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Introduction: Antiseptics are used for the prophylaxis of infections of acute wounds and for the treatment of critically colonized chronic wounds as well as localized infections of acute and chronic wounds. If an antiseptic with too much tissue toxicity and/or too little efficacy is used, the wound healing can be delayed.
Objective: The aim was to compare the irritation potency of frequently used wound antiseptics by using the hen's egg test on the chorioallantoic membrane (HET-CAM). Additionally, the influence of antiphlogistic active additives which might increase the tolerability was examined. To allow a more extensive comparison, antiseptics classified as obsolete such as hydrogen peroxide, creams on PVP- iodine base, silver sulfadiazine, chlorhexidine and nitrofural as well as the non-antiseptic wound treatment agents dexpanthenol and hemoglobin spray were also examined.
Method: The HET-CAM was used as a semi-in-vivo method to test the tolerability of wound antiseptics to tissues by observing the reactions that occur in the blood vessels of the highly vascularized CAM such as hemorrhage, lysis and coagulation. The irritation score (IS) was calculated and differentiated in 4 ranges according to Spielmann (1991).
Results: The vascular injuries of the CAM were considered as an indirect indicator of the tolerability. It is accepted that agents with no or low irritation potential on the CAM are to be preferred in the clinical practice if they are clinically effective.
Severe CAM reaction was observed after short-term application of octenidine based wound gel (active ingredient octenidine 0.05%) (IS: 10.3) and chlorhexidine digluconate 0.5% solution (IS: 9.5). Moderate reaction was observed for the combination of octenidine 0.05% in aqueous solution with panthenol 1.34% and allantoin 0.2% (IS: 8.7), hydrogen peroxide 1.5% in aqueous solution (IS: 6.1) and hydrogen peroxide 0.5% solution (IS: 5.5). Slight reaction was observed for hydrogen peroxide 1.5% solution in combination with sodium thiocyanate 0.698% (IS: 2.6), sodium thiocyanate 0.698% solution (IS: 2.1) and Dermacyn® (active ingredient NaOCl/HOCl each 0.004) (IS: 1.2). Polihexanide 0.04% in Ringer solution (IS: 0.9), Polihexanide 0.05% in Lipofundin, Granulox® (active agent hemoglobin 10%) (IS: 0) and dexpanthenol 5% solution (IS: 0) showed no reaction. In the long-term observation (24 hours after application), Dermacyn® showed the best results (59% of irritation remained alive after 24 hours). The addition of dexpanthenol and allantoin reduced the irritability only slightly, whereas the decrease of IS of hydrogen peroxide by addition of sodium thiocyanate was almost significant (p 0.0596).
Conclusion: It is suggested that agents with no or low irritation potential on the CAM are to be preferred in the clinical practice if they are clinically effective. It is suggested that further in vivo and in vitro studies are to be undertaken with these agents.
Solely regarding local tolerability, polihexanide and hypochlorite are the antiseptic agents of choice of the tested preparations. The wound oxygenizer hemoglobin spray is tolerated without irritation as well as the negative control 0.9% NaCl solution. Because of their other disadvantages in conjunction with their irritability, the outdated cream formulations on basis of silver sulfadiazine, PVP- iodine, chlorhexidine and nitrofural cannot be recommended for wound antisepsis.
A large portion of the earth's surface is covered with various vegetation classes (i.e. grassland, wetland and agricultural area, forest) of many diverse species and canopy configurations. The ability to assess and to monitor canopy parameters, such as biomass, leaf area index, and vegetation water content, is of vital importance to the study of different agronomic processes. Remote sensing techniques provide a unique capability towards probing different vegetation types and canopy by operating at different bands, observation angle etc. Over the past decades, significant progress has been made in remote sensing techniques of land processes specially vegetation characteristics through development of advanced ground-based, airborne and space-borne microwave sensors, methods and approaches such as theoretical, semi-empirical and empirical models, needed for analyzing the data. These activities have sharply increased in recent years since the launch of different active and passive satellites and sensors. Remote Sensing (RS) science and techniques combined with ground truth data can provide new tools for advanced agricultural crop applications. It has been demonstrated that RS has the ability to estimate biophysical parameters of agricultural crops over time at local, regional, and global scales. In this study, RS images in visible/near infrared (VIS/NIR) domain as well as microwave domain combined with ground truth data were used to assess biophysical parameters of agricultural crop during their whole growing season at Durable Environmental Multidisciplinary Monitoring Information Network (DEMMIN) test site in North East Germany. Ground truth studies were carried out for 31 weeks during 17th April – 13th November 2013 over three crop lands including winter wheat, barley and canola. Landsat 8 OLI, Landsat 7 ETM+ were used for the VIS/NIR studies and TerraSAR-X synthetic aperture radar (SAR) images were used to study biophysical parameters of agricultural crops in microwave part of electromagnetic spectrum. The analysis was conducted by calculating different vegetation indices (VIs) to estimate the biomass (fresh and dry), LAI, and vegetation water content (VWC) of three crops using Landsat 8 OLI and Landsat 7 ETM+ combined with ground truth data. A new concept of Soil Line retrieval from Landsat 8 image was also developed to estimate plant biophysical parameters using soil line related vegetation indices in optical domain of electromagnetic spectrum. Different approaches including univariate, multivariate stepwise regression and semi-empirical water cloud model was also used to estimate the biophysical parameters of agricultural crop using TerraSAR-X data in microwave domain of electromagnetic spectrum. Perhaps the most important conclusion of this study is that the RS approach can provide useful information about estimating agricultural crop parameters over time and local scale, which can therefore provide valuable information to aid the agronomy community.
The aim of the study was to develop and evaluate the reliability and agreement of new computer planimetric method for measurement and assessment of plaque on all types of removable dental prostheses RPDs. The instrument (new method) was tested by evaluating the efficacy of the rotating needles device in cleaning specific parts of RPD. From a database containing 780 images, which were taken in a standardized method for 65 RDPs for 49 participants, 55 images were selected randomly for image analysis. Adobe Photoshop software was used according to a standard operating procedure (SOP) by a main examiner two times in different sessions, and 1 time by 3 other examiners. In order to estimate the intra- and inter-examiner reliability, intraclass correlation coefficients ICC(2,1) was used. Three parameters were used to estimate agreement: standard error of measurement (SEM), smallest detectable change at 95% confidence level (SDC95%), and limits of agreement (LoA) according to Bland¨CAltman method. In the database, only 34 subjects were found with double crown retained removable denture and veneer over the secondary crown. 49x2 (before x after) images for 34 RDPs went under image analyses to calculate POP before and after cleaning the RDPs with the rotating needle device. Data were analysed using Wilcoxon signed-rank test. In all steps of image analysis, both intra-examiner and inter- examiner reliability were excellent with ICC(2,1) values > 0.85 at 95% confidence level. Intra- and inter-examiner values for both, SEM and SDC95% were ¡Ü 6% and ¡Ü17% respectively. The Bland¨CAltman analysis revealed a satisfactory level of agreement. POP is significantly more on the veneer than on the base(B-O), P <0.05. The rotating needles device is effective in cleaning the veneer and base(B-O), P <0.05 with absolute effect size 0.62. No statistical significance was detected in the effectiveness of the rotating needles device between base(B-O) and veneer. This study showed an excellent inter- and intra-examiner reproducibility, satisfactory level of examiners agreement, and acceptable measurement error of the new computer planimetric method . Furthermore, the method can be used with all types of RDPs. The rotating needles device can significantly reduce plaque on the double crown retained removable denture. The Computerized Planimetric Method (CPM) is more suitable for clinical researches because of its objectivity, reliability, high level of standardization, and the ability to detect and quantify small changes in plaque. Extra attention should be given to the veneer over the secondary crown as they are a potential part for RDP plaque accumulation.
Interoceptive sensations, that means, perceptions of the physiological body state, play an important role in the generation and expression of emotion. The focus of the research presented here is on respiratory sensations as specific interoceptive signals. Such respiratory sensations (like the feeling of dyspnea) play an important role in symptom perception in somatic (e.g., asthma) as well as in mental disorders (e.g., anxiety disorders). There are several different ways to manipulate respiratory sensations in an experimental environment, but many of them did not equal sensations in daily life. Here, stimuli (inspiratory resistive loads, caffeine) were used that trigger nearly naturally occurring interoceptive sensations. Taking into account that the elicited interoceptive experience also induces an unpleasant feeling state it is most likely that individuals show defensive physiological responding to such cues and try to avoid them. According to a bidirectional motivational system defensive behaviors are regulated by a defensive motivational system that is activated by threatening cues. From research with exteroceptive stimuli it is known that defensive responding is typically characterized by heightened autonomic arousal, increased respiration, and a potentiated startle eyeblink response. In contrast, only a few studies using interoceptive stimuli have incorporated the measurement of physiological data in their experimental designs. If included, studies show also heightened autonomic responding, whilst a heterogeneous respiratory as well as startle eyeblink responding is observed. Thus, the studies presented here were designed to clarify the factors that mediate defensive responding to interoceptive sensations. Study 1 investigated the influence of anxiety on the subjective, respiratory, and autonomic response to an individually determined inspiratory resistive load, while study 2 focuses on the effect of attentional modulation of the startle eyeblink response to a mild respiratory threat. In study 3 the modulation of subjective, respiratory and autonomic reactions by arousal expectations was examined. Therefore, caffeine, a respiratory stimulant, or a placebo were administered without the participants’ knowledge. The fourth study examined the influence of the process of worrying, a strategy to deal with unpleasant body symptoms, on defensive responding. Depending on the study design subjective, respiratory and autonomic (skin conductance level, heart rate) parameters were assessed as marker for defensive mobilization. In study 2 and 4 the startle eyeblink response was measured as further index of defensive activation. Besides that in study 2 also the P3 component of the event-related potential, as an index for attentional allocation, was recorded. The main findings of the presented dissertation are the following: Study 1 revealed that 1) only high anxiety sensitive individuals reporting also high suffocation fear respond to lower stimulus intensities with stronger defensive responding, and 2) that this group demonstrated a maladaptive compensatory breathing pattern. Additionally, study 2 exhibited that 1) the startle eyeblink response is relatively inhibited during a mild interoceptive threat, and 2) this inhibition corresponds to an attention allocation towards breathing as indicated by a reduced P3 amplitude to the startle noise as well as subjective report. Furthermore, highly anxiety sensitive individuals showed a more pronounced defensive responding if the interoceptive sensations were unexpected (study 3). Recently, study 4 demonstrated that worry led to an increased defensive response mobilization. All studies are discussed in the context of the theoretical background of the defensive response modulation to exteroceptive and interoceptive sensations with respect to mediating factors. Showing exaggerated defensive responding and maladaptive adaptation processes in high anxious individuals the results point towards the important role of interoceptive sensations in the etiology, maintenance and therapy of mental disorders, especially the anxiety disorders.
Abstract
Alkali ion beams are among the most intense produced by the ISOLDE facility. These were the first to be studied by the ISOLTRAP mass spectrometer and ever since, new measurements have been regularly reported. Recently the masses of very neutron-rich and short-lived cesium isotopes were determined at ISOLTRAP. The isotope 148Cs was measured directly for the first time by Penning-trap mass spectrometry. Using the new results, the trend of two-neutron separation energies in the cesium isotopic chain is revealed to be smooth and gradually decreasing, similar to the ones of the barium and xenon isotopic chains. Predictions of selected microscopic models are employed for a discussion of the experimental data in the region.
Existing literature evidences the association between adolescents’ school self-concept and engagement, both concepts being related to students’ perception of teachers and peers as motivators. However, few longitudinal studies explore the interplay of these factors. The present study aims to close this gap, applying latent cross-lagged panel design to two-wave data from German adolescent students [1088 8th grade students at T1 (Mage = 13.7, SD = 0.53; 53.9% girls) and 845 9th grade students at T2 (Mage = 14.86; SD = 0.57; 55% girls) from the initial sample]. Besides direct effects, three cross-lagged over-time paths were found to be significant: students’ perception of peers as positive motivators (PPMs) at the beginning of 8th grade (T1) positively predicts their behavioral school engagement at the end of 9th grade (T2), as well as emotional school engagement at the beginning of 8th grade positively predicts students’ perception of PPMs 1.5 years later. Furthermore, behavioral school engagement at T1 functions as a predictor of a student’s school self-concept at T2.
In this work, the regioselectivity of different Baeyer-Villiger monooxygenases (BVMOs) for the conversion of selected substrates was reversed or improved by protein engineering. These studies highlight the importance of substrate positioning for the regioselectivity and that the position of the substrate can be efficiently influenced by introducing proper mutations. It was shown that the beneficial mutations for all BVMOs were partly in corresponding positions. Additionally, the sulfoxidation activity and the stability of BVMOs were targeted and improved by applying protein engineering.
Resource and cost constraints in hospitals demand thorough planning of operating room schedules. Ideally, exact start times and durations are known in advance for each case. However, aside from the first case’s start, most factors are hard to predict. While the role of the start of the first case for optimal room utilization has been shown before, data for to-follow cases are lacking. The present study therefore aimed to analyze all elective surgery cases of a university hospital within 1 year in search of visible patterns. A total of 14,014 cases scheduled on 254 regular working days at a university hospital between September 2015 and August 2016 underwent screening. After eliminating 112 emergencies during regular working hours, 13,547 elective daytime cases were analyzed, out of which 4,346 ranked first, 3,723 second, and 5,478 third or higher in the daily schedule. Also, 36% of cases changed start times from the day before to 7:00 a.m., with half of these (52%) resulting in a delay of more than 15 min. After 7:00 a.m., 87% of cases started more than 10 min off schedule, with 26% being early and 74% late. Timeliness was 15 ± 72 min (mean ± SD) for first, 21 ± 84 min for second, and 25 ± 93 min for all to-follow cases, compared to preoperative day planning, and 21 ± 45, 23 ± 61, and 19 ± 74 min compared to 7:00 a.m. status. Start time deviations were also related to procedure duration, with cases of 61–90 min duration being most reliable (deviation 9.8 ± 67 min compared to 7:00 a.m.), regardless of order. In consequence, cases following after 61–90 min long cases had the shortest deviations of incision time from schedule (16 ± 66 min). Taken together, start times for elective surgery cases deviate substantially from schedule, with first and second cases falling into the highest mean deviation category. Second cases had the largest deviations from scheduled times compared to first and all to-follow cases. While planned vs. actual start times differ among specialties, cases of 61–90 min duration had the most reliable start times, with neither shorter nor longer cases seeming to improve timeliness of start times.
Pharmaceutical residues are found in increasing concentrations in the environment and in potable water where they have verifiable effects on aquatic life. Conventional methods for water treatment are not able to sufficiently abate these generally stable compounds. It was found that physical plasma generated directly in water can degrade several of these recalcitrant organic pollutants. Studies on the basic plasma chemical processes for the model system of phenol showed that the degradation is primarily caused by hydroxyl radicals. This was confirmed by reaction chemistry and spin trap enhanced electron paramagnetic resonance spectroscopy (EPR). The degradation of diclofenac and its by-products were investigated in detail to perform a first risk-assessment of the new technology. Findings are not limited to the application of plasma but applicable to other advanced oxidation processes (AOP) that are based on the generation of hydroxyl radicals as well. Additionally, pulsed corona plasma and pulsed electric fields were assessed for their capacity to kill Legionella pneumophila in water. Whereas it was possible to kill L. Pneumophila with both methods, plasma treatment resulted in an enhanced bacterial killing. Therefore, advanced oxidation processes (AOP) and plasma treatment in particular are some of the few feasible approaches to decompose recalcitrant compounds in water.
A New Kind of Permutation Entropy Used to Classify Sleep Stages from Invisible EEG Microstructure
(2017)
The intracellular life cycle of the human immunodeficiency virus (HIV) is modelled using ordinary differential equations (ODEs). Model parameters are obtained from the literature or fitted to experimental data using parameter estimation procedures. Key steps in the life cycle are inhibited singly and in combination to show the effects on viral replication. The results validate the success of highly active antiretroviral therapy (HAART), and in addition DNA nuclear import is identified as a novel influential therapeutic target.
In this work, the discovery, expression and characterization of new eukaryotic Baeyer-Villiger monooxygenases (BVMOs) from yeasts has been shown. A rational design of one of these enzymes led to the identification of key residues to alter the sulfoxidation activity of this group of enzymes. Additionally, in another rational design approach, the cofactor specificity of the BVMO cyclohexanone monooxygenase from Acinetobacter calcoaceticus could be substantially altered to accept the much cheaper and therefore industrially more relevant cofactor NADH.
Body sensations play a crucial role in the etiology and maintenance of diverse anxiety and health problems (e.g., in panic disorder or respiratory diseases) as they may be perceived as threatening and consequently elicit anxious responses. The factors that may affect the perception of bodily sensations as a threat and thus modulate the anxious response to body sensations have so far rarely been studied. Therefore, the present thesis targeted at elucidating the effect of contextual (i.e., the predictability, expectation, and proximity of a threat) and dispositional factors (i.e., tendency to fear arousal sensations or trait fear of suffocation) on the defensive response to body sensations.
In study 1, it was investigated how a personality factor, that is, fear of suffocation, affects the acquisition of fear to body sensations (i.e., mild dyspnea induced by inspiratory resistive loads) and contexts when faced with a predictable and unpredictable respiratory threat (i.e., severe dyspnea). Study 2 aimed at examining the main and interactive effects of the tendency to fear arousal sensations, again a personality trait factor, and current arousal expectations as varied by situational variables on anxious responding to arousal sensations. In this study, expected and unexpected arousal sensations were induced by administering caffeine in coffee or bitter lemon soda, respectively. Moreover, in study 3, it was explored how subjective anxiety, bodily symptoms, and defensive respiratory responses change and might culminate into active defense behavior (i.e., escape/active avoidance) during increasing dyspnea that was evoked by inspiratory resistive loads increasing in intensity. For a detailed analysis of the factors that contribute to the initiation and maintenance of avoidance of or escape from increasing dyspnea, in study 4 changes in subjective, autonomic, somatic reflex and brain responses were analyzed during repeated avoidance of increasing dyspnea.
In study 1, it was demonstrated that only individuals who fear suffocation learned to fear mild dyspnea preceding the onset of severe dyspnea and developed anxiety during a context of unpredictable respiratory threat. Moreover, the data from study 2 indicate that individuals who fear arousal sensations show an increased attention allocation towards unexpected arousal sensations and higher threat appraisal when expecting arousal sensations. Increasing intensity of dyspnea as provoked in study 3 led to increased defensive respiratory responses that were associated with increased symptom reports in individuals with high compared to low fear of suffocation. Moreover, culminating dyspnea elicited repeated avoidance behavior preceded by increases in defensive respiratory mobilization. The analysis of repeated avoidance of increasing dyspnea in study 4 revealed that physiological fear responses might be involved in the initial initiation of this avoidance behavior while no indication of response preparation and physiological arousal was related to persistent avoidance.
Taken together, the present data suggest that the fear of suffocation, as well as the tendency to fear arousal sensations along with the predictability, expectation, or proximity of interoceptive threat, may increase the perceived threat and thus the anxious response to body sensations. Therefore, contextual and dispositional factors may set the stage for the culmination of body sensations into defensive action and might contribute to the development of pathological anxiety and fear of body sensations. The present findings are integrated into the current literature and discussed in relation to the development and maintenance of pathological anxiety and fear of body sensations.
The M protein of Streptococcus canis (SCM) is a virulence factor and serves as a surface-associated receptor with a particular affinity for mini-plasminogen, a cleavage product of the broad-spectrum serine protease plasmin. Here, we report that SCM has an additional high-affinity immunoglobulin G (IgG) binding activity. The ability of a particular S. canis isolate to bind to IgG significantly correlates with a scm-positive phenotype, suggesting a dominant role of SCM as an IgG receptor. Subsequent heterologous expression of SCM in non-IgG binding S. gordonii and Western Blot analysis with purified recombinant SCM proteins confirmed its IgG receptor function. As expected for a zoonotic agent, the SCM-IgG interaction is species-unspecific, with a particular affinity of SCM for IgGs derived from human, cats, dogs, horses, mice, and rabbits, but not from cows and goats. Similar to other streptococcal IgG-binding proteins, the interaction between SCM and IgG occurs via the conserved Fc domain and is, therefore, non-opsonic. Interestingly, the interaction between SCM and IgG-Fc on the bacterial surface specifically prevents opsonization by C1q, which might constitute another anti-phagocytic mechanism of SCM. Extensive binding analyses with a variety of different truncated SCM fragments defined a region of 52 amino acids located in the central part of the mature SCM protein which is important for IgG binding. This binding region is highly conserved among SCM proteins derived from different S. canis isolates but differs significantly from IgG-Fc receptors of S. pyogenes and S. dysgalactiae sub. equisimilis, respectively. In summary, we present an additional role of SCM in the pathogen-host interaction of S. canis. The detailed analysis of the SCM-IgG interaction should contribute to a better understanding of the complex roles of M proteins in streptococcal pathogenesis.
Abstract
This work reports on the spatio-temporal characterization of the multiple current pulse regime of diffuse barrier discharges driven by sine-wave feeding voltage at a frequency of 2 kHz in helium with small nitrogen admixtures. The discharge gap of 3 mm is bounded by glass plates on both plane electrodes. Priority is given to the lateral discharge inhomogeneities, underlying volume- and surface-memory effects, and the breakdown mechanism. Therefore, relevant processes in the discharge volume and on the dielectric surfaces were investigated by ICCD camera imaging and optical emission spectroscopy in combination with electrical measurements and surface charge diagnostics using the electro-optic Pockels effect of a bismuth silicon oxide crystal. The number of current pulses per half-cycle of the sine-wave voltage rises with increasing nitrogen admixture to helium due to the predominant role of the Penning ionization. Here, the transition from the first glow-like breakdown to the last Townsend-like breakdown is favored by residual species from the former breakdowns which enhance the secondary electron emission during the pre-phase of the later breakdowns. Moreover, the surface charge measurements reveal that the consecutive breakdowns occur alternately at central and peripheral regions on the electrode surface. These spatial inhomogeneities are conserved by the surface charge memory effect as pointed out by the recalculated spatio-temporal development of the gap voltage.
Coastal and marginal seas – like the Baltic Sea – serve as natural reaction sites for the turnover and accumulation of land-derived inputs. The main location for the modification and deposition of the introduced material is, in most cases, not the water mass, but the sediment. Its key function as central reactor in the interaction between land and sea has so far been insufficiently studied and assessed. This study was part of the interdisciplinary SECOS project that aimed to identify and evaluate the service functions of sediments in German coastal seas in the context of human use with a focus on the Baltic Sea. One of its goals was to assess sediment functions related to the intermediate storage or final sink of imported material like nutrients and contaminants, and quantify their inventory as well as their mass accumulation rates on multi-decadal to multi-centennial time scales. For that, a detailed examination of the natural and anthropogenic processes that interfere with sediment accumulation in the south-western Baltic Sea basins is essential.
The four stranded G-quadruplexes are important secondary structures of nucleic acids formed by guanosine-rich sequences. Besides the application as scaffold for technological applications, they are involved in many cellular processes such as gene regulation, replication, or maintenance of chromosomal ends. Characteristically, a large diversity of quadruplex structures is observed, whereas the correlation between sequence and structure is still not fully understood. In this thesis, the effects of modified nucleotides on G-quadruplexes were analyzed using NMR-spectroscopy to gain insight into driving forces determining the folding process. Contrary to DNA quadruplexes, the folding landscape of RNA structures is mostly restricted to parallel topologies. Therefore, ribose moieties were introduced into DNA sequences to isolate the effect of the additional hydroxy group. In this way, sequential CHO hydrogen bonds between the 2′-OH and the H8 of the 3′-neighbored anti conformer were identified and subsequently detected within RNA structures. In a second part, 2′-fluoro-2′-deoxyribose was incorporated at positions with guanosine in unfavored syn orientation. Instead of a changed global fold, the direction of the hydrogen bond network in the modified tetrad was reversed. This first example of tetrad inversion within a unimolecular quadruplex yielded a unique (3+1)-hybrid topology with only homopolar stacking interactions. Additionally, the effect was reproduced for another sequence and high-resolution structures were determined. Unfavored interactions between the 2′-fluorine and the narrow groove of the quadruplex were identified as a reason for different sugar conformations and consequent structural rearrangements.
Foot-and-mouth disease virus (FMDV) is a positive-sense RNA virus of the family Picornaviridae that comprises of seven serotypes and is distinguished by a high contagiosity with the ability of rapid spread. Strategies for abatement and control are based on an early detection, quick initiation of retaliatory actions and mass vaccinations. Therefore, aim of the study was the development of a fast and easy method for genome sequencing as well as an investigation into the causes, why some cell lines that are mainly used for vaccine production, are resistant towards FMDV infection. Finally, adaptive sequence changes in different cell culture systems and associated effects on particle stability and immunogenicity were examined.
In case of an outbreak it is of major importance to detect and rapidly characterize the circulating virus isolate to choose an appropriate vaccine to minimize the viral spread. In addition, comprehensive genome analysis of the outbreak strain provides information about the origin of the virus and allows molecular epidemiology. A universal primer set, covering most parts of the open reading frame of the viral genome, was developed to perform quick sequence analyses, independently of the viral serotype (Paper I). Especially in endemic regions, vaccination of susceptible animal species is the main action to combat foot-and-mouth disease (FMD) in an acute outbreak situation as well as a preventive measure. Reasons, why some baby hamster kidney (BHK) cell lines are resistant towards an infection with FMDV, were examined in a second study that narrowed down the cause for this phenomenon to an impaired attachment of the virus to the cell surface. Furthermore, an alternative approach could be developed to successfully adapt the virus to the resistant vaccine-production cell line by using a FMDV-sensitive “wet-nurse” cell line (Paper II). Adaptive changes in the capsid-coding region of the viral genome caused through cultivation and passaging of the virus in different BHK cell systems were the topics of the third study. It was shown that capsid alterations are rather serotype-specific and dependent on the cell line used than influenced by the cell media. Viral titers and neutralization profiles of the adapted isolates were not affected compared to the original viruses (Paper III).
Overall, this work expanded our knowledge on the control and eradication of FMD and will support the global effort to combat the disease.
The thesis is about ideological change of political parties and the way parties gather information, learn by updating their beliefs and ultimately make "rational choices". Analyzing 1451 policy moves of 137 parties in 22 OECD-countries from 1950 to 2013 it is a story about rational learning, about emulating other parties abroad and chasing public opinion. Yet, the "internal life" of a party conditions the effects when activists have some influence over the formation of party policy. As volunteers facing a scarcity of time and resources, members of the party on the ground have a different information horizon, and may arrive at the opposite decision where to move than party elites which (can) rest their decision on a broader set of information resources. In some parties the party on the ground thus constitutes an "internal wall of resistance" to the strategy party elites would choose, if they were free from constraints.
The thyroid as the largest endocrine gland mainly produces and secretes the thyroid hormones (TH): 3,3’,5-triiodo-L-thyronine (T3) and its pro-hormone L-thyroxine (T4). Besides the impact on growth, normal development, bone marrow structure, the cardiovascular system, body weight and thermogenesis, TH play a vivid role in many metabolic regulatory mechanisms in almost all tissues. Thyroid diseases are relatively prevalent and cause, due to the resulting TH imbalances, a broad spectrum of effects. Many of them manifest in pathologically increased or decreased TH levels defined as hyperthyroidism or hypothyroidism, respectively. Routinely, determination of the thyroid state is based on the assessment of the classical markers TSH and free T4. However, this practice has several drawbacks. Moreover, elucidation of the pleiotropic effects of TH on multiple molecular pathways is mostly based on cell culture, tissue and rodent models. Analysis of animal biofluids like serum and urine using metabolomics approaches demonstrated the extensive impact of TH on other body compartments. In contrast, proteome profiling has not been exploited for the comprehensive characterization of the general metabolic effects of TH. Plasma as a large and diverse compartment of the human proteome provides a great opportunity to identify novel protein markers of thyroid function as well as to characterize metabolic effects of TH in humans.
Therefore, a study of experimental thyrotoxicosis was performed with 16 male volunteers treated with 0.25 mg/d levothyroxine (L-T4) for 8 weeks to induce a hyperthyroid state. Plasma samples were collected before the L-T4 application started, two times during the treatment and additionally two times after withdrawal. Proteome analysis revealed remarkable alterations including increased levels of two known proteins known to correlate with TH levels (sex hormone-binding globulin and cystatin C). The correlation with free T4 levels revealed 76 out of 437 detected proteins with a Pearson correlation coefficient of r ≥ |0.9|. One prominent signature included 10 coagulation cascade proteins exhibiting significantly increased plasma levels during thyrotoxicosis, thereby revealing a trend towards a hypercoagulative state in hyperthyroidism. To overcome the statistical drawbacks of the Pearson correlation analysis, additionally a mixed-effect linear regression model using serum free T4 concentrations as exposure and protein abundances as outcome while controlling for age, BMI, and batch was implemented. Application of this model resulted in the detection of 63 proteins with significant associations to free T4 levels. Besides the already mentioned augmented coagulation, a significant drop in the amounts of three apolipoproteins (ApoD, ApoB-100 and ApoC3) was observed. Furthermore, an increased abundance of proteins assigned to the complement system was detected.
Experimental studies in humans were complemented by corresponding analyses in murine models. In the current work, plasma samples of two murine studies including male C57BL/6 wildtype mice were analyzed to elucidate the impact of thyroid dysfunction on the plasma proteome. The first study was similarly designed as the human model of experimentally induced thyrotoxicosis and assigned the animals to three groups: a control group, a T4 treatment group, and a T4 recovery group, whereupon the latter first received T4 followed by a subsequent TH normalization period. A high proportion of plasma proteins exhibited significantly different protein levels during T4 application (n = 120), where 90 of these also showed a corresponding reverse trend after T4 withdrawal (T4 recovery vs. T4), thereby displaying transient alterations. The molecular pattern of hyperthyroidism in the murine model indicated, as in the human study, a pronounced decrease in apolipoproteins. However, in clear contrast to the human data, the levels of proteins related to the coagulation cascade and complement system were also transiently decreased in mice, while being increased in humans.
The second murine analysis focused on the impact of hyper- and hypothyroidism caused by T3 or T4 treatment and MMI/KClO4 application, respectively. In general, compared to the first murine study less clear alterations of protein levels were detected. Proteins related to the complement system revealed fewer changes in the T3 group and only marginal changes after T4 induction. Unexpectedly, the MMI/KClO4-induced hypothyroidism caused a reduction of the levels of several proteins assigned to the complement system, although different components and factors were affected.
Generally, rodent studies partially provided a divergent picture of TH action as compared to human studies. However, in spite of inconsistent results in studies regarding the effects of TH that are possibly due to species-specific differences, an important role of TH on several metabolic and other pathways, e.g. in the process of blood coagulation and apolipoprotein regulation, is evident. The results from both murine and human studies presented here provide novel insights into changes in the plasma proteome in the context of thyroid diseases which might contribute to a better understanding of TH action on metabolism and other pathways.
Inwiefern ist es strafbar, Schülern den Gang zur Toilette während des Unterrichts zu verbieten?
(2017)
Since its introduction in 2006, the NOD/scid mouse model has greatly contributed to the understanding of the pathomechanisms of antibody-mediated thrombocytopenia. This progress has however been hampered by inter-laboratory differences. With this work, we make several suggestions to minimise these differences:
We suggest that human platelets (blood group 0) be injected into the mice (age- and sex-matched, 8-16 weeks) via the tail vein. For antibody injection, scientists may choose between intraperitoneal and tail vein injection, each of which has strengths and drawbacks. In case of low antibody titer or low avidity antibodies, preincubation of the platelets with the patient serum prior to injection promotes platelet elimination where standard protocols fail. For subsequent sample preparation, we found that newly-launched ready-to-use kits present a good alternative to classical density gradient centrifugation by reducing man-hours and turnover time without affecting the quality of flow cytometry analysis.
In a second part, we used the revised mouse model to study anti-CD36 mediated thrombocytopenia in vivo. Anti-CD36 antibodies have been suggested as frequent case for FNAIT in Asia. The mechanisms behind this remain partly unclear. After injecting anti-CD36 monoclonal antibody or anti-CD36 patient immunoglobulin into the system, circulating human platelets were rapidly cleared. Interestingly, the polyclonal patient immunoglobulins used were not uniform in their anti-platelet reactivity. On further examination, we found that the anti-CD36 antibodies induce platelet activation and aggregation, which we were able to inhibit by the addition of an Fcγ-receptor blocking agent. This suggests a possible role for Fcγ-receptor in the activation and elimination process.
As our results from the experiments on the role of complement in the elimination process are however ambiguous, further studies are needed. The clinical relevance of anti-CD36 antibody-mediated platelet activation and aggregation for the high abortion rates in affected women has yet to be evaluated.
Numerous signalling pathways orchestrate the development, the functions, and the survival of cells, mostly in response to external stimuli. An overwhelming amount of data supports the concept of specific, spatio-temporal redox signalling pathways that affect the redox state of protein cysteinyl side chains and thus the biological function of these proteins. Glutaredoxins (Grxs) and thioredoxins (Trxs) catalyse reversible thiol-disulphide exchange reactions. The cytosolic Grx2 isoform Grx2c is essential for brain development and axonal outgrowth. A reversible dithiol-disulphide switch of CRMP2 has been identified as one of the major targets regulated by Grx2c. This CRMP2 redox switch is toggled in neuronal differentiation. Reduction of CRMP2 thiols induces profound conformational changes, modifying interactions and downstream elements of this redox switch. In [article I] and [manuscript V], we identified the Cys504 of CRMP2 to be the redox regulated residue. We used various in vitro assays with recombinant protein and molecular dynamics simulations to characterise the conformational change. The changes involve the solvent accessible surface area of at least one known phosphorylation site at the C-terminus of the protein. In [article III], we analysed the function of Grx2 and Trx1 in a model for perinatal asphyxia. Trx family proteins exhibit a very complex, cell-type and tissue specific expression pattern following hypoxia/ischemia and reoxygenation, especially Trx1 and Grx2. The results imply the clinical relevance for both proteins in perinatal asphyxia as well as many other neurological disorders. In agreement with the results presented in [articleI], Grx2 may be required for the re-establishment of neuronal integrity and connectivity. Cell shape, all forms of intracellular transport, and cell movement depend on the cytoskeleton, particularly on the fine tuned complex regulation of the dynamic re-arrangement of actin filaments and microtubules. In [article IV], we discuss the redox regulation of this dynamic cytoskeletal remodelling. Taking recent discoveries into account, we focus on redox signalling mechanisms, e.g. reversible thiol and methionyl switches. These switches are specifically controlled by enzymes such as Trx1 and Grx2c, for instance, and not the result of random modification by unspecific oxidants. Methionyl sulphoxidation of actin can be reversed by methionyl sulphoxide reductase (MsrA), promoting actin polymerisation. Human cells express two different Msr enzymes (MsrA and MsrB), that can reduce S- and R-methionyl sulphoxide, respectively. In the gram-positive Streptococcus pneumoniae, on the other hand, both Msr genes and thus enzymes were fused during evolution. In [article II], we characterised the surface-exposed thioredoxin family lipoproteins Etrx1 and 2 and regulators of this Msr (SpMsrAB). A loss of function of both Etrx proteins or SpMsrAB dramatically reduced pneumococcal virulence, enhanced the bacterial uptake by macrophages, and accelerated pneumococcal killing by H2O2 or free methionine sulphoxide. Identification and characterisation of components of this redox regulated system may contribute to the design of new antimicrobials. In [manuscript VI], we investigated the effects of Grx2c expression on cell morphology, migration, and invasion behaviour of cancer cells. Grx2c expressing cancer cells developed dramatic changes in phenotype, including alterations in cytoskeletal dynamics and significantly increased motility and invasiveness. We used quantitative proteomics and phopshoproteomic approaches to characterise the underlying mechanisms. Proteins and pathways regulating cytoskeletal dynamics, cell adhesion, and receptor-mediated signal transduction were detected to be specifically altered. We started a clinical pilot study with patients suffering from clear cell renal cell carcinoma (ccRCC). Grx2c was expressed with significantly higher frequency in ccRCC compared to healthy kidney tissue, associated with a strong trend for locally more advanced tumour stages and a clear tendency for a decreased cancer-specific survival, compared to patients without detectable Grx2c. These results were supported by data from "The Cancer Genome Atlas". In synopsis, the results presented and discussed in these articles and manuscripts, support the concept of specific redox signalling in different models and model organisms. They also demonstrate the importance of the specific redox control of signalling pathways that, in the case of errors or misinterpretations, contribute to pathophysiological alterations. The regulation of the CRMP2 redox switch by Grx2c, for instance, is physiologically essential for brain development, but might lead to cancer progression, if "switched on" in adult tissue. Identification of further interaction partners as well as the development of compounds modulating this redox switch and CRMP2s conformations, will be part of our future research.
: Human osteosarcoma (OS) is the most common primary malignant bone tumor occurring
most commonly in adolescents and young adults. Major improvements in disease-free survival have
been achieved by implementing a combination therapy consisting of radical surgical resection of the
tumor and systemic multi-agent chemotherapy. However, long-term survival remains poor, so novel
targeted therapies to improve outcomes for patients with osteosarcoma remains an area of active
research. This includes immunotherapy, photodynamic therapy, or treatment with nanoparticles.
Cold atmospheric plasma (CAP), a highly reactive (partially) ionized physical state, has been shown
to inherit a significant anticancer capacity, leading to a new field in medicine called “plasma oncology.”
The current article summarizes the potential of CAP in the treatment of human OS and reviews the
underlying molecular mode of action.
Introduction: Ketamine (KET) is widely used as anaesthetic drug. Beside its pronounced an-aesthetic effects as caused by antagonism of NMDA receptors, ketamine also causes potent analgesia. Moreover, There are ample new evidences, firstly, that 2R,6R/2S,6S-enantiomers of hydroxynorketamine (HNK), exert neuro-modulating effects by AMPA-receptor activation and, secondly, that the plasma levels of norketamine (n-KET) after oral dosing are higher than after intravenous administration. From the physicochemical point of view ketamine is expected to be a substrate of drug transporters. Thus, it was the aim of this study to separate and quantify KET and its metabolites in human serum, urine and feces; investigate the role of transporter proteins in the intestinal absorption, distribution and elimination of ketamine; and evaluate pharmacokinetics and metabolism of a newly developed prolonged-release keta-mine dosage form to confirm its suitability for chronic treatment of CNS-diseases (e.g. de-pression) according to the new “ketamine metabolite paradigm”. Materials and methods: Quantification of ketamine was done by a LC-MS/MS-based quantifi-cation method on the QTRAP4000 instrument. Samples were extracted by methyl tert-butyl ether after addition of sodium carbonate to liberate the free base; Single transfected MDCKII cells overexpressing OCT1, OCT2, OCT3, and MATE1 or MATE2K, and HEK293 cells over-expressing OATP2B1 were used to study the cellular uptake of ketamine. Inside-out lipovesi-cles were used to determine the affinity of ketamine to the efflux transporter P-glycoprotein (P-gp). Uptake into cells or vesicles was determined by liquid scintillation counting. Func-tionality of all in vitro systems was assured by using in each case appropriate probe sub-strates; The dose-escalation study was performed in five consecutive periods (7 days wash-out) in 15 healthy subjects (5 females and 10 males. 20-35 years, BMI 19.4-27.6 kg/m2). Results: We introduce for the first time the separation and quantification of the active me-tabolites 2R,6R/2S,6S-HNK; Ketamine was shown to be taken up significantly in a time- and concentration-dependent manner by OCT1-3. The affinity to OCT transporters at pH=6.5 was several fold higher than that at pH=7.4. ), ketamine showed a significant but low affinity to P-gp. In contrast to this, we could not detect any transport of ketamine by MATE1 / 2K or OACPT2B1; and PR-KET was safe and well tolerated with higher metabolites productivity, different pharmacokinetic properties and longer T1/2 when compared to IV-KET or IR-KET. Conclusion: the uptake transporters OCT1 & 3 and the efflux transporter P-gp may play a role in the intestinal absorption of the drug. On the other side, P-gp, MATE1 / 2K and OCT are not expected to contribute significantly to tissue (brain) distribution or renal excretion of ketamine; Moreover, the prolonged-release ketamine undergoes dose-dependent “first-pass” metabolism which generates substantially increased plasma exposure of downstream me-tabolites with potential neuro-modulating effects compared to ketamine after intravenous administration.
Monitoring of Calcite Precipitation in Hardwater Lakes with Multi-Spectral Remote Sensing Archives
(2017)
Deflected by the barrier function of topographical structures such as high mountain ranges, open water bodies or desert, migrating birds concentrate at certain points or corridors referred to as ‘bottlenecks’. An area like this was discovered at Mount Besh Barmag (Azerbaijan) in autumn 2007, but the data gathered during a four-week survey was insufficient to do more than hint at the existence of a major bird migration bottleneck. Therefore, a comprehensive bird migration study was conducted to analyse the magnitude of this potential bottleneck site. The study covers the periods from August to mid-November 2011 and from March to the end of May 2012 and includes daily counts at three observation points focusing on three different migrant types: passerine, waterbirds and soaring birds. In addition, a sound recorder with an omnidirectional microphone collected bird migration calls by both day and night. In total, 278 bird species were observed in an estimated passage of 1,239,369–1,514,267 diurnally migrating individuals in autumn 2011 and 646,733–817,183 individuals in spring 2012. Fifteen species passed through the study area in numbers exceeding 1% of their world populations and 34 species in more than 1% of their flyway populations in at least one of the observation periods. 84% of the observed migrating birds in autumn 2011 and 95% of them in spring 2012 passed through at heights below 50 m above ground exposing them imminently to the danger of collision with obstacles. In the analysis of nocturnal sound recordings, 119 bird species were identified of which 106 were expected to occur as migrants, and calculated estimates revealed the occurrence of 108,986 calls in autumn 2011 and 33,348 calls in spring 2012. The volume of diurnal bird migration emerging from the data with respect to species number and number of individuals is certainly a strong indication of the existence of a major bird migration bottleneck at Besh Barmag. On account of methodological constraints, the high number of night flight calls can only hint at a nocturnal bird migration bottleneck and confirmatory research aided by visual methods (radar, thermal imaging) is necessary to back up the acoustic results. The Besh Barmag bottleneck offers a great opportunity to establish a standardised long-term monitoring programme to investigate avian population dynamics in the vast and little known Eurasian landmass. Acoustic-based monitoring might be a cost-effective method, but it is limited to a few vocally prolific species only. The aim should rather be the establishment of a bird observatory as already successfully installed in a number of European bird migration bottlenecks.
Aiming at the goal of individualized medicine, this dissertation develops a generic methodology to individualize risk factors and phenotypes via metabolomic data from the urine. As metabolomic data can be seen as a holistic representation of the metabolism of an organism at certain time point, metabolomic data contain not only information about current life-style factors like diet and smoking but also about latent genetic traits. Utilizing this integrative attribute, the dissertation delivers a metric for biological age (the metabolic age score) which was shown to be informative beyond chronological age in three independent samples. It was associated with a broad range of age-related comorbidities in two large population-based cohorts, predicted independently of classical risk factors mortality and, moreover, it predicted weight loss subsequently to bariatric surgery in a small sample of heavily obese individuals.
Subsequently to this work, the dissertation built a definitional framework justifying the procedure underlying the metabolic age score, delivering a general framework for the construction of individualized phenotypes and thereby an operationalization of individualization in statistical terms. Conceptualizing individualization of the process of differentiation of individuals showing the same phenotype despite different underlying biological traits, it was shown formally that the prediction error of a statistical model approximating a phenotype is always informative about the underlying biology beyond the phenotype if the predictors fulfill certain statistical requirements. Thus, the prediction error facilitates the meaningful differentiation of individuals showing the same phenotype. The definitional framework presented here is not restricted to any kind of data and is therefore applicable to a broad range of medical research questions.
However, when utilizing metabolomic data, technical factors, data-preprocessing, pre-analytic features introduce unwanted variance into the statistical modeling. Thus, it is unclear whether predictive models like the metabolic age score are stable enough for clinical application. The third part of this doctoral thesis provided two statistical criteria to decide which normalization method to remove the dilution variance from urinary metabolome data performs best in terms of erroneous variance introduced by the different methods, aiding the minimization of biological irrelevant variance in metabolomic analyses.
In conclusion, this doctoral thesis developed a general, applicable, definitional framework for the construction of individualized phenotypes and demonstrated the value of the methodology for clinical phenotypes on metabolomic data, improving on the way the statistical treatment of urinary data regarding the dilution correction.
Purpose
Due to the demographic change morbidity raises the demand for medical hospital services as well as a need for medical specialization, while economic and human resources are diminishing. Unlike other industries hospitals do not have sufficient data and adequate models to relate growing demands and increasing performance to growth in staff capacity and to increase in staff competences.
Method
Based on huge medical data sample covering the years from 2010 to 2014 with more than 150,000 operations of the Department for Anesthesiology at the University Hospital Muenster, Germany, comparisons are drawn between the development of medical services and the development of personnel capacity and expertise.
Results
The numbers of surgical operations increased by 21% and “skin incision to closure” time by 17%. Simultaneously, personnel capacity grew by 16% largely resting upon recruiting first-time employees. Expertise measured as “years of professional experience” dwindled from 10 years to 5.4 years on average and staff turnover accelerated.
Conclusion
Static benchmark data collected at fixed reference dates do not sufficiently reflect the nexus between capacity and competence and do not reflect the dynamic changes in a hospital’s requirements for expertise and specialization, at all. Staff turnover leads to a loss of experience, which jeopardizes patient safety and hampers medical specialization. In consequence of the dramatic shortage of medical specialists, drop-off rates must be reduced and retention rates must be increased. To that end, working conditions need to be fundamentally converted for a multigeneration, multicultural, and increasingly female workforce.
Background: We assessed the effect of the uniform donor questionnaire (UDQ) on deferral rates in first-time and repeat donors. We focused on the introduced question about unprotected sexual contact with a new partner. Another goal was a stratified comparison of the deferral rates of the donor questionnaire (DQ) and UDQ. Methods: Data on donors and deferrals using the DQ and UDQ were collected at four blood establishments. The comparison included a 2-year period by questionnaire version. For the comparison of the questionnaires, an adjusted multinomial logistic regression was performed. Results: The analysis included 260,848 donations. First-time (FTD) and repeat donations (RD) showed higher deferral rates with the UDQ (FTD +5.4%, RD +1.4%). Deferral due to a new partner was 3.0% in first-time and 0.4% in repeat donors. The majority of these occurred in the youngest age groups. The most frequent deferral criterion was ‘disease' (5.1%). Conclusion: The regression revealed stronger predictors for deferral than the questionnaire version. Especially younger age carried a higher and independent risk for deferral. The additional deferrals of mainly young first-time donors due to a new sexual partner may identify those donors with potential heterosexual risk behavior who would otherwise not be identified.
Costs of reproduction. A demographical approach to examine life-history trade-offs ─ Abstract. Resource-allocation trade-offs are fundamental constraints of life-history evolution. In particular the trade-offs between reproduction and longevity and between present and future reproduction are expected to form reproductive patterns. Unfortunately, exploring such trade-offs in natural populations is complicated and may not be possible. In face of several limitations, zoo data appear to be useful to better understand the reproductive biology of endangered, rare or cryptic species. In the first step, it was sought after with a data-mining, comparative multi-species approach for broad patterns of correlations between lifespan and variables in bird-eating spiders (Theraphosidae). The subfamily Eumenophoriinae on average lived longest, followed by the Theraphosinae, Ornithoctinae, Grammostolinae, Selenocosmiinae, Ischnocolinae and finally the Avicularinae. Species inhabiting tropical, more humid and/or low-altitude environments lived longer, suggesting that more predictable environments favour the evolution of longer lifespans. Furthermore, large range size, low abundance, sub-terrestrial life-style, and aggressive behaviour were all linked with longer lifespans. An argument for resource allocation trade-offs was found as larger spiderling and prosoma size were negatively related to longevity. In the second step, a demographical approach has been applied for two old-world deer species (Vietnamese sika deer Cervus nippon pseudaxis, Mesopotamian fallow deer Dama dama mesopotamica). In both species, births peaked right before the onset of the rainy season in natural environments. Females reached high reproductive output earlier in life and had (in one species only) higher survival rates than males. Offspring number covaried positively rather than negatively with longevity. In females, the length of the reproductive phase correlated positively with longevity, birth rate within the entire lifespan, and offspring number, while it was negatively correlated to the birth rate during the reproductive phase (in one species). The length of the post-reproductive phase was positively related to longevity and negatively to birth rate during the entire lifespan. In the third section, life-histories of Asiatic (Equus hemionus ssp.) and African wild asses (Equus africanus ssp.) have been anlaysed in a comparative way with another demographical long-term approach. All taxa showed even in captivity peak birth rates during the periods of highest food availability in their natural environments. Sex-specific survival rates with females living longer than males were evident in Kulan and Onager but not in Kiang and Somali wild ass, pointing towards different life-history strategies even among closely related taxa. Females achieved their highest reproductive output earlier than males, which is typical for polygynous mating systems. Offspring number and longevity were rather positively correlated than negatively. Taken together evidence for reproductive trade-offs was weak, though the length of the reproductive period was negatively related to birth rates within the reproductive period. Birth intervals increased with female age, probably reflecting detrimental effects of senescence.
Objective: We performed a pilot RCT to prove the hypothesis that a controlled ingestion of polyphenol-rich beverages (soy drink, decaffeinated black tea) in nutritive dosages by nursing women has an effect on the composition (flavonoid concentration, total antioxidant capacity) of breast milk. Methods: Healthy nursing women were supplemented with either 250 mL of a soy drink (12 mg isoflavones; n = 18), 300 mL decaffeinated black tea (67 mg catechins; n = 18), or 300 mL water (n = 8, control) for 6 days. Milk samples were collected before, during, and after intervention. Flavonoid content (isoflavones/catechins, HPLC) and total antioxidant capacity of milk and test drinks in milk specimens were assessed. Results: Isoflavone content (genistein and daidzein) in breast milk increased up to 12 nmol/L after soy drink consumption; the major flavonoids constituents of black tea (catechin, epicatechin, and respective conjugates) could not be detected in milk samples. With both interventions, the total antioxidant capacity of breast milk was not affected. Conclusions: Mothers' daily consumption of a soy drink considerably increases isoflavone content of breast milk resulting in an estimated daily exposure of 9.6 nmol isoflavones in a 4-month-old suckling infant. Luminal flavanol uptake from black tea consumed by the nursing mother may be too low to affect flavanol concentrations in breast milk.
Humanity is plagued by many diseases. Beside environmental influences, many --- if not all --- diseases are also subject to genetic predisposition and then display molecular alterations such as proteomic or metabolic aberrations. The elucidation of the molecular principles underlying human diseases is one of the prime goals of biomedical research. To this end, there has been an advent of large-scale omics profiling studies. While the field of molecular biology has experienced tremendous development, data analysis remains a bottleneck. In the context of this thesis, we developed a number of analysis strategies for different types of omics data resulting from different experimental settings. These include approaches for associations studies for plasma miRNAs and time-resolved plasma omics data. Furthermore, we devised analyses of different RNA-Seq transcriptome profiling studies coping with problems such as lack of replicates or multifactorial experimental design. We also designed machine learning frameworks for the identification of discriminatory biomolecular signatures analysing case-control or time-to-event data. All of the strategies mentioned above were developed and applied in the contexts of multi-disciplinary endeavours. They aided in the identification of plasma miRNAs associated with age, sex, and BMI as well as plasma miRNAs bearing potential as diagnostic biomarkers for non-alcoholic fatty liver disease (NAFLD). This thesis significantly contributed to a study demonstrating the utility of plasma miRNAs as prognostic biomarkers for major cardiovascular events such as ST-elevation myocardial infarction. Our approaches for analysing RNA-Seq data aided in the characterisation of murine models for Alzheimers disease and the transcriptional response of human gingiva fibroblasts to ionizing radiation exposure. Furthermore, the developed approaches were applied for studying a human model for thyrotoxicosis and for the successful identification of a multi-omics plasma biomarker signature of thyroid status. We are only beginning to understand the molecular principles underlying human diseases. The approaches and results presented in this thesis will contribute to improved understanding of biomolecular processes involved in common diseases such as Alzheimers disease, NAFLD, and cardiovascular diseases.
Streptococcus pneumoniae (pneumococci), a human pathobiont, express and expose several proteinaceous colonization and virulence factors on its surface to facilitate on the one hand colonization of the upper respiratory tract and on the other hand pathogenesis in the host. In this study the interaction of two of such factors referred to as pneumococcal virulence factor A (PavA) and pneumococcal virulence factor B (PavB) and acting as microbial surface components recognizing adhesive matrix molecules (MSCRAMMs), was delineated with the two host matricellular proteins fibronectin (Fn) and vitronectin (Vn). Despite similarity in nomenclature, PavA and PavB represent two diverse pneumococcal proteins with respect to their structure and association with the pneumococcal surface. PavA is a non-classical surface protein (NCSP) with an ambiguous mode of secretion and anchorage while PavB is a characteristic MSCRAMM, anchored via sortase A to pneumococcal peptidoglycan. PavB has a signature of repetitive modules termed as streptococcal surface repeats (SSURE). Pneumococci preferentially interact with immobilized human Fn. In vitro cell culture adherence assays demonstrated that cell bound Fn facilitates the adherence of pneumococci to the host cells and this particular interaction is indifferent to host cell type and is species non-specific. Flow cytometry and immunoblot analyses further indicated the ability of pneumococci to interact with the soluble form of Fn in a dose-dependent but species non-specific manner. The molecular interaction of PavA and PavB (via its SSURE domains) with Fn was delineated further in detail via several direct protein-protein interaction approaches. Ligand overlay assays, surface plasmon resonance studies and SPOT peptide arrays demonstrated that PavA and PavB target at least 13 out of the 15 type III fibronectin domains located in the C-terminal part of Fn. Strikingly, both pneumococcal fibronectin-binding proteins (FnBPs) recognize similar peptides in targeted type III repeats. Structural comparisons revealed that the targeted type III epitopes cluster on the inner strands of both β-sheets forming the fibronectin domains. Importantly, synthetic peptides of FnIII1, FnIII5 or FnIII15 bind directly to FnBPs PavA and PavB, respectively. Thus, analysis of interaction of pneumococcal FnBPs PavA and PavB revealed a probable conserved and/or common pattern of molecular interaction with human Fn. In addition to Fn, pneumococcal PavB interacts with other host matricellular proteins such as human plasminogen (Plg) and human thrombospondin-1 (hTSP-1). Pneumococcal proteins such as PspC and PspC-like Hic have earlier been demonstrated to interact with hTSP-1 as well as human Vn, thereby depicting a redundant function as MSCRAMMs. In this study the role of PavB as a pneumococcal vitronectin binding protein (VnBP) was assessed. Flow cytometric analysis suggested PavB as VnBP, because strains deficient for PavB exhibited a significantly decreased ability to acquire vitronectin compared to wild-type pneumococci. When using a double knockout, deficient in expression of PavB and the VnBP PspC, the pneumococcal interaction with vitronectin was completely abolished. The direct protein-protein interaction assays such as far western ligand overlay, ELISA, and surface plasmon resonance indicated the interaction of SSURE domains with both soluble and immobilized Vn. However, the binding activity depends on the number of SSURE domains with five SSURE showing the highest binding activity to Vn. The interaction of PavB with Vn was charge dependent and heparin sensitive as analyzed by ELISA. The importance of the heparin binding domains of Vn in this interaction was further analyzed via direct protein-protein interaction approaches. Binding studies (far western ligand overlay, ELISA, and surface plasmon resonance) with truncated recombinant Vn fragments indicated that PavB targets the C-terminal heparin-binding domain (HBD3) of vitronectin, a characteristic shared with PspC, hence, suggesting a conserved molecular interaction of pneumococci with Vn. In addition to its function as an MSCRAMM, PavB has the capability to interact directly with host epithelial cells via an unknown cellular receptor. Thus, this study aimed to identify cellular receptor(s) for PavB. In vitro cell culture adherence and invasion assays confirmed that pneumococcal PavB is involved in promoting pneumococcal adherence to respiratory epithelial cells without employing any molecular bridge. The direct interaction between PavB and host epithelial cells was further confirmed via direct binding assays when using Cy5-labeled PavB and flow cytometric analysis. Strikingly, exogenously added human vitronectin competitively inhibited binding of PavB to respiratory epithelial cells. This observation led us to hypothesize that the major vitronectin receptor αvβ3 integrin acts as a potential receptor for PavB. This hypothesis was supported by functional blocking assays with monoclonal antibodies recognizing specific integrin subunits. The results revealed reduced binding of PavB in the presence of bound antibodies recognizing αv integrin indicating that PavB employs αvβ3 integrin as its direct receptor on eukaryotic cells. This was further confirmed via a direct binding assay of PavB to mouse embryonic fibroblasts (MEFs) where cells lacking αvβ3 demonstrated a marked decrease in binding to PavB. Although functional blocking assay and direct binding assay with MEFs supported the role of αvβ3 integrin as a direct adhesin for PavB, RNA interference of αv integrin in epithelial cells did not impair the binding of PavB in αv-knocked down cells in comparison to non-transfected cells. Finally, surface plasmon resonance (SPR) analysis indicated the direct interaction between pneumococcal PavB and recombinant αvβ3 integrin. In this study we report for the first time the interaction of a Gram-positive extracellular pathogen, namely Streptococcus pneumoniae, with one of the host ICAMs, namely the αvβ3 integrin. In conclusion, the present study analysed some of the aspects of molecular interaction of pneumococcal MSCRAMMs PavA and PavB with hFn and hVn. The hot spots of interaction on C-terminal FnIII repeats were delineated for PavA and PavB. HBD3 was revealed to be pivotal for PavB-Vn interaction. In addition the redundant role of pneumococcal PavB as an MSCRAMM was demonstrated. Furthermore this study successfully identifies a direct receptor for pneumococcal PavB, namely αvβ3 integrin. The mechanism and biological rationale of this newly identified interaction is a matter of debate and awaits further scientific analyses.
This work examines the influence of monovalent and divalent cations on tetramyristoyl cardiolipin (TMCL) monolayers. A lipid monolayer can undergo an ordering transition of the lipid alkyl chains from a disordered fluid phase (liquid-expanded (LE)) to an ordered gel phase (liquid-condensed (LC)). Compression of the lipid monolayer in a Pockels-Langmuir trough was monitored with a Wilhelmy plate tensiometer, yielding the surface pressure π in dependence of the area a molecule can occupy on average A, as a π-A-isotherm. The onset of the first order LE/LC phase transition is marked by an abrupt change in the isotherm at surface pressure πc.
These associated lipid membrane changes were characterized by variation of the compression speed, kind and concentration of the monovalent and divalent salt, pH, and temperature. The CL monolayer phase transition was found to depend on the compression speed, yielding only a small variation in the compression isotherms.
For monovalent cations on the cardiolipin monolayer, the dependence on salt concentration of the lipid liquid gel phase transition surface pressure πc was determined and a non-monotonic behavior was found, with a maximum in πc for a salt concentration of 0.1 mol/l. The maximum in πc can be shifted with pH (e.g. pH = 4.2). This behavior extended to potassium, sodium and cesium cations in the subphase. No ion specific effects were observed, which pointed to the prevalence of electrostatic interactions in the system.
Different divalent salt subphases, of either magnesium, calcium, strontium, manganese, iron or zinc salts, with fixed sodium chloride concentration of 0.15 mol/l at pH of 5.8 and 25 °C were investigated. πc decreases upon addition of divalent salts to the subphase. This points to increased screening and binding effects. Strongest binding effects were observed for calcium and manganese cations.
The electrostatic interactions of the system were modeled with a mean-field theory: Grahame’s equation, and a simple law of mass action. CL is modeled at half its molecular area and half its charge, with a proton dissociation constant of the phosphate group Ka,intrinsic(PO4) = 0.1 mol/l. The agreement with the experiment was satisfactory.
A linear dependence of πc on the temperature was found for cardiolipin monolayers on all subphases. The isothermal area compressibility modulus KA is calculated from selected isotherms. It was found that the flexibility of the monolayer decreases with temperature and the area per molecule for the cardiolipin fluid phase.
The compression speed, monovalent salt concentration, pH, and selected divalent cations were investigated with the BAM. For all a sigmoidal growth of xgel with compression was observed. For high salt concentrations non-circular and dendritic domains were observed.
A simple model for the nucleation process was introduced, yielding an estimate of 20 nm for the critical domain radius, which is below the resolution of the BAM, but a common length scale in biological systems.
This thesis aims to develop a palaeogeographic and chronostratigraphic model of the southwestern Baltic Sea area, to improve our understanding of the depositional history of the Late Pleistocene on both a local and a transregional scale. New sedimentological, palaeontological and numerical age data will be presented from three reference sites located at the coast of NE Germany. So far, the chronostratigraphic assignment of Saalian and Weichselian sediments of NE Germany has been based mainly on lithostratigraphic methods and on sparse numerical age data, resulting in a fragmentary age database. Modern sedimentological approaches, such as facies analyses, have been applied only at a few isolated profiles. Thus, a reliable reconstruction of the depositional environments and their stratigraphic positions is still missing for the study area, which makes the correlation between Pleistocene successions from NE Germany and other circum-Baltic regions problematic. To address these lithostratigraphic and geochronologic issues, three crucial profiles were re-investigated using a multiproxy approach, including sedimentological, geochronological, and palaeontological techniques. The Glowe and Kluckow sites are located on the peninsula of Jasmund (Rügen Island), whereas the Klein Klütz Höved (KKH) section is situated between Wismar and Travemünde at the coast of the Mecklenburg Bay. The age-constraining of critical horizons was conducted by luminescence dating of feldspar and quartz grain minerals. Together, these successions represent the Late Saalian to Late Weichselian period and give rise to the following picture. The Glowe and Kluckow sections reveal that ice-free conditions dominated the study site between 47 and 42 ka. Deposition occurred in a steppe-like environment with moderate summers and cool winters. Meandering and braided river systems inhabited by various freshwater species, such as Anodonta cygnea, Pisidium amnicum and Perca fluviatilis, shaped the landscape. A subsequent cooling phase resulted in the establishment of a periglacial landscape and the formation of ice-wedges. This phase is shown in this thesis to be connected to the Klintholm advance documented at 34±4 ka in Denmark. Furthermore, the data indicate the formation of a lacustrine basin during the transition of MIS 3 to MIS 2 under sub-arctic climate conditions. A potential link to the Kattegat ice advance (29 – 26 ka) will be proposed. At 23±2 ka, the study area was characterised by proglacial and ice-contact lakes related to the Last Glacial Maximum ice advance of the Scandinavian Ice Sheet (SIS). This is the first documented SIS advance of Weichselian age, which reached Jasmund at 22±2 ka. The KKH sedimentary succession comprises deposits of Late Saalian to Late Weichselian age: after a period of deglaciation between ~139-134 ka (Termination II; MIS 6), which is preserved in a glaciofluvial sequence deposited in a braided river system, a lacustrine environment was established in an arctic to subarctic climate. During this time, the landscape was vegetated by typical Late Saalian flora communities. The Eemian interglacial is represented by lacustrine to brackish deposits covering the reference pollen zones 1 to 3. During this initial part of the Eemian, thermophile forest elements spread (Quercus, Ulmus), indicating a deciduous forest. The presence of brackish ostracods represents the influence of a marine transgression between 300 and 750 years after the beginning of the Eemian period. A hiatus of more than 90,000 years separates the Eemian from the overlying Late Weichselian sediments. During the Late Weichselian period, the deposition at KKH was dominated by glaciolacustrine and subglacial facies, where the first Weichselian ice advance occurred at 20±2 ka. The sedimentological and geochronological findings in this thesis provide valuable information for the reconstruction of the palaeoenvironmental history from the Late Saalian to Late Weichselian period. The Late Saalian palaeoenvironmental setting is reconstructed, including Termination II and the initial phase of the Eemian interglacial. Furthermore, the Eemian marine transgression is shown to have occurred 300 to 750 years after the beginning of this interglacial. The first proven Weichselian advance of the SIS approached NE Germany between ~23 and ~20 ka. In contrast, there is no evidence to support a pre-LGM advance of Weichselian age to the study area, as proposed by several authors, neither at Glowe and Kluckow, nor at the KKH site. Based on the presented results, and contra what was previously assumed, the MIS 3 Ristinge and Klintholm advance of the SIS, documented in Denmark, did not reach NE Germany.
Background: ‘Quality in medicine' is a term used in a broad sense. In this work the definition and dimensions of quality in medicine and the implementation of a measurement and reporting system in Germany are discussed. Existing applications are described and possible future effects are pointed out. Methods: The ongoing process of implementing a quality reporting system into the German healthcare system is studied by publicly available legal texts, published reactions of stakeholders and publications of G-BA and IQTIG. Definitions of quality, dimensions of quality and quality measurement in medicine are studied by using textbooks as well as the world wide web and PubMed search. Results: Donabedian‘s ‘dimensions of quality' are fundamental in dealing with quality in medicine. Existing measurement and reporting systems have immanent strengths and weaknesses, as the definition of quality is affected by one‘s point of view. The legislator will have to decide which ‘dimension of quality' is mandatory and how to measure it. Conclusion: Quality has become a control instrument with unforeseeable consequences. A clear definition of the used quality concept is as essential as the use of feasible measurement and reporting systems. The use of routine data could be an interesting option.
Background: The plasminogen activator system plays a key role in ovarian cancer (OC) tumor progression. The plasminogen activator inhibitor type 1 (PAI-1) and the recently identified PAI-1 RNA binding protein 1 (PAI-RBP1) are primary regulators of plasminogen activation and thus are putative biomarkers for OC progression. Methods: One hundred fifty six OC patients were analyzed to identify the presence of PAI-1 and PAI-RBP1 and subsequently correlated to clinicopathological parameters. Primary cells obtained from OC patient samples were applied in fluorescence microscopy analysis for examination of PAI-1 and PAI-RBP1 distribution. Results: PAI-1 and PAI-RBP1 have been found to be predictive markers for OC patients' outcome. PAI-1 levels significantly correlated with volume of ascites, FIGO staging, and lymph node status. PAI-RBP1 expression significantly correlated with age at first diagnosis, histological tumor type, presence of distant metastasis (pM), and recurrence. PAI-1 showed a trend toward association and PAI-RBP1 was significantly associated with progression-free survival. Notably, PAI-1 protein in recurrent OC tissues was exclusively localized in the nucleus. Conclusion: This study has shown that a combination of PAI-1 and PAI-RBP1 may represent novel prognostic factor for OC. Prospective trials are needed.
Certain basal Teleostei from the Early Jurassic of Mecklenburg-Western Pomerania (Germany) and the Late Jurassic of the Franconian Alb (Bavaria, Germany), the Swabian Alb (Baden-Württemberg, Germany) and the western Jura-Mountains (Ain, France) are described. The present doctoral dissertation includes four studies, dealing with representatives of “Pholidophoriformes”, Leptolepidae and Orthogonikleithridae. These studies include anatomical descriptions of new taxa and reviews of poorly known fishes. Furthermore, the stratigraphic and palaeobiogeographical distributions of the examined taxa are discussed.
Background
There is a lack of data concerning socioeconomic outcome and quality of life (QoL) in patients after status epilepticus (SE) in Germany.
Patients and methods
Adult patients treated between 2011 and 2015 due to SE at the university hospitals in Frankfurt, Greifswald, and Marburg were asked to fill out a questionnaire regarding long-term outcome of at least 3 months after discharge. The SE cohort consisted of 25.9% patients with an acute symptomatic, 42% with a remote symptomatic and previous epilepsy, 22.2% with a new-onset remote symptomatic, and 9.9% with other or unknown etiology. A matched case–control analysis was applied for comparison with patients with drug refractory epilepsy and seizure remission, both not previously affected by SE.
Results
A total of 81 patients (mean age: 58.7 ± 18.0 years; 58% female) participated. A non-refractory course was present in 59.3%, while 27.2% had a refractory SE (RSE) and 13.6% had a superrefractory SE (SRSE). Before admission, a favorable modified Rankin Scale (mRS) of 0–3 was found in 82.7% (67/81), deteriorating to 38.3% (31/81) (p = 0.003) at discharge. The majority returned home [51.9% (42/81)], 32.1% entered a rehabilitation facility, while 12.3% were transferred to a nursing home and 3.7% to another hospital. The overall mRS at follow-up did not change; 61.8% (45/74) reached an mRS of 0–3. In RSE and SRSE, the proportion with a favorable mRS increased from 45.5% at discharge to 70% at follow-up, while QoL was comparable to a non-refractory SE course. Matched epilepsy controls in seizure remission were treated with a lower mean number of anticonvulsants (1.3 ± 0.7) compared to controls with drug refractory epilepsy (1.9 ± 0.8; p < 0.001) or SE (1.9 ± 1.1; p < 0.001). A major depression was found in 32.8% of patients with SE and in 36.8% of drug refractory epilepsy, but only in 20.3% of patients in seizure remission. QoL was reduced in all categories (QOLIE-31) in SE patients in comparison with patients in seizure remission, but was comparable to patients with drug refractory epilepsy.
Discussion
Patients after SE show substantial impairments in their QoL and daily life activities. However, in the long term, patients with RSE and SRSE had a relatively favorable outcome comparable to that of patients with a non-refractory SE course. This underlines the need for efficient therapeutic options in SE.
Wound antisepsis has undergone a renaissance due to the introduction of highly effective wound-compatible antimicrobial agents and the spread of multidrug-resistant organisms (MDROs). However, a strict indication must be set for the application of these agents. An infected or critically colonized wound must be treated antiseptically. In addition, systemic antibiotic therapy is required in case the infection spreads. If applied preventively, the Wounds-at-Risk Score allows an assessment of the risk for infection and thus appropriateness of the indication. The content of this updated consensus recommendation still largely consists of discussing properties of octenidine dihydrochloride (OCT), polihexanide, and iodophores. The evaluations of hypochlorite, taurolidine, and silver ions have been updated. For critically colonized and infected chronic wounds as well as for burns, polihexanide is classified as the active agent of choice. The combination 0.1% OCT/phenoxyethanol (PE) solution is suitable for acute, contaminated, and traumatic wounds, including MRSA-colonized wounds due to its deep action. For chronic wounds, preparations with 0.05% OCT are preferable. For bite, stab/puncture, and gunshot wounds, polyvinylpyrrolidone (PVP)-iodine is the first choice, while polihexanide and hypochlorite are superior to PVP-iodine for the treatment of contaminated acute and chronic wounds. For the decolonization of wounds colonized or infected with MDROs, the combination of OCT/PE is preferred. For peritoneal rinsing or rinsing of other cavities with a lack of drainage potential as well as the risk of central nervous system exposure, hypochlorite is the superior active agent. Silver-sulfadiazine is classified as dispensable, while dyes, organic mercury compounds, and hydrogen peroxide alone are classified as obsolete. As promising prospects, acetic acid, the combination of negative pressure wound therapy with the instillation of antiseptics (NPWTi), and cold atmospheric plasma are also subjects of this assessment.
Background
Signs of an inflammatory process have been described in major depression.
Methods
In a double-blind, randomized study of celecoxib or placebo add-on to reboxetine in 40 depressed patients, celecoxib treatment has beneficial effects. In order to evaluate the tryptophan/kynurenine metabolism and to identify predictors for remission, tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QUIN) were estimated in the serum of 32 patients before and after treatment and in a group of 20 healthy controls.
Results
KYN levels were significantly lower in patients (p = 0.008), and the QUIN/KYN ratios were significantly higher (p = 0.028). At baseline, the higher KYN/TRP ratio was predictive for remission during celecoxib add-on treatment (p = 0.04) as well as for remission in the overall patient group (p = 0.01). In the placebo group, remitters showed a higher KYNA/QUIN ratio (p = 0.032). In the overall group, remitters showed lower KYNA/KYN (p = 0.035) and QUIN/KYN (p = 0.011) ratios. The lower the formation of downstream metabolites, especially QUIN, the better the treatment outcome.
Conclusion
The high KYN/TRP ratio predicted remission after treatment with celecoxib in this small sample of depressed patients. Eventually, the KYN/TRP ratio might be a marker for those patients, which benefit from an additional anti-inflammatory treatment.
In healthy older adults, resveratrol supplementation has been shown to improve long-term glucose control, resting-state functional connectivity (RSFC) of the hippocampus, and memory function. Here, we aimed to investigate if these beneficial effects extend to individuals at high-risk for dementia, i.e., patients with mild cognitive impairment (MCI). In a randomized, double-blind interventional study, 40 well-characterized patients with MCI (21 females; 50–80 years) completed 26 weeks of resveratrol (200 mg/d; n = 18) or placebo (1,015 mg/d olive oil; n = 22) intake. Serum levels of glucose, glycated hemoglobin A1c and insulin were determined before and after intervention. Moreover, cerebral magnetic resonance imaging (MRI) (3T) (n = 14 vs. 16) was conducted to analyze hippocampus volume, microstructure and RSFC, and neuropsychological testing was conducted to assess learning and memory (primary endpoint) at both time points. In comparison to the control group, resveratrol supplementation resulted in lower glycated hemoglobin A1c concentration with a moderate effect size (ANOVARM p = 0.059, Cohen's d = 0.66), higher RSFC between right anterior hippocampus and right angular cortex (p < 0.001), and led to a moderate preservation of left anterior hippocampus volume (ANOVARM p = 0.061, Cohen's d = 0.68). No significant differences in memory performance emerged between groups. This proof-of-concept study indicates for the first-time that resveratrol intake may reduce glycated hemoglobin A1c, preserves hippocampus volume, and improves hippocampus RSFC in at-risk patients for dementia. Larger trials with longer intervention time should now determine if these benefits can be validated and extended to cognitive function.
Background: Mild-to-moderate chronic kidney disease (CKD G3a) is prevalent in older adults. Substantial evidence suggests that individuals with advanced CKD face a high risk for common geriatric conditions, like functional impairment and cognitive decline, whereas the relationships between mild-to-moderate CKD and functional impairment and cognitive decline, but also poor nutritional status and mood disorders, are still unclear. Objective: The aim of this study was to explore associations between mild-to-moderate CKD and impairments in the core domains of geriatric assessment (GA) in a large cohort of community-dwelling older adults. Methods: This was a cross-sectional analysis of 1,476 participants of the Berlin Aging Study II. Study participants were stratified as to presence or absence of CKD G3a (estimated glomerular filtration rate [eGFR] 45-59 mL/min/1.73 m<sup>2</sup> vs. eGFR ≥60 mL/min/1.73 m<sup>2</sup>). GA comprised the following instruments: the Activities of Daily Living Scale (ADL), the Timed up and Go (TUG), the Tinetti test (Tinetti), the Mini-Mental-State Examination (MMSE), the Geriatric Depression Scale (GDS), and the Mini Nutritional Assessment (MNA). We used logistic regression models to estimate multivariable-adjusted associations between CKD G3a and impairments in the respective domains. Results: A total of 282 subjects with mild-to-moderate CKD (CKD G3a) were identified (19.1%). Overall, the prevalence of impairments identified was higher among subjects with compared to without CKD G3a (21 vs. 15.9%, p = 0.043). In multivariable-adjusted models, CKD G3a was consistently associated with increased odds of an impaired gait performance as to the TUG (adjusted odds ratio 2.06, 95% CI 1.04-4.09). In contrast, on average, individuals with and without CKD G3a did not differ as to their results in the MMSE, the ADL, the MNA, and the GDS. Conclusion: GA identified impairments in 21 versus 15.9% of older adults with and without mild-to-moderate CKD, respectively. However, except for an increased likelihood of impaired gait performance (TUG) with mild-to-moderate CKD, we did not find independent associations between mild-to-moderate CKD and geriatric conditions.
Lead-cluster investigations
(2017)
In this thesis, investigations on lead clusters stored in a Penning trap are presented. The measurements are performed at the ClusterTrap setup at the Institute of Physics of the University of Greifswald. A Penning trap with a superconducting magnet (B=12 Tesla) makes up the central part of the experiment. In this trap, singly positively or negatively charged lead clusters (a group of lead atoms) are stored, their amplitudes of motion are cooled, and a specific cluster size is selected. Thus, clusters of only a single size are prepared for experimental investigation. After interactions with electrons and/or photons, the trap content is extracted and analyzed by time-of-flight mass spectrometry.
In the first experiment, the size-selected clusters are excited by a frequency-doubled Nd:YAG laser, which leads to fragmentation processes. The preferred fragmentation pathway, which is observed to be break-off of a seven-atom neutral cluster is unusual for metal clusters, which typically evaporate monomers. Furthermore, the already known magic cluster sizes are observed.
In a subsequent experiment, positively charged lead clusters with 31 atoms are irradiated with laser light and fragmentation processes are time resolved investigated. The assumption that lead clusters fragment by break-off of neutral heptamers is confirmed.
In the following experiment, an electron beam is guided through the Penning trap to ionize pulsed-in argon atoms. While the positive argon ions leave the trap, the secondary electrons are trapped together with the selected lead clusters. This allows the electrons to attach to the singly charged lead clusters, which leads to multiply negatively charged lead clusters. The relative abundance of multiply-charged clusters is measured with respect to the cluster size, from which the appearance sizes of di- and trianions can be calculated. In addition to the attachment of electrons, fragmentation products similar to those of the photoexcitation measurements are observed. Furthermore, the cluster sizes 10 and 12 are observed regardless of the investigated precursor size, together with clusters of the precursor size reduced by 10 and 12. This is a first hint for a fission process of doubly negatively charged lead clusters into two singly charged products. In a following measurement, doubly charged lead clusters are produced and photoexcited. The observed abundance spectra confirm this assumption.
Longitudinal Effects of Student-Perceived Classroom Support on Motivation – A Latent Change Model
(2017)
This two-wave longitudinal study examined how developmental changes in students’ mastery goal orientation, academic effort, and intrinsic motivation were predicted by student-perceived support of motivational support (support for autonomy, competence, and relatedness) in secondary classrooms. The study extends previous knowledge that showed that support for motivational support in class is related to students’ intrinsic motivation as it focused on the developmental changes of a set of different motivational variables and the relations of these changes to student-perceived motivational support in class. Thus, differential classroom effects on students’ motivational development were investigated. A sample of 1088 German students was assessed in the beginning of the school year when students were in grade 8 (Mean age = 13.70, SD = 0.53, 54% girls) and again at the end of the next school year when students were in grade 9. Results of latent change models showed a tendency toward decline in mastery goal orientation and a significant decrease in academic effort from grade 8 to 9. Intrinsic motivation did not decrease significantly across time. Student-perceived support of competence in class predicted the level and change in students’ academic effort. The findings emphasized that it is beneficial to create classroom learning environments that enhance students’ perceptions of competence in class when aiming to enhance students’ academic effort in secondary school classrooms.