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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)
- Helmholtz Institute for RNA-based Infection Research (HIRI) (2)
- 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)
Three novel tetracationic bis‐triarylboranes with 3,4‐ethylenedioxythiophene (EDOT) linkers, and their neutral precursors, showed significant red‐shifted absorption and emission compared to their thiophene‐containing analogues, with one of the EDOT‐derivatives emitting in the NIR region. Only the EDOT‐linked trixylylborane tetracation was stable in aqueous solution, indicating that direct attachment of a thiophene or even 3‐methylthiophene to the boron atom is insufficient to provide hydrolytic stability in aqueous solution. Further comparative analysis of the EDOT‐linked trixylylborane tetracation and its bis‐thiophene analogue revealed efficient photo‐induced singlet oxygen production, with the consequent biological implications. Thus, both analogues bind strongly to ds‐DNA and BSA, very efficiently enter living human cells, accumulate in several different cytoplasmic organelles with no toxic effect but, under intense visible light irradiation, they exhibit almost instantaneous and very strong cytotoxic effects, presumably attributed to singlet oxygen production. Thus, both compounds are intriguing theranostic agents, whose intracellular and probably intra‐tissue location can be monitored by strong fluorescence, allowing switching on of the strong bioactivity by well‐focused visible light.
The development of controlled biodegradable materials is of fundamental importance in immunodrug delivery to spatiotemporally controlled immune stimulation but avoid systemic inflammatory side effects. Based on this, polycarbonate nanogels are developed as degradable micellar carriers for transient immunoactivation of lymph nodes. An imidazoquinoline‐type TLR7/8 agonist is covalently conjugated via reactive ester chemistry to these nanocarriers. The nanogels not only provide access to complete disintegration by the hydrolysable polymer backbone, but also demonstrate a gradual disintegration within several days at physiological conditions (PBS, pH 6.4–7.4, 37 °C). These intrinsic properties limit the lifetime of the carriers but their payload can still be successfully leveraged for immunological studies in vitro on primary immune cells as well as in vivo. For the latter, a spatiotemporal control of immune cell activation in the draining lymph node is found after subcutaneous injection. Overall, these features render polycarbonate nanogels a promising delivery system for transient activation of the immune system in lymph nodes and may consequently become very attractive for further development toward vaccination or cancer immunotherapy. Due to the intrinsic biodegradability combined with the high chemical control during the manufacturing process, these polycarbonate‐based nanogels may also be of great importance for clinical translation.
Background and purpose
Impaired kidney function is associated with an increased risk of vascular events in acute stroke patients, when assessed by single measurements of estimated glomerular filtration rate (eGFR). It is unknown whether repeated measurements provide additional information for risk prediction.
Methods
The MonDAFIS (Systematic Monitoring for Detection of Atrial Fibrillation in Patients with Acute Ischemic Stroke) study randomly assigned 3465 acute ischemic stroke patients to either standard procedures or an additive Holter electrocardiogram. Baseline eGFR (CKD‐EPI formula) were dichotomized into values of < versus ≥60 ml/min/1.73 m\(^{2}\). eGFR dynamics were classified based on two in‐hospital values as “stable normal” (≥60 ml/min/1.73 m\(^{2}\)), “increasing” (by at least 15% from baseline, second value ≥ 60 ml/min/1.73 m\(^{2}\)), “decreasing” (by at least 15% from baseline of ≥60 ml/min/1.73 m\(^{2}\)), and “stable decreased” (<60 ml/min/1.73 m\(^{2}\)). The composite endpoint (stroke, major bleeding, myocardial infarction, all‐cause death) was assessed after 24 months. We estimated hazard ratios in confounder‐adjusted models.
Results
Estimated glomerular filtration rate at baseline was available in 2947 and a second value in 1623 patients. After adjusting for age, stroke severity, cardiovascular risk factors, and randomization, eGFR < 60 ml/min/1.73 m\(^{2}\) at baseline (hazard ratio [HR] = 2.2, 95% confidence interval [CI] = 1.40–3.54) as well as decreasing (HR = 1.79, 95% CI = 1.07–2.99) and stable decreased eGFR (HR = 1.64, 95% CI = 1.20–2.24) were independently associated with the composite endpoint. In addition, eGFR < 60 ml/min/1.732 at baseline (HR = 3.02, 95% CI = 1.51–6.10) and decreasing eGFR were associated with all‐cause death (HR = 3.12, 95% CI = 1.63–5.98).
Conclusions
In addition to patients with low eGFR levels at baseline, also those with decreasing eGFR have increased risk for vascular events and death; hence, repeated estimates of eGFR might add relevant information to risk prediction.
Digital platforms, such as Amazon, represent the major beneficiaries of the Covid‐19 crisis. This study examines the role of digital platforms and their engagement in digitalisation initiatives targeting (small) brick‐and‐mortar retailers in Germany, thereby contributing to a better understanding of how digital platforms augment, substitute or reorganise physical retail spaces. This study applies a mixed‐method approach based on qualitative interviews, participant observation as well as media analysis. First, the study illustrates the controversial role of digital platforms by positioning themselves as supporting partners of the (offline) retailers, while simultaneously shifting power towards the platforms themselves. Second, digital platforms have established themselves not only as infrastructure providers but also as actors within these infrastructures, framing digital as well as physical retail spaces, inter alia due to their role as publicly legitimised retail advisers. Third, while institutions want to help retailers to survive, they simultaneously enhance retailers' dependency on digital platforms.
Although inclusion is the declared goal, the transition from a system based on special schools to an inclusive school system has only been progressing very slowly in individual countries. In an evolving school system, the existing special schools keep struggling to justify their existence. This study investigates the regional distribution effects based on official school data and shows the influence of a pull effect on special schools as a distance effect of special schools affecting the placement of students. For this purpose, official school statistics including all students at special and regular schools in the years 2010, 2015 and 2020 (N = 11 280 040) are evaluated in a spatiotemporal comparison using Educational Data Mining. In a hierarchical regression model on school placement in inclusive schools, the distance between primary and special schools has the highest influence (β = 0.48) on the inclusion rate (i.e., the proportion of students with special needs who are educated in regular schools in relation to all students with disabilities), along with the size (β = −0.14) and the density of special schools in a district (β = −0.12). The effects differ according to the population density of the region and are stronger in large cities. When the proportion of students with and without SEN in regular schools is considered (support rate), the density of special schools has the greatest impact on school placement (ß = 43.44). Self‐preservation of schools, traditional funding systems and regional differences between urban and rural areas are discussed as possible reasons.
Aims
To investigate Epstein‐Barr virus (EBV) latency types in 19 cases of EBV‐positive nodular lymphocyte‐predominant Hodgkin lymphoma (NLPHL), as such information is currently incomplete.
Methods and results
Immunohistochemistry (IHC) for CD20, CD79a, PAX5, OCT2, CD30, CD15, CD3 and programmed cell death protein 1 was performed. For EBV detection, in‐situ hybridisation (ISH) for EBV‐encoded RNA (EBER) was employed combined with IHC for EBV‐encoded latent membrane protein (LMP)‐1, EBV‐encoded nuclear antigen (EBNA)‐2, and EBV‐encoded BZLF1. In 95% of the cases, neoplastic cells with features of Hodgkin and Reed–Sternberg (HRS) cells were present, mostly showing expression of CD30. In all cases, the B‐cell phenotype was largely intact, and delineation from classic Hodgkin lymphoma (CHL) was further supported by myocyte enhancer factor 2B (MEF2B) detection. All tumour cells were EBER‐positive except in two cases. EBV latency type II was most frequent (89%) and type I was rare. Cases with latency type I were CD30‐negative. Five cases contained some BZLF1‐positive and/or EBNA‐2‐positive bystander lymphocytes.
Conclusions
As HRS morphology of neoplastic cells and CD30 expression are frequent features of EBV‐positive NLPHL, preservation of the B‐cell transcription programme, MEF2B expression combined with NLPHL‐typical architecture and background composition facilitate distinction from CHL. EBER ISH is the method of choice to identify these cases. The majority present with EBV latency type II, and only rare cases present with latency type I, which can be associated with missing CD30 expression. The presence of occasional bystander lymphocytes expressing BZLF1 and/or EBNA‐2 and the partial EBV infection of neoplastic cells in some cases could indicate that EBV is either not primarily involved or is only a transient driver in the pathogenesis of EBV‐positive NLPHL.
The extracellular matrix (ECM) of soft tissues in vivo has remarkable biological and structural properties. Thereby, the ECM provides mechanical stability while it still can be rearranged via cellular remodeling during tissue maturation or healing processes. However, modern synthetic alternatives fail to provide these key features among basic properties. Synthetic matrices are usually completely degraded or are inert regarding cellular remodeling. Based on a refined electrospinning process, a method is developed to generate synthetic scaffolds with highly porous fibrous structures and enhanced fiber‐to‐fiber distances. Since this approach allows for cell migration, matrix remodeling, and ECM synthesis, the scaffold provides an ideal platform for the generation of soft tissue equivalents. Using this matrix, an electrospun‐based multilayered skin equivalent composed of a stratified epidermis, a dermal compartment, and a subcutis is able to be generated without the use of animal matrix components. The extension of classical dense electrospun scaffolds with high porosities and motile fibers generates a fully synthetic and defined alternative to collagen‐gel‐based tissue models and is a promising system for the construction of tissue equivalents as in vitro models or in vivo implants.
Bone marrow lesions (BML) represent areas of deteriorated bone structure and metabolism characterized by pronounced water‐equivalent signaling within the trabecular bone on magnetic resonance imaging (MRI). BML are associated with repair mechanisms subsequent to various clinical conditions associated with inflammatory and non‐inflammatory injury to the bone. There is no approved treatment for this condition. Bisphosphonates are known to improve bone stability in osteoporosis and other bone disorders and have been used off‐label to treat BML. A randomized, triple‐blind, placebo‐controlled phase III trial was conducted to assess efficacy and safety of single‐dose zoledronic acid (ZOL) 5 mg iv with vitamin D 1000 IU/d as opposed to placebo with vitamin D 1000 IU/d in 48 patients (randomized 2:1) with BML. Primary efficacy endpoint was reduction of edema volume 6 weeks after treatment as assessed by MRI. After treatment, mean BML volume decreased by 64.53% (±41.92%) in patients receiving zoledronic acid and increased by 14.43% (±150.46%) in the placebo group (p = 0.007). A decrease in BML volume was observed in 76.5% of patients receiving ZOL and in 50% of the patients receiving placebo. Pain level (visual analogue scale [VAS]) and all categories of the pain disability index (PDI) improved with ZOL versus placebo after 6 weeks but reconciled after 6 additional weeks of follow‐up. Six serious adverse events occurred in 5 patients, none of which were classified as related to the study drug. No cases of osteonecrosis or fractures occurred. Therefore, single‐dose zoledronic acid 5 mg iv together with vitamin D may enhance resolution of bone marrow lesions over 6 weeks along with reduction of pain compared with vitamin D supplementation only.
A starlike heterocyclic molecule containing an electron‐deficient nonaaza‐core structure and three peripheral isoquinolines locked by three tetracoordinate borons, namely isoquinoline‐nona‐starazine (QNSA), is synthesized by using readily available reactants through a rather straightforward approach. This new heteroatom‐rich QNSA possesses a quasi‐planar π‐backbone structure, and bears phenyl substituents on borons which protrude on both sides of the π‐backbones endowing it with good solubility in common organic solvents. Contrasting to its starphene analogue, QNSA shows intense fluorescence with a quantum yield (PLQY) of up to 62 % in dilute solution.
Macrocyclic Donor‐Acceptor Dyads Composed of Oligothiophene Half‐Cycles and Perylene Bisimides
(2022)
A series of donor‐acceptor (D−A) macrocyclic dyads consisting of an electron‐poor perylene bisimide (PBI) π‐scaffold bridged with electron‐rich α‐oligothiophenes bearing four, five, six and seven thiophene units between the two phenyl‐imide substituents has been synthesized and characterized by steady‐state UV/Vis absorption and fluorescence spectroscopy, cyclic and differential pulse voltammetry as well as transient absorption spectroscopy. Tying the oligothiophene strands in a conformationally fixed macrocyclic arrangement leads to a more rigid π‐scaffold with vibronic fine structure in the respective absorption spectra. Electrochemical analysis disclosed charged state properties in solution which are strongly dependent on the degree of rigidification within the individual macrocycle. Investigation of the excited state dynamics revealed an oligothiophene bridge size‐dependent fast charge transfer process for the macrocyclic dyads upon PBI subunit excitation.
The composition and richness of herbivore and plant assemblages change along climatic gradients, but knowledge about associated shifts in specialization is scarce and lacks controlling for the abundance and phylogeny of interaction partners. Thus, we aimed to test whether the specialization of phytophagous insects in insect‐plant interaction networks decreases toward cold habitats as predicted by the ‘altitude niche‐breadth hypothesis’ to forecast possible consequences of interaction rewiring under climate change. We used a non‐invasive, standardized metabarcoding approach to reconstruct dietary relationships of Orthoptera species as a major insect herbivore taxon along a broad temperature gradient (~12°C) in Southern Germany. Based on Orthoptera surveys, feeding observations, collection of fecal pellets from >3,000 individuals of 54 species, and parallel vegetation surveys on 41 grassland sites, we quantified plant resource availability and its use by herbivores. Herbivore assemblages were richer in species and individuals at sites with high summer temperatures, while plant richness peaked at intermediate temperatures. Corresponding interaction networks were most specialized in warm habitats. Considering phylogenetic relationships of plant resources, however, the specialization pattern was not linear but peaked at intermediate temperatures, mediated by herbivores feeding on a narrow range of phylogenetically related resources. Our study provides empirical evidence of resource specialization of insect herbivores along a climatic gradient, demonstrating that resource phylogeny, availability, and temperature interactively shape the specialization of herbivore assemblages. Instead of low specialization levels only in cold, harsh habitats, our results suggest increased generalist feeding due to intraspecific changes and compositional differences at both ends of the microclimatic gradient. We conclude that this nonlinear change of phylogeny‐based resource specialization questions predictions derived from the ‘altitude‐niche breadth hypothesis’ and highlights the currently limited understanding of how plant‐herbivore interactions will change under future climatic conditions.
Drosophila’s lateral posterior neurons (LPNs) belong to a small group of circadian clock neurons that is so far not characterized in detail. Thanks to a new highly specific split‐Gal4 line, here we describe LPNs’ morphology in fine detail, their synaptic connections, daily bimodal expression of neuropeptides, and propose a putative role of this cluster in controlling daily activity and sleep patterns. We found that the three LPNs are heterogeneous. Two of the neurons with similar morphology arborize in the superior medial and lateral protocerebrum and most likely promote sleep. One unique, possibly wakefulness‐promoting, neuron with wider arborizations extends from the superior lateral protocerebrum toward the anterior optic tubercle. Both LPN types exhibit manifold connections with the other circadian clock neurons, especially with those that control the flies’ morning and evening activity (M‐ and E‐neurons, respectively). In addition, they form synaptic connections with neurons of the mushroom bodies, the fan‐shaped body, and with many additional still unidentified neurons. We found that both LPN types rhythmically express three neuropeptides, Allostatin A, Allostatin C, and Diuretic Hormone 31 with maxima in the morning and the evening. The three LPN neuropeptides may, furthermore, signal to the insect hormonal center in the pars intercerebralis and contribute to rhythmic modulation of metabolism, feeding, and reproduction. We discuss our findings in the light of anatomical details gained by the recently published hemibrain of a single female fly on the electron microscopic level and of previous functional studies concerning the LPN.
We present an exceptional case of recurrent cycling‐induced spontaneous pneumomediastinum and pneumopericardium in a female patient without any trauma. Radiological and endoscopic examinations were carried out to exclude other differential diagnoses. Decision for in‐hospital observation and conservative treatment was made. No symptoms were reported 12 months after return to sports activity.
Increasing global competition forces organizations to improve their processes to gain a competitive advantage. In the manufacturing sector, this is facilitated through tremendous digital transformation. Fundamental components in such digitalized environments are process-aware information systems that record the execution of business processes, assist in process automation, and unlock the potential to analyze processes. However, most enterprise information systems focus on informational aspects, process automation, or data collection but do not tap into predictive or prescriptive analytics to foster data-driven decision-making. Therefore, this dissertation is set out to investigate the design of analytics-enabled information systems in five independent parts, which step-wise introduce analytics capabilities and assess potential opportunities for process improvement in real-world scenarios.
To set up and extend analytics-enabled information systems, an essential prerequisite is identifying success factors, which we identify in the context of process mining as a descriptive analytics technique. We combine an established process mining framework and a success model to provide a structured approach for assessing success factors and identifying challenges, motivations, and perceived business value of process mining from employees across organizations as well as process mining experts and consultants. We extend the existing success model and provide lessons for business value generation through process mining based on the derived findings. To assist the realization of process mining enabled business value, we design an artifact for context-aware process mining. The artifact combines standard process logs with additional context information to assist the automated identification of process realization paths associated with specific context events. Yet, realizing business value is a challenging task, as transforming processes based on informational insights is time-consuming.
To overcome this, we showcase the development of a predictive process monitoring system for disruption handling in a production environment. The system leverages state-of-the-art machine learning algorithms for disruption type classification and duration prediction. It combines the algorithms with additional organizational data sources and a simple assignment procedure to assist the disruption handling process. The design of such a system and analytics models is a challenging task, which we address by engineering a five-phase method for predictive end-to-end enterprise process network monitoring leveraging multi-headed deep neural networks. The method facilitates the integration of heterogeneous data sources through dedicated neural network input heads, which are concatenated for a prediction. An evaluation based on a real-world use-case highlights the superior performance of the resulting multi-headed network.
Even the improved model performance provides no perfect results, and thus decisions about assigning agents to solve disruptions have to be made under uncertainty. Mathematical models can assist here, but due to complex real-world conditions, the number of potential scenarios massively increases and limits the solution of assignment models. To overcome this and tap into the potential of prescriptive process monitoring systems, we set out a data-driven approximate dynamic stochastic programming approach, which incorporates multiple uncertainties for an assignment decision. The resulting model has significant performance improvement and ultimately highlights the particular importance of analytics-enabled information systems for organizational process improvement.
Objective: Gait adaptation to environmental challenges is fundamental for independent and safe community ambulation. The possibility of precisely studying gait modulation using standardized protocols of gait analysis closely resembling everyday life scenarios is still an unmet need.
Methods: We have developed a fully-immersive virtual reality (VR) environment where subjects have to adjust their walking pattern to avoid collision with a virtual agent (VA) crossing their gait trajectory. We collected kinematic data of 12 healthy young subjects walking in real world (RW) and in the VR environment, both with (VR/A+) and without (VR/A-) the VA perturbation. The VR environment closely resembled the RW scenario of the gait laboratory. To ensure standardization of the obstacle presentation the starting time speed and trajectory of the VA were defined using the kinematics of the participant as detected online during each walking trial.
Results: We did not observe kinematic differences between walking in RW and VR/A-, suggesting that our VR environment per se might not induce significant changes in the locomotor pattern. When facing the VA all subjects consistently reduced stride length and velocity while increasing stride duration. Trunk inclination and mediolateral trajectory deviation also facilitated avoidance of the obstacle.
Conclusions: This proof-of-concept study shows that our VR/A+ paradigm effectively induced a timely gait modulation in a standardized immersive and realistic scenario. This protocol could be a powerful research tool to study gait modulation and its derangements in relation to aging and clinical conditions.
Macroautophagy (hereafter referred to as autophagy) is a homeostatic process that preserves cellular integrity. In mice, autophagy regulates pancreatic ductal adenocarcinoma (PDAC) development in a manner dependent on the status of the tumor suppressor gene Trp53. Studies published so far have investigated the impact of autophagy blockage in tumors arising from Trp53-hemizygous or -homozygous tissue. In contrast, in human PDACs the tumor suppressor gene TP53 is mutated rather than allelically lost, and TP53 mutants retain pathobiological functions that differ from complete allelic loss. In order to better represent the patient situation, we have investigated PDAC development in a well-characterized genetically engineered mouse model (GEMM) of PDAC with mutant Trp53 (Trp53\(^{R172H}\)) and deletion of the essential autophagy gene Atg7. Autophagy blockage reduced PDAC incidence but had no impact on survival time in the subset of animals that formed a tumor. In the absence of Atg7, non-tumor-bearing mice reached a similar age as animals with malignant disease. However, the architecture of autophagy-deficient, tumor-free pancreata was effaced, normal acinar tissue was largely replaced with low-grade pancreatic intraepithelial neoplasias (PanINs) and insulin expressing islet β-cells were reduced. Our data add further complexity to the interplay between Atg7 inhibition and Trp53 status in tumorigenesis.
Background
Dystrophinopathies caused by variants in the DMD gene are a well‐studied muscle disease. The most common type of variant in DMD are large deletions. Very rarely reported forms of variants are chromosomal translocations, inversions and deep intronic variants (DIVs) because they are not detectable by standard diagnostic techniques (sequencing of coding sequence, copy number variant detection). This might be the reason that some clinically and histologically proven dystrophinopathy cases remain unsolved.
Methods
We used whole genome sequencing (WGS) to screen the entire DMD gene for variants in one of two brothers suffering from typical muscular dystrophy with strongly elevated creatine kinase levels.
Results
Although a pathogenic DIV could not be detected, we were able to identify a pericentric inversion with breakpoints in DMD intron 44 and Xq13.3, which could be confirmed by Sanger sequencing in the index as well as in his brother and mother. As this variation affects a major part of DMD it is most likely disease causing.
Conclusion
Our findings elucidate that WGS is capable of detecting large structural rearrangements and might be suitable for the genetic diagnostics of dystrophinopathies in the future. In particular, inversions might be a more frequent cause for dystrophinopathies as anticipated and should be considered in genetically unsolved dystrophinopathy cases.
This paper intends to trace the introduction of an English-induced, COVID-related neologism, covidiota, into the Spanish language. The study is based on a corpus of tweets, starting in March 2020. It examines several specific features which mark the word as a new, unfamiliar item, such as different ways of graphical highlighting, for example. On the other hand, the paper aims to detect possible indicators of an integration of covidiota into the Spanish language use in the tweet corpus compiled for this case study.
Purpose
Glioma patients face a limited life expectancy and at the same time, they suffer from afflicting symptoms and undesired effects of tumor treatment. Apart from bone marrow suppression, standard chemotherapy with temozolomide causes nausea, emesis and loss of appetite. In this pilot study, we investigated how chemotherapy-induced nausea and vomiting (CINV) affects the patients' levels of depression and their quality of life.
Methods
In this prospective observational multicentre study (n = 87), nausea, emesis and loss of appetite were evaluated with an expanded MASCC questionnaire, covering 10 days during the first and the second cycle of chemotherapy. Quality of life was assessed with the EORTC QLQ-C30 and BN 20 questionnaire and levels of depression with the PHQ-9 inventory before and after the first and second cycle of chemotherapy.
Results
CINV affected a minor part of patients. If present, it reached its maximum at day 3 and decreased to baseline level not before day 8. Levels of depression increased significantly after the first cycle of chemotherapy, but decreased during the further course of treatment. Patients with higher levels of depression were more severely affected by CINV and showed a lower quality of life through all time-points.
Conclusion
We conclude that symptoms of depression should be perceived in advance and treated in order to avoid more severe side effects of tumor treatment. Additionally, in affected patients, delayed nausea was most prominent, pointing toward an activation of the NK1 receptor. We conclude that long acting antiemetics are necessary totreat temozolomide-induced nausea.
Presence is often considered the most important quale describing the subjective feeling of being in a computer-generated and/or computer-mediated virtual environment. The identification and separation of orthogonal presence components, i.e., the place illusion and the plausibility illusion, has been an accepted theoretical model describing Virtual Reality (VR) experiences for some time. This perspective article challenges this presence-oriented VR theory. First, we argue that a place illusion cannot be the major construct to describe the much wider scope of virtual, augmented, and mixed reality (VR, AR, MR: or XR for short). Second, we argue that there is no plausibility illusion but merely plausibility, and we derive the place illusion caused by the congruent and plausible generation of spatial cues and similarly for all the current model’s so-defined illusions. Finally, we propose congruence and plausibility to become the central essential conditions in a novel theoretical model describing XR experiences and effects.
Distributed practice is a well-known learning strategy whose beneficial effects on long-term learning are well proven by various experiments. In learning from texts, the benefits of distribution might even go beyond distributed practice, i.e. distribution of repeated materials. In realistic learning scenarios as for example school or university learning, the reader might read multiple texts that not repeat but complement each other. Therefore, distribution might also be implemented between multiple texts and benefit long-term learning in analogy to distributed practice. The assumption of beneficial effects of this distributed learning can be deduced from theories about text comprehension as the landscape model of reading (van den Broek et al., 1996) in combination with theories of desirable difficulties in general (R. A. Bjork & Bjork, 1992) and distributed practice in particular (Benjamin & Tullis, 2010). This dissertation aims to investigate (1) whether distributed learning benefits learning; (2) whether the amount of domain-specific prior knowledge moderates the effects of distribution, (3) whether distributed learning affects the learner’s meta-cognitive judgments in analogy to distributed practice and (4) whether distributed practice is beneficial for seventh graders in learning from single text.
In Experiment 1, seventh graders read two complementary texts either massed or distributed by a lag of one week between the texts. Learning outcomes were measured immediately after reading the second text and one week later. Judgements of learning were assessed immediately after each text. Experiment 2 replicated the paradigm of Experiment 1 while shortening the lag between the texts in the distributed condition to 15 min. In both experiments, an interaction effect between learning condition (distributed vs. massed) and retention interval (immediate vs. delayed) was found. In the distributed condition, the participants showed no decrease in performance between the two tests, whereas participants in the massed condition did. However, no beneficial effects were found in the delayed test for the distributed condition but even detrimental effects for the distributed condition in the immediate test. In Experiment 1, participants in the distributed condition perceived learning as less difficult but predicted lower success than the participants in the massed condition.
Experiment 3 replicated the paradigm of Experiment 1 with university students in the laboratory. In the preregistered Experiment 4, an additional retention interval of two weeks was realized. In both experiments, the same interaction between learning condition and retention interval was found. In Experiment 3, the participants in the distributed condition again showed no decrease in performance between the two tests, whereas participants in the massed condition did. However, even at the longer retention interval in Experiment 4, no beneficial effects were found for the distributed condition. Domain-specific prior knowledge was positively associated with test performance in both experiments. In Experiment 4, the participants with low prior knowledge seemed to be impaired by distributed learning, whereas no difference was found for participants with medium or high prior knowledge.
In the preregistered Experiment 5, seventh graders read a single text twice. The rereading took place either massed or distributed with one week. Immediately after rereading, judgements of learning were assessed. Learning outcomes were assessed four min after second reading or one week later. Participants in the distributed condition predicted lower learning success than participants in the massed condition. An interaction effect between learning condition and retention interval was found, but no advantage for the distributed condition. Participants with low domain-specific prior knowledge showed lower performance in short-answer questions in the distributed condition than in the massed condition.
Overall, the results seem less encouraging regarding the effectiveness of distribution on learning from single and multiple texts. However, the experiments reported here can be perceived as first step in the realistic investigation of distribution in learning from texts.
Protein-DNA interactions are central to many biological processes and form the bedrock of gene transcription, DNA replication, and DNA repair processes. Many proteins recognize specific sequences in DNA- a restriction enzyme must only cut at the correct sequence and a transcription factor should bind at its consensus sequence. Some proteins are designed to bind to specific structural or chemical features in DNA, such as DNA repair proteins and some DNA modifying enzymes. Target-specific DNA binding proteins initially bind to non-specific DNA and then search for their target sites through different types of diffusion mechanisms. Atomic force microscopy (AFM) is a single-molecule technique that is specifically well-suited to resolve the distinct states of target-specific as well as nonspecific protein-DNA interactions that are vital for a deeper insight into the target site search mechanisms of these enzymes. In this thesis, protein systems involved in epigenetic regulation, base excision repair (BER), and transcription are investigated by single-molecule AFM analyses complemented by biochemical and biophysical experiments.
The first chapter of this thesis narrates the establishment of a novel, user-unbiased MatLab-based tool for automated DNA bend angle measurements on AFM data. This tool has then been employed to study the initial lesion detection step of several DNA glycosylases. These results promoted a model describing the altered plasticities of DNA at the target lesions of DNA glycosylases as the fundamental mechanism for their enhanced efficiency of lesion detection.
In the second chapter of this thesis, the novel automated tool has been further extended to provide protein binding positions on the DNA along with corresponding DNA bend angles and applied to the study of DNMT3A DNA methyltransferase. These AFM studies revealed preferential co-methylation at specific, defined distances between two CpG sites by the enzyme and when combined with biochemical analyses and structural modelling supported novel modes of CpG co-methylation by DNMT3A.
In the third chapter of this thesis, the role of 8-oxo-guanine glycosylase (hOGG1) in Myc-mediated transcription initiation has been investigated. AFM analyses revealed that in the presence of oxidative damage in DNA, Myc is recruited to its target site (E-box) by hOGG1 through direct protein-protein interactions, specifically under oxidizing conditions. Intriguingly, oxidation of hOGG1 was further observed to result in dimerization of hOGG1, which may also play a role in the mechanism of transcription regulation by hOGG1 under oxidative stress.
Detecting anomalies in transaction data is an important task with a high potential to avoid financial loss due to irregularities deliberately or inadvertently carried out, such as credit card fraud, occupational fraud in companies or ordering and accounting errors. With ongoing digitization of our world, data-driven approaches, including machine learning, can draw benefit from data with less manual effort and feature engineering. A large variety of machine learning-based anomaly detection methods approach this by learning a precise model of normality from which anomalies can be distinguished. Modeling normality in transactional data, however, requires to capture distributions and dependencies within the data precisely with special attention to numerical dependencies such as quantities, prices or amounts.
To implicitly model numerical dependencies, Neural Arithmetic Logic Units have been proposed as neural architecture. In practice, however, these have stability and precision issues.
Therefore, we first develop an improved neural network architecture, iNALU, which is designed to better model numerical dependencies as found in transaction data. We compare this architecture to the previous approach and show in several experiments of varying complexity that our novel architecture provides better precision and stability.
We integrate this architecture into two generative neural network models adapted for transaction data and investigate how well normal behavior is modeled. We show that both architectures can successfully model normal transaction data, with our neural architecture improving generative performance for one model.
Since categorical and numerical variables are common in transaction data, but many machine learning methods only process numerical representations, we explore different representation learning techniques to transform categorical transaction data into dense numerical vectors. We extend this approach by proposing an outlier-aware discretization, thus incorporating numerical attributes into the computation of categorical embeddings, and investigate latent spaces, as well as quantitative performance for anomaly detection.
Next, we evaluate different scenarios for anomaly detection on transaction data. We extend our iNALU architecture to a neural layer that can model both numerical and non-numerical dependencies and evaluate it in a supervised and one-class setting. We investigate the stability and generalizability of our approach and show that it outperforms a variety of models in the balanced supervised setting and performs comparably in the one-class setting. Finally, we evaluate three approaches to using a generative model as an anomaly detector and compare the anomaly detection performance.
Although the field of fungal infections advanced tremendously, diagnosis of invasive pulmonary aspergillosis (IPA) in immunocompromised patients continues to be a challenge. Since IPA is a multifactorial disease, investigation from different aspects may provide new insights, helpful for improving IPA diagnosis. This work aimed to characterize the human immune response to Aspergillus fumigatus in a multilevel manner to identify characteristic molecular candidates and risk factors indicating IPA, which may in the future support already established diagnostic assays. We combined in vitro studies using myeloid cells infected with A. fumigatus and longitudinal case-control studies investigating patients post allogeneic stem cell transplantation (alloSCT) suffering from IPA and their match controls.
Characteristic miRNA and mRNA signatures indicating A. fumigatus-infected monocyte-derived dendritic cells (moDCs) demonstrated the potential to differentiate between A. fumigatus and Escherichia coli infection. Transcriptome and protein profiling of alloSCT patients suffering from IPA and their matched controls revealed a distinctive IPA signature consisting of MMP1 induction and LGAL2 repression in combination with elevated IL-8 and caspase-3 levels. Both, in vitro and case-control studies, suggested cytokines, matrix-metallopeptidases and galectins are important in the immune response to A. fumigatus. Identified IPA characteristic molecular candidates are involved in numerous processes, thus a combination of these in a distinctive signature may increase the specificity. Finally, low monocyte counts, severe GvHD of the gut (grade ≥ 2) and etanercept administration were significantly associated with IPA diagnosis post alloSCT. Etanercept in monocyte-derived macrophages (MDM) infected with A. fumigatus downregulates genes involved in the NF-κB and TNF-α pathway and affects the secretion of CXCL10.
Taken together, identified characteristic molecular signatures and risk factors indicating IPA may in the future in combination with established fungal biomarkers overcome current diagnostic challenges and help to establish tailored antifungal therapy. Therefore, further multicentre studies are encouraged to evaluate reported findings.
Abstract
Purpose: To compare ab interno trabeculectomy by trabecular meshwork excision to plasma-mediated ablation in primary open-angle glaucoma.
Methods: Retrospectively collected data of TrabEx+ (n=56) and Trabectome (n=99) were compared by coarsened exact matching to reduce confounding and matched based on baseline intraocular pressure and age. Primary outcomes were intraocular pressure and the number of glaucoma medications. Complications and the need for additional glaucoma surgery were assessed. Patients were followed for up to one year.
Results: 53 TrabEx+ could be matched to Trabectome. Baseline intraocular pressure was 16.5 ± 4.6 mmHg in both; age was 73.7 ± 8.8 years and 71.5 ± 9.9 years in TrabEx+ and Trabectome, respectively. TrabEx+ were taking more medications than Trabectome (p<0.001). Intraocular pressure was reduced to 14.8±4.3 in TrabEx+ and 13.4±3.4 in Trabectome at 6 months, and to 14.9±6.0 (p=0.13) in TrabEx+ and to 14.1±3.8 mmHg (all p<0.05) in Trabectome at 12 months. Medications were reduced at both 6 and 12 months (p< 0.05). No differences were seen between both groups at 6 and 12 months. In TrabEx+, only one serious complication occurred, and two patients required further glaucoma surgery.
Conclusion: Although both groups had a baseline intraocular pressure considered low for ab interno trabeculectomy, intraocular pressure and medications were reduced further at 6 and 12 months. Intraocular pressure reduction did not reach significance in TrabEx+ at 12 months. The inter-group comparison did not reveal any significant differences. Both had a low complication rate.
Microbial, mammalian and plant cells produce and contain secondary metabolites, which typically are soluble in water to prevent cell damage by crystallization. The formation of ion pairs, e.g. with carboxylic acids or mineral acids, is a natural blueprint to keep basic metabolites in solution. It was aimed at showing whether the mostly large carboxylates form soluble protic ionic liquids (PILs) with basic natural products resulting in enhanced aqueous solubility. Furthermore, their supramolecular pattern in aqueous solution was studied. Thereby, naturally occurring carboxylic acids were identified being appropriate counterions for natural basic compounds and facilitate the formation of PILs with their beneficial characteristics, like improved dissolution rate and enhanced apparent solubility.
In the field of biofabrication, biopolymer-based hydrogels are often used as bulk materials with defined structures or as bioinks. Despite their excellent biocompatibility, biopolymers need chemical modification to fulfill mechanical stability.
In this thesis, the primary alcohol of hyaluronic acid was oxidized using TEMPO/TCC oxidation to generate aldehyde groups without ring-opening mechanism of glycol cleavage using sodium periodate. For crosslinking reaction of the aldehyde groups, adipic acid dihydrazide was used as bivalent crosslinker for Schiff Base chemistry. This hydrogel system with fast and reversible crosslinking mechanism was used successfully as bulk hydrogel for chondrogenic differentiation with human mesenchymal stem cells (hMSC).
Gelatin was modified with pentenoic acid for crosslinking reaction via light controllable thiol-ene reaction, using thiolated 4-arm sPEG as multivalent crosslinker. Due to preservation of the thermo responsive property of gelatin by avoiding chain degradation during modification reaction, this gelatin-based hydrogel system was successfully processed via 3D printing with low polymer concentration. Good cell viability was achieved using hMSC in various concentrations after 3D bioprinting and chondrogenic differentiation showed promising results.
Context. In active galaxies, matter is accreted onto super massive black holes (SMBH). This accretion process causes a region roughly the size of our solar system to outshine the entire host galaxy, forming an active galactic nucleus (AGN). In some of these active galaxies, highly relativistic particle jets are formed parallel to the rotation axis of the super massive black hole. A fraction of these sources is observed under a small inclination angle between the pointing direction of the jet and the observing line of sight. These sources are called blazars. Due to the small inclination angle and the highly relativistic speeds of the particles in the jet, beaming effects occur in the radiation of these particles. Blazars can be subdivided into the high luminosity flat spectrum radio quasars (FSRQs) and the low luminosity BL Lacertae objects (BL Lacs). As all AGN, blazars are broadband emitters and therefore observable from the longest wavelengths in the radio regime to the shortest wavelengths in the gamma-ray regime. In this thesis I will analyze blazars at these two extremes with respect to their parsec-scale properties in the radio and their time evolution properties in gamma-ray flux.
Method. In the radio regime the technique of very long baseline interferometry (VLBI) can be used in order to spatially resolve the synchrotron radiation coming from those objects down to sub-parsec scales. This information can be used to observe the time evolution of the structure of such sources. This is done in large monitoring programs such as the MOJAVE (15 GHz) and the Boston University blazar monitoring program (43 GHz). In this thesis I utilize data of 28 sources from these monitoring programs spanning 10 years of observation from 2003 to 2013, resulting in over 1800 observed epochs, to study the brightness temperature and diameter gradients of these jets. I conduct a search for systematic geometry transitions in the radio jets. The synchrotron cooling time in the radio core of the jets is used to determine the magnetic field strength in the radio core. Considering the jet geometry, these magnetic field strengths are scaled to the ergosphere of the SMBH in order to obtain the distance of the radio core to the SMBH.
In the gamma-regime these blazars cannot be spatially resolved. Due to this, it is hard to put strong constrains onto where the gamma-ray emitting region is. Blazars have shown to be variable at high energies on time scales down to minutes. The nature of this variability can be studied in order to put constrains on the particle acceleration mechanism and possibly the region and size of the gamma-ray emitting region. The variability of blazars in the energy range between 0.1 GeV and 1 GeV can for example be observed with the pair-conversion telescope on board the Fermi satellite. I use 10 years of data from the Fermi-LAT (LAT: Large Area Telescope) satellite in order to study the variability of a large sample of blazars (300-800, depending on the used significance filters for data points). I quantify this variability with the Ornstein-Uhlenbeck (OU) parameters and the power spectral density (PSD) slopes. The same procedure is applied to 20 light curves available for the radio sample.
Results. The diameter evolution along the jet axis of the radio sources suggests, that FSRQs feature flatter gradients than BL Lacs. Fitting these gradients, it is revealed that BL Lacs are systematically better described by a simple single power law than FSRQs. I found 9 sources with a strongly constrained geometry transition. The sources are 0219+421, 0336-019, 0415+379, 0528+134, 0836+710, 1101+384, 1156+295, 1253-055 and 2200+420. In all of these sources, the geometry transition regions are further out in the jet than the Bondi sphere. The magnetic field strengths of BL Lacs is systematically larger than that of FSRQs. However the scaling of these fields suggest that the radio cores of BL Lac objects are closer to the SMBHs than the radio cores of FSRQs. Analyzing the variability of Fermi-LAT light curves yields consistent results for all samples. FSRQs show systematically steeper PSD slopes and feature OU parameters more favorable to strong variability than BL Lacs. The Fermi-LAT light curves of the sub-sample of radio jets, suggest an anticorrelation between the jet complexity from the radio observations and the OU-parameters as well as the PSD slopes from the gamma-ray observations.
Conclusion.
The flatter diameter gradients of FSRQs suggest that these sources are more collimated further down the jet than BL Lacs. The systematically better description of the diameter and brightness temperature gradient by a single power law of BL Lacs, suggest that FSRQs are more complex with respect to the diameter evolution along the jet and the surface brightness distribution than BL Lac objects. FSRQs often feature regions where recollimation can occur in distinct knots within the jets. For the sources where a geometry transition could be constrained, the Bondi radius, being systematically smaller than the position of the transition region along the jet axis, suggest that changing pressure gradients are not the sole cause for these systematic geometry transitions. Nevertheless they may be responsible for recollimation regions, found typically downstream the jet, beyond the Bondi radius and the transition zone. The difference in the distance of the radio cores between FSRQs and BL Lacs is most likely due to the combination of differences in SMBH masses and systematically smaller jet powers in BL Lacs. The variability in energy ranges above 100 MeV and above 1 GeV-regime suggest that many light curves of BL Lac objects are more likely to be white noise while the PSD slopes and the OU parameters of FSRQ gamma-ray light curves favor stronger variability on larger time scales with respect to the time binning of the analyzed light curve. Although the anticorrelation of the jet complexity acquired from the radio observations and the PSD slopes and OU parameters from the gamma-observations suggest that more complex sources favor OU parameters and PSD slopes resulting in more variability (not white noise) it is beyond the scope of this thesis to pinpoint whether this correlation results from causation. The question whether a complex jet causes more gamma-ray variability or more gamma-ray variability causes more complex jets cannot be answered at this point. Nevertheless the computed correlation measures suggest that this dependence is most likely not linear and therefore an indication that these effects might even interact.
Parkinson’s Disease (PD) constitutes a major healthcare burden in Europe. Accounting for aging alone, ~700,000 PD cases are predicted by 2040. This represents an approximately 56% increase in the PD population between 2005 and 2040, with a consequent rise in annual disease‐related medical costs. Gait and balance disorders are a major problem for patients with PD and their caregivers, mainly because to their correlation with falls. Falls occur as a result of a complex interaction of risk factors. Among them, Freezing of Gait (FoG) is a peculiar gait derangement characterized by a sudden and episodic inability to produce effective stepping, causing falls, mobility restrictions, poor quality of life, and increased morbidity and mortality. Between 50–70% of PD patients have FoG and/or falls after a disease duration of 10 years, only partially and inconsistently improved by dopaminergic treatment and Deep Brain Stimulation (DBS). Treatment-induced worsening has been also observed under certain conditions. Effective treatments for gait disturbances in PD are lacking, probably because of the still poor understanding of the supraspinal locomotor network.
In my thesis, I wanted to expand our knowledge of the supraspinal locomotor network and in particular the contribution of the basal ganglia to the control of locomotion. I believe this is a key step towards new preventive and personalized therapies for postural and gait problems in patients with PD and related disorders. In addition to patients with PD, my studies also included people affected by Progressive Supranuclear Palsy (PSP). PSP is a rare primary progressive parkinsonism characterized at a very early disease stage by poor balance control and frequent backwards falls, thus providing an in vivo model of dysfunctional locomotor control.
I focused my attention on one of the most common motor transitions in daily living, the initiation of gait (GI). GI is an interesting motor task and a relevant paradigm to address balance and gait impairments in patients with movement disorders, as it is associated with FoG and high risk of falls. It combines a preparatory (i.e., the Anticipatory Postural Adjustments [APA]) and execution phase (the stepping) and allows the study of movement scaling and timing as an expression of muscular synergies, which follow precise and online feedback information processing and integration into established feedforward patterns of motor control.
By applying a multimodal approach that combines biomechanical assessments and neuroimaging investigations, my work unveiled the fundamental contribution of striatal dopamine to GI in patients with PD. Results in patients with PSP further supported the fundamental role of the striatum in GI execution, revealing correlations between the metabolic intake of the left caudate nucleus with diverse GI measurements. This study also unveiled the interplay of additional brain areas in the motor control of GI, namely the Thalamus, the Supplementary Motor Area (SMA), and the Cingulate cortex. Involvement of cortical areas was also suggested by the analysis of GI in patients with PD and FoG. Indeed, I found major alterations in the preparatory phase of GI in these patients, possibly resulting from FoG-related deficits of the SMA. Alterations of the weight shifting preceding the stepping phase were also particularly important in PD patients with FoG, thus suggesting specific difficulties in the integration of somatosensory information at a cortical level. Of note, all patients with PD showed preserved movement timing of GI, possibly suggesting preserved and compensatory activity of the cerebellum. Postural abnormalities (i.e., increased trunk and thigh flexion) showed no relationship with GI, ruling out an adaptation of the motor pattern to the altered postural condition. In a group of PD patients implanted with DBS, I further explored the pathophysiological functioning of the locomotor network by analysing the timely activity of the Subthalamic Nucleus (STN) during static and dynamic balance control (i.e., standing and walking). For this study, I used novel DBS devices capable of delivering stimulation and simultaneously recording Local Field Potentials (LFP) of the implanted nucleus months and years after surgery. I showed a gait-related frequency shift in the STN activity of PD patients, possibly conveying cortical (feedforward) and cerebellar (feedback) information to mesencephalic locomotor areas. Based on this result, I identified for each patient a Maximally Informative Frequency (MIF) whose power changes can reliably classify standing and walking conditions. The MIF is a promising input signal for new DBS devices that can monitor LFP power modulations to timely adjust the stimulation delivery based on the ongoing motor task (e.g., gait) performed by the patient (adaptive DBS).
Altogether my achievements allowed to define the role of different cortical and subcortical brain areas in locomotor control, paving the way for a better understanding of the pathophysiological dynamics of the supraspinal locomotor network and the development of tailored therapies for gait disturbances and falls prevention in PD and related disorders.
Clostridioides difficile is a bacterial species well known for its ability to cause C. difficile
infection (also known as CDI). The investigation of the role of this species in the human
gut has been so far dominated by a disease-centred perspective, focused on studying
C. difficile in relation to its associated disease.
In this context, the first aim of this thesis was to combine publicly available
metagenomic data to analyse the microbial composition of stool samples from patients
diagnosed with CDI, with a particular focus on identifying a CDI-specific microbial
signature.
However, similarly to many other bacterial species inhabiting the human gut, C.
difficile association with disease is not valid in absolute terms, as C. difficile can be
found also among healthy subjects. Further aims of this thesis were to 1) identify
potential C. difficile reservoirs by screening a wide range of habitats, hosts, body sites
and age groups, and characterize the biotic context associated with C. difficile
presence, and 2) investigate C. difficile within-species diversity and its toxigenic
potential across different age groups.
The first part of the thesis starts with the description of the concepts and
definitions used to identify bacterial species and within-species diversity, and then
proceeds to provide an overview of the bacterial species at the centre of my
investigation, C. difficile. The first Chapter includes a detailed description of the
discovery, biology and physiology of this clinically relevant species, followed by an
overview of the diagnostic protocols used in the clinical setting to diagnose CDI.
The second part of the thesis describes the methodology used to investigate
the questions mentioned above, while the third part presents the results of such
investigative effort. I first show that C. difficile could be found in only a fraction of the
CDI samples and that simultaneous colonization of multiple enteropathogenic species
able to cause CDI-like clinical manifestations is more common than previously
thought, raising concerns about CDI overdiagnosis. I then show that the CDIassociated
gut microbiome is characterized by a specific microbial signature,
distinguishable from the community composition associated with non-CDI diarrhea.
Beyond the nosocomial and CDI context, I show that while rarely found in adults, C.
difficile is a common member of the infant gut microbiome, where its presence is
associated with multiple indicators typical of a desirable healthy microbiome
development.
In addition, I describe C. difficile extensive carriage among asymptomatic
subjects, of all age groups and a potentially novel clade of C. difficile identified
exclusively among infants.
Finally, I discuss the limitations, challenges and future perspectives of my
investigation.
The immune system has the function to defend organisms against a variety of pathogens
and malignancies. To perform this task, different parts of the immune system work in concert and
influence each other to balance and optimize its functional output upon activation. One aspect that
determines this output and ultimately the outcome of the infection is the tissue context in which the
activation takes place. As such, it has been shown that dendritic cells can relay information from
the infection sites to draining lymph nodes. This way, the ensuing adaptive immune response that
is initiated by dendritic cells, is optimized to the tissue context in which the infection needs to be
cleared.
Here, we set out to investigate whether unconventional T cells (UTC) could have a similar
function in directing a site-specific immune response. Using flow cytometry, scRNA-sequencing
and functional assays we demonstrated that UTC indeed drive a characteristic immune response
in lymph nodes depending on the drained tissues. This function of UTC was directly connected to
their lymphatic migration from tissues to draining lymph nodes reminiscent of dendritic cells.
Besides these tissue-derived UTC that migrated via the lymph, we further identified circulatory UTC
that migrated between lymph nodes via the blood. Functional characterization of UTC following
bacterial infection in wt and single TCR-based lineage deficient mice that lacked subgroups of UTC
further revealed that both tissue-derived and circulatory UTC were organized in functional units
independent of their TCR-based lineage-affiliation (MAIT, NKT, gd T cells). Specific reporter mouse
models revealed that UTC within the same functional unit were also located in the same
microanatomical areas of lymph nodes, further supporting their shared function. Our data show that
the numbers and function of UTC were compensated in single TCR-based lineage deficient mice
that lacked subgroups of UTC.
Taken together, our results characterize the transcriptional landscape and migrational
behavior of UTC in different lymph nodes. UTC contribute to a functional heterogeneity of lymph
nodes, which in turn guides optimized, site-specific immune responses. Additionally, we propose
the classification of UTC within functional units independent of their TCR-based lineage. These
results add significantly to our understanding of UTC biology and have direct clinical implications.
We hope that our data will guide targeted vaccination approaches and cell-based therapies to
optimize immune responses against pathogens and cancer.
Bile solubilization plays a major role in the absorption of poorly water-soluble drugs. Excipients used in oral drug formulations impact bile-colloidal properties and their molecular interactions. Polymer-induced changes of bile colloids, e.g., by Eudragit E, reduced the flux of the bile interacting drug Perphenazine whereas bile non-interacting Metoprolol was not impacted. This study corroborates these in vitro findings in rats. Eudragit E significantly reduced systemic availability of Perphenazine but not Metoprolol compared to the oral administrations without polymer. This study confirms the necessity to carefully select polymers for bile interacting drugs whereas non-bile interacting drugs are more robust in terms of excipient choice for formulation. The perspective of bile interaction may introduce interesting biopharmaceutical leverage for better performing oral formulations of tomorrow.
Salience bias and overwork
(2022)
In this study, we enrich a standard principal–agent model with hidden action by introducing salience-biased perception on the agent's side. The agent's misguided focus on salient payoffs, which leads the agent's and the principal's probability assessments to diverge, has two effects: First, the agent focuses too much on obtaining a bonus, which facilitates incentive provision. Second, the principal may exploit the diverging probability assessments to relax participation. We show that salience bias can reverse the nature of the inefficiency arising from moral hazard; i.e., the principal does not necessarily provide insufficient incentives that result in inefficiently low effort but instead may well provide excessive incentives that result in inefficiently high effort.
Interleukin 2 (IL-2) was the first cytokine applied for cancer treatment in human history. It has been approved as monotherapy for renal cell carcinoma and melanoma by the FDA and does mediate the regression of the tumors in patients. One of the possible mechanisms is that the administration of IL-2 led to T lymphocytes expansion, including CD4+ and CD8+ T cells. In addition, a recent study demonstrated that antigen-specific T cells could also be expanded through the induction of IL-2, which plays a crucial role in mediating tumor regression. However, despite the long-term and extensive use of IL-2 in the clinic, the ratio of patients who get a complete response was still low, and only about one-fifth of patients showed objective tumor regression. Therefore, the function of IL-2 in cancer treatment should continue to be optimized and investigated. A study by Franz O. Smith et al. has shown that the combination treatment of IL-2 and tumor-associated antigen vaccine has a strong trend to increased objective responses compared to patients with melanoma receiving IL-2 alone. Peptide vaccines are anti-cancer vaccines able to induce a powerful tumor antigenspecific immune response capable of eradicating the tumors. According to the type of antigens, peptide vaccines can be classified into two distinct categories: Tumor-associated antigens (TAA) vaccine and tumor-specific neoantigens (TSA) vaccine. Currently, Peptide vaccines are mainly investigated in phase I and phase II clinical trials of human cancer patients with various advanced cancers such as lung cancer, gastrointestinal tumors, and breast cancers. Vaccinia virus (VACV) is one of the safest viral vectors, which has been wildly used in cancer treatment and pathogen prevention. As an oncolytic vector, VACV can carry multiple large foreign genes, which enable the virus to introduce diagnostic and therapeutic agents without dramatically reducing the viral replication. Meanwhile, the recombinant vaccinia virus (rVACV) can be easily generated by homologous recombination. Here, we used the vaccinia virus as the therapeutic cancer vector, expressing mouse Interleukin 2 (IL-2) and tumor-associated antigens simultaneously to investigate the combined effect of anti-tumor immune response in the 4T1 mouse tumor model. As expected, the VACV driven mIL-2 expression remarkably increased both CD4+ and CD8+ populations in vivo, and the virus-expressed tumor-associated peptides successfully elicited theantigen-specific T cell response to inhibit the growth of tumors. Furthermore, the experiments with tumor-bearing animals showed that the mIL-2 plus tumor antigens expressing VACV vector gave a better anti-cancer response than the mIL-2 alone expressing vector. The combinations did significantly more inhibit tumor growth than mIL-2 treatment alone. Moreover, the results confirmed our previous unpublished data that the mIL-2 expression driven by synthetic early/late promoter in the Lister strain VACV could enhance the tumor regression in the 4T1 mouse model.
Cadherin-13 (CDH13) is a member of the cadherin superfamily that lacks the typical transmembrane domain for classical cadherins and is instead attached to the cell membrane with a GPI-anchor. Over the years, numerous genome-wide association (GWA) studies have identified CDH13 as a risk factor for neurodevelopmental disorders, including attention- deficit/hyperactivity disorder (ADHD) and autism spectrum disorder. Further evidence using cultured cells and animal models has shown that CDH13 plays important roles in cell migration, neurite outgrowth and synaptic function of the central nervous system. Research in our laboratory demonstrated that the CDH13 deficiency resulted in increased cell density of serotonergic neurons of the dorsal raphe (DR) in developing and mature mouse brains as well as serotonergic hyperinnervation in the developing prefrontal cortex, one of the target areas of DR serotonergic neurons. In this study, the role of CDH13 was further explored using constitutive and serotonergic system-specific CDH13-deficient mouse models. Within the adult DR structure, the increased density of DR serotonergic neurons was found to be topographically restricted to the ventral and lateral-wing, but not dorsal, clusters of DR. Furthermore, serotonergic hyperinnervation was observed in the target region of DR serotonergic projection neurons in the lateral wings. Unexpectedly, these alterations were not observed in postnatal day 14 brains of CDH13-deficient mice. Additionally, behavioral assessments revealed cognitive deficits in terms of compromised learning and memory ability as well as impulsive-like behaviors in CDH13-deficient mice, indicating that the absence of CDH13 in the serotonergic system alone was sufficient to impact cognitive functions and behavioral competency. Lastly, in order to examine the organization of serotonergic circuitries systematically and to tackle limitations of conventional immunofluorescence, a pipeline of the whole-mount immunostaining in combination with the iDISCO+ based rapid tissue clearing techniques was established. This will facilitate future research of brain neurotransmitter systems at circuitry and/or whole-brain levels and provide an excellent alternative for visualizing detailed and comprehensive information about a biological system in its original space. In summary, this study provided new evidence of CDH13’s contribution to proper brain development and cognitive function in mice, thereby offering insights into further advancement of therapeutic approaches for neurodevelopmental disorders.
The synaptic cleft is of central importance for synaptic transmission, neuronal plasticity and memory and thus well studied in neurobiology. To target proteins of interest with high specificity and strong signal to noise conventional immunohistochemistry relies on the use of fluorescently labeled antibodies. However, investigations on synaptic receptors remain challenging due to the defined size of the synaptic cleft of ~20 nm between opposing pre- and postsynaptic membranes. At this limited space, antibodies bear unwanted side effects such as crosslinking, accessibility issues and a considerable linkage error between fluorophore and target of ~10 nm. With recent single molecule localization microscopy (SMLM) methods enabling localization precisions of a few nanometers, the demand for labeling approaches with minimal linkage error and reliable recognition of the target molecules rises.
Within the scope of this work, different labeling techniques for super-resolution fluorescence microscopy were utilized allowing site-specific labeling of a single amino acid in synaptic proteins like kainate receptors (KARs), transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor regulatory proteins (TARPs), γ-aminobutyric acid type A receptors (GABA-ARs) and neuroligin 2 (NL2). The method exploits the incorporation of unnatural amino acids (uAAs) in the protein of interest using genetic code expansion (GCE) via amber suppression technology and subsequent labeling with tetrazine functionalized fluorophores. Implementing this technique, hard-to-target proteins such as KARs, TARPs and GABA-ARs could be labeled successfully, which could only be imaged insufficiently with conventional labeling approaches. Furthermore, functional studies involving electrophysiological characterization, as well as FRAP and FRET experiments validated that incorporation of uAAs maintains the native character of the targeted proteins. Next, the method was transferred into primary hippocampal neurons and in combination with super-resolution microscopy it was possible to resolve the nanoscale organization of γ2 and γ8 TARPs. Cluster analysis of dSTORM localization data verified synaptic accumulation of γ2, while γ8 was homogenously distributed along the neuron. Additionally, GCE and bioorthogonal labeling allowed visualization of clickable GABA-A receptors located at postsynaptic compartments in dissociated hippocampal neurons. Moreover, saturation experiments and FRET imaging of clickable multimeric receptors revealed successful binding of multiple tetrazine functionalized fluorophores to uAA-modified dimeric GABA-AR α2 subunits in close proximity (~5 nm). Further utilization of tetrazine-dyes via super-resolution microscopy methods such as dSTORM and click-ExM will provide insights to subunit arrangement in receptors in the future.
This work investigated the nanoscale organization of synaptic proteins with minimal linkage error enabling new insights into receptor assembly, trafficking and recycling, as well as protein-protein interactions at synapses. Ultimately, bioorthogonal labeling can help to understand pathologies such as the limbic encephalitis associated with GABA-AR autoantibodies and is already in application for cancer therapies.
Fabry Disease (FD) is a genetic lysosomal storage disorder based on mutations in the gene encoding α-Galactosidase A (α-GalA) leading to accumulation of globotriaosylceramide (Gb3). Missense mutations induce an amino acid exchange (AAE) in the α-GalA. Pain is a predominant symptom in FD and the pathophysiology is unclear. Skin punch biopsies were obtained from 40 adult FD patients and ten healthy controls and dermal fibroblast cultures were generated for cell culture experiments to investigate Gb3 load, gene and protein expression patterns and ion channel activity. The 3D-structure of α-GalA was downloaded into Pymol Graphics System and the AAE was depicted and located in order to investigate the correlation between the AAE location type in the α-GalA and the clinical FD phenotype.
FD dermal fibroblasts showed high Gb3 load depending on treatment interval and expressed Kca1.1 channels. Activity was reduced in FD cells at baseline, but increased over-proportionately upon Gb3-cleavage by enzyme replacement therapy. Gene and protein expression of Kca1.1 was increased in FD cells. FD dermal fibroblasts showed higher gene expression of Notch1 and several cytokines. Further, it was shown that three different AAE location types can be differentiated: mutations in the active site (‘active site’), those buried in the core of α-GalA (‘buried’) and those at another location, mostly on the protein surface (‘other’). FD patients carrying active site or buried mutations showed a severe clinical phenotype with multi-organ manifestation and early disease onset. Patients with other mutations were less severely affected with oligo-organ manifestation sparing the nervous system and later disease onset.
These results show that dermal fibroblasts may be involved in FD-associated pain and that stratification of FD patients carrying missense mutations by AAE location type may be an advantageous parameter that can help in the management of FD patients.
The expansion of renewable energies is being driven by the gradual phaseout of fossil fuels in order to reduce greenhouse gas emissions, the steadily increasing demand for energy and, more recently, by geopolitical events. The offshore wind energy sector is on the verge of a massive expansion in Europe, the United Kingdom, China, but also in the USA, South Korea and Vietnam. Accordingly, the largest marine infrastructure projects to date will be carried out in the upcoming decades, with thousands of offshore wind turbines being installed. In order to accompany this process globally and to provide a database for research, development and monitoring, this dissertation presents a deep learning-based approach for object detection that enables the derivation of spatiotemporal developments of offshore wind energy infrastructures from satellite-based radar data of the Sentinel-1 mission.
For training the deep learning models for offshore wind energy infrastructure detection, an approach is presented that makes it possible to synthetically generate remote sensing data and the necessary annotation for the supervised deep learning process. In this synthetic data generation process, expert knowledge about image content and sensor acquisition techniques is made machine-readable. Finally, extensive and highly variable training data sets are generated from this knowledge representation, with which deep learning models can learn to detect objects in real-world satellite data.
The method for the synthetic generation of training data based on expert knowledge offers great potential for deep learning in Earth observation. Applications of deep learning based methods can be developed and tested faster with this procedure. Furthermore, the synthetically generated and thus controllable training data offer the possibility to interpret the learning process of the optimised deep learning models.
The method developed in this dissertation to create synthetic remote sensing training data was finally used to optimise deep learning models for the global detection of offshore wind energy infrastructure. For this purpose, images of the entire global coastline from ESA's Sentinel-1 radar mission were evaluated. The derived data set includes over 9,941 objects, which distinguish offshore wind turbines, transformer stations and offshore wind energy infrastructures under construction from each other. In addition to this spatial detection, a quarterly time series from July 2016 to June 2021 was derived for all objects. This time series reveals the start of construction, the construction phase and the time of completion with subsequent operation for each object.
The derived offshore wind energy infrastructure data set provides the basis for an analysis of the development of the offshore wind energy sector from July 2016 to June 2021. For this analysis, further attributes of the detected offshore wind turbines were derived. The most important of these are the height and installed capacity of a turbine. The turbine height was calculated by a radargrammetric analysis of the previously detected Sentinel-1 signal and then used to statistically model the installed capacity. The results show that in June 2021, 8,885 offshore wind turbines with a total capacity of 40.6 GW were installed worldwide. The largest installed capacities are in the EU (15.2 GW), China (14.1 GW) and the United Kingdom (10.7 GW). From July 2016 to June 2021, China has expanded 13 GW of offshore wind energy infrastructure. The EU has installed 8 GW and the UK 5.8 GW of offshore wind energy infrastructure in the same period. This temporal analysis shows that China was the main driver of the expansion of the offshore wind energy sector in the period under investigation.
The derived data set for the description of the offshore wind energy sector was made publicly available. It is thus freely accessible to all decision-makers and stakeholders involved in the development of offshore wind energy projects. Especially in the scientific context, it serves as a database that enables a wide range of investigations. Research questions regarding offshore wind turbines themselves as well as the influence of the expansion in the coming decades can be investigated. This supports the imminent and urgently needed expansion of offshore wind energy in order to promote sustainable expansion in addition to the expansion targets that have been set.
The article deals with the notion of internet aggression (cyber aggression). It considers the mentioned term from both psychological and communicative approaches. The paper also provides detailed analyses of the cyber aggression in political discourse. The provided ex-amples are taken from the speeches of politicians during the time of Covid pandemic. The author also identifies several types of cyber aggression.
English language is being taught as a second foreign language in India. For most of the learners in India, English still a foreign language or target language. The study of this language is important to fulfill different kinds of academic and professional requirements. Still, there is a big gulf between demand and supply for which the failure of the system is largely responsible as its main emphasis on to adherence to the foreign curriculum. The government tries to impose this curriculum on English teachers, but, in fact, the curriculum is outdated.
This research paper concentrates on the analysis of the aphoristic potential of G. W. Bush’s presidential rhetoric. Aphorisms are the most ancient laconic forms of expressing original and completed thoughts which reveal the peculiarity of their authors’ world perception and worldview. From this perspective, these units can serve as the means of values codification. Repeatability and widespread use of aphorisms in various communications contribute to transmitting the values and ideas between the generations.
Political aphorisms, which are a combination of aphoristic expressions from political communication and discourse, play an important role in this process. The authors of these expressions are not only politicians, but also philosophers, historians, writers, celebrities of different nationalities and generations. Presidential rhetoric is an integral and significant part of political discourse.
The use of aphorisms as the means of codification of national and common human values in President G. W. Bush’s formal addresses and speeches is intentional. It makes them concise and original, influential and convincing. Aphoristic expressions denoting common human values show the ideas and beliefs of their authors, as well as the politician, about life, justice, equality, freedom, faith, family. Aphorisms defining national values become the means of updating concepts of democracy, unity and diversity, freedom and security, success, and opportunity to fulfill one’s potential in American society. The distinctive feature of G.W. Bush’s rhetoric is the frequent use of aphorisms whose authors are the Founding Fathers.
The paper focuses on digital discourse. This is a speech-intellectual product of innovative information technologies, a phenomenon, which needs further interdisciplinary and linguistic interpretation. The English-language digital discourse shows how linguistic verbal communication is mediated by digits and to what extent these Signum and Verbum unity reigns over the world.
The paper analyzes the ways and methods of integrated and differential use of verbal and non-verbal sign systems in the English language as compared to programming languages, considering the types of synchronous changes in the socio-cultural dimension of the sign. This research describes the processes of signs transformation during their functioning in programming languages and in the English language, common and distinctive features in the arrangement of grammatical, lexical-semantic, and graphic means of (natural) English and (artificial) programming languages in their projection on different modes of communication in the system Human ↔ Machine.
Programming languages are constituted by verbal means of the English language with additional use of its own semiotic resources, which testifies to their integrative linguistic and mathematical nature. The specific representation of ElDD conveys its reciprocal nature when the English language using its own tools combines them with the elements of the programming languages thus creating an effective toolkit for self-process
In the present chapter, an attempt has been made to discuss the need to create Zambian English to address English language variations in Zambia. No language in the world can remain the same after interacting with other languages. The present chapter intends to propose and support the idea of using ‘Zambian English’ for both formal and informal business. Such a measure would create the communicative competence that the majority of the Zambians have always longed for. In Zambia, the purpose of using English language office is to deliberate day to day’s business. On the contrary, this has been found to be an obstacle to those who lack principles of command in the language usage, but are able to construct sentences for communicative purposes yet are deprived in international interactions. The views expressed in this chapter are those of the language experts who were engaged in a conversation with regard to the possibility of creating what would be known as Zambian English (ZamEnglish).
The paper analyses specific characteristics of language that influence the development of culture and societies. The problem of the connection between language and culture has occupied the minds of many famous scientists: some believe that language is a part of the culture as a whole; others think that language is only a form of cultural expression. Undoubtedly, language constitutes a vital component of the cultural background underlying social development. Language is an essential means of communication and interaction. However, language is at the same time sovereign about culture as a whole and can be separate from culture or compared to culture as an equal element (i.e., that language is neither a form nor a component of culture).
Teaching comprises all types of disciplines and teachers need to look outside the confines of English as a Second Language. The acquisition of knowledge comes in a variety of the learners’ educational potential. English as a Second Language in teaching and learning, focuses on active learner’s involvement and reduction of coercion. Indeed, Gibran’s thoughts remain true that “wisdom leads one to discuss his or her potentials. To realize this, teachers in all educational levels have to portray a less dominant classroom role in accord with the importance of classroom interaction in the teaching learning process.
N.A. Flaunders retorted that “in the average classroom someone is talking for two-thirds of the time, two-thirds of the task is direct influence.” What does this mean? Students’ participation or interaction in the classroom has a significant content to enhance their linguistic competence and its core basis is how to use the language as the most important factor in the classroom. Comprehending the information caters one to establish a fair and well-balanced condition that teachers are facilitators, and the learners are to stay in the frontline.
In today’s classroom setting, the adoption-adaption of teaching strategies focuses on the learners’ ability to have a strong command or fluency of the language. ESL is learned around the globe and the learners’ interests are the primary goals in the teaching and learning process. Colin Blakemore once said that “True knowledge, as Plato argues, must be within us all, and learning consists of solely of discussing what we already know.”
In an ESL classroom, discovery of knowledge is not a new game. Teachers do perform their tasks and the learners serve not as passive listeners but as active recipients in the transformation-sharing of all the five macro skills namely speaking, reading, writing, listening, and viewing. In fact, if commitment, knowledge of subject-matter for independent learning, and management of learning are packaged in one big box, both the teachers and the learners will operate a mutual process of generating a lively culture and quality of educational life.
With the aforementioned views I had experienced in teaching ESL, the teacher’s passion for teaching and attitude in dealing with the learners create a strong impact on the learners cognitive, affective, and psychomotor domains.
To reopen educational institutions and return to the classroom, we all need to modify how we act to successfully face the challenges of the new normal resulting from the COVID-19 pandemic and entailing our insights into and the after-effects of the pandemic. More specifically, the new normal might encompass online education we are getting used to during the pandemic and the age-old onsite education as well. Thoughtfully integrated, online and onsite learning combine to create blended learning. However, the pertinent literature reveals that English as a foreign language (EFL) students and teachers differently perceive and react to blended learning in diverse contexts. This study was designed to explore student and teacher perceptions of and reactions to blended learning in the Department of English, Jahangirnagar University in the new normal. Fifty undergraduates of EFL and eight teachers of the department participated in the study. To collect data from them, the Student Questionnaire and the Teacher Questionnaire were used. And the data were processed by applying the SPSS programme module. The findings revealed that the majority of the students and the teachers had mostly positive perceptions of blended learning, although the former did not have sufficient exposure to online learning and the latter lacked adequate insights into online teaching. Further, both the students and the teachers expressed mostly positive reactions to blended learning in the new normal, though the former deemed online examinations inadequately smooth and reliable, and the latter had insufficient experience of online instruction and assessment. The study categorically recommends reforming the curriculum, adopting relevant instructional strategies, developing suitable materials, customizing the assessment, integrating and installing technology, training the teachers, upskilling the students for blended learning, improving the infrastructure, and adjusting the management.
A Case Study of the Basic Learners’ Struggles in Guessing from Context to Retain Words Learned
(2022)
Guessing meaning from context is a challenging strategy for Second Language Learners (SLLs). In using the strategy, research found that poor students or low proficiency learners struggled in their attempts to use it. Mainly, it was reported that it was due to their vocabulary knowledge was limited. In another aspect, retaining vocabulary learnt is also important. Such is essential since learning vocabulary does not mean knowing the definition only. Yet, learners must also be able to use the vocabulary as they engage in language skills such as reading, writing, speaking and listening. The study aims at finding the hindrances faced among poor students’ using contextual clues in retaining vocabulary. The study employed a case study to collect data from two basic students studying at a tertiary level. The study found that their hindrances in guessing meaning contexts were due to their being confused in guessing meaning when reading a sentence. Also, it was found that they were not able to find clues since they lacked vocabulary to guess correctly. The study implied that guessing meaning from context required sizeable vocabulary knowledge. Therefore, more training is necessary to assist basic learners in being successful in guessing from contexts.
Studies in Modern English
(2022)
The book "Studies in Modern English" interprets English-language communication in the humanitarian paradigm of knowledge within the linguistic and psycho-sociocultural study of speech activity prioritizing cognitive and communicative paradigms. Digital discourse as the formation of new semiotic phenomena has crowned the rapid scientific and technological progress. Researchers' scientific achievements represented in the book are systemic and valid in terms of evidence-based narratives, which reflect the transformational horizon of information theory, communication theory, and theory of linguodidactics in modern English verbal, creative and digital environments. The book represents an integrated approach to the study of modern English as an open synergetic system, which requires a description of the relationship between verbal and nonverbal notions in digital space. The book integrates such innovative perspectives as the interaction of natural English and programming languages, cyber aggression as a communicative pattern in English-language digital discourse, ethics, and democratization of modern English language, relevant developments in the field of English language as a Foreign Language, and other related issues. A complex focus of the book in the realm of modern English-language communication concerns verbal and nonverbal notions analyzed in the context of socio-cultural and digital communicative spaces.
Societal Impact Statement
Pollen relates to many aspects of human and environmental health, which protection and improvement are endorsed by the United Nations Sustainable Development Goals. By highlighting these connections in the frame of current challenges in monitoring and research, we discuss the need of more integrative and multidisciplinary pollen research related to societal needs, improving health of humans and our ecosystems for a sustainable future.
Summary
Pollen is at once intimately part of the reproductive cycle of seed plants and simultaneously highly relevant for the environment (pollinators, vector for nutrients, or organisms), people (food safety and health), and climate (cloud condensation nuclei and climate reconstruction). We provide an interdisciplinary perspective on the many and connected roles of pollen to foster a better integration of the currently disparate fields of pollen research, which would benefit from the sharing of general knowledge, technical advancements, or data processing solutions. We propose a more interdisciplinary and holistic research approach that encompasses total environmental pollen diversity (ePD) (wind and animal and occasionally water distributed pollen) at multiple levels of diversity (genotypic, phenotypic, physiological, chemical, and functional) across space and time. This interdisciplinary approach holds the potential to contribute to pressing human issues, including addressing United Nations Sustainable Development Goals, fostering social and political awareness of these tiny yet important and fascinating particles.
The strict human pathogen Streptococcus pyogenes causes infections of varying severity, ranging from self-limiting suppurative infections to life-threatening diseases like necrotizing fasciitis or streptococcal toxic shock syndrome. Here, we show that the non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase GapN is an essential enzyme for S. pyogenes. GapN converts glyceraldehyde 3-phosphate into 3-phosphoglycerate coupled to the reduction of NADP to NADPH. The knock-down of gapN by antisense peptide nucleic acids (asPNA) significantly reduces viable bacterial counts of S. pyogenes laboratory and macrolide-resistant clinical strains in vitro. As S. pyogenes lacks the oxidative part of the pentose phosphate pathway, GapN appears to be the major NADPH source for the bacterium. Accordingly, other streptococci that carry a complete pentose phosphate pathway are not prone to asPNA-based gapN knock-down. Determination of the crystal structure of the S. pyogenes GapN apo-enzyme revealed an unusual cis-peptide in proximity to the catalytic binding site. Furthermore, using a structural modeling approach, we correctly predicted competitive inhibition of S. pyogenes GapN by erythrose 4-phosphate, indicating that our structural model can be used for in silico screening of specific GapN inhibitors. In conclusion, the data provided here reveal that GapN is a potential target for antimicrobial substances that selectively kill S. pyogenes and other streptococci that lack the oxidative part of the pentose phosphate pathway.
1. Protection against desiccation and chemical communication are two fundamental functions of cuticular hydrocarbons (CHCs) in insects. In the parasitoid jewel wasp Nasonia vitripennis (Walker), characterised by a cosmopolitan distribution through largely different environments, CHCs function as universally recognised female sex pheromones. However, CHC uniformity as basis for sexual recognition may conflict with the desiccation protection function, expected to display considerable flexibility through adaptation to different environmental conditions.
2. We compared male and female CHC profiles of N. vitripennis across a wide latitudinal gradient in Europe and correlated their CHC variation with climatic factors associated with desiccation. Additionally, we tested male mate discrimination behaviour between populations to detect potential variations in female sexual attractiveness.
3. Results did not conform to the general expectation that longer, straight‐chain CHCs occur in higher proportions in warmer and drier climates. Instead, unexpected environmental correlations of intermediate chain‐length CHCs (C31) were found exclusively in females, potentially reflecting the different life histories of the sexes in N. vitripennis.
4. Furthermore, we found no indication of population‐specific male mate preference, confirming the stability of female sexual attractiveness, likely conveyed through their CHC profiles. C31 mono‐ and C33 di‐methyl‐branched alkanes were consistently and most strongly associated with sexual dimorphism, suggesting their potential role in encoding the female‐specific sexual signalling function.
5. Our study sheds light on how both adaptive flexibility and conserved sexual attractiveness can potentially be integrated and encoded in CHC profiles of N. vitripennis females across a wide distribution range in Europe.
Aim
This study aimed to identify and compare age stereotypes of registered nurses and supervisors in clinical inpatient settings.
Design
Generic qualitative study using half‐standardized interviews.
Method
Nineteen face‐to‐face interviews and five focus groups (N = 50) were conducted with nurses of varying levels at a hospital of maximum medical care in Germany between August and November 2018 and were subjected to structured qualitative content analysis.
Results
Reflecting the ageing process and cooperation in mixed‐age teams, nursing staff and supervisors defined similar age stereotypes towards older and younger nurses reminiscent of common generational labels ‘Baby Boomers’ and Generations X. Their evaluation created an inconsistent and contradictory pattern differing to the respective work context and goals. Age stereotypes were described as both potentially beneficial and detrimental for the individual and the cooperation in the team. If a successfully implemented diversity management focuses age stereotypes, negative assumptions can be reduced and cooperation in mixed‐age teams can be considered beneficial.
Conclusion
Diversity management as measures against age stereotypes and for mutual acceptance and understanding should include staff from various hierarchical levels of the inpatient setting.
Utilizing Pd‐catalyzed [5+2] annulation a series of heptagon‐extended corannulenes could be synthesized from a borinic acid precursor furnished by C−H borylation strategy. Single‐crystal X‐ray analysis revealed the presence of two conformational enantiomers crystallizing in a racemic mixture. Through their embedded five‐ and seven‐membered rings these polycyclic aromatic hydrocarbons (PAHs) exhibit both negative and positive curvature and UV/Vis/NIR absorption spectroscopy as well as cyclic voltammetry experiments provided insights into the influence of larger flanking aromatic systems and electron‐donating substituents encompassing the heptagonal ring. Through [5+2] annulation of acenaphthylene an azulene‐containing PAH with intriguing optoelectronical properties including a very small bandgap and absorption over the whole visible spectrum could be obtained. Theoretical calculations were employed to elucidate the long‐wavelength absorption and aromaticity.
Floral nectar is considered the most important floral reward for attracting pollinators. It contains large amounts of carbohydrates besides variable concentrations of amino acids and thus represents an important food source for many pollinators. Its nutrient content and composition can, however, strongly vary within and between plant species. The factors driving this variation in nectar quality are still largely unclear.
We investigated factors underlying interspecific variation in macronutrient composition of floral nectar in 34 different grassland plant species. Specifically, we tested for correlations between the phylogenetic relatedness and morphology of plants and the carbohydrate (C) and total amino acid (AA) composition and C:AA ratios of nectar.
We found that compositions of carbohydrates and (essential) amino acids as well as C:AA ratios in nectar varied significantly within and between plant species. They showed no clear phylogenetic signal. Moreover, variation in carbohydrate composition was related to family‐specific structural characteristics and combinations of morphological traits. Plants with nectar‐exposing flowers, bowl‐ or parabolic‐shaped flowers, as often found in the Apiaceae and Asteraceae, had nectar with higher proportions of hexoses, indicating a selective pressure to decelerate evaporation by increasing nectar osmolality.
Our study suggests that variation in nectar nutrient composition is, among others, affected by family‐specific combinations of morphological traits. However, even within species, variation in nectar quality is high. As nectar quality can strongly affect visitation patterns of pollinators and thus pollination success, this intra‐ and interspecific variation requires more studies to fully elucidate the underlying causes and the consequences for pollinator behaviour.
This thesis addresses the identification and characterization of spin states in optoelectronic materials and devices using multiple spin-sensitive techniques. For this purpose, a systematic study focussing on triplet states as well as associated loss pathways and excited state kinetics was carried out. The research was based on comparing a range of donor:acceptor systems, reaching from organic light emitting diodes (OLEDs) based on thermally activated delayed fluorescence (TADF) to organic photovoltaics (OPV) employing fullerene and multiple non-fullerene acceptors (NFAs). By developing new strategies, e.g., appropriate modeling, new magnetic resonance techniques and experimental frameworks, the influence of spin states in the fundamental processes of organic semiconductors has been investigated. Thereby, the combination of techniques based on the principle of electron paramagnetic resonance (EPR), in particular transient EPR (trEPR) and optically detected magnetic resonance (ODMR), with all-optical methods, such as transient electroluminescence (trEL) and transient absorption (TA), has been employed. As a result, excited spin states, especially molecular and charge transfer (CT) states, were investigated in terms of kinetic behavior and associated pathways, which revealed a significant impact of triplet states on efficiency-limiting processes in both optoelectronic applications.
Deadwood provides a variety of habitats for saproxylic beetles. Whereas the understanding of the drivers promoting saproxylic beetle diversity has improved, the process of deadwood colonisation and beetle's potential to trace resources is poorly understood. However, the mechanisms facilitating deadwood detection by saproxylic beetles appears to be essential for survival, as deadwood is usually scattered in time and space.
To investigate whether saproxylic beetles distinguish before their arrival on potential hosts between alive trees and deadwood (lying, stumps, standing), deadwood arrangement (aggregated, distributed) and different heights on standing resources (bottom = 0.5 m, middle = 4–5 m, top = 7.30–11.60 m), we sampled saproxylic beetles with sticky traps in a deadwood experiment.
We found on average 67% higher abundance, 100% higher species numbers and 50–130% higher species diversity of colonising saproxylic beetles consistently for all deadwood types compared to alive trees with a distinct community composition on lying deadwood compared to the other resource types. Aggregated deadwood arrangement, which is associated with higher sun‐exposure, had a positive effect on species richness. The abundance, species number and diversity, was significantly higher for standing deadwood and alive trees at the bottom section of tree trunks. In contrast to living trees, however, the vertical position had an additional effect on the community composition on standing deadwood.
Our results indicate that saproxylic beetles are attracted to potential deadwood habitats and actively select specific trunk sections before arriving on potential hosts. Furthermore, this study highlights the importance of sun‐exposed resources for species richness in saproxylic beetles.
Spray‐drying is a scalable process enabling one to assemble freely chosen nanoparticles into supraparticles. Atomic layer deposition (ALD) allows for controlled thin film deposition of a vast variety of materials including exotic ones that can hardly be synthesized by wet chemical methods. The properties of coated supraparticles are defined not only by the nanoparticle material chosen and the nanostructure adjusted during spray‐drying but also by surface functionalities modified by ALD, if ALD is capable of modifying not only the outer surfaces but also surfaces buried inside the porous supraparticle. Simultaneously, surface accessibility in the porous supraparticles must be ensured to make use of all functionalized surfaces. In this work, iron oxide supraparticles are utilized as a model substrate as their magnetic properties enable the use of advanced magnetic characterization methods. Detailed information about the structural evolution upon individual ALD cycles of aluminium oxide, zinc oxide and titanium dioxide are thereby revealed and confirmed by gas sorption analyses. This demonstrates a powerful and versatile approach to freely designing the functionality of future materials by combination of spray‐drying and ALD.
Background
The influence of the stomatognatic system on human posture control has been investigated under static conditions, but the effects on dynamic balance have not yet been considered.
Objective
Investigating the influence of different functional stomatognatic activities (jaw clenching (JAW), tongue pressing (TON) and habitual jaw position (HAB)) on postural performance during a dynamic reactive balance task.
Methods
Forty‐eight physically active and healthy adults were assigned to three groups differing in oral‐motor tasks (JAW, TON or HAB). Dynamic reactive balance was assessed by an oscillating platform which was externally perturbed in four directions. Performance was quantified by means of Lehr's damping ratio. Mean speeds of the selected anatomical regions (head, trunk, pelvis, knee and foot) were analysed to determine significant performance differences.
Results
The groups differed significantly in balance performance in direction F (i.e., forwards acceleration of the platform). Post hoc tests revealed that the JAW group had significantly better performance compared with both the HAB and TON groups. Better performance was associated with a decreased mean speed of the analysed anatomical regions.
Conclusion
JAW can improve dynamic reactive balance but the occurrence of positive effects seems to be task‐specific and not general. TON seems not to have any observable effects on dynamic reactive balance performance, at least when evaluating it with an oscillating platform. JAW might be a valuable strategy which could possibly reduce the risk of falls in elderly people; however, further investigations are still needed.
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.