells, thereby contributing to chemotherapy-resistance. Here we report that the deubiquitylase USP28 is recruited to sites of DNA damage in cisplatin-treated cells. ATR phosphorylates USP28 and increases its enzymatic activity. This phosphorylation event is required to positively regulate the DNA damage repair in SCC by stabilizing ∆Np63. Knock-down or inhibition of USP28 by a specific inhibitor weakens the ability of SCC to cope with DNA damage during platin-based chemotherapy. Hence, our study presents a novel mechanism by which ∆Np63 expressing SCC can be targeted to overcome chemotherapy resistance. Limited treatment options and low response rates to chemotherapy are particularly common in patients with squamous cancer. The SCC specific transcription factor ∆Np63 enhances the expression of Fanconi Anemia genes, thereby contributing to recombinational DNA repair and Cisplatin resistance. Targeting the USP28-∆Np63 axis in SCC tones down this DNA damage response pathways, thereby sensitizing SCC cells to cisplatin treatment.
Background
Prostate cancer (PCa) is the most frequent cancer in men. The prognosis of PCa is heterogeneous with many clinically indolent tumors and rare highly aggressive cases. Reliable tissue markers of prognosis are lacking. Active cholesteryl ester synthesis has been associated with prostate cancer aggressiveness. Sterol-O-Acyl transferases (SOAT) 1 and 2 catalyze cholesterol esterification in humans.
Objective
To investigate the value of SOAT1 and SOAT2 tissue expression as prognostic markers in high risk PCa.
Patients and Methods
Formalin-fixed paraffin-embedded tissue samples from 305 high risk PCa cases treated with radical prostatectomy were analyzed for SOAT1 and SOAT2 protein expression by semi-quantitative immunohistochemistry. The Kaplan-Meier method and Cox proportional hazards modeling were used to compare outcome.
Main Outcome Measure
Biochemical recurrence (BCR) free survival.
Results
SOAT1 expression was high in 73 (25%) and low in 219 (75%; not evaluable: 13) tumors. SOAT2 was highly expressed in 40 (14%) and at low levels in 249 (86%) samples (not evaluable: 16). By Kaplan-Meier analysis, we found significantly shorter median BCR free survival of 93 months (95% confidence interval 23.6-123.1) in patients with high SOAT1 vs. 134 months (112.6-220.2, Log-rank p < 0.001) with low SOAT1. SOAT2 expression was not significantly associated with BCR. After adjustment for age, preoperative PSA, tumor stage, Gleason score, resection status, lymph node involvement and year of surgery, high SOAT1 but not SOAT2 expression was associated with shorter BCR free survival with a hazard ratio of 2.40 (95% CI 1.57-3.68, p < 0.001). Time to clinical recurrence and overall survival were not significantly associated with SOAT1 and SOAT2 expression CONCLUSIONS: SOAT1 expression is strongly associated with BCR free survival alone and after multivariable adjustment in high risk PCa. SOAT1 may serve as a histologic marker of prognosis and holds promise as a future treatment target.
Multiple myeloma remains a largely incurable disease of clonally expanding malignant plasma cells. The bone marrow microenvironment harbors treatment-resistant myeloma cells, which eventually lead to disease relapse in patients. In the bone marrow, CD4\(^{+}\)FoxP3\(^{+}\) regulatory T cells (Tregs) are highly abundant amongst CD4\(^{+}\) T cells providing an immune protective niche for different long-living cell populations, e.g., hematopoietic stem cells. Here, we addressed the functional role of Tregs in multiple myeloma dissemination to bone marrow compartments and disease progression. To investigate the immune regulation of multiple myeloma, we utilized syngeneic immunocompetent murine multiple myeloma models in two different genetic backgrounds. Analyzing the spatial immune architecture of multiple myeloma revealed that the bone marrow Tregs accumulated in the vicinity of malignant plasma cells and displayed an activated phenotype. In vivo Treg depletion prevented multiple myeloma dissemination in both models. Importantly, short-term in vivo depletion of Tregs in mice with established multiple myeloma evoked a potent CD8 T cell- and NK cell-mediated immune response resulting in complete and stable remission. Conclusively, this preclinical in-vivo study suggests that Tregs are an attractive target for the treatment of multiple myeloma.
Chapter 1 – General introduction
Anthropogenic land-use and climate change are the major drivers of the global biodiversity loss. Yet, biodiversity is essential for human well-being, as we depend on the availability of potable water, sufficient food and further benefits obtained from nature. Each species makes a somewhat unique contribution to these ecosystem services. Furthermore, species tolerate environmental stressors, such as climate change, differently. Thus, biodiversity is both the "engine" and the "insurance" for human well-being in a changing climate. Here, I investigate the effects of temperature and land use on herbivory (Chapter 2), predation (Chapter 3) and pest control (Chapter 4), and at the same time identify features of habitats (e.g. plant richness, proximity to different habitat types) and landscapes (e.g. landscape diversity, proportion of oilseed rape area) as potential management targets in an adaptation strategy to climate change. Finally, I discuss the similarities and differences between factors influencing herbivory, predation and pest control, while placing the observations in the context of climate change as a multifaceted phenomenon, and highlighting starting points for sustainable insect pest management (Chapter 5).
Chapter 2 – Plant richness, land use and temperature differently shape invertebrate leaf-chewing herbivory on major plant functional groups
Invertebrate herbivores are temperature-sensitive. Rising temperatures increase their metabolic rates and thus their demand for carbon-rich relative to protein-rich resources, which can lead to changes in the diets of generalist herbivores. Here, we quantified leaf-area loss to chewing invertebrates among three plant functional groups (legumes, non-leguminous forbs and grasses), which largely differ in C:N (carbon:nitrogen) ratio. This reseach was conducted along spatial temperature and land-use gradients in open herbaceous vegetation adjacent to different habitat types (forest, grassland, arable field, settlement). Herbivory largely differed among plant functional groups and was higher on legumes than forbs and grasses, except in open areas in forests. There, herbivory was similar among plant functional groups and on legumes lower than in grasslands. Also the presence of many plant families lowered herbivory on legumes. This suggests that open areas in forests and diverse vegetation provide certain protection against leaf damage to some plant families (e.g. legumes). This could be used as part of a conservation strategy for protected species. Overall, the effects of the dominant habitat type in the vicinity and diverse vegetation outweighed those of temperature and large-scale land use (e.g. grassland proportion, landscape diversity) on herbivory of legumes, forbs and grasses at the present time.
Chapter 3 – Landscape diversity and local temperature, but not climate, affect arthropod predation among habitat types
Herbivorous insects underlie top-down regulation by arthropod predators. Thereby, predation rates depend on predator community composition and behaviour, which is shaped by temperature, plant richness and land use. How the interaction of these factors affects the regulatory performance of predators was unknown. Therefore, we assessed arthropod predation rates on artificial caterpillars along temperature, and land-use gradients. On plots with low local mean temperature (≤ 7°C) often not a single caterpillar was attacked, which may be due to the temperature-dependent inactivity of arthropods. However, multi-annual mean temperature, plant richness and the dominant habitat type in the vicinity did not substantially affect arthropod predation rates. Highest arthropod predation rates were observed in diverse landscapes (2-km scale) independently of the locally dominanting habitat type. As landscape diversity, but not multi-annual mean temperature, affected arthropod predation rates, the diversification of landscapes may also support top-down regulation of herbivores independent of moderate increases of multi-annual mean temperature in the near future.
Chapter 4 – Pest control and yield of winter oilseed rape depend on spatiotemporal crop-cover dynamics and flowering onset: implications for global warming
Winter oilseed rape is an important oilseed crop in Europe, yet its seed yield is diminished through pests such as the pollen beetle and stem weevils. Damage from pollen beetles depends on pest abundances, but also on the timing of infestation relative to crop development as the bud stage is particularly vulnerable. The development of both oilseed rape and pollen beetles is temperature-dependent, while temperature effects on pest abundances are yet unknown, which brings opportunities and dangers to oilseed rape cropping under increased temperatures. We obtained measures of winter oilseed rape (flowering time, seed yield) and two of its major pests (pollen beetle, stem weevils) for the first time along both land-use and temperature gradients. Infestation with stem weevils was not influenced by any temperature or land-use aspect considered, and natural pest regulation of pollen beetles in terms of parasitism rates of pollen beetle larvae was low (< 30%), except on three out of 29 plots. Nonetheless, we could identify conditions favouring low pollen beetle abundances per plant and high seed yields. Low pollen beetle densities were favoured by a constant oilseed rape area relative to the preceding year (5-km scale), whereas a strong reduction in area (> 40%) caused high pest densities (concentration effect). This occurred more frequently in warmer regions, due to drought around sowing, which contributed to increased pollen beetle numbers in those regions. Yet, in warmer regions, oilseed rape flowered early, which possibly led to partial escape from pollen beetle infestation in the most vulnerable bud stage. This is also suggested by higher seed yields of early flowering oilseed rape fields, but not per se at higher temperatures. Thus, early flowering (e.g. cultivar selection) and the interannual coordination of oilseed rape area offer opportunities for environmental-friendly pollen beetle management.
Chapter 5 – General discussion
Anthropogenic land-use and climate change are major threats to biodiversity, and consequently to ecosystem functions, although I could show that ecosystem functions such as herbivory and predation barely responded to temperature along a spatial gradient at present time. Yet, it is important to keep several points in mind: (i) The high rate of climate warming likely reduces the time that species will have to adapt to temperature in the future; (ii) Beyond mean temperatures, many aspects of climate will change; (iii) The compensation of biodiversity loss through functional redundancy in arthropod communities may be depleted at some point; (iv) Measures of ecosystem functions are limited by methodological filters, so that changes may be captured incompletely. Although much uncertainty of the effects of climate and land-use change on ecosystem functions remains, actions to halt biodiversity loss and to interfere with natural processes in an environmentally friendly way, e.g. reduction of herbivory on crops, are urgently needed. With this thesis, I contribute options to the environment-friendly regulation of herbivory, which are at least to some extent climate resilient, and at the same time make a contribution to halt biodiversity loss. Yet, more research and a transformation process is needed to make human action more sustainable. In terms of crop protection, this means that the most common method of treating pests with fast-acting pesticides is not necessarily the most sustainable. To realize sustainable strategies, collective efforts will be needed targeted at crop damage prevention through reducing pest populations and densities in the medium to long term. The sooner we transform human action from environmentally damaging to biodiversity promoting, the higher is our insurance asset that secures human well-being under a changing climate.
Chimeric antigen receptors (CARs) are able to specifically direct T cells to tumor antigens and therapy with anti-CD19 CARs has already cured cancer patients with B-cell lymphomas who have undergone long-term therapy non-successful. Despite this impressive result, the therapy is currently only approved as a last treatment option for blood cancers due to its life-threatening deficiencies. For patient safety and to enable additional application such as the treatment of solid tumors, CAR-T cells must be controllable, e. g. by chemically programmable CARs (cpCARs) regulated by hapten-like compounds.
This thesis reports the synthesis and characterization of such hapten-like compounds. In the first step, seven different warheads with two different spacers were bound to biotin in order to find a suitable warhead for programming the cpCAR.
In a second step, synthetic routes for the three pharmacophores folate, c(RGD), and an RGD peptidomimetic were developed. The routes allow the modification of the pharmacophores with one of the warheads from the first step. CuAAC was chosen as a bioorthogonal approach to link pharmacophores and warheads.
In total, three different pharmacophores were modified with the 1,3-diketone motif of compound 21 leading to 112, 113 and 128. Activation of the T-cell signaling cascade was tested after binding of these hapten-like compounds to the cpCAR in the presence of suitable target structures. For 112, only a slight, non-significant, activation of the T-cell signaling cascade was observed, whereas for 113 and 128, a significant activation of the T-cell signaling cascade was observed.
The poor solubility of the folate compounds led to alternative strategies. Folic acid was exchanged by pteroic acid and the bifunctional, linear compounds were enlarged to trifunctional dendrimers.
Besides the reported regioisomer in 112, a second one, which was not reported to date, occurred by the cyclization of the linear RGD pentapeptide leading to 113.
After the reported synthesis of an RGD peptidomimetic analogous to 128 could not be reproduced, a new synthetic route was developed. It also consists of 17 steps, but reduces the number of linear steps from 13 to 10. Moreover, the developed route contains an asymmetric hydrogenation step and is, compared to the published one, more flexible by the use of the copper-catalyzed azide-alkyne cycloaddition (CuAAC). In addition, an unknown reaction was observed. Instead of the formation of a Schiff base in the reductive amination of 129, an insertion of propargylamine occurred forming 131. The reaction is almost quantitative and in high purity. After requiring no purification, it could be predestined for industrial purposes, such as the synthesis of N-functionalized 1,2-dihydroquinolines or as a building block with various orthogonal functional groups.
Besides the sulfonamide 16, the diketone (21, 27, 31) and lactam compounds (39 – 41), experiments on adapter molecules with further warheads were performed. In the synthesis of a proadapter approach, in which the warhead is formed only after the retro-aldol reaction catalyzed by the mAb, 6 of 10 steps were successfully performed. A newly developed synthesis to keto-sulfonyl and keto-sulfoxide compounds could not be completed but was performed on a small scale to the point of keto-sulfonyl and keto-sulfoxide. Furthermore, a universal synthesis route was designed to allow the introduction of the warhead at the end of the synthesis by acylation. Thus, after 5 shared steps, 3 of them in quantitative yield, different warheads may be introduced. Moreover, this also facilitates the purification and the analysis of the compounds by the absence of tautomerism or labile groups. However, the acylation experiments were not successful with either the acid cyanide or the Weinreb amide.
In summary, this thesis has proven that the 1,3-diketone motif is a suitable warhead for programming the cpCAR, which was developed by Hudecek et al. (unpublished data). The hapten-like compounds 112, 113 and 128 simultaneously bind to integrin ${\alpha}_v{\beta}_3$ and the cpCAR activating the T-cell signaling cascade. The modular synthesis strategy and the use of the bioorthogonal CuAAC allow straightforward access to these valuable immunotherapeutics but revealed the need for an additional purification step to remove copper ions.
Background and Purpose
The standard treatment of glioblastoma patients consists of surgery followed by normofractionated radiotherapy (NFRT) with concomitant and adjuvant temozolomide chemotherapy. Whether accelerated hyperfractionated radiotherapy (HFRT) yields comparable results to NFRT in combination with temozolomide has only sparsely been investigated. The objective of this study was to compare NFRT with HFRT in a multicenter analysis.
Materials and Methods
A total of 484 glioblastoma patients from four centers were retrospectively pooled and analyzed. Three-hundred-ten and 174 patients had been treated with NFRT (30 × 1.8 Gy or 30 × 2 Gy) and HFRT (37 × 1.6 Gy or 30 × 1.8 Gy twice/day), respectively. The primary outcome of interest was overall survival (OS) which was correlated with patient-, tumor- and treatment-related variables via univariable and multivariable Cox frailty models. For multivariable modeling, missing covariates were imputed using multiple imputation by chained equations, and a sensitivity analysis was performed on the complete-cases-only dataset.
Results
After a median follow-up of 15.7 months (range 0.8-88.6 months), median OS was 16.9 months (15.0-18.7 months) in the NFRT group and 14.9 months (13.2-17.3 months) in the HFRT group (p = 0.26). In multivariable frailty regression, better performance status, gross-total versus not gross-total resection, MGMT hypermethylation, IDH mutation, smaller planning target volume and salvage therapy were significantly associated with longer OS (all p < 0.01). Treatment differences (HFRT versus NFRT) had no significant effect on OS in either univariable or multivariable analysis.
Conclusions
Since HFRT with temozolomide was not associated with worse OS, we assume HFRT to be a potential option for patients wishing to shorten their treatment time.
For the past 20 years, chronic kidney disease (CKD) has remained one of the major causes of death worldwide. Cardiovascular events account for approximately 50% of deaths in CKD patients, underscoring the clinical relevance of the observed cardiac changes. These changes define uremic cardiomyopathy (UCM) and include left-ventricular hypertrophy (LVH), LV dilatation, and LV systolic and diastolic dysfunction. LVH is seen as the primary manifestation of UCM and is caused by a multitude of different systems including in-creased pre- and afterload and the renin-angiotensin system (RAS). More recent studies found that myocardial dysfunction is apparent before changes in the ventricular geome-try, like hypertrophy, occur to the uremic heart. This leads to the conclusion that LVH is not the cause of cardiac dysfunction, but one of the alterations caused by factors related to the uremic state itself. Among these factors that are independent of pressure and vol-ume overload, are cardiotonic steroids as well as the parathyroid hormone and the endo-thelin (ET-1) system. But we suggest a different substance to play an important role in UCM: Urea. Patients in end-stage renal disease (ESRD) display increased oxidative stress and urea has been found to increase levels of oxidative stress, at least in endothelial cells. Therefore, we investigated the effect that elevated urea levels, as seen in patients undergoing dialysis, have on cardiomyocytes. As the oxidative stress in a cell is regulated by mitochondrial processes, we suspected the mitochondrial orchestrator PGC-1α to play an important role.
The uremic heart is in a state of elevated oxidative stress. This has been presented by multiple authors before. By conducting immunofluorescent staining for reactive oxygen species (ROS), we tried to replicate their findings and illustrate elevated levels of ROS. As the fluorescence analysis did not bear significant results, we approached oxidative stress from a different angle: Via mass spectrometry, we looked at the amino acids methionine, cysteine and betaine which are highly involved in sustaining the oxidative balance in the cell. Our findings in the media of urea-treated HL-1 cells lead us to the conclusion, that these cardiomyocytes were in a state of low antioxidative resources.
Next, to find the intracellular mechanisms that connect uremia to oxidative stress and compromised energetics, we investigated possible downstream effectors of uremia. The urea-treated cardiomyocytes exhibited significant alterations regarding upstream effec-tors of PGC-1α: The protein kinases Akt and Erk were expressed and phosphorylated dif-ferently in a western blot analysis of uremic h9c2 cells and in mice with induced kidney failure. To combine these findings regarding the protein kinases Akt and Erk and oxidative stress, the Erk/p38 pathways seems conclusive (figure 20). This pathway links uremia and oxidative stress to intracellular effectors that have been found to influence the develop-ment of uremic cardiomyopathy.
Another life-threatening alteration in uremic cardiomyopathy is a corrupted cardiac func-tion. The myocardium of uremic patients has shown to be more susceptible to ischemic damage and most patients receiving dialysis experience repeated episodes of intradialytic impairments in cardiac function. The urea-treated cardiomyocytes had a significantly higher oxygen consumption rate due to an inefficiently increased metabolism, most likely caused by an increased level of uncoupling.
Taken together, the results of this study indicate that urea by itself plays a role in the de-velopment of uremic cardiomyopathy. So-called high-physiologic levels of urea have led to a mitochondrial inefficiency and an increase of oxidative stress in cardiomyocytes. The protein kinases Akt and Erk may work as effectors of urea to induce these changes via the Erk/p38 pathway. It seems very likely that the mitochondrial changes are mediated by the mitochondrial orchestrator PGC-1α. These observations might lead to further studies in-vestigating urea levels in dialysis patients. In the future, these might lead to a change of practice regarding tolerated urea levels in dialysis and help reduce the cardiac mortality of patients with chronic kidney disease.
A sequentialquadratic Hamiltonian schemefor solving open-loop differential Nash games is proposed and investigated. This method is formulated in the framework of the Pontryagin maximum principle and represents an efficient and robust extension of the successive approximations strategy for solving optimal control problems. Theoretical results are presented that prove the well-posedness of the proposed scheme, and results of numerical experiments are reported that successfully validate its computational performance.
This paper argues that applied ethics can itself be morally problematic. As illustrated by the case of Peter Singer’s criticism of social practice, morally loaded communication by applied ethicists can lead to protests, backlashes, and aggression. By reviewing the psychological literature on self-image, collective identity, and motivated reasoning three categories of morally problematic consequences of ethical criticism by applied ethicists are identified: serious psychological discomfort, moral backfiring, and hostile conflict. The most worrisome is moral backfiring: psychological research suggests that ethical criticism of people’s central moral convictions can reinforce exactly those attitudes. Therefore, applied ethicists unintentionally can contribute to a consolidation of precisely those social circumstances that they condemn to be unethical. Furthermore, I argue that the normative concerns raised in this paper are not dependent on the commitment to one specific paradigm in moral philosophy. Utilitarianism, Aristotelian virtue ethics, and Rawlsian contractarianism all provide sound reasons to take morally problematic consequences of ethical criticism seriously. Only the case of deontological ethics is less clear-cut. Finally, I point out that the issues raised in this paper provide an excellent opportunity for further interdisciplinary collaboration between applied ethics and social sciences. I also propose strategies for communicating ethics effectively.
Objectives
Magnesium phosphate-based cements begin to catch more attention as bone substitute materials and especially as alternatives for the more commonly used calcium phosphates. In bone substitutes for augmentation purposes, atraumatic materials with good biocompatibility and resorbability are favorable. In the current study, we describe the in vivo testing of novel bone augmentation materials in form of spherical granules based on a calcium-doped magnesium phosphate (CaMgP) cement.
Materials and Methods
Granules with diameters between 500 and 710 μm were fabricated via the emulsification of CaMgP cement pastes in a lipophilic liquid. As basic material, two different CaMgP formulations were used. The obtained granules were implanted into drill hole defects at the distal femoral condyle of 27 New Zealand white rabbits for 6 and 12 weeks. After explantation, the femora were examined via X-ray diffraction analysis, histological staining, radiological examination, and EDX measurement.
Results
Both granule types display excellent biocompatibility without any signs of inflammation and allow for proper bone healing without the interposition of connective tissue. CaMgP granules show a fast and continuous degradation and enable fully adequate bone regeneration.
Conclusions
Due to their biocompatibility, their degradation behavior, and their completely spherical morphology, these CaMgP granules present a promising bone substitute material for bone augmentation procedures, especially in sensitive areas.
Clinical Relevance
The mostly insufficient local bone supply after tooth extractions complicates prosthetic dental restoration or makes it even impossible. Therefore, bone augmentation procedures are oftentimes inevitable. Spherical CaMgP granules may represent a valuable bone replacement material in many situations.
Objectives
Posttraumatic stress disorder (PTSD) is triggered by extremely stressful environmental events and characterized by high emotional distress, re-experiencing of trauma, avoidance and hypervigilance. The present study uses polygenic risk scores (PRS) derived from the UK Biobank (UKBB) mega-cohort analysis as part of the PGC PTSD GWAS effort to determine the heritable basis of PTSD in the South Eastern Europe (SEE)-PTSD cohort. We further analyzed the relation between PRS and additional disease-related variables, such as number and intensity of life events, coping, sex and age at war on PTSD and CAPS as outcome variables.
Methods
Association of PRS, number and intensity of life events, coping, sex and age on PTSD were calculated using logistic regression in a total of 321 subjects with current and remitted PTSD and 337 controls previously subjected to traumatic events but not having PTSD. In addition, PRS and other disease-related variables were tested for association with PTSD symptom severity, measured by the Clinician Administrated PTSD Scale (CAPS) by liner regression. To assess the relationship between the main outcomes PTSD diagnosis and symptom severity, each of the examined variables was adjusted for all other PTSD related variables.
Results
The categorical analysis showed significant polygenic risk in patients with remitted PTSD and the total sample, whereas no effects were found on symptom severity. Intensity of life events as well as the individual coping style were significantly associated with PTSD diagnosis in both current and remitted cases. The dimensional analyses showed as association of war-related frequency of trauma with symptom severity, whereas the intensity of trauma yielded significant results independently of trauma timing in current PTSD.
Conclusions
The present PRS application in the SEE-PTSD cohort confirms modest but significant polygenic risk for PTSD diagnosis. Environmental factors, mainly the intensity of traumatic life events and negative coping strategies, yielded associations with PTSD both categorically and dimensionally with more significant p-values. This suggests that, at least in the present cohort of war-related trauma, the association of environmental factors and current individual coping strategies with PTSD psychopathology was stronger than the polygenic risk.
Purpose
Patients suffering from aggressive systemic peripheral lymphoma with primary central nervous system involvement (PCL) are a rare and sparsely investigated population. Recommended treatment regimens include a combination of intrathecal and systemic chemotherapy as well as whole brain radiotherapy while offering relatively poor survival.
Methods
We conducted a single-center retrospective study that analyzed safety and outcome of 4 + 4 cycles Rituximab (R)-CHOP and R-high-dose Methotrexate (HD-MTX) for newly diagnosed, transplant-eligible patients ("Ping-Pong"), followed by Cytarabine (AraC)/Thiotepa (TT), BCNU/TT, and autologous hematologic stem cell transplantation (aHSCT). We retrospectively analyzed a set of 16 patients with high-intermediate or high-risk IPI status.
Results
Overall response rate to Ping-Pong was 100% measured by CT/MRI, including 93.75% complete remissions after BCNU/TT followed by PBSCT. One patient failed to qualify for high-dose chemotherapy due to progression when receiving Cytarabine/TT. All patients experienced grade III adverse events, 3 of them a grade IV adverse event. Estimated progression-free survival is 93.75% after a 4.8-year follow-up currently.
Conclusion
Our study suggests high effectivity of R-CHOP with mid-cycle MTX with aHSCT consolidation towards acceptable OS results in this challenging patient population.
Creativity, specifically divergent thinking, has been shown to benefit from unrestrained walking. Despite these findings, it is not clear if it is the lack of restriction that leads to the improvement. Our goal was to explore the effects of motor restrictions on divergent thinking for different movement states. In addition, we assessed whether spontaneous eye blinks, which are linked to motor execution, also predict performance. In experiment 1, we compared the performance in Guilford's alternate uses task (AUT) during walking vs. sitting, and analysed eye blink rates during both conditions. We found that AUT scores were higher during walking than sitting. Albeit eye blinks differed significantly between movement conditions (walking vs. sitting) and task phase (baseline vs. thinking vs. responding), they did not correlate with task performance. In experiment 2 and 3, participants either walked freely or in a restricted path, or sat freely or fixated on a screen. When the factor restriction was explicitly modulated, the effect of walking was reduced, while restriction showed a significant influence on the fluency scores. Importantly, we found a significant correlation between the rate of eye blinks and creativity scores between subjects, depending on the restriction condition. Our study shows a movement state-independent effect of restriction on divergent thinking. In other words, similar to unrestrained walking, unrestrained sitting also improves divergent thinking. Importantly, we discuss a mechanistic explanation of the effect of restriction on divergent thinking based on the increased size of the focus of attention and the consequent bias towards flexibility.
Systemic sclerosis (SSc) is a severe chronic disease with a broad spectrum of clinical manifestations. SSc displays disturbed lymphocyte homeostasis. Immunosuppressive medications targeting T or B cells can improve disease manifestations. SSc clinical manifestations and immunosuppressive medication in itself can cause changes in lymphocyte subsets. The aim of this study was to investigate peripheral lymphocyte homeostasis in SSc with regards to the immunosuppression and to major organ involvement. 44 SSc patients and 19 healthy donors (HD) were included. Immunophenotyping of peripheral whole blood by fluorescence-activated cell sorting was performed. Cytokine secretions of stimulated B cell cultures were measured. SSc patients without immunosuppression compared to HD displayed lower γδ T cells, lower T helper cells (CD3+/CD4+), lower transitional B cells (CD19+/CD38++/CD10+/IgD+), lower pre-switched memory B cells (CD19+/CD27+/IgD+), and lower post-switched memory B cells (CD19+/CD27+/IgD-). There was no difference in the cytokine production of whole B cell cultures between SSc and HD. Within the SSc cohort, mycophenolate intake was associated with lower T helper cells and lower NK cells (CD56+/CD3-). The described differences in peripheral lymphocyte subsets between SSc and HD generate further insight in SSc pathogenesis. Lymphocyte changes under effective immunosuppression indicate how lymphocyte homeostasis in SSc might be restored.
Adrenocortical carcinoma (ACC) is a rare, aggressive cancer with still partially unknown pathogenesis, heterogenous clinical behaviour and no effective treatment for advanced stages. Therefore, there is an urgent clinical unmet need for better prognostication strategies, innovative therapies and significant improvement of the management of the individual patients. In this review, we summarize available studies on molecular prognostic markers and markers predictive of response to standard therapies as well as newly proposed drug targets in sporadic ACC. We include in vitro studies and available clinical trials, focusing on alterations at the DNA, RNA and epigenetic levels. We also discuss the potential of biomarkers to be implemented in a clinical routine workflow for improved ACC patient care.
Observing physicians acting with different levels of empathy modulates later assessed pain tolerance
(2022)
Objectives
The patient–physician relationship is essential for treatment success. Previous studies demonstrated that physicians who behave empathic in their interaction with patients have a positive effect on health outcomes. In this study, we investigated if the mere perception of physicians as empathic/not empathic modulates pain despite an emotionally neutral interaction with the patients.
Methods
N = 60 women took part in an experimental study that simulated a clinical interaction. In the paradigm, each participant watched two immersive 360° videos via a head-mounted display from a patient’s perspective. The physicians in the videos behaved either empathic or not empathic towards a third person. Importantly, these physicians remained emotionally neutral in the subsequent virtual interaction with the participants. Finally, participants received a controlled, painful pressure stimulus within the narratives of the videos.
Results
The physicians in the high compared with the low empathy videos were rated as more empathic and more likable, indicating successful experimental manipulation. In spite of later neutral behaviour of physicians, this short observation of physicians’ behaviour towards a third person was sufficient to modulate pain tolerance of the participants.
Conclusions
The finding of this study that the mere observation of physicians’ behaviour towards a third person modulates pain, despite a neutral direct interaction with the participants, has important clinical implications. Further, the proposed paradigm enables investigating aspects of patient–physician communication that are difficult to examine in a clinical setting.
Background
Cancer patients' mental health and quality of life can be improved through professional support according to their needs. In previous analyses of the UNSAID study, we showed that a relevant proportion of cancer patients did not express their needs during the admission interview of inpatient rehabilitation. We now examine trajectories of mental health, quality of life, and utilization of professional help in cancer patients with unexpressed needs.
Methods
We enrolled 449 patients with breast, prostate, and colon cancer at beginning (T0) and end (T1) of a 3-week inpatient rehabilitation and 3 (T2) and 9 (T3) months after discharge. We explored depression (PHQ-2), anxiety (GAD-2), emotional functioning (EORTC QLQ-C30), fear of progression (FoP-Q-SF), and global quality of life (EORTC QLQ-C30) using structuring equation models. Furthermore, we evaluated self-reports about expressing needs and utilization of professional help at follow-up.
Results
Patients with unexpressed needs (24.3%, n = 107) showed decreased mental health compared to other patients (e.g., depression: d T0 = 0.32, d T1-T3 = 0.39). They showed a significant decline in global quality of life at discharge and follow-up (d = 0.28). Furthermore, they had a higher need for support (Cramer's V T2 = 0.10, T3 = 0.15), talked less about their needs (Cramer’s V T2 = 0.18), and made less use of different health care services at follow-up.
Conclusion
Unexpressed needs in cancer patients may be a risk factor for decreased mental health, quality of life, and non-utilization of professional help in the long term. Further research should clarify causal relationships and focus on this specific group of patients to improve cancer care.
Charge transfer in ternary solar cells employing two fullerene derivatives: where do electrons go?
(2022)
Earlier reports demonstrated that ternary organic solar cells (OSC) made of donor polymers (D) blended with different mixtures of fullerene acceptors (A : A) performed very similarly. This finding is surprising, as the corresponding fullerene LUMO levels are slightly different, which might result in decisive differences in the charge transfer step. We investigate ternary OSC (D : A : A) made of the donor polymer P3HT with stoichiometric mixtures of different fullerene derivatives, PC\(_{60}\)BM : PC\(_{70}\)BM and PC\(_{70}\)BM : IC\(_{60}\)BA, respectively. Using quantitative electron paramagnetic resonance (EPR) we can distinguish between positive and negative polarons, localized on the specific molecules. We found that after the initial charge transfer step, the electrons are re-distributed over two nearby acceptors in agreement with their stoichiometry and their relative LUMO energy difference. Remarkably, the measured ΔLUMO differences in fullerene mixtures are reduced by an order of magnitude compared to that of the pristine materials, i. e., below 1 meV for PC\(_{60}\)BM : PC\(_{70}\)BM and (20±5) meV for PC\(_{70}\)BM : IC\(_{60}\)BA. Furthermore, we found that this reduced ΔLUMO explains the shift in open circuit voltage for D : A : A organic solar cells. We attribute these findings to hybridization, leading to an effective fullerene LUMO. Consequently, multi-acceptor blends are indeed a viable option for photodetectors and solar cells, as they combine the best electron acceptor and light absorbing properties.
The multi-agent therapy “VDT-PACE” represents an established regimen in relapsed/refractory multiple myeloma (RRMM). Here, we report on our experience with a “modified VDT-PACE” incorporating new generation anti-MM agents daratumumab and carfilzomib (“Dara-KDT-P(A)CE”). We retrospectively analyzed 38 patients with RRMM treated with “Dara-KDT-P(A)CE”. The median age was 62 (range 45–82) years, and the patients were heavily pretreated with a median of 5 (range 2–12) prior lines of therapy. Twenty-one (55%) patients suffered from penta-refractory MM. High-risk cytogenetics was present in 31 (81%) patients. The patients received a median of 2 (range 1–10) cycles of this therapy, and the overall response rate (ORR) was 70%. Patients with penta-refractory MM and high-risk cytogenetics showed similar ORR of 65% and 79%, respectively. The median progression-free survival (PFS) and overall survival were 4.1 (95% CI 2.7–5.4) and 8.4 (95% CI 6.7–10.0) months, respectively. Patients with lactate dehydrogenase >250 IU/L showed significantly shorter PFS in comparison with others patients (p = 0.006). We used this regimen as bridging therapy prior to chimeric antigen receptor T-cell infusion in four patients. In conclusion, “Dara-KDT-P(A)CE” is an effective salvage therapy for patients with heavily pretreated, multi-refractory, high-risk RRMM lacking alternative options.
The neuropeptide pigment-dispersing factor (PDF) plays a prominent role in the circadian clock of many insects including honey bees. In the honey bee brain, PDF is expressed in about 15 clock neurons per hemisphere that lie between the central brain and the optic lobes. As in other insects, the bee PDF neurons form wide arborizations in the brain, but certain differences are evident. For example, they arborize only sparsely in the accessory medulla (AME), which serves as important communication center of the circadian clock in cockroaches and flies. Furthermore, all bee PDF neurons cluster together, which makes it impossible to distinguish individual projections. Here, we investigated the developing bee PDF network and found that the first three PDF neurons arise in the third larval instar and form a dense network of varicose fibers at the base of the developing medulla that strongly resembles the AME of hemimetabolous insects. In addition, they send faint fibers toward the lateral superior protocerebrum. In last larval instar, PDF cells with larger somata appear and send fibers toward the distal medulla and the medial protocerebrum. In the dorsal part of the medulla serpentine layer, a small PDF knot evolves from which PDF fibers extend ventrally. This knot disappears during metamorphosis and the varicose arborizations in the putative AME become fainter. Instead, a new strongly stained PDF fiber hub appears in front of the lobula. Simultaneously, the number of PDF neurons increases and the PDF neuronal network in the brain gets continuously more complex.
Dye–dye interactions affect the optical and electronic properties in organic semiconductor films of light harvesting and detecting optoelectronic applications. This review elaborates how to tailor these properties of organic semiconductors for organic solar cells (OSCs) and organic photodiodes (OPDs). While these devices rely on similar materials, the demands for their optical properties are rather different, the former requiring a broad absorption spectrum spanning from the UV over visible up to the near‐infrared region and the latter an ultra‐narrow absorption spectrum at a specific, targeted wavelength. In order to design organic semiconductors satisfying these demands, fundamental insights on the relationship of optical properties are provided depending on molecular packing arrangement and the resultant electronic coupling thereof. Based on recent advancements in the theoretical understanding of intermolecular interactions between slip‐stacked dyes, distinguishing classical J‐aggregates with predominant long‐range Coulomb coupling from charge transfer (CT)‐mediated or ‐coupled J‐aggregates, whose red‐shifts are primarily governed by short‐range orbital interactions, is suggested. Within this framework, the relationship between aggregate structure and functional properties of representative classes of dye aggregates is analyzed for the most advanced OSCs and wavelength‐selective OPDs, providing important insights into the rational design of thin‐film optoelectronic materials.
Background: Acute respiratory failure is the most important organ dysfunction of COVID-19 patients. While non-invasive ventilation (NIV) and high-flow nasal cannula (HFNC) oxygen are frequently used, efficacy and safety remain uncertain. Benefits and harms of awake prone positioning (APP) in COVID-19 patients are unknown. Methods: We searched for randomized controlled trials (RCTs) comparing HFNC vs. NIV and APP vs. standard care. We meta-analyzed data for mortality, intubation rate, and safety. Results: Five RCTs (2182 patients) were identified. While it remains uncertain whether HFNC compared to NIV alters mortality (RR: 0.92, 95% CI 0.65–1.33), HFNC may increase rate of intubation or death (composite endpoint; RR 1.22, 1.03–1.45). We do not know if HFNC alters risk for harm. APP compared to standard care probably decreases intubation rate (RR 0.83, 0.71–0.96) but may have little or no effect on mortality (RR: 1.08, 0.51–2.31). Conclusions: Certainty of evidence is moderate to very low. There is no compelling evidence for either HFNC or NIV, but both carry substantial risk for harm. The use of APP probably has benefits although mortality appears unaffected.
(1) Background: Data on coronavirus 2 infection during pregnancy vary. We aimed to describe maternal characteristics and clinical presentation of SARS-CoV-2 positive women requiring intensive care treatment for COVID-19 during pregnancy and postpartum period based on data of a comprehensive German surveillance system in obstetric patients. (2) Methods: Data from COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS), a prospective multicenter registry for SARS-CoV-2 positive pregnant women, was analyzed with respect to ICU treatment. All women requiring intensive care treatment for COVID-19 were included and compared regarding maternal characteristics, course of disease, as well as maternal and neonatal outcomes. (3) Results: Of 2650 cases in CRONOS, 101 women (4%) had a documented ICU stay. Median maternal age was 33 (IQR, 30–36) years. COVID-19 was diagnosed at a median gestational age of 33 (IQR, 28–35) weeks. As the most invasive form of COVID-19 treatment interventions, patients received either continuous monitoring of vital signs without further treatment requirement (n = 6), insufflation of oxygen (n = 30), non-invasive ventilation (n = 22), invasive ventilation (n = 28), or escalation to extracorporeal membrane oxygenation (n = 15). No significant clinical differences were identified between patients receiving different forms of ventilatory support for COVID-19. Prevalence of preterm delivery was significantly higher in women receiving invasive respiratory treatments. Four women died of COVID-19 and six fetuses were stillborn. (4) Conclusions: Our cohort shows that progression of COVID-19 is rare in pregnant and postpartum women treated in the ICU. Preterm birth rate is high and COVID-19 requiring respiratory support increases the risk of poor maternal and neonatal outcome.
Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) profoundly impacts hemostasis and microvasculature. In the light of the dilemma between thromboembolic and hemorrhagic complications, in the present paper, we systematically investigate the prevalence, mortality, radiological subtypes, and clinical characteristics of intracranial hemorrhage (ICH) in coronavirus disease (COVID-19) patients. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed a systematic review of the literature by screening the PubMed database and included patients diagnosed with COVID-19 and concomitant ICH. We performed a pooled analysis, including a prospectively collected cohort of critically ill COVID-19 patients with ICH, as part of the PANDEMIC registry (Pooled Analysis of Neurologic Disorders Manifesting in Intensive Care of COVID-19). Results: Our literature review revealed a total of 217 citations. After the selection process, 79 studies and a total of 477 patients were included. The median age was 58.8 years. A total of 23.3% of patients experienced the critical stage of COVID-19, 62.7% of patients were on anticoagulation and 27.5% of the patients received ECMO. The prevalence of ICH was at 0.85% and the mortality at 52.18%, respectively. Conclusion: ICH in COVID-19 patients is rare, but it has a very poor prognosis. Different subtypes of ICH seen in COVID-19, support the assumption of heterogeneous and multifaceted pathomechanisms contributing to ICH in COVID-19. Further clinical and pathophysiological investigations are warranted to resolve the conflict between thromboembolic and hemorrhagic complications in the future.
Point-spread function engineering for single-molecule localization microscopy in brain slices
(2022)
Single-molecule localization microscopy (SMLM) is the method of choice to study biological specimens on a nanoscale level. Advantages of SMLM imply its superior specificity due to targeted molecular fluorescence labeling and its enhanced tissue preservation compared to electron microscopy, while reaching similar resolution. To reveal the molecular organization of protein structures in brain tissue, SMLM moves to the forefront: Instead of investigating brain slices with a thickness of a few µm, measurements of intact neuronal assemblies (up to 100 µm in each dimension) are required. As proteins are distributed in the whole brain volume and can move along synapses in all directions, this method is promising in revealing arrangements of neuronal protein markers. However, diffraction-limited imaging still required for the localization of the fluorophores is prevented by sample-induced distortion of emission pattern due to optical aberrations in tissue slices from non-superficial planes. In particular, the sample causes wavefront dephasing, which can be described as a summation of Zernike polynomials. To recover an optimal point spread function (PSF), active shaping can be performed by the use of adaptive optics. The aim of this thesis is to establish a setup using a deformable mirror and a wavefront sensor to actively shape the PSF to correct the wavefront phases in a super-resolution microscope setup. Therefore, fluorescence-labeled proteins expressed in different anatomical regions in brain tissue will be used as experiment specimen. Resolution independent imaging depth in slices reaching tens of micrometers is aimed.
Due to a usually late diagnosis, drug resistance and early metastases, pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of global cancer deaths. Thus, there is an urgent need to develop new therapeutic concepts. Two different approaches have in recent years become the focus of intense research: (1) targeting cancer-associated metabolic rearrangements, and (2) targeting genetic vulnerabilities with combination therapy. Both concepts potentially have advantages such as increased efficacy, which decreases the likelihood of therapy-resistance, and reduced side effects, that are often associated with high concentrations of chemotherapeutic drugs. Autophagy is an evolutionary conserved signalling pathway that regulates cellular homeostasis. Regarding cancer, autophagy can either promote or suppress tumor growth. However, mouse models that allow genetic regulation of autophagy in established tumor tissue are not yet established. Therefore, we analysed new inducible shRNA mouse models targeting Atg5 or Atg7 with regard to functionality and toxicity. Both, shRNA Atg5- and shRNA Atg7-mediated knockdown anteceded functional autophagy impairment, and revealed unexpected profound phenotypic differences. Knockdown of Atg5 neither impaired the animal nor caused any grossly or microscopically detectable organ damage, whereas knockdown of Atg7 caused pancreatic destruction and eventually death. It is currently unclear whether mice died as a result of exocrine or endocrine collapse or due to a combination of both. The presented mouse models are highly potent RNAi mice that allow widespread and regulable inhibition of autophagy upon administration of doxycycline and provide a valuable and versatile toolbox for future autophagy and cancer research. In PDAC, argininosuccinate synthase 1 (ASS1) deficiency has been associated with higher recurrence rates, shorter disease-free survival, and shorter overall survival. During cancer development, rate-limiting enzymes of de novo arginine synthesis, like ASS1 or OTC, are downregulated via epigenetic silencing of their respective promotor. Known as ‘arginine auxotrophy‘, loss of these essential enzymes results in dependence on extracellular arginine. Based on this assumption, sensitivity of various cell lines to arginine deprivation was reported. However, the underlying mechanism is still unclear and the anti-tumor effects of the monotherapy are not sufficient to completely abrogate cancer cells. Therefore, the effects of arginine deprivation via rhArgI-PEG5000 were investigated in murine and human PDAC cells. In this study, we highlighted that arginine deprivation induced profound alterations such as autophagosome accumulation, induction of senescence and the ISR in pancreatic cancer cells. These alterations are potential genetic vulnerabilities that can be targeted by additional means to induce tumor cell death.
RNA molecules play diverse roles in biological systems. Post-transcriptional RNA modifications and dynamic structures enhance the functional diversity of RNA. A prerequisite for studying their biological significance is the availability of reliable methods for the detection of RNA modifications and structures. Several promising approaches have been developed in the last few decades; however, efficient, and versatile tools are still required to study the dynamic features of RNA. This thesis focuses on the development of nucleic acid catalysts as a tool to address the current needs in studying RNA. The major part of this thesis aimed at the development of deoxyribozymes as a tool for the detection of RNA modifications. Using in vitro selection from a random DNA library, we found deoxyribozymes that are sensitive to N 6 -isopentenyladenosine (i6A), a native tRNA modification and structural analogue of m6A. The in vitro evolution identified three classes of DNA enzymes: AA, AB08, and AC17 DNAzymes that showed distinct response to i6A modification and showed strong discrimination between structural analogues, i.e., m6A and i6A. In the continuation of the project, we attempted to develop RNA-cleaving deoxyribozymes that differentially respond to monomethylated cytidine isomers, 3-methylcytidine (m3C), N4 - methylcytidine (m4C), and 5-methylcytidine (m5C). Several deoxyribozymes were identified from in vitro selection, which are selective for a specific methylated cytidine isomer. The characterization of AL112, AM101, AN05, and AK104 catalysts confirmed the successful evolution of modification-specific and general deoxyribozymes that showed a broad substrate scope. In order to accelerate the DNAzymes discovery, a high throughput sequencing method (DZ-seq) was established that directly quantifies the RNA cleavage activity and cleavage site from deep sequencing data. The libraries contained information about cleavage status, cleavage site and sequence of deoxyribozymes and RNA substrate. The fraction cleaved (FC) data obtained from Dz-seq was validated for a subset of deoxyribozmes using conventional gel based kinetic assay and showed a good linear correlation (R2 = 0.91). Dz-seq possesses a great potential for the discovery of novel deoxyribozymes for the analysis of various RNA modifications in the future. The second objective of the current study was the development of structure-specific RNA labeling ribozymes. Here, we attempted to develop ribozymes that targets RNA of interest by structure-specific interaction rather than base-pairing and focused on a specific RNA G-quadruplex as the target. Two subsequent selection experiments led to the identification of the adenylyltransferase ribozymes AO10.2 and AR9. The partial characterization of these catalysts showed that A010.2 was unable to recognize intact BCL2 structure, but it turned out as the first reported trans-active ribozyme that efficiently labeled uridine in a defined substrate RNA hybridized to the ribozyme. The other ribozyme AR9 was shown to serve as a trans-active, self-labeling ribozyme that catalyzed adenylyl transferase reaction in the presence of the intact BCL2 sequence. Based on these preliminary findings, we envision that AR9 could potentially serve as a reporter RNA by self-labeling in the presence of an RNA G-quadruplex. However, both AO10.2 and AR9 still require more detailed characterization for their potential applications.
Tribenzotriquinacene (TBTQ) is a polycyclic aromatic framework with a particularly rigid, C3v symmetrical, bowl-shaped core bearing three mutually fused indane wings. It has been discussed as a defect center for a nanographene by Kuck and colleagues. Therefore, extended TBTQ structures are promising models for saturated defect structures in graphene and graphene like molecules and could be used to investigate the role of defects for the electronic properties of graphene. With this motivation, three different pi-extended TBTQ derivatives have been synthesized in this work. Several different Scholl reaction conditions were tried to obtain fully annulated product of hexaphenyl substituted TBTQ. The desired benzannulated TBTQ derivative could not be obtained due to unfavourable electron density in the respective positions of the molecule and increased reactivity of the bay position of the precursor. As an another method for benzannulation is the on-surface synthesis of graphene flakes and can be carried out using electron beams e.g. in a tunneling microscope (STM). According to our previous research, the parent system TBTQ and centro-methyl TBTQ on silver and gold surfaces showed that the gas phase deposition of these molecules gives rise to the formation of highly ordered two-dimensional assemblies with unique structural features. This shows the feasibility for the formation of defective graphene networks starting from the parent structures. Therefore, the same deposition technique was used to deposit Me-TBTQ(OAc)3Ph6, and investigate the molecular self-assembly properties directly on the surface of Cu (111). In summary, the substrate temperature dependent self-assembly of Me-TBTQ(OAc)3Ph6 molecules on Cu(111), shows the following evolution of orientations. At room temperature, molecules form dimers, which construct a higher-coverage honeycomb lattice. Furthermore, one of the acetyl group located in the bay positions of the TBTQ core is cleaved and the remaining two induce the metal-molecule interaction. It was presumed that by increasing the temperature to 393 K, the remaining acetyl and methyl groups would beeliminated from the molecular structure.In addition, the smaller TBTQ-Ph6 molecules preferably lie flat on Cu(111) crystal and allowing the molecules to settle into a C3-symmetry and form a dense hexagonal structure.
This dissertation describes the synthesis of an unsymmetrically-substituted triarylborane. This term describes a three-coordinate boron atom that is bound to three different aromatic systems, namely 2,6-dimethylphenyl, mesityl, and 4-(N,N-dimethylamino)-2,6-dimethylphenyl. It is also demonstrated that the amine functionality can be converted with methyl triflate into an ammonium moiety. The investigation of photophysical and electrochemical properties of this compound in comparison with the non-aminated and di-aminated analogues of the triarylborane is described besides other investigations of e. g. singlet oxygen sensitization, rotational barriers, and fundamental DFT calculations. Based on these investigations, selectively mono-, bis- and tris-dimethylamino- and trimethylammonium-substituted bis-triarylborane bithiophene chromophores were synthesized and their photophysical, and electrochemical properties were investigated together with the water solubility and singlet oxygen sensitizing efficiency of the cationic compounds Cat1+, Cat2+, Cat(i)2+, and Cat3+. Comparing these properties with the results obtained for the mono-triarylboranes reveals a large influence of the bridging unit on the investigated properties of the bis-triarylboranes. In addition, the interaction of the cationic bis-triarylboranes with different polynucleotides were investigated in buffered solutions as well as the ability of these selectively charged compounds to enter and localize within organelles of human lung carcinoma and normal lung cells. All these investigations demonstrate that the number of charges and their distribution influences the interactions and staining properties as well as most of the other properties investigated.
In addition, preliminary investigations on H2O2-cleavable boronate esters in the presence of stochiometric amounts of H2O2 are described for three different aryl boronate esters.
This thesis focuses on investigating magneto-transport properties of a ferromagnetic topological insulator (V,Bi,Sb)2Te3. This material is most famously known for exhibiting the quantum anomalous Hall effect, a novel quantum state of matter that has opened up possibilities for potential applications in quantum metrology as a quantum standard of resistance, as well as for academic investigations into unusual magnetic properties and axion electrodynamics. All of those aspects are investigated in the thesis.
The digital transformation facilitates new forms of collaboration between companies along the supply chain and between companies and consumers. Besides sharing information on centralized platforms, blockchain technology is often regarded as a potential basis for this kind of collaboration. However, there is much hype surrounding the technology due to the rising popularity of cryptocurrencies, decentralized finance (DeFi), and non-fungible tokens (NFTs). This leads to potential issues being overlooked. Therefore, this thesis aims to investigate, highlight, and address the current weaknesses of blockchain technology: Inefficient consensus, privacy, smart contract security, and scalability.
First, to provide a foundation, the four key challenges are introduced, and the research objectives are defined, followed by a brief presentation of the preliminary work for this thesis.
The following four parts highlight the four main problem areas of blockchain. Using big data analytics, we extracted and analyzed the blockchain data of six major blockchains to identify potential weaknesses in their consensus algorithm. To improve smart contract security, we classified smart contract functionalities to identify similarities in structure and design. The resulting taxonomy serves as a basis for future standardization efforts for security-relevant features, such as safe math functions and oracle services. To challenge privacy assumptions, we researched consortium blockchains from an adversary role. We chose four blockchains with misconfigured nodes and extracted as much information from those nodes as possible. Finally, we compared scalability solutions for blockchain applications and developed a decision process that serves as a guideline to improve the scalability of their applications.
Building on the scalability framework, we showcase three potential applications for blockchain technology. First, we develop a token-based approach for inter-company value stream mapping. By only relying on simple tokens instead of complex smart-contracts, the computational load on the network is expected to be much lower compared to other solutions. The following two solutions use offloading transactions and computations from the main blockchain. The first approach uses secure multiparty computation to offload the matching of supply and demand for manufacturing capacities to a trustless network. The transaction is written to the main blockchain only after the match is made. The second approach uses the concept of payment channel networks to enable high-frequency bidirectional micropayments for WiFi sharing. The host gets paid for every second of data usage through an off-chain channel. The full payment is only written to the blockchain after the connection to the client gets terminated.
Finally, the thesis concludes by briefly summarizing and discussing the results and providing avenues for further research.
Breaking inversion symmetry in crystalline solids enables the formation of spin-polarized electronic states by spin-orbit coupling without the need for magnetism. A variety of interesting physical phenomena related to this effect have been intensively investigated in recent years, including the Rashba effect, topological insulators and Weyl semimetals. In this work, the interplay of inversion symmetry breaking and spin-orbit coupling and, in particular their general influence on the character of electronic states, i.e., on the spin and orbital degrees of freedom, is investigated experimentally. Two different types of suitable model systems are studied: two-dimensional surface states for which the Rashba effect arises from the inherently broken inversion symmetry at the surface, and a Weyl semimetal, for which inversion symmetry is broken in the three-dimensional crystal structure. Angle-resolved photoelectron spectroscopy provides momentum-resolved access to the spin polarization and the orbital composition of electronic states by means of photoelectron spin detection and dichroism with polarized light. The experimental results shown in this work are also complemented and supported by ab-initio density functional theory calculations and simple model considerations.
Altogether, it is shown that the breaking of inversion symmetry has a decisive influence on the Bloch wave function, namely, the formation of an orbital angular momentum. This mechanism is, in turn, of fundamental importance both for the physics of the surface Rashba effect and the topology of the Weyl semimetal TaAs.
An enduring engineering problem is the creation of unreliable software leading to unreliable systems. One reason for this is source code is written in a complicated manner making it too hard for humans to review and understand. Complicated code leads to other issues beyond dependability, such as expanded development efforts and ongoing difficulties with maintenance, ultimately costing developers and users more money.
There are many ideas regarding where blame lies in the reation of buggy and unreliable systems. One prevalent idea is the selected life cycle model is to blame. The oft-maligned “waterfall” life cycle model is a particularly popular recipient of blame. In response, many organizations changed their life cycle model in hopes of addressing these issues. Agile life cycle models have become very popular, and they promote communication between team members and end users. In theory, this communication leads to fewer misunderstandings and should lead to less complicated and more reliable code.
Changing the life cycle model can indeed address communications ssues, which can resolve many problems with understanding requirements.
However, most life cycle models do not specifically address coding practices or software architecture. Since lifecycle models do not address the structure of the code, they are often ineffective at addressing problems related to code complicacy.
This dissertation answers several research questions concerning software complicacy, beginning with an investigation of traditional metrics and static analysis to evaluate their usefulness as measurement tools. This dissertation also establishes a new concept in applied linguistics by creating a measurement of software complicacy based on linguistic economy. Linguistic economy describes the efficiencies of speech, and this thesis shows the applicability of linguistic economy to software. Embedded in each topic is a discussion
of the ramifications of overly complicated software, including the relationship of complicacy to software faults. Image recognition using machine learning is also investigated as a potential method of identifying problematic source code.
The central part of the work focuses on analyzing the source code of hundreds of different projects from different areas. A static analysis was performed on the source code of each project, and traditional software metrics were calculated. Programs were also analyzed using techniques developed by linguists to measure expression and statement complicacy and identifier complicacy. Professional software engineers were also directly surveyed to understand mainstream perspectives.
This work shows it is possible to use traditional metrics as indicators of potential project bugginess. This work also discovered it is possible to use image recognition to identify problematic pieces of source code. Finally, this work discovered it is possible to use linguistic methods to determine which statements and expressions are least desirable and more complicated for programmers.
This work’s principle conclusion is that there are multiple ways to discover traits indicating a project or a piece of source code has characteristics of being buggy. Traditional metrics and static analysis can be used to gain some understanding of software complicacy and bugginess potential. Linguistic economy demonstrates a new tool for measuring software complicacy, and machine learning can predict where bugs may lie in source code. The significant implication of this work is developers can recognize when a project is becoming buggy and take practical steps to avoid creating buggy projects.
To investigate trabeculopuncture (TP) for predicting the outcome of ab interno trabeculectomy (AIT). Ex vivo porcine anterior segments were perfused and sequentially underwent two procedures, TP and AIT. We concluded that a 10% reduction in IOP after TP can be used to predict the success (>20% IOP decrease) of AIT in porcine eyes. As porcine eyes share many similarities with human eyes, our findings may have implications on the validity of this test as a predictor for surgical outcomes of AITs in humans.
Purpose: The threat of national and international terrorism remains high. Preparation is the key requirement for the resilience of hospitals and out-of-hospital rescue forces. The scientific evidence for defining medical and tactical strategies often feeds on the analysis of real incidents and the lessons learned derived from them. This systematic review of the literature aims to identify and systematically report lessons learned from terrorist attacks since 2001.
Methods: PubMed was used as a database using predefined search strategies and eligibility criteria. All countries that are part of the Organization for Economic Cooperation and Development (OECD) were included. The time frame was set between 2001 and 2018.
Results: 68 articles were included in the review. From these, 616 lessons learned were extracted and summarized into 15 categories. The data shows that despite the difference in attacks, countries, and casualties involved, many of the lessons learned are similar. We also found that the pattern of lessons learned is repeated continuously over the time period studied.
Conclusions: The lessons from terrorist attacks since 2001 follow a certain pattern and remained constant over time. Therefore, it seems to be more accurate to talk about lessons identified rather than lessons learned. To save as many victims as possible, protect rescue forces from harm, and to prepare hospitals at the best possible level it is important to implement the lessons identified in training and preparation.
1 Summary
Left ventricular (LV) ejection fraction (EF) and global longitudinal strain (GLS) are the most commonly used measures of LV function. Yet, they are highly dependent on loading conditions since higher afterload yields lower systolic deformation and thereby a lower LVEF and GLS – despite presumably unchanged LV myocardial contractile strength. Invasive pressure-volume loop measurements represent the reference standard to assess LV function, also considering loading conditions. However, this procedure cannot be used in serial investigations or large sample populations due to its invasive nature. The novel concept of echocardiography-derived assessment of myocardial work (MyW) is based on LV pressure-strain loops, may be a valuable alternative to overcome these challenges, and may also be used with relative ease in large populations. As MyW also accounts for afterload, it is considered less load-dependent than LVEF and GLS.
The current PhD work addresses the application and clinical characterization of MyW, an innovative echocardiographic tool. As the method is new, we focused on four main topics:
(a) To establish reference values for MyW indices, i.e., Global Work Index (GWI), Global Constructive Work (GCW), Global Wasted Work (GWW), and Global Work Efficiency (GWE); we addressed a wide age range and evaluated the association of MyW indices with age, sex and other clinical and echocardiography parameters in apparently cardiovascular healthy individuals.
(b) To investigate the impact of cardiovascular (CV) risk factors on MyW indices and characterize the severity of subclinical LV deterioration in the general population.
(c) To assess the association of the LV geometry, i.e., LV mass and dimensions, with MyW indices.
(d) To evaluate in-hospital dynamics of MyW indices in patients hospitalized for acute heart failure (AHF).
For the PhD thesis, we could make use of two larger cohorts:
The STAAB population-based cohort study prospectively recruited and phenotyped a representative sample (5,000 individuals) of the general population of the City of Würzburg, aged 30-79 years and free from symptomatic heart failure at the time of inclusion. We focused on the first half of the study sample (n=2473 individuals), which fulfilled the anticipated strata regarding age and sex.
The Acute Heart Failure (AHF) Registry is a prospective clinical registry recruiting and phenotyping consecutive patients admitted for decompensated AHF to the Department of Medicine I, University Hospital Würzburg, and observing the natural course of the disease. The AHF Registry focuses on the pathophysiological understanding, particularly in relation to the early phase after cardiac decompensation, with the aim to improve diagnosis and better-tailored treatment of patients with AHF. For the current study, we concentrated on patients who provided pairs of echocardiograms acquired early after index hospital admission and prior to discharge.
The main findings of the PhD thesis were:
From the STAAB cohort study, we determined the feasibility of large-scale MyW derivation and the accuracy of the method. We established reference values for MyW indices based on 779 analyzable, apparently healthy participants (mean age 49 ± 10 years, 59% women), who were in sinus rhythm, free from CV risk factors or CV disease, and had no significant LV valve disease. Apart from GWI, there were no associations of other MyW indices with sex. Further, we found a disparate association with age, where MyW showed stable values until the age of 45 years, with an upward shift occurring beyond the age of 45. A higher age decade was associated with higher GWW and lower GWE, respectively. MyW indices only correlated weakly with common echocardiographic parameters, suggesting that MyW may add incremental information to clinically established parameters.
Further analyses from the STAAB cohort study contributed to a better understanding of the impact of CV risk factors on MyW indices and the association of LV geometry with LV performance. We demonstrated that CV risk factors impacted selectively on GCW and GWW. Hypertension appears to profoundly compromise the work of the myocardium, in particular, by increasing both GCW and GWW. The LV in hypertension seems to operate at a higher energy level yet lower efficiency. Other classical CV risk factors (Diabetes mellitus, Obesity, Dyslipidemia, Smoking) – independent of blood pressure – impacted consistently and adversely on GCW but did not affect GWW. Further, all CV risk factors affected GWE adversely.
We observed that any deviation from a normal LV geometric profile was associated with alterations on MyW. Of note, MyW was sensitive to early changes in LV mass and dimensions. Individuals with normal LV geometry yet established arterial hypertension exhibited a MyW pattern that is typically found in LV hypertrophy. Therefore, such a pattern might serve as an early sign of myocardial damage in hypertensive heart disease and might aid in risk stratification and primary prevention.
From the AHF Registry, we selected individuals with serial in-hospital echocardiograms and described in-hospital changes in myocardial performance during recompensation. In patients presenting with a reduced ejection fraction (HFrEF), decreasing N-terminal pro-natriuretic peptide (NT-proBNP) levels as a surrogate of successful recompensation were associated with an improvement in GCW and GWI and consecutively in GWE. In contrast, in patients presenting with a preserved ejection fraction (HFpEF), there was no significant change in GCW and GWI. However, unsuccessful recompensation, i.e., no change or an increase in NT-proBNP levels, was associated with an increase in GWW. This suggests a differential myocardial response to de- and recompensation depending on the HF phenotype.
Further, GWW as a surrogate of inappropriate LV energy consumption was elevated in all patients with AHF (compared to reference values) and was not associated with conventional markers as LVEF or NT-proBNP. In an exploratory analysis, GWW predicted the risk of death or rehospitalization within six months after discharge. Hence, GWW might carry incremental information beyond conventional markers of HF severity.
Time-to-Live (TTL) caches decouple the occupancy of objects in cache through object-specific validity timers. Stateof- the art techniques provide exact methods for the calculation of object-specific hit probabilities given entire cache hierarchies with random inter-cache network delays. The system hit probability is a provider-centric metric as it relates to the origin offload, i.e., the decrease in the number of requests that are served by the content origin server. In this paper we consider a user-centric metric, i.e., the response time, which is shown to be structurally different from the system hit probability. Equipped with the state-of-theart exact modeling technique using Markov-arrival processes we derive expressions for the expected object response time and pave a way for its optimization under network delays.
In scientific research, the independent reproduction of experiments is the source of trust. Detailed documentation is required to enable experiment reproduction. Reproducibility awards were created to honor the increased documentation effort. In this work, we propose a novel approach toward reproducible research—a structured experimental workflow that allows the creation of reproducible experiments without requiring additional efforts of the researcher. Moreover, we present our own testbed and toolchain, namely, plain orchestrating service (pos), which enables the creation of such experimental workflows. The experiment is documented by our proposed, fully scripted experiment structure. In addition, pos provides scripts enabling the automation of the bundling and release of all experimental artifacts. We provide an interactive environment where pos experiments can be executed and reproduced, available at https://gallenmu.github.io/single-server-experiment.
LoRaWAN Network Planning in Smart Environments: Towards Reliability, Scalability, and Cost Reduction
(2022)
The goal in this work is to present a guidance for LoRaWAN planning to improve overall reliability for message transmissions and scalability. At the end, the cost component is discussed. Therefore, a five step approach is presented that helps to plan a LoRaWAN deployment step by step: Based on the device locations, an initial gateway placement is suggested followed by in-depth frequency and channel access planning. After an initial planning phase, updates for channel access and the initial gateway planning is suggested that should also be done periodically during network operation. Since current gateway placement approaches are only studied with random channel access, there is a lot of potential in the cell planning phase. Furthermore, the performance of different channel access approaches is highly related on network load, and thus cell size and sensor density. Last, the influence of different cell planning ideas on expected costs are discussed.
Civil society organizations only started to be considered a sector in the 1970s in the United States. Amitai Etzioni pioneered the use of the expression third sector, which became common in academic and political literature. However, in the United States, the non-profit sector concept gradually became more robust and was spread internationally based on the studies conducted by Lester Salomon and associated researchers.
The theory built on the concept of the non-profit sector is strongly related to the North American cultural context, marked by the tradition of philanthropy and volunteerism, but with little importance given to associative and cooperative organizations.
The non-profit sector is implicitly or explicitly conceived as part of the private sphere. In contrast, theoretical currents such as liberal communitarianism, the theories of cooperation, common goods, social capital, European social economy, and the Latin American solidarity economy highlight the primacy of cooperation in solving collective problems. These theories underpin the associative approach of the third sector and link it to the community, not to the market.
This paper argues that the associative approach is more appropriate for international studies on the third sector and the relevance of self-organization. The third sector, i.e., the set of organizations created and maintained by civil society, is the inheritor of the millennial associative tradition, including both entities whose values are compatible with the common good and those with particularistic values, authoritarian and contrary to human rights. The third sector is not entirely virtuous, but it is a vital sector for solving great human problems.
Lightning has fascinated humanity since the beginning of our existence. Different types of lightning like sprites and blue jets were discovered, and many more are theorized. However, it is very likely that these phenomena are not exclusive to our home planet. Venus’s dense and active atmosphere is a place where lightning is to be expected. Missions like Venera, Pioneer, and Galileo have carried instruments to measure electromagnetic activity. These measurements have indeed delivered results. However, these results are not clear. They could be explained by other effects like cosmic rays, plasma noise, or spacecraft noise. Furthermore, these lightning seem different from those we know from our home planet. In order to tackle these issues, a different approach to measurement is proposed. When multiple devices in different spacecraft or locations can measure the same atmospheric discharge, most other explanations become increasingly less likely. Thus, the suggested instrument and method of VELEX incorporates multiple spacecraft. With this approach, the question about the existence of lightning on Venus could be settled.
The first step towards aerial planetary exploration has been made. Ingenuity shows extremely promising results, and new missions are already underway. Rotorcraft are capable of flight. This capability could be utilized to support the last stages of Entry, Descent, and Landing. Thus, mass and complexity could be scaled down.
Autorotation is one method of descent. It describes unpowered descent and landing, typically performed by helicopters in case of an engine failure. MAPLE is suggested to test these procedures and understand autorotation on other planets. In this series of experiments, the Ingenuity helicopter is utilized. Ingenuity would autorotate a ”mid-air-landing” before continuing with normal flight. Ultimately, the collected data shall help to understand autorotation on Mars and its utilization for interplanetary exploration.
Shannon channel capacity estimation, based on large packet length is used in traditional Radio Resource Management (RRM) optimization. This is good for the normal transmission of data in a wired or wireless system. For industrial automation and control, rather short packages are used due to the short-latency requirements. Using Shannon’s formula leads in this case to inaccurate RRM solutions, thus another formula should be used to optimize radio resources in short block-length packet transmission, which is the basic of Ultra-Reliable Low-Latency Communications (URLLCs). The stringent requirement of delay Quality of Service (QoS) for URLLCs requires a link-level channel model rather than a physical level channel model. After finding the basic and accurate formula of the achievable rate of short block-length packet transmission, the RRM optimization problem can be accurately formulated and solved under the new constraints of URLLCs. In this short paper, the current mathematical models, which are used in formulating the effective transmission rate of URLLCs, will be briefly explained. Then, using this rate in RRM for URLLC will be discussed.
We attempt to identify sequences of signaling dialogs, to strengthen our understanding of the signaling behavior of IoT devices by examining a dataset containing over 270.000 distinct IoT devices whose signaling traffic has been observed over a 31-day period in a 2G network [4]. We propose a set of rules that allows the assembly of signaling dialogs into so-called sessions in order to identify common patterns and lay the foundation for future research in the areas of traffic modeling and anomaly detection.
This work proposes a novel approach to disperse dense transmission intervals and reduce bursty traffic patterns without the need for centralized control. Furthermore, by keeping the mechanism as close to the Long Range Wide Area Network (LoRaWAN) standard as possible the suggested mechanism can be deployed within existing networks and can even be co-deployed with other devices.
Utilizing multiple access technologies such as 5G, 4G, and Wi-Fi within a coherent framework is currently standardized by 3GPP within 5G ATSSS. Indeed, distributing packets over multiple networks can lead to increased robustness, resiliency and capacity. A key part of such a framework is the multi-access proxy, which transparently distributes packets over multiple paths. As the proxy needs to serve thousands of customers, scalability and performance are crucial for operator deployments. In this paper, we leverage recent advancements in data plane programming, implement a multi-access proxy based on the MP-DCCP tunneling approach in P4 and hardware accelerate it by deploying the pipeline on a smartNIC. This is challenging due to the complex scheduling and congestion control operations involved. We present our pipeline and data structures design for congestion control and packet scheduling state management. Initial measurements in our testbed show that packet latency is in the range of 25 μs demonstrating the feasibility of our approach.
Future mobile communication networks, such as 5G and beyond, can benefit from Virtualized Network Functions (VNFs) when deployed on cloud infrastructures to achieve elasticity and scalability. However, new challenges arise as to managing states of Network Functions (NFs). Especially control plane VNFs, which are mainly found in cellular core networks like the 5G Core (5GC), received little attention since the shift towards virtualizing NFs. Most existing solutions for these core networks are often complex, intrusive, and are seldom compliant with the standard. With the emergence of 5G campus networks, UEs will be mainly machine-type devices. These devices communicate more deterministically, bringing new opportunities for elaborated state management. This work presents an emulation environment to perform rigorous measurements on state access patterns. The emulation comes with a fully parameterized Markov model for the UE to examine a wide variety of different devices. These measurements can then be used as a solid base for designing an efficient, simple, and standard conform state management solution that brings us further towards stateless core networks.
Tactile Internet aims at allowing perceived real-time interactions between humans and machines. This requires satisfying a stringent latency requirement of haptic data streams whose data rates vary drastically as the results of perceptual codecs. This introduces a complex problem for the underlying network infrastructure to fulfill the pre-defined level of Quality of Service (QoS). However, novel networking hardware with data plane programming capability allows processing packets differently and opens up a new opportunity. For example, a dynamic and network-aware resource management strategy can help satisfy the QoS requirements of different priority flows without wasting precious bandwidth. This paper introduces virtual queues for service differentiation between different types of traffic streams, leveraging protocol independent switch architecture (PISA). We propose coordinating the management of all the queues and dynamically adapting their sizes to minimize packet loss and delay due to network congestion and ensure QoS compliance.
This document presents a networking latency measurement setup that focuses on affordability and universal applicability, and can provide sub-microsecond accuracy. It explains the prerequisites, hardware choices, and considerations to respect during measurement. In addition, it discusses the necessity for exhaustive latency measurements when dealing with high availability and low latency requirements. Preliminary results show that the accuracy is within ±0.02 μs when used with the Intel I350-T2 network adapter.