Non-O1/non-O139 Vibrio cholerae (NOVC) is a natural inhabitant of aquatic ecosystems. It can cause both intestinal and extraintestinal infections in humans through the consumption of contaminated food or direct contact with contaminated surfaces, such as seawater or sediment. Previous studies have identified virulence-associated genes in NOVC that may contribute to its ability to cause infections. This doctoral thesis aimed to characterize the virulence mechanisms of NOVC isolated from food and environmental sources. A literature review was conducted to explore the infection routes of NOVC and its virulence-associated gene profiles. The genes were then compared with whole genome sequences of NOVC isolates from seafood (63 strains) and the German sea coastline (31 strains) to determine the presence of virulence-associated genes. Phylogenetic analysis was also performed. Additionally, phenotypic tests, including biofilm formation, hemolytic activity, motility, and serum resistance, were carried out to further validate the genetic findings. The antimicrobial resistance (AMR) of NOVC was also examined at both the genetic and phenotypic levels. Virulence-associated genes were classified into five stages, representing the infection process from ingestion to detachment from the human host. Most of these genes were detected in NOVC isolates from both food and environmental sources, including key toxin-encoding genes (hlyA, rtxA, chxA, stn), pathogenicity islands (VPI-2 and VSP-2), and secretion systems (T3SS and T6SS). A close core genome relationship was observed between the NOVC strains in this study and clinical NOVC strains. Notably, all NOVC strains exhibited increased motility at 37°C compared to 25°C, and most were capable of forming strong biofilms at both temperatures. All strains showed hemolytic activity against both human and sheep erythrocytes, but only a small subset of (6%) NOVC could survive in 60% human serum. In antimicrobial susceptibility tests, five NOVC strains developed non-wildtype resistance to antimicrobials across three different classes (penicillin, carbapenem, cephalosporin). In conclusion, this study characterized the virulence profiles of NOVC isolates from seafood and German coastal waters, highlighting the need for further monitoring and research.
Weniger anzeigenNeurodegenerative diseases (NDDs) encompass a heterogeneous group of chronic neurological disorders characterized by progressive neuron degeneration within specific regions of the central nervous system (CNS). Among these, Alzheimer's disease (AD) stands out as the most prevalent cause of dementia, accounting for approximately 60-80% of all dementia cases. Neuropathologically, AD is marked by the presence of two prominent protein pathological hallmarks: 1) the extracellular accumulation of aggregated amyloid-beta (Aβ) peptides, leading to the formation of amyloid-plaques, and 2) the intracellular aggregation of fibrillar structures composed of neuronal microtubule-associated protein Tau, forming neurofibrillary tangles (NFTs). Despite extensive and prolonged research efforts spanning several decades, the underlying molecular mechanisms of this intricate neurodegenerative condition remain only partially understood. In this context, the present study employs a well-established HEK sensor cell line, constitutively expressing the aggregation-prone mutant Tau repeat domain fused to either cyan fluorescent protein (CFP) or yellow fluorescent protein (YFP) (TauRDP301S-CFP/YFP). By introducing pre-aggregated Tau forms into these cells, a spectrum of distinct Tau assemblies is generated, encompassing large amorphous cytosolic aggregates (CYT) and amyloid-like structures (AMY), compact cytosolic Tau clusters (CLUS), Tau clusters near the nuclear envelope (NE), and nuclear spherical accumulations (NUC). After determining the sequence of accumulation type occurrence by live cell time-lapse imaging, I characterized the packing density of Tau in the different accumulation types using a multimodal microscopy approach. High-resolution FLIM/FRET microscopy, in which the fluorescent lifetime quenching of CFP serves as a proxy for the packing density of Tau, revealed distinct differences between Tau accumulations, as well as confirming a time-dependent hardening of Tau condensates in vitro. Optical diffraction tomography (ODT), which measures absolute protein concentration, revealed differences in the molecular and physical density of Tau accumulations. Additionally, it unveiled a drastic restructuring of 24-hour-old Tau 14 condensates compared to freshly formed 1-hour-old condensates, suggesting the potential transition from soluble Tau to fibrillar Tau aggregates. Lastly, 3D confocal reconstruction microscopy and StED microscopy provided insight into the precise positioning of different Tau accumulations regarding cytoskeletal fibers and cellular landmark organelles, such as the nuclear envelope and the endoplasmic reticulum (ER), revealing multiple interaction partners of Tau and implying possible downstream effects of Tau on cellular processes and mechanisms. By employing various light microscopy techniques, insights into Tau aggregation at different stages was gained, contributing to a deeper understanding of Tau aggregation formation and its implications for cellular processes. Furthermore, ODT emerged as a valuable tool for studying Tau aggregation in both cellular environments and in vitro conditions, revealing new structural insights. This research may offer prospects for understanding Tau transition and potential drug development.
Weniger anzeigenOur lab focuses on studying mobile genetic elements and their contribution to genome evolution. The remnants of mobile genetic elements can be repurposed by the host. For example, they serve as enhancers, alternative poly(A) signals, splice sites, exons, or entirely new genes. This study investigates the domestication of DNA transposons to form entirely new genes. PiggyBac-derived elements (PGBDs) are transposase-like genes that have been repeatedly domesticated into vertebrate genomes, suggesting that they may have important functions in host biology. The human genome comprises five PGBD genes, PGBD1-5. However, little is known about the molecular mechanisms underlying their domestication or their physiological roles. Therefore, we investigated the evolutionary history and possible molecular functions of the human PGBD family, especially PGBD1 and PGBD5, as an example of host transposase domestication events. First, we investigated the domestication event of PGBD1 and found that it had captured an N-terminal SCAN and KRAB domain in its ancestral condition. However, while the transposase domain was under strong evolutionary constraints, the N-terminal domains (NTDs) were under lesser purifying selection. In the KRAB domain that showed Ka/Ks ratios bigger than 1, amino acid substitution may have been beneficial for PGBD1 function, including 252M, which might have compromised Tripartite motif containing 28 (TRIM28) binding capacity. Additional losses and decays of the N-terminal domain of PGBD1 highlight the functional dominance of the domesticated transposase domain. Hence, host domains might facilitate the capture of DNA transposases to the host genome, but their function could be submissive to the protein function. In the second part, we investigated the molecular functions of PGBD5 and found that it is doubtfully an active transposase, and we identified that it interacts with another nuclease, topoisomerase II α (TOP2A). We show that PGBD5 is enhancing TOP2A function in-vitro and that it, together with topoisomerase II β (TOP2B), might regulate the transcription of a subset of immediate early genes (IEGs), namely FOS, NPAS4, NR4A1 and DUSP1 in the brain. Further, we show that PGBD5 interacts with several proteins involved in histone modifications, transcriptional regulation, and DNA repair. Altogether we provide an alternative mechanism by which PGBD5 contributes to DNA double-strand breaks (DSBs) and genomic rearrangements. Additionally, we show that PGBD5 adds an extra layer of IEG control that is specific to the brain and thereby contributes to brain-specific signaling. The thesis contributes to the knowledge of the molecular mechanisms underlying the domestication of transposase-like genes and their physiological roles in the host genome.
Weniger anzeigenThe development of flexible photovoltaic technology with low production costs is crucial for expanding access to solar energy and promoting its widespread adoption. One of the objectives of the CUSTOM-ART project (under grant agreement no. 952982) is to develop ultra-barrier films to protect photovoltaic cells using common, affordable plastic materials. To achieve this, the strategy adopted is based on the use of multi-nano-layer (MNL) polymer film co-extrusion technology aimed at orienting 2D montmorillonite nano-fillers dispersed in a poly(ethylene) matrix to produce films with a high degree of tortuosity. Therefore, this study focuses on characterizing the orientation of montmorillonite by systematic texture X-ray diffraction analysis. The results indicate that the orientation of montmorillonite with the MNL co-extrusion technology has a limited effect when the poly(ethylene) is in the molten state. However, the orientation is significantly improved with a biaxial stretching post-treatment of the films, which is performed at a temperature below the melting point of poly(ethylene). This raises the question of the influence of the matrix and the relationship between montmorillonite and poly(ethylene) on montmorillonite orientation. Further investigation of the crystallization of the poly(ethylene) phase revealed that it occurs around montmorillonite nano-fillers, allowing preferential orientation of poly(ethylene) crystals without affecting the rate of poly(ethylene) crystallinity. Consequently, the way poly(ethylene) crystallizes affects the orientation of montmorillonite. However, despite these variations in orientation, no significant improvement in the water barrier properties of the films was observed. Although the film has a controlled nanostructure, only 35% (including both montmorillonite and poly(ethylene) contributions) of the film consists of crystals, which may limit their ability to influence water diffusion through the films.
Weniger anzeigenThe oxygen reduction reaction (ORR) is a key limiting factor in fuel cell technology, driving extensive research efforts over the past few decades. Studies based on experiments and theoretical calculations on model single-crystal electrodes have helped establish fundamental trends across transition metal catalysts. In heterogeneous electrocatalysis, local electric field effects at the electrical double layer significantly influence the energies of reaction intermediates and impact catalyst performance in acidic or alkaline environments. However, these local field effects are challenging to model computationally and are frequently omitted. First, this work focuses on O2 adsorption as the initial step of the ORR to understand the role of the elec- tric field. The first part of the study focuses on the weak binding Au(111) metal catalyst surface, which favors the formation of hydrogen peroxide over water, with its activity strongly dependent on the (absolute) electrode potential. The underlying microscopic mechanisms remain unclear, likely involving key elementary reaction steps. We systematically enhance the double-layer model to clarify and compare the physical effects of the local field on O2 adsorption. This progression includes an applied saw-tooth potential in vacuum, an implicit solvent model, and explicit water modeling via ab initio molecular dynamics (AIMD). Two main contributions are identified to the potential dependence of O2 adsorption. Firstly, a dominant dipole- field interaction favors O2 binding going to reducing conditions across all models. Additionally, we observe stabilization from explicit H-bonding that can only be ob- served in AIMD, leading to a peroxo-O2* and a significant field response near the ORR onset. Since the O2* adsorption becomes favorable close to experimental ORR onsets and can explain experimental SHE-driven ORR activity, we predict that O2 adsorption is a potential-dependent, potentially rate-determining step of the ORR on the weak binding Au(111). These findings highlight the necessity of incorporating local electric field effects and explicit water in electrochemical interface models. Secondly, we draw a comparison to the more reactive Pt(111) surface. We conduct AIMD simulations to analyze and compare the properties of the metal/water interface Au(111) vs. Pt(111). Unlike Au(111), Pt(111) exhibits negligible potential dependence under realistic ORR conditions due to the inherently different reactivity of the two metals. We find a closely adsorbed peroxo O2* state with a relatively constant number of H-bonds, irrespective of the potential or surface coverage on the Pt(111). In contrast, the interfacial water structure on Pt(111) undergoes significant changes due to the inclusion of more realistic surface coverages and potential variations. In our set-up, we observe O2* dissociation determining the ORR selectivity towards H2O. We find an indirect effect of the potential through surface coverage: The O2* dissociation is promoted by desorption of H2O* at reducing conditions. Our overall results emphasize the importance of accounting for local field effects, which i) can directly impact reaction steps but ii) can also indirectly impact the reaction mechanism through a more complex interplay between potential, surface coverage, and water structure.
Weniger anzeigenThe formation, maintenance, and regeneration of skeletal muscle tissue depend on the interplay between muscle progenitor cells, known as myoblasts, and other local cell populations. Successful myogenesis requires precise regulation of multiple cellular processes, culminating in the formation of myofibers, multinuclear contractile syncytia from myoblasts. Proliferating myoblasts migrate to the muscle formation region, adhere to each other, express terminal differentiation markers, and eventually fuse their cytoplasmic contents. These processes are characterized by dynamic alterations in cytoskeletal architecture. The cytoskeleton comprises polymerizing proteins such as microfilaments, microtubules, intermediate filaments, and septins, forming an interconnected network of filaments. While the roles of actin, tubulin, and intermediate filaments are well studied, septins have only recently begun to emerge in the myogenic context. In my thesis, I investigated the expression and organization of septin paralogues in dividing and differentiating myoblasts, describing septins as a necessary component of the myoblast cytoskeleton. I propose the existence of septin octamers in myoblasts consisting of Septin2-7-11 and 9, with Septin9 undergoing substantial changes in expression. Septin9 mRNA is induced as quiescent cells transition to activated progenitors in regenerating mouse muscle and is downregulated by the end of the regenerative process. Septin9 mRNA and protein expression were also reduced during in vitro differentiation in C2C12 and primary myoblasts. Cycling myoblasts incorporate Septin9 into actin-decorating septin filaments that form primarily near the nucleus, in close proximity to the plasma membrane. However, these filaments undergo substantial reorganization after myogenic differentiation is induced. I observed that a fraction of Myogenin-positive cells exhibits short, curved septin rods and filament remnants, with no co-localization with actin filaments. This reorganization potentially coincides with the accumulation of muscle specific actin and myosin proteins. These findings were confirmed via live-cell microscopy using an endogenously tagged eGFP-Septin9 C2C12 cell line. Furthermore, nascent myotubes showed septin filaments extending across the perinuclear area in the basal plane, while the rest of the sarcoplasm contained filamentous remnants and rings. Mature myotubes, which exhibit sarcomeric actin organization, were mostly devoid of septin structures. SiRNA-mediated depletion of Septin9 resulted in the disruption of septin filaments and in a premature transition from proliferating to committed transcriptional signature in C2C12 and primary myoblasts, as evident from RNASeq analysis. Additionally, Septin9-deficient myoblasts showed signs of premature cell cycle exit, increased apoptosis, and a precocious onset of myogenic differentiation during in vitro differentiation. Taken together, my findings establish Septin9 as a critical regulator of myoblast differentiation during the initial commitment phase. We propose that filamentous septin structures are part of a temporal regulatory mechanism governing myogenic differentiation, with their reorganization marking the progress of unfolding myoblast differentiation.
Weniger anzeigenThe Varroa destructor parasitisation has remained one of the main causes for colony losses all around the world since the introduction of the mite in Apis mellifera populations. One of the natural defence mechanisms used by the honeybee in the fight against V. destructor is hygienic behaviour, particularly a specialized form of it – Varroa-sensitive hygiene (VSH) – which includes the uncapping and removing of parasite-infested, or dead brood. When infested, capped brood changes its cuticular profile sending an olfactory signal which only a few workers in the colony can sense. Subsequently, the brood cell is opened, and the mite removed. Hygienic behaviour and olfactory sensitivity to brood-related odours are observed to be strongly influenced by genetics. Breeding efforts with the goal of enhancing the European honeybee’s resilience have been ongoing for more than three decades, but to date no breeding strategy has reached a broad-scale host-parasite balance. Due to the strong environmental dependence of resistance traits, the reproductive and genetic peculiarities of the honeybee, as well the small-scale structure of the German beekeeping community, very labour-intensive traditional breeding programmes for this species are in need of transformation. Having this in mind, this project focused on the development of a new strategy that has the potential to make breeding in honeybees significantly more efficient by utilising drones’ olfactory as a selection trait. As drones are haploid, the genetic potential for Varroa-resistance can be assessed on the gametes. This allows genetic differences to be recognised significantly better and enables faster selection success. The proboscis extension response (PER) conditioning as a non-invasive method of observing olfactory sensitivity in both workers and drones enabled the gathering of insights into VSH and its inheritance and was chosen for the selection of the most suitable individuals. In a first step, workers bred for VSH and nonselected control line workers were tested via PER conditioning for differences in their speed and perception ability when presented with highly diluted stimuli. Two pairs of odours (Pair 1: citral as Cs+: linalool as Cs-; Pair 2: Varroa-parasitised brood extract as Cs+, isopropanol as Cs-) were used as tactile stimuli for the differential conditioning. Citral – a floral odour – and the brood extract were especially chosen in order to observe whether breeding for resistance in one of the tested groups had an effect on odour sensitivity to all or only to special odours connected to VSH. The VSH-selected line exhibited a significantly higher speed of perception for the parasitised brood extract than the nonselected line. The two lines showed no differences when conditioned with the floral stimulus citral as Cs+. The results suggested an increased specific sensitivity to chemical stimuli emanating from the brood in VSH-selected workers, which could play a role in recognising and removing V. destructor. In a second step, the odour sensitivity of drones to the Varroa-parasitised-brood extract was examined through PER conditioning. Sperm from drones, sensitive/insensitive to two Varroa-parasitised-brood odours concentrations was extracted, and queens from VSH-selected and nonselected lines were inseminated accordingly, following a mating scheme. The VSH behaviour of the offspring was observed, and the genetic origin of queens and drones as well as the drones’ perception of the brood odour were considered. While drone PER conditioning did not significantly correlate with VSH results, the genetic origin of participating queens and drones played a crucial role in VSH manifestation. A tendency for maternal effects for the inheritance of VSH was observed, suggesting that the choice of father drones would have less influence on VSH than that of mothers as genes connected to VSH are inherited via mitochondrial DNA of the mother. Additive genetic effects were also observed when drones from the VSH-selected line were paired with queens from the VSH-selected line, suggesting that drone’s genes nevertheless play an important role in resistance breeding. The role of the drone should therefore not be underestimated.
Weniger anzeigenThis dissertation aimed to evaluate passive behavioural data as a new data source in the field of public mental health. To date, research in the field of public mental health has primarily used written or oral self-report data as a method, which requires great effort, is time-consuming, and is susceptible to report bias. The conceptualisation of prevention measures and needs in the space of public mental health requires data that are as up-to-date and precise as possible. The use of smartphone-assessed passive behavioural data has already been discussed as additional objective measurement method to identify symptoms of mental disorders. Standardised parameters of passive behavioural data do not yet exist within the public mental health context. However, before passive behavioural data can be integrated as a new data source in the field of public mental health research, it must be evaluated on the basis of quality criteria. The evaluation of passive behavioural data is accompanied by essential ethical (and data protection) questions. Due to the currently high prevalence of depressive disorders worldwide and their tremendous individual and social consequences, the evaluation of passive behavioural data in the present dissertation was carried out by using depressive symptoms as the example. The three research projects in this dissertation were based on data collection aiming to predict depressive symptoms with the help of passive behavioural data. The results from Research Project 1 suggested that passive behavioural smartphone data offered added content value compared to survey data of established self-reported predictors of depressive symptoms. Of the included passive behavioural smartphone data, messenger use and video calls, as correlates of social interaction, contributed significantly to the prediction of depressive symptoms. The results of Research Project 1 suggested that passive behavioural data could be used as measures of depressive symptoms; a precise attribution of passive behavioural data points to individual depressive symptoms is still pending. This would enable continuous data collection in the public mental health sector and thus early identification of trends in the prevalence of depressive symptoms. This, in turn, provides the basis for the equally timely planning and implementation of preventive measures. In addition, Research Project 2 investigated the contribution of regional data derived from official statistics based on GPS location to the prediction of individual depressive symptoms. The results showed that regional information could be helpful in identifying risk groups in the public mental health sector. The results were not transferable to the postpandemic period due to the survey being conducted during the COVID-19 pandemic but, at the same time, provide valuable information on groups particularly at risk for depressive symptoms during a pandemic. Research project 3 investigated the extent to which characteristics of passive behavioural data are valid as correlates of depressive symptoms across individuals. To this end, we tested the extent to which personality facets and perceived social support were associated with the relationship between media use and physical activity levels (measured as behavioural data) and depressive symptoms. Some behavioural data points were found to be related to depressive symptoms independently of individual characteristics, while others were related to depressive symptoms in differential ways. Thus, the results of Research Project 3 highlighted the relevance of interindividual differences in the assessment of passive behavioural data. Overall, the results indicated that defining consistent behavioural data measures for the public mental health field is challenging, as some behavioural data measures show different strengths of associations with depressive symptoms between individuals. As a practical implication, both an individual-centred approach and the inclusion of person-specific control variables are recommended.
Weniger anzeigenThis thesis examines how cognitive and emotional individual differences predispose biased mindsets and suggestiveness in formal and informal questioning of children about child sexual abuse (CSA) suspicions. Across five empirical studies, presented in three articles, the Cognitions and Emotions about Child Sexual Abuse (CECSA) scales were developed, validated, and tested for their relationship to biased judgments and suggestive questioning, and for their responsiveness to training. Article 1 outlines the development and initial validation of three CECSA scales – Naive Confidence (NC), Emotional Reactivity (ER), and Justice System Distrust (JSD) – in a sample of 801 human sciences students. The scales demonstrated good model fit, acceptable to good reliability and, importantly, predicted participants’ bias toward the abuse hypothesis when judging vague CSA suspicions. Article 2 presents three mock case studies for predicting bias and suggestive questioning using varying formats for question posing: a single-choice format, a free-writing format, and a natural language format in a virtual reality (VR) simulation. Results for a total of 674 students from diverse disciplines (human sciences, teaching, police studies) showed that NC and ER, but not JSD, robustly predicted biased mindsets and a suggestive questioning style across the three studies and a meta-analytic integration. Article 3 evaluates a training program aimed at improving questioning techniques and related constructs. A secondary analysis of the data showed that a two-day seminar-style training significantly reduced NC and ER scores, while the results for JSD were inconclusive. These findings establish the CECSA scales NC and ER as reliable predictors of bias and a suggestive questioning style and show that both are modifiable through training. The scales are of diagnostic and evaluative value for training development or personnel selection, and can be used and extended to further investigate differential aspects of child sexual abuse investigations.
Weniger anzeigenPolitical regulations are an efficient instrument to reduce emissions, but developing mitigation strategies require information on the source contributions. Informations on local traffic emissions are usually available, but the contribution to the regional background is often missing. CTMs are widely used to assess the air pollution and support policy decisions. This study focuses on improving the quantification of the source contribution to the concentration levels of PM, NO2 and O3 in Germany. A source apportionment was performed to identify the most important sources for NOX in Germany and Berlin. Contributions to NOX were calculated using the labeling system in LOTOS-EUROS. Most important contributions to NO2 are road transport (~45 %), non-road transport (~24 %), energy & industry (~20 %) and households (~10 %). The impact of emission reduction was calculated using the brute force technique. Main differences between potential impacts (upscaling the impact to 100 %) and contributions were observed for ozone-limiting conditions. At night and in winter, the non-linear photochemical reaction between source sectors is often hampered and no regime change in the titration of O3 takes place. In the urban background, the sum of the potential impacts from each source sector overestimates the unperturbed baseline concentration for NO by about 50 % on annual average. For rural background sites, the overestimation is roughly 10 % lower. Larger overestimation was observed for hourly time series and small-sized source categories. For NO2, the attributed concentration from the brute force simulation is about 5 % lower close to emission sources than that of the labeling system. For larger cities, differences between the two calculations are about -15 %. The differences between both techniques increase with smaller NOX reduction. A 25 % reduction in NOX emissions was identified as the limit for application of the brute force technique. As prior research studies show similar deficiencies for PM, the source attribution for PM was performed using the labeling system. Combustion processes from residential heating (~30 %), industry & energy production (~19 %) and road-transport (~12 %) are the most important sources in Berlin. Agriculture and the boundary contribute about 12 % and about 14 % respectively on annual average. The remaining contribution is explained by natural emissions. Domestic sources from Berlin (~25 %) and Germany (~24 %) explain about a half to the annual average concentration. About 33 % originate from transboundary transport. The rest can be attributed to natural sources. For PM episodes in winter up to a third of the PM concentration originates from sources in neighboring countries further east. Seasonal variations were caused by emissions from residential heating and energy production, most important in winter. Agriculture is a large source of PM in spring and summer. Households (~53 %) and road-transport (~17 %) contribute most to the urban increment in Berlin. Road transport explains about 22 % of coarse material in urban background sites. Previous research studies show larger traffic contributions of up to a factor of 4 in summer. Incomplete reporting of non-exhaust emissions from road traffic and land management activities may partly explain the underestimation. Model simulations with COSMO-CLM were performed to downscale meteorological reanalysis from ECMWF to the national scale for Germany and were used for the first time as input data in LOTOS-EUROS. This paves the way for forthcoming modeling in Germany and to incorporate meteorological forecasts from DWD. The study shows improved statistics for meteorological conditions in Germany with COSMO-CLM compared to the lower resolved ECMWF forecasts. Simulations with the dynamic mixed-layer set-up show too high mixing from the planetary boundary layer to higher model layers in LOTOS-EUROS. Different turbulence parameterizations were used in COSMO-CLM, but show no clear indication to improve the mixing in LOTOS-EUROS. The pollutants stay closer to the surface when a larger number of vertical layers is used. The refined vertical layering improves the modeling with LOTOS-EUROS for Berlin and lowers the bias in the urban background, especially for cold and stagnating weather conditions in winter. Ammonium and nitrate responded most sensitive to the higher resolved vertical layering and show increased concentrations. Modeling of O3 with LOTOS-EUROS for Germany was evaluated with three other CTMs in a national scale multi model inter-comparison. The individual models often show lower model-measurement agreement and a lower statistical skill than the ensemble mean of all models, especially at night and for high ozone levels. A dynamic model evaluation was designed that compares modeled and observed concentration regimes for temperature and humidity. Room for improvement was identified to reproduce the O3 sensitivity to temperature, where a large spread was observed between the models. LOTOS-EUROS captures the regional build-up and removal of O3 for day-to-day and season-to-season variations, but underestimates the O3 sensitivity to temperature. Different sensitivities of O3 to temperature between rural and urban background sites and spring and summer are captured with LOTOS-EUROS. Detailing the emission inventories at national level, the integration of resuspended coarse material as an additional source and the use of the high resolved vertical layering are recommended for future modeling with LOTOS-EUROS. Contributions from the labeling system must be the first guess for emission reduction scenarios using the brute-force technique. The calculation of potential impacts must be avoided for NO and for small-sized emission categories. The implementation of the labeling system for O3 will allow to account for the contributions of O3 in Germany with LOTOS-EUROS. The dynamic evaluation must be expanded to longer timeframes and to other pollutants.
Weniger anzeigenUveal melanoma (UM) is a challenging cancer which is a rare type of melanoma. It originates from the melanocytes, which bear GNAQ/GNA11 mutations, localized in the ocular tract, and progress with a high risk of metastasis associated with poor prognosis and limited therapeutic options. When the primary cancer cells metastasize, the median survival is on average twelve months. There are two main UM subtypes differing by their genomic profile and metastatic properties in the literature. UMs with Monosomy 3 (M3) subtype which is characterized by the loss of chromosome 3 and BAP1 mutation are associated with a worse prognosis. UMs with Disomy 3 (D3) do not show the loss of chromosome 3 yet, they carry mutually exclusive EIF1AX or SF3B1 mutations and exhibit better prognosis. In contrast to the D3 subtype, the underlying reasons why the M3 subtype with BAP1 mutations are linked to very high metastatic risk within the disease mechanisms are not fully understood. The low tumor mutation burden of UM suggests a contribution of epigenetic components to the disease mechanism. BAP1 is a member of the Polycomb repressive deubiquitinase (PR-DUB) complex acting as a tumor suppressor and an epigenetic regulator. Given the relevance of BAP1 loss in UM, we hypothesized that repatterning in the epigenetic landscape and regulation might be affected by the absence of BAP1, causing novel TF interplay that contributes to reprogramming the cells towards malignancy. Thus, we compared the genome-wide patterns in BAP1 wild-type versus BAP1 mutant cases. Within this scope, this thesis aims to decipher the altered gene regulation networks investigating the effects of BAP1 loss in UM. We set out to model BAP1 loss in UM cell lines to better understand the molecular programs related to the subtype. Then, we investigated the differences between transcriptomic and epigenomic landscapes in an integrative manner. Our findings demonstrated that BAP1 predominantly binds to active regulatory regions, particularly transcription start sites and enhancers. Its binding influences the chromatin landscape and facilitates interactions with pioneering transcription factors TFAP2A and TFAP2C, which may contribute to transcriptional reprogramming observed in BAP1-deficient UM cells. Furthermore, the loss of BAP1 leads to aberrations in the histone landscape, including alterations in H3K4me3, H3K4me1, H3K27ac, and H3K27me3, as well as chromatin remodeling at functional genomic elements, accompanied by changes in chromatin accessibility.
Weniger anzeigenThe remarkable morphological diversity observed across the animal kingdom is a result of the evolutionary modifications of developmental processes. A striking example of such diverse morphologies is the tetrapod limb where profound phenotypic adaptations enabled species to colonize diverse terrestrial, aquatic, and aerial habitats. This organ thus provides a compelling model for examining the cellular mechanisms driving such diversification. Among mammals, powered flight evolved uniquely within the order Chiroptera, commonly known as bats. This remarkable ability is attributed to their wing structure, which is characterized by massively elongated digits connected by a specialized tissue membrane, the chiropatagium, a distinctive feature found only in this species. However, the molecular origins and the extent of developmental reprogramming necessary to achieve this dramatic morphological adaptation remain poorly understood. To address this, we employed comparative single-cell and functional genomics approaches to investigate limb developmental cell states in both mice and bats. Our analysis revealed a significant conservation of cell states and processes across species. In contrast to previous hypotheses, this also included the process of interdigital apoptosis, which typically eliminates interdigital tissue in species with separated digits. Through microdissection of embryonic chiropatagium and subsequent single-cell transcriptomics profiling of this tissue, we discovered that the chiropatagium originates from fibroblasts that are distinct from apoptosis-related interdigital cells. We furthermore revealed that these fibroblasts in the distal, autopodial limb region repurpose a developmental program otherwise found in the proximal limb. Genes expressed in this chiropatagium cell program showed enrichment in functions related to cell proliferation, migration, and extracellular matrix organization, highlighting the significance of these processes in wing development. Functional genomics and gene network analyses identified the developmental transcription factors MEIS2 and TBX3 as key regulators of this cell program. Importantly, ectopic expression of these genes in distal mesenchymal cells of transgenic mice led to the activation of genes linked to chiropatagium development. As a result, mutant limbs exhibited significant morphological changes, including increased cell number, enhanced extracellular matrix content, and retention of interdigital tissue. Lastly, the bat MEIS2 and TBX3 regulatory landscapes revealed significant differences in enhancer activity and 3D chromatin structure, suggesting species-specific genomic features that mediate their activity during wing formation. Altogether, our findings unravel fundamental molecular mechanisms underlying bat wing development and demonstrate how drastic morphological changes, such as the emergence of a wing, can arise from the repurposing of existing developmental programs.
Weniger anzeigenEukaryotic cells employ membrane-bound compartments to spatially organize their internal components. However, the recent discovery of biomolecular condensates, liquid-like structures not limited by a membrane, has emerged as a novel mechanism for cellular organization. These condensates often assemble by liquid-liquid phase separation (LLPS), a phenomenon in which an initially homogeneous liquid mixture spontaneously separates into two (or more) distinct liquid phases. LLPS is emerging as an important principle for understanding the organization and dynamics at the synapse and cellular pathology in neurodegeneration. For instance, synaptic vesicle (SV) clusters are shown to assemble via condensation of synapsins, a highly abundant family of synaptic phosphoproteins, and SVs. This thesis investigates the roles of α-synuclein, a protein involved in the SV cycle and implicated in the pathology of Parkinson's disease (PD), in modulating biomolecular condensates and their interplay with membrane-bound organelles. The first part of the thesis examines the contribution of α-synuclein to maintaining SV clusters. α-Synuclein enriches the liquid phase of SVs/synapsin, preserving their biophysical properties while maintaining high mobility. The results show that the presence of SVs enhances the condensation rate between synapsin and α-synuclein, indicating that SVs act as catalysts for synapsin condensate formation. Importantly, α-synuclein alone is unable to cluster isolated SVs under physiological conditions, emphasizing the importance of the synapsin/α-synuclein molar ratio in assembling functional and physiological condensates. The second part of the thesis focuses on understanding the aberrant LLPS process that leads to the formation of α- synuclein-containing protein aggregates, specifically Lewy bodies (LBs). LBs are associated with synucleinopathies like PD. By employing a minimal system comprising α-synuclein and synphilin 1, another protein implicated in PD, LB-like structures (LBLs) are recapitulated. Remarkably, synphilin 1 can independently form fluid condensates, while α-synuclein envelops these condensates, forming a core-shell structure resembling LBs. Additionally, LBLs disrupt the fibrillar actin network and accumulate membrane-bound organelles, leading to mitochondrial collapse and their accumulation at the interface of the aggregates. These observations highlight the connection between α-synuclein-driven aberrant phase separation and the formation of membrane-containing inclusions. Together, this thesis contributes to our understanding of the intricate dynamics and functional consequences of biomolecular condensates, specifically focusing on the role of α-synuclein in modulating their formation and interplay with membrane-bound organelles. The findings presented here deepen our understanding of the molecular mechanisms underlying neurodegenerative disorders, particularly PD, and pave the way for future research aimed at developing therapeutic interventions targeting these aberrant processes.
Weniger anzeigenThe book examines the changing approach of courts in reviewing foreign affairs decisions of the executive. Traditionally, the judiciary awarded deference to executive decisions in that area, a notion that clashes with the idea of general judicial oversight in the modern constitutional state. As the problem is often looked at solely from a national angle, this thesis chooses a comparative approach taking into account the development in three democratic countries to identify general trends as well as differences. Thereby, it shows the development of a new judicial approach, which does not per se defer to executive assessments in the field.
Weniger anzeigenThis thesis presents advances in the description of quantum magnets, primarily through the development of a new method called the pseudo-Majorana functional renormalization group (PMFRG). The PMFRG is capable of accurately describing strongly interacting quantum magnets in challenging scenarios where most other methods fail.
Fundamental to the formalism of the PMFRG is a resummation of Feynman diagrams, which allows direct treatment of the many-body problem in the thermodynamic limit of infinitely many particles. While exact resummation schemes are impossible, the PMFRG uses the framework of the renormalization group to perform a numerical summation of several classes of diagrams to infinite order. Notable examples of such diagrams are associated with common phenomena such as magnetic order, as well as more exotic quantum spin liquids, which are phases described by emergent gauge theories and fractionalization. To exploit this advantage, spin operators for which diagrammatic techniques are limited are mapped to auxiliary Majorana fermions. This mapping proves to be advantageous compared to the more commonly used complex fermions. After establishing its formalism, the PMFRG is applied to paradigmatic problems in the field of frustrated magnetism at finite temperature. The numerical results obtained with the PMFRG are shown to be quantitatively accurate, typically providing errors of less than 10% compared to exact solutions. In particular, the PMFRG remains applicable to more general scenarios of frustrated three-dimensional magnets where exact solutions are unavailable, and where most other methods are infeasible.
In addition, this thesis investigates emergent higher-rank gauge theories with immobile quasiparticle excitations known as fractons. The physics of several pinch point features associated with these gauge theories is then analyzed. Using the PMFRG, it is found that these phases are very fragile under the inclusion of quantum fluctuations. Finally, a new fracton spin model is constructed that exhibits an exactly soluble point with a spin liquid phase. The stability of this phase is then verified by numerically exact quantum Monte Carlo simulations of the spin model compared to the analytical solution of the emergent rank-2 lattice gauge theory, making it the first two-body spin model with an emergent fracton quantum spin liquid. The following chapters therefore present substantial progress in two important areas: numerical solutions of the quantum many-body problem and the study of emergent gauge theories in spin systems.
Weniger anzeigenDie klassischen Prognosefaktoren wie FIGO-Stadium und makroskopische Tumorfreiheit konnten als die wichtigsten Prognosefaktoren für Langzeitüberleben mit Ovarialkarzinom bestätigt werden. Zu den positiven prognostischen Faktoren zählten auch das Ansprechen auf die platinbasierte Therapie, während Aszites und das Auftreten von Rezidiven prognostisch negativ waren. Bezüglich des Tumorbefallmusters war ein Befall des oberen Abdomens bei Langzeitüberlebenden auch nach Matching für die wichtigsten Prognosefaktoren seltener im Vergleich zur Kontrollgruppe. Polypharmazie war nicht mit dem Gesamtüberleben assoziiert, es bestand jedoch eine positive Korrelation mit dem progressionsfreien Überleben. Neben den klassischen klinischen Prognosefaktoren sind auch Lebensqualität und Tumor- bzw. Therapie-assoziierte Symptomen von Bedeutung. Sowohl Chemotherapie-induzierte Übelkeit und Erbrechen als auch Schmerzen waren mit einem schlechteren Gesamtüberleben assoziiert. Dies ist vor allem therapeutisch interessant und es sollte in zukünftigen Studien prospektiv evaluiert werden, ob eine suffiziente Therapie von Krebs- und Therapie-assoziierten Symptomen nicht nur die Lebensqualität, sondern auch das Überleben von Ovarialkarzinompatientinnen verbessern kann. Die Charakterisierung von Langzeitüberlebenden mit Ovarialkarzinom und die Identifikation von Prognosefaktoren sollten sowohl klinisch als auch auf molekularer Ebene weiterverfolgt werden, um die Erkenntnisse zukünftigen Patientinnen zugutekommen zu lassen, z.B. im Hinblick auf eine personalisierte Medizin. Langzeitüberleben bedeutet nicht automatisch geheilt oder gesund zu sein. Knapp die Hälfte der Langzeitüberlebenden hat (mindestens) ein Rezidiv entwickelt und ein Teil der Patientinnen befindet sich unter Krebstherapie. Auch leidet fast jede zweite Langzeitüberlebende mit Ovarialkarzinom noch an körperlichen bzw. psychischen Spätfolgen, wie z.B. Lymphödemen, Fatigue, Distress oder neurologischen Langzeitnebenwirkungen. Auch Zweitkarzinome sind eine nicht zu unterschätzende Spätfolge. Neben der Erkennung von potenziellen Rezidiven gehören daher auch die Diagnostik und Behandlung von Spätfolgen, aber auch die Prävention zu den Säulen der Nachsorge bzw. Survivorship Care. Die große Herausforderung ist die Koordination der einzelnen Disziplinen und Stakeholder. Ein individueller Survivorship Care Plan, der gemeinsam mit der Patientin erstellt werden sollte, kann die wichtigsten Behandlungsziele für die Patientin zusammenfassen und stellt eine Grundlage für eine transparente interdisziplinäre Versorgung der Langzeitüberlebenden dar. Ob eine multidimensionale spezialisierte Survivorship Sprechstunde die Lebensqualität und den Gesundheitszustand verbessern kann, wird derzeit in der Versorgungsforschungsstudie Survivorship Clinic untersucht (www.survivorship-clinic.de). Die Erkenntnisse aus den Studien über Langzeitüberleben mit Eierstockkrebs sollten genutzt werden, um auch die Versorgung der Patientinnen innerhalb der ersten fünf Jahre nach der Krebsdiagnose zu verbessern. Ziel ist es, durch eine holistische Versorgung bereits ab der Krebsdiagnose die Lebensqualität, den Gesundheitszustand und das Überleben nachhaltig zu verbessern. Langfristig angelegte Interventionsstudien mit Beginn zum Zeitpunkt der Diagnose wären hier wünschenswert, sind aber auch sehr kostenintensiv. Es gibt erste vielversprechende Studien, die neben der Krebstherapie bei Erstdiagnose auch den Einfluss von physischer Aktivität, Ernährung und Gesundheitskompetenz auf den Therapieerfolg und die Lebensqualität untersuchen. Hier seien die KORE-Studie und die BENITA-Studie als Beispiel für holistische Konzepte genannt. Solche Forschungsaktivitäten sollten langfristig fortgeführt und finanziert werden, um die Versorgung unserer Patientinnen nachhaltig zu verbessern.
Weniger anzeigenDie vorliegende Habilitationsschrift befasst sich mit Behandlungsstrategien der periprothetischen Infektion des Hüftgelenks. Diese Infektionen sind mit langen Behandlungszeiten, hohen Kosten und Komplikationsraten verbunden. Ziel der Arbeit war die Evaluierung verschiedener diagnostischer und therapeutischer Konzepte.
Die Studienergebnisse zeigen, dass eine zweizeitige Hüftprothesenimplantation bei septischer Arthritis auch ohne Gelenkspacer vergleichbare klinische und radiologische Ergebnisse liefert. Die Analyse von intraoperativen Proben bei Wechseloperationen aufgrund vermeintlich aseptischer Hüftprothesenlockerung ergab eine unerwartet hohe Rate positiver Befunde, wobei die Abgrenzung zwischen Infektion und Kontamination schwierig ist. Eine weitere Untersuchung befasste sich mit dem zweizeitigen Hüftprothesenwechsel bei chronischen Infektionen mit ausgeprägten Knochen- und Weichteildefekten. Hierbei wurden fehlgeschlagene septische Revisionen, größere femorale Knochendefekte und verlängerte Intervallzeiten als Risikofaktoren für eine Reinfektion identifiziert. Die Anwendung einer erweiterten Trochanterosteotomie beim septischen Prothesenwechsel erzielte vergleichbare Ergebnisse, ging aber mit einer geringeren Anzahl an Débridements einher. Zudem wurde gezeigt, dass eine Infektion eines zementierten Implantates mit einem erhöhten Risiko für eine Reinfektion und erneute Revision assoziiert war.
Diese Arbeit verdeutlicht, dass eine differenzierte diagnostische und chirurgische Vorgehensweise dazu beitragen, die Ergebnisse zu optimieren. Dennoch bleibt die hohe Rate an Reinfektionen und diagnostischen Unsicherheiten eine Herausforderung, die weitere Forschung erfordert, um Muster zu erkennen, die den Behandlungserfolg verbessern.
Weniger anzeigenIncreasing reports of anthelmintic resistance of the liver fluke Fasciola hepatica pose a threat to sheep farming in many countries worldwide. Particularly resistance to triclabendazole, the only flukicide effective against the highly pathogenic juvenile flukes, is of major concern. However, data about the susceptibility of F. hepatica to flukicides in Germany were lacking. Therefore, a field study was conducted from 2020-2022 to evaluate the frequency of F. hepatica on German sheep farms and to test the efficacy of triclabendazole and albendazole by means of a Faecal Egg Count Reduction Test (FECRT) and a Coproantigen Reduction Test (CRT). In advance of the field study, a systemic comparison between three coproscopical methods was conducted in order to determine the most appropriate method for the FECRT. Sufficient fasciolicidal efficacy of albendazole was proven on 1/1 farm and triclabendazole was efficient on 10/11 farms. One one farm, complete failure of triclabendazole, even in double the recommended dose, was observed associated with massive animal losses due to acute fasciolosis. This is the first report of triclabendazole resistance in Germany. The results indicate, that flukicide resistance is not widespread in Germany so far, but the observations clearly illustrate the drastic consequences of triclabendazole resistance. Due to the lack of alternative drugs to eliminate juvenile flukes, triclabendazole resistance should be considered a serious therapy emergency in sheep and resistance might spread in the future.
Weniger anzeigenKardiale Pathologien sind häufige und häufig unentdeckte Ursachen eines ischämischen Schlaganfalls. Gleichzeitig treten nach einem Schlaganfall vermehrt kardiale Komplikationen auf, die einen entscheidenden Einfluss auf die kurz- und langfristige Prognose haben. Neben der Echokardiographie stehen weitere Methoden wie die kardiovaskuläre MRT zur morphologischen und funktionellen Beurteilung des Herzens in der Akutphase nach ischämischem Schlaganfall zur Verfügung. In einer prospektiven Beobachtungsstudie konnten wir zeigen, dass ein kombinierter Einsatz der kardiovaskulären MRT einschließlich MR-Angiographie des Aortenbogens sowie ein prolongiertes EKG-Monitoring die Detektionsrate präspezifizierter pathologischer Befunde im Vergleich zur Routinediagnostik erhöhen und die Rate der als kryptogen klassifizierten Schlaganfälle signifikant reduzieren konnte. In einer zweiten Arbeit wurde die Bedeutung des kardialen Biomarkers Troponin T für das Auftreten kardiovaskulärer Komplikationen im langfristigen Verlauf nach ischämischem Schlaganfall oder TIA untersucht. Hierbei war ein Troponinwert über dem Assay-spezifischen Referenzlimit bei Aufnahme mit einem bis zu zweifach erhöhten Risiko für ein schwerwiegendes kardiovaskuläres Ereignis während eines durchschnittlichen Nachverfolgungszeitraums von über drei Jahren assoziiert. Für bestimmte kardiale Pathologien stellt eine orale Antikoagulation (OAK) die leitliniengerechte Sekundärprävention nach Schlaganfall dar, wobei hier insbesondere das Vorhofflimmern zu nennen ist. Bis Ende 2010 standen hierfür nur Vitamin K-Antagonisten (VKA) zur Verfügung. In einer retrospektiven Analyse untersuchten wir, ob die Verfügbarkeit sog. Nicht-Vitamin K-abhängiger oraler Antikoagulanzien (NOAK) ab 2010/2011 einen Einfluss auf die Verschreibepraxis bei Patient*innen mit Vorhofflimmern und einer Indikation für eine OAK hatte. Während hier annähernd eine Verdopplung der OAK-Rate nachgewiesen werden konnte, blieb dennoch jede*r Zweite ohne adäquate Behandlung. Ischämische Schlaganfälle treten auch bei Patient*innen mit Vorhofflimmern unter bestehender Antikoagulation auf. In einer retrospektiven multizentrischen Analyse betrachteten wir die mutmaßliche Schlaganfallätiologie, Sekundärprävention und Behandlungsergebnisse in einem Kollektiv solcher Patient*innen. Hier zeigte sich, dass jede*r Vierte eine konkurrierende Schlaganfallursache (zusätzlich zum bekannten Vorhofflimmern) aufwies, jede*r Dritte unzureichend antikoaguliert war und nahezu jede*r Zweite einen kardio-embolischen Schlaganfall trotz bestehender (suffizienter) Antikoagulation erlitt. Nach drei Monaten hatte bereits mehr als jede*r Vierte ein schwerwiegendes Folgeereignis erlitten (erneuter Schlaganfall, intrazerebrale Blutung oder Tod), wobei einzig die Einnahme eines NOAK einen protektiven Einfluss aufwies. Abschließend untersuchten wir die Hypothese, dass die Einnahme eines NOAK bei Patient*innen mit bekanntem VHF einen positiven Einfluss auf den Schlaganfallschweregrad haben könnte. Patient*innen mit Einnahme eines NOAK erlitten hierbei signifikant seltener einen schweren Schlaganfall, vergleichbar mit Patient*innen unter wirksamer Einnahme eines VKA. Eine solche Assoziation zeigte sich auch für ein schlechtes funktionelles Behandlungsergebnis bei Entlassung und die Aufenthaltsdauer im Krankenhaus. Die in dieser Habilitationsschrift vorgestellten Arbeiten tragen zum besseren Verständnis der pathophysiologischen Zusammenhänge zwischen Herz und Hirn im Kontext des ischämischen Schlaganfalls bei. Eine erweiterte kardiale Diagnostik erscheint zumindest bei ausgewählten Patient*innen eine sinnvolle Ergänzung. Der kardiale Biomarker Troponin ist mit dem langfristigen Auftreten kardiovaskulärer Rezidiv- und Folgeereignisse assoziiert. Diese Erkenntnisse können Grundlage für weiterführende Studien einer individualisierteren Risikoprädiktion und Sekundärprophylaxe sein.
Weniger anzeigenDie Anzahl der Implantationen inverser Schultertotalendoprothesen (iSTEP) steigt stetig und das Ziel dieser Arbeit ist es Erkenntnisse zur Optimierung der Ergebnisse dieser Operation bei Patienten mit Defektarthropathie zu teilen. Dabei ging es neben dem möglichst reinen Designvergleich auch um die kritische Auseinandersetzung mit objektivierbaren Messmethoden des Prothesendesigns. Des Weiteren wurde im Rahmen der vorhersehbaren Ergebnisoptimierung einer solchen Operation auch eine formal sehr risikobehaftete Population der Ältesten untersucht. Patienten über 85 Jahre, die eine primäre iSTEP erhielten, zeigten eine hervorragende Verbesserung der Schulterfunktion bei niedriger Komplikationsrate. Gute kurzfristige klinische Ergebnisse und eine hohe Patientenzufriedenheit sind zu erwarten und die iSTEP ist selbst bei diesen ältesten Patienten ein sicheres Verfahren mit niedriger Rate an lokalen und systemischen Komplikationen. Beim Vergleich lateralisierter und nicht lateralisierter Implantate für verschiedene Hamada-Stadien der Defekarthropathie war bewusst, dass es beim Vergleich von Prothesendesigns mehrere Störfaktoren gibt, und diese wurden so ausführlich wie möglich beseitigt. Es wurde sorgfältig eine Gruppe von Patienten mit vergleichbarem Status der Rotatorenmanschette, Rotatorenmanschettenrissmuster und Gelenkstatus ausgewählt. Berücksichtigung fand auch die Anatomie des Glenoids und des Scapulahalses und die Positionierung des Implantats, indem mehrere spezifische Parameter gemessen wurden, um bereits bestehende anatomische Unterschiede zwischen unseren Gruppen auszuschließen. Der einzige eindeutig signifikante Unterschied zwischen den Prothesengruppen war der Parameter der Lateralisierung, der einen echten Vergleich zwischen einer lateralisierten und einer nicht-lateralisierten iSTEP ermöglichte. Bei der Aussenrotation und dem Skapulanotching wurden Unterschiede zugunsten des lateralisierten Implantats festgestellt. Mit einem ähnlichen Studiendesign verglichen wir drei Implantate um die Variablen der Lateralisierung und Distalisierung, sowie auch deren Kombination zu untersuchen. In einer großen Stichprobe von 226 Patienten und einer homogenen Verteilung der drei Patientenkohorten mit jeweils gleicher Implantatkonfiguration und Diagnose sowie kontinuierlichem Nachuntersuchungsprotokoll wurde gezeigt, dass der Hals-Schaft-Winkel nicht der einzige wichtige Faktor ist. Verantwortlich für die bessere Funktion bei Patienten mit iSTEP bei Defektarthropathie ist vielmehr das kombinierte Ausmass der Humeruslateralisierung und -distalisierung. Darüber hinaus reduziert die Glenoidlateralisierung in Kombination mit einem Hals-Schaft-Winkel, der niedriger ist als beim ursprünglichen Grammont-Design, das skapuläre Notching, das durch einen suffizienten unteren Überhang der Glenosphäre weiter verringert wird.
Weniger anzeigen